Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission

  • Review
  • Intervention

Authors


Abstract

Background

The 8-aminoquinoline (8AQ) drugs act on Plasmodium falciparum gametocytes, which transmit malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to malaria treatment schedules in low-transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose-6-phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear.

Objectives

To assess the effects of single dose or short-course PQ (or an alternative 8AQ) alongside treatment for people with P. falciparum malaria.

Search methods

We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using ‘malaria*', ‘falciparum', ‘primaquine', ‘8-aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017.

Selection criteria

Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. falciparum malaria.

Data collection and analysis

Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non-artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups.

Main results

We included 24 RCTs and one quasi-RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non-artemisinin treatments (13 arms), and two trials included both artemisinin and non-artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing.

No cluster trials evaluating community effects on malaria transmission met the inclusion criteria.

With artemisinin treatment

Low dose PQ

Infectiousness (participants infectious to mosquitoes) was reduced (day 3 or 4: RR 0.12, 95% CI 0.02 to 0.88, 3 trials, 105 participants; day 8: RR 0.34, 95% CI 0.07 to 1.58, 4 trials, 243 participants; low certainty evidence). This translates to a reduction in percentage of people infectious on day 3 or 4 from 14% to 2%, and, for day 8, from 4% to 1%; the waning infectiousness in the control group by day 8 making the absolute effect smaller by day 8. For gametocytes detected by PCR, there was little or no effect of PQ at day 3 or 4 (RR 1.02, 95% CI 0.87 to 1.21; 3 trials, 414 participants; moderate certainty evidence); with reduction at day 8 (RR 0.52, 95% CI 0.41 to 0.65; 4 trials, 532 participants; high certainty evidence). Severe haemolysis was infrequent, with or without PQ, in these groups with few G6PD-deficient individuals (RR 0.98, 95% CI 0.69 to 1.39; 4 trials, 752 participants, moderate certainty evidence).

Moderate dose PQ

Infectiousness was reduced (day 3 or 4: RR 0.13, 95% CI 0.02 to 0.94; 3 trials, 109 participants; day 8 RR 0.33, 95% CI 0.07 to 1.57; 4 trials, 246 participants; low certainty evidence). Illustrative risk estimates for moderate dose were the same as low dose. The pattern and level of certainty of evidence with gametocytes detected by PCR was the same as low dose, and severe haemolysis was infrequent in both groups.

High dose PQ

Infectiousness was reduced (day 4: RR 0.2, 95% CI 0.02 to 1.68, 1 trial, 101 participants; day 8: RR 0.18, 95% CI 0.02 to 1.41, 2 trials, 181 participants, low certainty evidence). The effects on gametocyte prevalence showed a similar pattern to moderate and low dose PQ. Trials did not systematically report evidence of haemolysis.

With non-artemisinin treatment

Trials with non-artemisinin treatment have been conducted only for moderate and high dose PQ. With high dose, infectiousness appeared markedly reduced on day 5 (RR 0.09, 95% CI 0.01 to 0.62; 30 participants, very low certainty evidence), with similar reductions at day 8. For both moderate dose (two trials with 221 people) and high dose (two trials with 30 people), reduction in gametocytes (detected by microscopy) showed similar patterns as for artemisinin treatments, with little or no effect at day 4 or 5, and larger effects by day 8. No trials with non-artemisinin partner drugs systematically sought evidence of severe haemolysis.

Two trials comparing bulaquine with PQ suggest bulaquine may have larger effects on gametocytes by microscopy on day 8 (RR 0.41, 95% CI 0.26 to 0.66; 2 trials, 112 participants).

Authors' conclusions

A single low dose of PQ (0.25 mg/kg) added to artemisinin-based combination therapy for malaria reduces infectiousness of people to mosquitoes at day 3-4 and day 8, and appears as effective as higher doses. The absolute effect is greater at day 3 or 4, and smaller at day 8, in part because of the lower infectiousness in the control group. There was no evidence of increased haemolysis at 0.25 mg/kg, but few G6PD-deficient individuals were included in the trials. The effect on infectiousness precedes the effect of PQ on gametocyte prevalence. We do not know whether single dose PQ could reduce malaria transmission at community level.

Plain language summary

A single dose of primaquine added to malaria treatment to prevent malaria transmission

What is the aim of this review?

To assess the effects of adding a single dose of primaquine (PQ) to treatment for falciparum malaria to reduce disease transmission. This Cochrane Review update includes 25 controlled trials. The date of latest search was 21 July 2017.

Key messages

A single low dose of PQ, at 0.25 mg/kg, which the World Health Organization (WHO) recommends adding to artemisinin-based combination therapy for malaria, reduces infectiousness (transmission from people to mosquitoes). In the trials, the percentage of people who infected mosquitoes three to four days after treatment was reduced from 14% to 2%, with a smaller effect at day 8, from 4% to 1%, with no evidence of harm.

What was studied in the review

PQ kills gametocytes (malaria transmission stages) of the falciparum malaria parasite. Gametocytes infect mosquitoes during a bite, thus perpetuating transmission. There is concern that PQ may cause red blood cells to burst (haemolysis) in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a genetically-determined condition common in many malaria-endemic settings, which can lead to anaemia. Recognizing concerns about the risk of haemolysis, the WHO reduced the recommended PQ dose from 0.75 mg/kg to 0.25 mg/kg in 2012.

Ideally, this approach would be tested by randomly assigning villages to standard malaria treatment, or standard treatment plus a low dose of PQ, then measuring the effect on malaria over time but this would be difficult and expensive. So, indirect indicators are used to shed light on effectiveness, including feeding studies, in which mosquitoes are allowed to feed on people (or their blood), comparing those who were assigned PQ with those who were not. Alternatively, researchers may simply monitor the presence (prevalence), number (density), and duration (time of persistence) of gametocytes in the blood of people after different treatments, assuming that gametocytes are viable irrespective of exposure to PQ.

What the research says

The 25 included trials span several decades and include a variety of treatments and PQ doses. Related to safety assessment, some trials tested participants for G6PD activity. Other trials reported results based on their G6PD status, others did not test (or did not say whether they did), and others tested and excluded people with G6PD deficiency.

There were no ideal community-level studies that would answer the question directly.

Five feeding trials with multiple arms included three low-dose, three medium-dose, and two high-dose comparisons, showing a markedly reduced proportion of people infectious who received PQ in trials with any events. Two trials using older malaria treatments and high dose PQ had similar results.

The other trials focused on indirect measures of potential infectiousness of humans to mosquitoes. In these trials, PQ shortened the period of potential infectiousness, with a lower prevalence and density of gametocytes up to day 8 after treatment. The effect was similar at all PQ dose levels.

Few serious haemolytic events occurred in these trials, but PQ did affect non-serious haemoglobin measures, even at low doses.

What are the main results of the review?

A single low dose of PQ added to an artemisinin regimen for malaria reduces infectiousness to mosquitoes and is relatively safe for most people.

PQ at WHO-recommended dose reduces infectiousness to mosquitoes on day 3-4 and day 8 with no evidence of harm. It is unclear whether this reduction would materially reduce malaria transmission in communities.

Summary of findings(Explanation)

Summary of findings for the main comparison. Single dose primaquine at 0.2 to 0.25 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission
  1. 1Downgraded by 2 for imprecision: the CIs are wide; in addition, there is a large effect combined with a low number of events, which creates further uncertainty around the point estimate.
    2Downgraded by 1 for imprecision: the CIs are wide.

Low-dose primaquine (PQ) given with artemisinin combination treatment

Participants or population: adults and children with malaria being treated with artemisinin combination treatment

Settings: Mali, Burkina Faso, The Gambia, Tanzania, Senegal

Intervention: single dose PQ dose 0.2 to 0.25 mg/kg

Comparison: no PQ

OutcomesNumber of participants
(trials)
Relative effect
(95% CI)
Anticipated absolute effects* (95% CI)Certainty of the evidence
(GRADE)
Comments
Risk with no PQ, with artemisinin partnerRisk with single dose PQ at 0.2 to 0.25 mg/kg
Participants infectious at day 3-4105
(3 RCTs)
RR 0.12
(0.02 to 0.88)
14 per 1002 per 100
(0 to 13)

⊕⊕⊝⊝
LOW1

Due to imprecision

Low-dose PQ may reduce infectiousness
Participants infectious at day 8243
(4 RCTs)
RR 0.34
(0.07 to 1.58)
4 per 1001 per 100
(0 to 6)

⊕⊕⊝⊝
LOW1

Due to imprecision

Low-dose PQ may reduce infectiousness
Participants with gametocytes at day 3 to 4 by PCR414
(3 RCTs)
RR 1.02
(0.87 to 1.21)
52 per 10053 per 100
(45 to 63)

⊕⊕⊕⊝
MODERATE2

Due to imprecision

Low-dose PQ probably has little or no effect on gametocytes detected by PCR at day 3 to 4
Participants with gametocytes at day 8 by PCR532
(4 RCTs)
RR 0.52
(0.41 to 0.65)
47 per 10025 per 100
(19 to 31)
⊕⊕⊕⊕
HIGH
Low-dose PQ reduces gametocytes detected by PCR at day 8
Participants with severe haemolysis752
(4 RCTs)
RR 0.98
(0.69 to 1.39)
13 per 10013 per 100
(9 to 18)

⊕⊕⊕⊝
MODERATE2

Due to imprecision

Low-dose PQ probably has little or no effect on severe haemolysis
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Summary of findings 2 Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission

Summary of findings 2. Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission
  1. 1Downgraded by 2 for imprecision: the CIs are wide; in addition, there is a large effect combined with a low number of events, which creates further uncertainty around the point estimate.
    2Downgraded by 1 for imprecision: the CIs are wide.
    3Downgraded by 2 for imprecision: the CIs are very wide.

Moderate-dose primaquine (PQ) given with artemisinin combination treatment

Participants or population: adults and children with malaria being treated with artemisinin combination treatment

Settings: Mali, Burkina Faso, The Gambia, Uganda

Intervention: single dose PQ 0.4 to 0.5 mg/kg

Comparison: no PQ

OutcomesNumber of participants
(trials)
Relative effect
(95% CI)
Anticipated absolute effects* (95% CI)Certainty of the evidence
(GRADE)
Comments
Risk with no PQ, with artemisinin partner,Risk with single dose PQ at 0.4 to 0.5 mg/kg
Participants infectious at day 3-4109
(3 RCTs)
RR 0.13
(0.02 to 0.94)
14 per 1002 per 100
(0 to 13)

⊕⊕⊝⊝
LOW1

Due to imprecision

Medium dose PQ may reduce infectiousness
Participants infectious at day 8246
(4 RCTs)
RR 0.33
(0.07 to 1.57)
4 per 100

1 per 100

(0 to 6)

⊕⊕⊝⊝
LOW1

Due to imprecision

Medium dose PQ may reduce infectiousness
Participants with gametocytes at day 3-4, by PCR418
(3 RCTs)
RR 1.09
(0.93 to 1.28)
52 per 100

57 per 100

(48 to 67)

⊕⊕⊕⊝
MODERATE2

Due to imprecision

Medium dose PQ probably has little or no effect on gametocytes detected by PCR on day 3 to 4
Participants with gametocytes at day 8, by PCR758
(5 RCTs)
RR 0.37
(0.29 to 0.48)
43 per 100

16 per 100

(13 to 21)

⊕⊕⊕⊕
HIGH
Medium dose PQ reduces gametocytes detected by PCR on day 8
Participants with severe haemolysis260
(2 RCTs)
RR 1.54
(0.38 to 6.30)
2 per 100

4 per 100

(1 to 15)

⊕⊕⊝⊝
LOW3

Due to imprecision

Medium dose PQ may increase severe haemolysis
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Summary of findings 3 Single dose primaquine at 0.75 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission

Summary of findings 3. Single dose primaquine at 0.75 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission
  1. 1Downgraded by 2 for imprecision: the CIs are wide; in addition, there is a large effect combined with a low number of events, which creates further uncertainty around the point estimate. In addition, in this one trial baseline.
    2Baseline values for this outcome were unbalanced, but the downgrading by 2 for imprecision takes this in to account, as it could be a chance finding.
    3Downgraded by 1 for indirectness: all the data for the results come from one trial.
    4Downgraded by 1 for imprecision: the CIs are wide.

High-dose primaquine (PQ) given with artemisinin combination treatment

Participants or population: adults and children with malaria being treated with artemisinin combination treatment

Settings: Cambodia, Mali, Burkina Faso, The Gambia, Tanzania, Sudan, Uganda

Intervention: single dose PQ 0.75 mg/kg

Comparison: no PQ

OutcomesNumber of participants
(trials)
Relative effect
(95% CI)
Anticipated absolute effects* (95% CI)Certainty of the evidence
(GRADE)
Comments
Risk with no PQ, with artemisinin partnerRisk with single dose PQ at 0.75mg/kg
Participants infectious at day 3-4101
(1 RCT)

RR 0.20

(0.02 to 1.68)

10 per 100

2 per 100

(0 to 16)

⊕⊕⊝⊝

LOW1,2

Due to imprecision

We do not know if high dose PQ may reduce infectiousness
Participants infectious at day 8181
(2 RCTs)
RR 0.18
(0.02 to 1.41)
5 per 100

1 per 100

(0 to 8)

⊕⊕⊝⊝
LOW1

Due to imprecision

High dose PQ may reduce infectiousness
Participants with gametocytes at day 3-4, by PCR290
(2 RCTs)
RR 0.92
(0.75 to 1.13)
38 per 100

35 per 100

(29 to 43)

⊕⊕⊝⊝
LOW3,4

Due to indirectness and imprecision

High dose PQ may have little or no effect on gametocytes detected by PCR
Participants with gametocytes at day 8, by PCR793
(5 RCTs)
RR 0.31
(0.23 to 0.43)
36 per 100

11 per 100

(8 to 16)

⊕⊕⊕⊕
HIGH
High dose PQ reduces gametocytes detected by PCR
Participants with severe haemolysis106
(1 RCT)
No estimateNot estimableNot estimableNo dataWe don't know if high dose PQ impacts on haemolysis
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Summary of findings 4 Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with non-artemisinin partner, for reducing P. falciparum transmission

Summary of findings 4. Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with non-artemisinin partner, for reducing P. falciparum transmission
  1. 1Downgraded by 1 for indirectness: all the results are from one setting.

Moderate-dose primaquine (PQ) given with non-artemisinin treatment

Participants or population: adults and children with malaria being treated with non-artemisinin treatment

Settings: Pakistan

Intervention: single dose PQ 0.4 to 0.5 mg/kg

Comparison: no PQ

OutcomesNumber of participants
(trials)
Relative effect
(95% CI)
Anticipated absolute effects* (95% CI)Certainty of the evidence
(GRADE)
Comments
Risk with no PQ, with non-artemisinin partnerRisk with single dose PQ at 0.4 to 0.5 mg/kg
Participants with gametocytes at day 4-5, by microscopy221
(2 RCTs)
RR 0.83
(0.62 to 1.13)
48 per 100

40 per 100

(30 to 54)

⊕⊕⊕⊝
MODERATE 1

Due to indirectness

Medium dose PQ probably reduces gametocytes detected by microscopy
Participants with gametocytes at day 8, by microscopy216
(2 RCTs)
RR 0.60
(0.49 to 0.75)
81 per 100

49 per 100

(40 to 61)

⊕⊕⊕⊝
MODERATE 1

Due to indirectness

Medium dose PQ probably reduces gametocytes detected by microscopy
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Summary of findings 5 Single dose primaquine at 0.75 mg/kg compared to no primaquine, with non-artemisinin partner, for reducing P. falciparum transmission

Summary of findings 5. Single dose primaquine at 0.75 mg/kg compared to no primaquine, with non-artemisinin partner, for reducing P. falciparum transmission
  1. 1Downgraded by 1 for risk of bias: unclear risk of bias in several domains from both studies.
    2Downgraded by 2 for imprecision: the CIs are wide; in addition, there is a large effect combined with a low number of events, which creates further uncertainty around the point estimate.
    3Downgraded by 1 for risk of bias: Arango 2012 had serious risk for selection bias and Chen 1993a had unclear risk of bias in several domains.
    4Downgraded by 1 for imprecision: the CIs are wide.
    5Downgraded by 1 for risk of bias: Arango 2012 had serious risk for selection bias and Chen 1993a had unclear risk of bias in several domains. Kamtekar 2004 had serious risk of bias for several domains.

Medium-dose primaquine (PQ) given with non-artemisinin treatment

Participants or population: adults and children with malaria being treated with non-artemisinin treatment

Settings: China, Colombia, India, Indonesia

Intervention: single dose PQ 0.75 mg/kg

Comparison: no PQ

OutcomesNumber of participants
(trials)
Relative effect
(95% CI)
Anticipated absolute effects* (95% CI)Certainty of the evidence
(GRADE)
Comments
Risk with no PQ, with non-artemisinin partnerRisk with single dose PQ at 0.75 mg/kg
Participants infectious at day 530
(2 RCTs)
RR 0.09
(0.01 to 0.62)
67 per 100

6 per 100

(1 to 41)

⊕⊝⊝⊝
VERY LOW1,2

Due to risk of bias and imprecision

We are uncertain whether high dose PQ reduces infectiousness
Participants infectious at day 830
(2 RCTs)
RR 0.07
(0.01 to 0.45)
93 per 100

7 per 100

(1 to 42)

⊕⊝⊝⊝
VERY LOW1,2

Due to risk of bias and imprecision

We are uncertain whether high dose PQ reduces infectiousness
Participants with gametocytes at day 5, by microscopy52
(2 RCTs)
RR 0.85
(0.48 to 1.50)
50 per 100

43 per 100

(24 to 75)

⊕⊕⊝⊝
LOW3,4

Due to risk of bias and imprecision

High dose PQ may reduce gametocytes detected by microscopy
Participants with gametocytes at day 8, by microscopy186
(4 RCTs)
RR 0.39
(0.25 to 0.62)
48 per 100

19 per 100

(12 to 29)

⊕⊕⊕⊝
MODERATE5

Due to risk of bias

High dose PQ probably reduces gametocytes detected by microscopy
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Background

Description of the condition

Malaria is a febrile illness due to infection with the Plasmodium parasite, and is transmitted between humans via mosquitoes (Phillips 2017). Of the five Plasmodium species known to cause illness in humans, Plasmodium falciparum is the most common, especially in sub-Saharan Africa, and causes the majority of severe illnesses and deaths (WHO 2016). The clinical illness develops due to the presence of asexual stage parasites (merozoites and schizonts) in the person's bloodstream, but transmission to mosquitoes is via sexual stage parasites (gametocytes), which develop from other blood stages at some point after infection (Phillips 2017).

Artemisinin-based combination therapies (ACTs) are currently recommended worldwide as the primary treatment for infection with P. falciparum (WHO 2010). The artemisinin derivatives treat the clinical illness by rapidly reducing the number of circulating schizonts and merozoites, which also reduces the potential for these stages to develop into gametocytes for onward transmission. The artemisinin derivatives have been shown to kill early developing gametocytes, but they have no direct effects on mature gametocytes (Price 1996; Chotivanich 2006; Okell 2008a; Okell 2008b). The partner drugs in ACTs (mefloquine, amodiaquine, piperaquine, lumefantrine, and sulfadoxine-pyrimethamine) are schizonticides with variable effects on gametocytes, and none adequately targets mature gametocytes (Drakeley 2006; Barnes 2008). In untreated infection, gametocytes can remain present for months as successive new generations are produced, and even following treatment they may persist for several weeks (Smalley 1977; Eichner 2001; Bousema 2010).

The mean circulation time of a mature P. falciparum gametocyte in humans has been estimated by microscopy or polymerase chain reaction (PCR) to be between 3.4 and 6.5 days (Smalley 1977; Eichner 2001; Bousema 2010). The infectivity of a person depends on the density of gametocytes in the bloodstream (Carter 1988; Bousema 2012). The percentage of bites on people that result in mosquito infection ranges between 0.3% and 46%, although most estimates are in the range of 1% to 10% (Graves 1988; Killeen 2006; Churcher 2013).

After uptake of a P. falciparum-infected blood-meal by the mosquito, the haploid gametocytes mature into male and female gametes. When fertilized, diploid oocysts develop on the mosquito's stomach wall and subsequently mature into sporozoites that migrate to the salivary glands, ready to be released when biting the next host. The median number of oocysts formed in wild-caught infected mosquitoes is two to three (Rosenberg 2008). Each oocyst develops thousands of sporozoites, but only about 20% are thought to reach the mosquito salivary glands and fewer than 25 sporozoites on average are ejected during mosquito blood-feeding (Rosenberg 1990; Rosenberg 2008).

Description of the intervention

Primaquine (PQ) is the only drug in common use that is known to kill mature P. falciparum gametocytes (Burgess 1961; Pukrittayakamee 2004; Chotivanich 2006), and with the recent emphasis on malaria elimination, there has been a renewed interest and emerging literature on PQ's potential value in reducing malaria transmission (Eziefula 2012; White 2012; WHO 2012b; White 2013). PQ is an 8-aminoquinoline (8AQ) whose pharmacokinetic mode of action is not well understood, but it is known to be rapidly metabolized, with a half-life of six hours (White 1992). PQ does not directly affect P. falciparum asexual stages which cause the clinical illness (Arnold 1955; Pukrittayakamee 2004), and does not appear to affect the early or maturing gametocytes (Bhasin 1984; White 2008). Consequently, a combination of PQ and an artemisinin derivative (as part of ACT) would target all gametocyte stages and have the greatest potential for reducing onward transmission to mosquitoes (WHO 2012b; White 2013).

One of the constraints to widespread use of PQ is that the drug is known to be a haemolytic trigger in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The deficiency is X-linked and expressed in a wide variety of variants and levels of G6PD deficit (Howes 2013). PQ can occasionally cause serious haemolytic anaemia, haemoglobinaemia, and renal failure. The effect depends on the degree of enzyme deficiency, the dose of PQ, and the pattern of the exposure. These occasional, but clearly serious, adverse effects have led to a reputation of being "unsafe" (Ashley 2014). Although the haemolysis appears less likely at lower dose, there have been few studies in G6PD-deficient people at low doses of PQ (Olalekan 2017).

The WHO 2010 Guidelines for the Treatment of Malaria recommended adding a single dose of PQ at 0.75 mg/kg to treatment for uncomplicated P. falciparum malaria in people who are not G6PD-deficient with the goal of reducing transmission at the community level (WHO 2010). However, since testing for G6PD deficiency was rarely done and due to the concerns about the safety of this single dose, the WHO convened a special expert review group in 2012 to reconsider this recommendation (WHO 2012a). The expert group concluded that:

  • G6PD testing should be done more widely;

  • countries already implementing single-dose PQ should reduce the dose to 0.25 mg/kg in G6PD-deficient patients; and

  • countries not currently implementing single-dose PQ but which are targeting malaria elimination, or are threatened by artemisinin resistance, should add 0.25 mg/kg PQ to treatment for uncomplicated P. falciparum malaria (White 2012).

These conclusions were then incorporated into a revised WHO recommendation in treatment guidelines (WHO 2012b) for 0.25 mg/kg PQ in the above circumstances, with the goal of reducing transmissibility of treated P. falciparum infections (except in pregnant women, infants under six months of age, and women breastfeeding infants under six months of age). A slightly revised policy was then included in an updated policy brief (WHO 2015a), and in the third edition of the WHO Guidelines for the Treatment of Malaria (WHO 2015b), which expanded the area of recommendation to all "low transmission areas"; this was a strong recommendation with low certainty evidence and it was stated that G6PD deficiency testing was not required.

How the intervention might work

A single dose of PQ could contribute to reducing malaria transmission through its effects on mature gametocytes, and it is reasonable to assume that reducing the density and duration of gametocytes in the blood of infected people (gametocytaemia) will reduce the duration of potential infectiousness to mosquitoes at the level of the individual (see Figure 1). However, any subsequent effects on the number of mosquitoes infected from infected people (infectiousness) or the number of new malaria infections in the community (transmission) cannot be assumed and requires estimation of these effects using reliable methods and some direct evidence.

Figure 1.

Review logic framework: the potential points in the Plasmodium parasite life cycle that could be impacted by PQ and the outcomes used to measure impact. Abbreviations: AUC: area under the curve. EIR: entomological inoculation rate; PQ: primaquine.

Infectiousness to mosquitoes can be measured directly by allowing mosquitoes to feed on infected individuals (or their blood) who have been treated with and without PQ (Killeen 2006; Bousema 2012; Dicko 2016; Gonçalves 2016a; Gonçalves 2016b; Okebe 2016; Lin 2017), or estimated indirectly by measuring the infection rates of wild-caught mosquitoes (Graves 1990; Lines 1991).

Community-level transmission can be measured through large cluster-randomized trials, or less reliably through controlled before-and-after studies. Within any community there are people who are carriers of P. falciparum gametocytes but who do not seek treatment (Bousema 2011). This is most apparent in areas of high endemicity, where much of the adult population has acquired immunity, so low-level parasitaemias do not produce symptoms. This reservoir of gametocytes in untreated adults will continue to facilitate community level transmission and may dilute any possible effect of PQ in moderate to high level transmission settings. Indeed, these dilutional effects may even be important in low transmission settings (Ouédraogo 2009; Bousema 2014; Stone 2015).

Recently, with the move toward a target of elimination, some policy makers are considering mass treatment strategies to reduce transmission or contain outbreaks once transmission is reduced to low levels (von Seidlein 2003; Sturrock 2013). In this situation, it seems more likely that a higher proportion of the population with gametocytes will be detected or treated, or both, and that this could be effective in reducing or interrupting transmission. This policy is being considered in countries with lower intensity transmission, or on islands or at the northern and southern fringes of malaria distribution, or both (GMAP 2008; Mendis 2009). Effective antimalarial drugs are likely to play a large role in this new strategy. One question in this effort is whether there is a role for PQ given in addition to curative antimalarial drugs, including ACTs, to further reduce the infection transmissibility (White 2008). Recent modelling has questioned the value of the additional impact of PQ to mass drug administration (MDA) (Johnston 2014; WHO 2015c).

The transmission blocking potential of PQ has also been suggested as a strategy to reduce the spread of artemisinin-resistant parasites in Southeast Asia (Breman 2012). While it is certainly important to urgently expand access to treatment for persons with such parasites, PQ does not act on asexual stages, which would still produce gametocytes as usual in resistant infections. Thus it is not clear how this would work, and it may actually be counterproductive (Hastings 2006).

Why it is important to do this review

PQ could play a role in P. falciparum malaria control, particularly malaria elimination and possibly eradication. Defining the strategies in which PQ will be most effective depends on getting the details right on dose, timing, and the situations in which it is used. It has become clear that ACTs have differing effects on gametocyte carriage following treatment, even without PQ (WWARN 2016). Therefore the effectiveness may vary considerably, but adverse effects — particularly the haemolytic effects of PQ — occur independently of effectiveness. That is, even if used in situations when it is largely ineffective, the rate of adverse reactions will be constant. Since it is the haemolytic effects that are often foremost in the minds of government health staff, building a case for the use of the drug depends on convincing evidence of its value in malaria control, including in implementation of WHO recommendations.

Objectives

1. To summarize any reliable direct research evidence that community programmes of single low dose PQ reduce malaria transmission.

2. For currently recommended artemisinin combination treatments for P. falciparum infections, to summarize reliable research evidence on the effect of adding a single dose of PG/8AQ on infectiousness of infected people to mosquitoes, gametocytaemia and any evidence of haemolysis, stratified by:

  • the current standard recommended dose of 0.25 mg/kg;

  • previously recommended doses (up to 0.75 mg/kg).

3. To repeat the analysis of effects of single dose PQ, stratified by dose, for non-artemisinin based combination treatments for P. falciparum infections.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) or quasi-RCTs including individual- or cluster-RCTs. Cluster-RCTs must have had at least two clusters per arm.

Types of participants

Adults or children with P. falciparum infection or a mixed infection of P. falciparum and other Plasmodium species. For individual RCTs, eligible studies must have diagnosed patients by blood slide, rapid diagnostic test, or other valid molecular method; for cluster-RCTs, diagnosis could have been by clinical judgment if that was standard in the trial area at the time of the trial.

Types of interventions

Intervention

A single dose or short course (up to seven days) of PQ (at doses of 0.2 mg/kg per day or above) or other 8AQ added to malaria treatment(s).

Control

Identical treatment for malaria not including PQ/8AQ (or substituting placebo for PQ/8AQ); or using a different 8AQ with same malaria treatment, or using different dose of PQ/8AQ with same malaria treatment(s).

Types of outcome measures

Transmission

Any measure of community burden or incidence of malaria (entomological inoculation rate (EIR) measured in mosquitoes, incidence of new malaria infections, or prevalence of malaria infection).

Infectiousness
  • Number of participants infectious (leading to infection with oocysts or sporozoites in at least one mosquito fed on them or their blood) at day 3-5 and day 8.

  • Proportion of mosquitoes infected by direct or membrane feeding on blood of participants at day 3-5 and day 8.

Potential infectiousness
  • Number of participants with gametocytes detected by PCR on day 3-4 and day 8.

  • Number of participants with gametocyte detected by microscopy on day 3-4 and day 8.

Other measures of gametocytes including gametocyte clearance time (time to disappearance of gametocytes from the blood) and area under the curve of gametocyte density over time where reported.

Adverse effects
  • Serious adverse events leading to hospital admission or death.

  • Participants with severe haemolysis as defined by the trial authors. It was defined as drop of ≥ 25% (Dicko 2016; Mwaiswelo 2016), ≥ 2 g (Gonçalves 2016b), or ≥ 2 g of haemoglobin (Tine 2017) over the course of follow-up.

We also describe maximum or average absolute or percent change in haemoglobin or packed cell volume (PCV) when this is reported.

Figure 1 provides an outline of transmission of malaria to help clarify the outcomes.

Search methods for identification of studies

We attempted to identify all relevant trials, regardless of language or publication status (published, unpublished, in press, and in progress).

Electronic searches

Databases

We searched the following databases up to 21 July 2017 using the search terms and strategy described in Appendix 1: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (Issue 1, 2017); MEDLINE (PubMed; 1966 to 21 July 2017); Embase (OVID; 1980 to 21 July 2017); and LILACS (BIREME, 1982 to 21 July 2017). Also, we checked ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home) and the WHO International Clinical Trials Registry Platform (ICTRP); http://www.who.int/ictrp/en/; both accessed 21 July 2017) using ‘malaria*', ‘falciparum', ‘primaquine', ‘8-aminoquinoline', and eight other individual 8AQ names as search terms. 

Conference proceedings

We searched the following conference proceedings for relevant abstracts: the MIM Pan-African Malaria Conferences and the American Society of Tropical Medicine and Hygiene (ASTMH) to December 2009.

Searching other resources

Researchers and organizations

We contacted researchers who were authors of some of the included and in-progress trials, other trial authors, and other experts in the field of malaria chemotherapy.

Reference lists

We checked the reference lists of all studies identified by the above methods.

Data collection and analysis

Selection of studies

Two review authors (PMG and HG) independently screened all citations and abstracts identified by the search strategy, including ongoing studies, for potentially eligible studies. We independently assessed full reports of potentially eligible studies for inclusion in the review. Notably, we did not contact any trial authors for clarification regarding inclusion (although we later contacted several about trial details) because it was clear whether trials were or were not eligible for inclusion. We used translations of eight papers published in Chinese to assess eligibility. We resolved differences of opinion by discussion with PG. We listed all studies excluded after full-text assessment, and their reasons for exclusion, in the ‘Characteristics of excluded studies' table. We have illustrated the study selection process in a PRISMA diagram.

Data extraction and management

Two review authors (PMG and HG) independently extracted the following information for each trial using a data extraction form.

Trial characteristics
  • Design (RCT or quasi-RCT, type of randomization).

  • Dates and duration of trial.

Participant characteristics
  • Number of participants.

  • Age and sex of participants.

  • Proportion with G6PD deficiency.

  • Proportion with gametocytes at onset of trial.

  • Inclusion criteria.

  • Exclusion criteria.

Intervention characteristics
  • Type of drug, dose, and schedule.

Presented outcomes
  • Description of outcomes presented in the papers.

Other
  • Location of trial, setting, and source of funding.

  • Local endemicity of malaria.

Outcomes data

For each trial, two review authors (PMG and HG) extracted data on the trial outcomes eligible for inclusion in this review for the PQ and non-PQ groups. We extracted the number of participants randomized and the numbers analysed in each treatment group for each outcome. For dichotomous data outcomes (proportion of participants infectious to mosquitoes, proportion of participants with gametocytes, proportion of mosquitoes infected), we extracted the number of participants experiencing the event of interest and the total number of participants or mosquitoes in each treatment arm of each trial. We noted details on the method of determining parasite presence and density, for example light microscopy (if so, the method of staining and number of fields examined), PCR, or other methods.

For G6PD deficiency, we noted the sex of the carrier (if stated) and the method used to determine G6PD deficiency, either phenotypically (by enzyme function) or genotypically (PCR). We adopted the definition of ‘deficient' used in the trials that assessed this outcome. We extracted adverse event data for each individual type of event wherever possible. Where adverse events were reported separately for more than one dose (for short-course regimens), we attempted to record the average number of people reporting each adverse event for each dose. If trials reported the occurrence of adverse events at more than one time point following a single dose, but did not record the total number of people reporting each event, we attempted to record the events occurring in the first time period.

In cases of disagreement, we double checked the data and we reached consensus through discussion between all review authors.

Assessment of risk of bias in included studies

Two review authors (PMG and HG) independently assessed the risk of bias of the included trials as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For each included trial, we assigned a judgement of low, unclear, or high risk of bias for the following components: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other biases.

For sequence generation and allocation concealment, we described the methods used, if given. For blinding, we described who was blinded and the blinding method. For incomplete outcome data, we reported the percentage and proportion of loss to follow-up (the number of participants for whom outcomes are not measured of the number randomized), if given. For selective outcome reporting, we stated any discrepancies between the methods and the results in terms of the outcomes measured and the outcomes reported; we also stated if we knew that an outcome was measured but was not reported in the publication. For other biases we described any other trial features that could have affected the trial's results (for example, whether a trial was stopped early or if no sample size calculation was included). We resolved any disagreements through discussion.

We reported the results of the risk of bias assessment in a ‘Risk of bias' table and displayed them in a ‘Risk of bias' summary and ‘Risk of bias' graph (Figure 2; Figure 3).

Figure 2.

‘Risk of bias' summary: review authors' judgements about each risk of bias item for each included trial.

Figure 3.

‘Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.

Measures of treatment effect

We analysed the data using Review Manager 5 (RevMan 5) (RevMan 2014). For dichotomous data, we estimated the risk ratio (RR) and used the Mantel-Haenszel method with fixed-effect, or with random-effects if there was heterogeneity. For continuous data, we estimated the mean difference (MD). All results are presented with 95% confidence intervals (CIs). We reported results only for days after the first day of PQ treatment, which, in some trials, was later than the beginning of primary treatment.

When one trial contained more than one comparison with the same placebo group and there was an analysis total or subtotal, we divided the placebo group participants between the comparisons to avoid double-counting participants and falsely overestimating the precision.

Unit of analysis issues

All the included trials were individually randomized and analysed accordingly.

Dealing with missing data

Where data were missing from the trials or details were unclear, we attempted to contact the trial authors. We used complete case analysis (that is, excluding dropouts rather than ‘intention to treat' analysis) for trials with missing data.

Assessment of heterogeneity

We assessed heterogeneity between the trials by examining the forest plots to check for overlapping CIs, using the Chi2 test for heterogeneity with a 10% level of significance and the I2 statistic with a value of 50% to represent moderate levels of heterogeneity.

Assessment of reporting biases

There were insufficient trials (less than 10) within each comparison to assess the likelihood of small trial effects, such as publication bias, by examining a funnel plot for asymmetry (Higgins 2011).

Data synthesis

We prespecified subgroups for analysis by artemisinin or non-artemisinin based malaria treatment regimens and described which antimalarial drug was used for each comparison in a footnote. We prespecified strata by PQ dose category: low (0.2 to 0.25 mg/kg), medium (0.4 to 0.5 mg/kg), and high (0.75 mg/kg dose); and grouped the 8AQ drugs as PQ and other. Throughout this review, to enable standardization between trials, we designated the first day of any treatment drug as day 1 rather than day 0 as reported in some trials.

Where not stated as mg/kg, we reported the PQ dose as the adult dose with the equivalent dose reported as mg/kg; most trials stated that the dose was adjusted for children and if not stated, we made this assumption.

When there was no statistically significant heterogeneity between trials, we applied the fixed-effect meta-analysis model. When we observed statistically significant heterogeneity within groups that could not be explained by subgroup or sensitivity analyses, we used a random-effects meta-analysis model. When we determined substantial heterogeneity from the assessments of heterogeneity (I² statistic value > 50%), we did not undertake meta-analysis but instead presented a Forest plot with the pooled effect suppressed.

Certainty of the evidence

We assessed the certainty of the evidence using the GRADE approach (Guyatt 2011). We rated each primary outcome as described by Balshem 2011 as follows.

  • High: we are very confident that the true effect lies close to that of the estimate of the effect.

  • Moderate: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect.

  • Low: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.

  • Very low: we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.

RCTs start as high certainty evidence but can be downgraded if there are valid reasons within the following five categories: risk of bias, imprecision, inconsistency, indirectness, and publication bias. Studies can also be upgraded if there is a large effect; a dose response effect; and if all plausible residual confounding would reduce a demonstrated effect or would suggest a spurious effect if no effect was observed (Balshem 2011). We summarized our findings in a ‘Summary of findings’ table.

Subgroup analysis and investigation of heterogeneity

In our protocol, we stated we would investigate heterogeneity in relation to drug resistance pattern, the parasite density before treatment, and the local endemicity of malaria. However, we identified too few trials for inclusion to perform these analyses.

Sensitivity analysis

There were insufficient trials to conduct a sensitivity analysis to investigate the robustness of the results to the quality (risk of bias) components.

Results

Description of studies

Results of the search

In the last published version of this review, Graves 2015, we included a total of 18 trials. There was one instance of duplicate reports of the same trial in different languages (Chen 1994). Trials frequently included arms with distinct comparisons of different malaria treatment partner drugs, doses, or schedules; thus the 18 previously included trials had 30 arms.

For this update, a literature search update to 21 July 2017 identified 53 new records. Four new publications (Eziefula 2013; Eziefula 2014; Pett 2014; Chang 2016) were additional reports from a previously included trial (Eziefula 2013). Of the remainder, 10 records were selected for full text review and we excluded 39 records.

Ten new publications described seven new trials published since the last revision (Dicko 2016; Gonçalves 2016a; Gonçalves 2016b; Mwaiswelo 2016; Okebe 2016; Lin 2017; Tine 2017). The Goncalves study is regarded as two trials because the two phases had different inclusion criteria (Gonçalves 2016a; Gonçalves 2016b).

The seven new trials included a total of 16 separate comparison arms. Therefore, this update now includes 25 trials which had 46 total arms (Table 1). There were 14 trials with artemisinin-only arms (seven with one arm, two with two arms, three with three arms, one with four arms, and one with five arms). There were nine trials with non-artemisinin only arms (six with one arm and three with two arms). Two trials had both artemisinin and non-artemisinin arms. Three artemisinin arms in two trials were excluded because they used doses lower than 0.2 mg/kg (Eziefula 2013; Dicko 2016), leaving 43 included arms in the 25 trials.

Table 1. Trial locations, partner drugs, gametocyte status at onset, G6PD status, and PQ dose and treatment schedule
  1. *first day of any treatment = day 1

    **arm excluded as dose < 0.2 mg/kg

    1G6PD colorimetric method, R&D diagnostics, Papagos, Greece.
    2G6PD by fluorescence spot test.
    3G6PD by Binax Now Alere rapid test.
    4G6PD by fluorescent spot test (R&D diagnostics, Greece) and quantitative enzyme activity testing (Trinity Biotech, Ireland).
    5G6PD (phenotypic) by CareStart ™ Access Bio test; (genotypic) by PCR and RFLP digestion for the two most common Afrcian G6PD polymorphisms.
    6G6PD by detection of single nucleotide polymorphisms (G202A, A376G) by PCR and ELISA.
    7G6PD by qualitative test.
    8G6PD by Brewer's methaemoglobin reduction test.
    9G6PD by semi-quantitative G6PD assay.
    10G6PD method not reported.

    Abbreviations: G6PD = glucose-6-phosphate dehydrogenase; FST = fluorescent spot test; PQ = primaquine; CQ = chloroquine; SP = sulfadoxine-pyrimethamine; MQ = mefloquine; QN = quinine; AS = artesunate; ACT = artemisinin-based combination therapy; 8AQ: 8-aminoquinoline; AQ = amodiaquine; AL = artemether-lumefantrine; DHAP = dihydroxyartemisinin-piperaquine; BQ = bulaquine; i.v. = intravenous injection; i.m. = intramuscular injection; Mic = microscopy; Pf = P. falciparum; Pv = P. vivax.

ComparatorTrialArmPlaceG6PD statusParasite speciesPartner or alternative drugProportion with gametocytes at onset (control group)Proportion with gametocytes at onset (experimental group)Day(s)* PQ givenTarget PQ dose per day
Artemisinin-based partner
AS or ACTArango 2012bColombiaNot reportedPf only

AS+MQ

days 1 to 3

34.8% Mic

(N = 23)

26.3% Mic

(N = 19)

day 20.75 mg/kg
Dicko 2016aMaliOnly non-deficient included1Pf only

DHAP

days 1 to 3

100% Mic

(N = 15)

Table 1

100% Mic (N = 16)day 10.0625 mg/kg**
b100% Mic (N = 16)day 10.125 mg/kg**
c100% Mic (N = 15)day 10.25 mg/kg
d100% Mic (N = 17)day 10.5 mg/kg
El-Sayed 2007 

Sudan

(east)

Not reportedPf only

AS+SP

days 1 to 3

11.5% PCR

(N = 52)

Table 2

11.5% PCR

(N = 52)

day 40.75 mg/kg
Eziefula 2013aUganda

Only non-deficient included2

(PCR testing of those included after FST)

Pf only

AL

days 1 to 3

23.1% Mic

(N = 117)

79.8% PCR

(N = 114)

Table 1

24.3% MIc

(N = 115)

86.7% PCR

(N = 113)

day 30.1 mg/kg**
b

20.4% Mic

(N = 113)

78.7% PCR

(N = 108)

day 30.4 mg/kg
c

22.4% Mic

(N = 116)

82.0% PCR

(N = 111)

day 30.75 mg/kg
Gonçalves 2016aaBurkina FasoOnly non-deficient included3Pf only

AL

days 1 to 3

17.7% Mic

(N = 62)

Table 2

32% Mic (N = 75)

92.9% PCR (N = 70)

day 30.25 mg/kg
b

20.5% Mic

(N = 73)

85.5% PCR (N = 62)

day 30.4 mg/kg
Gonçalves 2016baBurkina FasoOnly non-deficient included3Pf only

AL

days 1 to 3

69.4% Mic

(N = 49)

Table 2

55.3% Mic (N = 47)

93.7% PCR (N = 48)

day 30.25 mg/kg
b

83.3% Mic (N = 46)

100.0% PCR (N = 46)

day 30.4 mg/kg
Lin 2017 CambodiaScreened and severely deficient excluded4Pf or Pf+Pv

DHAP

days 1 to 3

10% Mic

44% PCR

(N = 51)

Table 1

8% Mic

49% PCR

(N = 50)

Table 1

day 30.75 mg/kg
Mwaiswelo 2016 TanzaniaScreened and all included5Pf only

AL

days 1 to 3

1 patient had gametocytes at recruitment but treatment group not given

0.5% Mic

(N = 220)

both groups

day 10.25 mg/kg
Okebe 2016aThe GambiaOnly non-deficient included2Pf only

DHAP

days 1 to 3

47.7% PCR

(N = 153)

Table 1

53.4% PCR (N = 148)day 30.2 mg/kg
b

54.6% PCR

(N = 152)

day 30.4 mg/kg
c

53.4% PCR

(N = 146)

day 30.75 mg/kg
Pukrittayakamee 2004cThailandOnly non-deficient included10Pf only

AS

days 1 to 7

26.1% Mic

(N = 23)

Table 3

26.0% Mic

(N = 50)

days 1 to 70.5 mg/kg
Shekalaghe 2007 

Tanzania

(North east)

Screened and all included6Pf only

AS+SP

days 1 to 3

26.4% Mic (N = 63)

88.2% PCR

(N = 51)

Table 1

18.9% Mic

(N = 53)

90.6% PCR

(N = 53)

day 30.75 mg/kg
Smithuis 2010a

Myanmar

(3 states)

Not screenedPf or mixed

AS+AQ

days 1 to 3

32.1% Mic

(N = 84)

36.6% Mic

(N = 71)

day 10.75 mg/kg
b

AL

days 1 to 3

34.5% Mic

(N = 84)

32.1% Mic

(N = 78)

day 10.75 mg/kg
c

AS+MQ

fixed dose

days 1 to 3

31.3% Mic

(N = 83)

27.9%% Mic

(N = 86)

day 10.75 mg/kg
d

AS

days 1 to 3 + MQ day 1 loose

30.5% Mic

(N = 82)

26.6% Mic

(N = 79)

day 10.75 mg/kg
e

DHAP

days 1 to 3

43.6% Mic

(N = 78)

32.5% Mic

(N = 83)

day 10.75 mg/kg
Sutanto 2013 

Indonesia

(south Sumatra)

Only non-deficient included7Pf only

DHAP

days 1 to 3

17.4% Mic

(N = 178)

Figure 1

24.0% Mic

(on day 3)

(N = 171)

day 40.75 mg/kg
Tine 2017aSenegalScreened and all included5Pf only

AL

days 1 to 3

6.7% Mic

(N = 135)

Table 5

7.9% Mic

(N = 139)

Table 5

day 10.25 mg/kg
b

DHAP

days 1 to 3

c

AS+AQ

days 1 to 3

Vásquez 2009 Colombia (Antioquia)Not reportedPf only

AS+MQ

days 1 to 3

(MQ only on day 2 for children < 6)

16% Mic

(N = 25)

Figure 1 estimated

24.0% Mic

(N = 25)

day 3

45 mg

(˜0.75 mg/kg)

Wang 2006 GabonNot reportedPf

AS i.m.

days 1 to 5

Not reported

(N = 106)

Not reported

(N = 108)

days 1 to 5

22.5 mg

(˜0.38 mg/kg)

Non-artemisinin partner

CQ or

(CQ+SP)

Kamtekar 2004aIndia (Mumbai)Not screenedPf only

CQ

days 1 to 3 or

CQ

days 1 to 3 + SP day 1

100% Mic

(N = 44)

100% Mic

(within 3 days)

(N = 45)

day 4

45 mg

(˜0.75 mg/kg)

Khoo 1981 Malaysia (Sabah)Only deficient included8Pf, Pv or mixed

CQ

days 1 to 3

Not reportedNot reporteddays 1 to 3

25 mg

(˜0.42 mg/kg)

Kolaczinski 2012a

Pakistan

(3 Afghan refugee camps)

Not reportedPf onlyCQ days 1 to 3

17.6% Mic

(N = 239)

Table 2 (combined CQ, CQ+AS, SP, SP+AS groups)

19.7% Mic

(N = 76)

day 3

0.5

mg/kg

Lederman 2006aIndonesia (Central Java)Only non-deficient included9Pf only

CQ

days 1 to 3 + SP day 1

8.2% Mic

(N = 61)

Figure 3 est (combined CQ, CQ+SP groups)

25% Mic

(N = 28)

Figure 3 est

day 1

45 mg

(˜0.75 mg/kg)

b

14.3%

(N = 28)

Figure 3 est

day 3

45 mg

(˜0.75 mg/kg)

SPKolaczinski 2012bPakistan (2 Afghan refugee camps)Not reportedPf onlySP day 1See above under Kolaczinski 2012 a

27.1% Mic

(N = 85)

day 10.5 mg/kg
AQ+SPArango 2012aColombiaNot reportedPf only

AQ

days 1 to 3 + SP day 1

15% Mic

(N = 20)

Table 3

30% Mic

(N = 20)

day 20.75 mg/kg
MQ or (MQ+SP)Chen 1993a ChinaNot reportedPf onlyMQ day 1

100% Mic

(N = 6)

100% Mic

(N = 6)

day 145 mg (˜0.75 mg/kg)
Chen 1994 China (Hainan province)Not reportedPf only

MQ

day 1

100% Mic

(N = 9)

MQ group only

100% Mic

(N = 9)

day 1

45 mg

(˜0.75 mg/kg)

Singhasivanon 1994 Thailand (Bangkok)Not reportedPf onlyMQ+SP fixed day 1

Not reported

(N = 11)

Not reported

(N = 7)

day 10.75 mg/kg
QNKamtekar 2004bIndia (Mumbai)Not screenedPf only

QN i.v.

days 1 to 2 and orally days 1 to 7

88.6% Mic

(N = 44)

100% Mic

(within 3 days)

(N = 45)

day 8

45 mg

(˜0.75 mg/kg)

Pukrittayakamee 2004aThailandOnly non-deficient included10Pf only

QN

days 1 to 7

23.3% Mic

(N = 60)

QN, QN+TC groups

18.6% Mic

(N = 59)

days 1 to 70.25 mg base/kg
b

22.4% Mic

(N = 67)

days 1 to 70.5 mg base/kg
Comparison of different 8AQ
PQ versus BulaquineGogtay 2004 

India

(Mumbai)

Only non-deficient included10Pf

QN + doxycycline days 1 to 7

+ BQ day 4

No control group without 8-AQ

100% Mic

(N = 22)

day 4

45 mg

(˜0.75 mg/kg)

Gogtay 2006 India

Only non-deficient

included10

Pf

QN + doxycycline days 1 to 7

+ BQ day 4

No control group without 8-AQ

100% Mic

(N = 93)

day 4

45 mg

(˜0.75 mg/kg)

We updated Figure 4, which shows the flow diagram of included studies, accordingly. We still could not locate three articles that were cited in the ‘Studies awaiting classification' section in the previous and this version.

Figure 4.

Study flow diagram

Included studies

The 25 included trials comprised 24 individually randomized RCTs and one quasi-RCT which used alternate allocation (Arango 2012). Two trials compared PQ and bulaquine (BQ), while 23 trials compared PQ versus no PQ. One trial of PQ, Khoo 1981, did not distinguish between participants given a short or long course of PQ and therefore no outcomes are included in this review. Two trials did not include any gametocyte outcomes (Wang 2006; Mwaiswelo 2016).

Trials reporting community transmission

No cluster trials examining malaria transmission intensity in communities met the inclusion criteria.

Trials reporting infectiousness

Five trials reported on infectiousness of participants to mosquitoes by direct or membrane feeding of people given ACTs compared to ACT+PQ (Dicko 2016; Gonçalves 2016a; Gonçalves 2016b; Okebe 2016; Lin 2017). These trials were conducted in Burkina Faso (partner drug AL), Mali (DHAP), The Gambia (DHAP), and Cambodia (DHAP), respectively. In addition, Mwaiswelo 2016 planned to test infectivity in Tanzania with AL as partner drug, but no infectiousness or gametocyte outcomes were reported.

For direct measures of infectiousness with non-ACT partner drugs, two small trials in China evaluated the infectiousness to mosquitoes of people treated with mefloquine (MQ) compared to MQ+PQ (Chen 1993a; Chen 1994).

Trials reporting potential infectiousness

Twenty-two trials examined the impact of PQ or 8AQ on various measures of potential infectiousness, such as gametocyte prevalence or density over time in participants after treatment, gametocyte clearance time, or gametocyte circulation time. Three trials with artemisinin partners assessed gametocyte prevalence by PCR only (El-Sayed 2007; Dicko 2016; Okebe 2016). Five trials reported both microscopy and PCR gametocyte detection (Shekalaghe 2007; Eziefula 2013; Gonçalves 2016a; Gonçalves 2016b; Lin 2017), and the others with either artemisinin or non-artemsisinin partners reported gametocyte prevalence by microscopy only.

Five trials with artemisinin partners reported area under curve (AUC) or log(10)AUC as a summary combined measure of gametocyte prevalence and density over time, using PCR estimates of density (Shekalaghe 2007; Eziefula 2013; Dicko 2016; Gonçalves 2016b; Tine 2017).

Trials reporting adverse effects

Eleven trials reported adverse effects quantitatively, with 44 different types of effects reported. Nine trials included anaemia outcomes (El-Sayed 2007; Shekalaghe 2007; Eziefula 2013; Dicko 2016; Gonçalves 2016a; Mwaiswelo 2016; Okebe 2016; Lin 2017; Tine 2017), and two reported only non haemolytic effects (Wang 2006; Sutanto 2013) (Analysis 1.9 to Analysis 1.18, and Analysis 3.6).

Participants
Place of recruitment

Participants were usually people attending health clinics for treatment, but Dicko 2016 actively recruited participants from the community for a second phase of the trial when insufficient infective participants were found in phase 1.

Age

Four trials did not state the participants' ages (Khoo 1981; Chen 1993a; Chen 1994; El-Sayed 2007), and five trials included children only: Singhasivanon 1994 (five to 12 years); Shekalaghe 2007 (three to 15 years); Eziefula 2013 (one to 10 years); Gonçalves 2016a and Gonçalves 2016b (two to 15 years). Nine trials used a wide age range of children and adults: Wang 2006 (six to 60 years); Vásquez 2009 (≥ one year); Smithuis 2010 (> six months); Arango 2012 (one to 75 years); Kolaczinski 2012 (three to 70 years); Sutanto 2013 (≥ five years); Mwaiswelo 2016 (≥ one year); Okebe 2016 (> one year) and Dicko 2016 (five to 50 years). The remaining seven trials included teenagers and adults only: Gogtay 2004 (> 18 years); Kamtekar 2004 (> 16 years); Lin 2017 (18 to 65 years); Tine 2017 (18 to 74 years); Pukrittayakamee 2004 (15 to 62 years); Gogtay 2006 (> 16 years); and Lederman 2006 (≥ 15 years). See the ‘Characteristics of included studies' section.

G6PD deficiency

For G6PD deficiency, two trials did not screen participants (Kamtekar 2004; Smithuis 2010), three trials screened and included all participants (Shekalaghe 2007; Mwaiswelo 2016; Tine 2017), one trial included only G6PD-deficient participants (Khoo 1981), 11 trials included only non-severely deficient participants (Gogtay 2004; Pukrittayakamee 2004; Gogtay 2006; Lederman 2006; Sutanto 2013; Eziefula 2013; Dicko 2016; Gonçalves 2016a; Gonçalves 2016b; Okebe 2016; Lin 2017), and the remaining eight studies made no comment (Chen 1993a; Chen 1994; Singhasivanon 1994; Wang 2006; El-Sayed 2007; Vásquez 2009; Arango 2012; Kolaczinski 2012); see Table 1.

Baseline infectiousness

In Dicko 2016, baseline infectiousness (proportion of persons infectious) prior to treatment in both groups combined was 58/73 (79%), with no obvious imbalance between the treatment groups. In Goncalves phase 1, no baseline infectiousness was measured (Gonçalves 2016a); in phase 2, 79 of the 149 participants were tested for infectiousness at baseline, and 30/79 (38%) were infectious (all groups combined) (Gonçalves 2016b). In Lin 2017, baseline infectiousness of participants reported on day 0 appeared unbalanced: DHAP 6/51 (12%); DHAP+PQ 1/51 (2%). This is assumed to reflect selection bias or a failure of randomization.

Interventions
Background drug

Sixteen trials (31 treatment arms) evaluated PQ given alongside artemisinin-based treatments: artesunate (AS) (two trials, two arms), AS+SP (two trials, two arms), AS+MQ (three trials, four arms), AS+AQ (two trials, two arms), artemether-lumefantrine (AL) (five trials, ten arms) and dihydroxyartemisinin-piperaquine (DHAP) (six trials, 11 arms). Two trials included two and one arms, respectively, with doses too low (< 0.2 mg/kg) to be included here (Eziefula 2013; Dicko 2016). One trial, Tine 2017, included arms with AL, DHAP and ASAQ, but they were combined in the paper and here for analysis.

Eleven trials (15 treatment arms) evaluated PQ or BQ, given alongside non-artemisinin-based treatments. Nine trials (13 treatment arms) evaluated PQ given alongside the following: chloroquine alone (CQ) (three trials, four arms), CQ alone or CQ+SP (one trial, one arm), SP (one trial, one arm), mefloquine (MQ) (two trials, two arms), MQ+SP (one trial, one arm), quinine (QN) (two trials, three arms), and amodiaquine (AQ)+SP (one trial, one arm). Two trials (two treatment arms) evaluated BQ given alongside the following: QN (one trial, one arm) and QN plus doxycycline (one trial, one arm).

Dose

Sixteen trials included the previous standard dose of 0.75 mg/kg PQ per day (adult dose 45 mg/day); see Table 1. The trials using different doses were as follows.

  • Khoo 1981: adult dose of 25 mg or approximately 0.42 mg/kg/day.

  • Kolaczinski 2012: (two arms) 0.5 mg/kg or adult dose 30 mg/day.

  • Pukrittayakamee 2004: the trial with QN had two arms, one with 0.25 mg/kg and the other 0.5 mg/kg per day (adult dose 15 mg or 30 mg per day, respectively); the comparison with AS used 0.5 mg/kg per day (adult dose 30 mg per day).

  • Wang 2006: adult dose of 22.5 mg or approximately 0.38 mg/kg per day.

  • Eziefula 2013: 0.1 (not included in this review), 0.4 and 0.75 mg/kg.

  • Dicko 2016: 0.125 (not included in this review) and 0.5 mg/kg in phase 1 and 0.0625 (not included in this review) and 0.25 mg/kg in phase 2.

  • Gonçalves 2016a: 0.2 and 0.4 mg/kg.

  • Gonçalves 2016b: 0.2 and 0.4 mg/kg.

  • Okebe 2016: 0.2, 0.4 and 0.75 mg/kg.

  • Mwaiswelo 2016: 0.25 mg/kg.

  • Tine 2017: 0.25 mg/kg.

This review reports the results for clinically important doses only: 0.2 to 0.25 mg/kg, 0.4 to 0.5 mg/kg, and 0.75 mg/kg.

Schedule

We regarded the first day of any treatment as day 1. Most trials used a single dose of PQ given on the following days.

Three trials used a longer course of PQ.

Length of follow-up

The maximum time of follow-up varied between trials. It was restricted here to eight days after treatment to enable maximum comparison between trials (some of which terminated at this point). Therefore, not all results from Kamtekar 2004 could be included since PQ was given on day 8 in one arm.

Prevalence of gametocytes at start of trial

The trials varied in inclusion criteria and hence in how representative they were of the gametocyte prevalence of the general or clinic population. Five trials included only people with microscopically detected gametocytes at onset (Chen 1993a; Chen 1994; Gogtay 2004; Gogtay 2006; Dicko 2016). In Kamtekar 2004 over 90% of participants were gametocyte positive by microscopy, but this variable was reported as "within 3 days" rather than on day 1. The Gonçalves 2016b trial had the next highest prevalence by microscopy, of 69%. The five arms of the Smithuis 2010 trial showed moderately high gametocyte prevalence (microscopy) between 29% and 38% depending on the arm. Trials with initial gametocyte prevalence between 15% and 27% by microscopy were: Pukrittayakamee 2004; Shekalaghe 2007; Vásquez 2009; Arango 2012; Kolaczinski 2012; Eziefula 2013; Gonçalves 2016a; and Sutanto 2013. The remaining three trials had low (< 15%) gametocyte prevalence by microscopy at onset (Mwaiswelo 2016; Lin 2017; Tine 2017).

Two trials reported PCR prevalence only: El-Sayed 2007, with 10.5% and Okebe 2016, with 48%. Four trials did not report the prevalence of gametocytes at onset (Khoo 1981; Singhasivanon 1994; Lederman 2006; Wang 2006).

The details of the trial locations, malaria treatments, gametocyte prevalence at onset, 8-AQ doses, and schedules are in Table 1.

Outcomes
Transmission

For malaria transmission intensity (prevalence, incidence or EIR), we found no community cluster-RCTs measuring these outcomes that met inclusion criteria.

Infectiousness

Infectiousness includes two components: proportion of participants infectious, and proportion of mosquitoes infected. Six trials intended to measure infectiousness with artemisinin partner drugs (DHAP, ASAQ, or AL) (Gonçalves 2016a; Gonçalves 2016b; Dicko 2016; Mwaiswelo 2016; Okebe 2016; Lin 2017) and five (all except Mwaiswelo 2016) provided such data. Two trials measured infectiousness with non-artemisinin drugs (in both cases MQ) with and without PQ (Chen 1993a; Chen 1994). Results are reported here for two time points after commencement of treatment. The first day of treatment is day 1. The goal was reporting at day 4 and 8, but day 4 was varied to day 3 or 5 for some trials.

Potential infectiousness

All other trials (except Wang 2006 and Mwaiswelo 2016) reported potential infectiousness: that is, the effects of PQ on gametocyte prevalence, density, or clearance time, or all three outcomes using either microscopy or PCR. The same time points are reported as for infectiousness (day 3, 4, or 5, and day 8).

Nine trials reported gametocyte clearance time (Singhasivanon 1994; Pukrittayakamee 2004; Shekalaghe 2007; Smithuis 2010; Eziefula 2013; Dicko 2016; Gonçalves 2016b; Lin 2017; Tine 2017). Four of these also reported a summary measure of potential infectiousness using area under the curve (AUC) of gametocyte density over time (Pukrittayakamee 2004; Smithuis 2010; Gonçalves 2016b; Lin 2017).

Wang 2006 and Mwaiswelo 2016 reported only asexual stage outcomes and Khoo 1981 reported data that could not be used as the length of PQ course for each participant was not clear.

Excluded studies

We have listed the reasons for exclusion of 48 trials in the ‘Characteristics of excluded studies' section. Some additional details of these trials and reasons for exclusion are expanded in a previous edition of this review (Graves 2014).

We sought publications for Chinese trials cited in White 2012 and White 2013 and by personal communication from Professor Li Guo Qiao. We were unable to locate two (Chen 1993b; Li 2006); the others were translated where required. We excluded the following studies on the basis of no appropriate comparison (either all groups got PQ or there was no comparator group with same dose of malaria treatment drug but no PQ): (Che 1987; Yang 1989; Che 1990; Huang 1996; Lin 2004; Sun 2011) or lack of randomization (Cai 1985; Huang 1993). Three other trials of artemether with and without PQ in Africa were stated to be randomized (Huang 2001; Li 2007; Li 2010), but we excluded them due to the late administration of PQ (after five to seven days of artemether) and lack of gametocyte outcomes.

Risk of bias in included studies

The ‘Risk of bias' assessment for each of the 25 included trials is shown in Figure 2 with a summary by component in Figure 3. There was low risk of bias in 50% or more of trials for random sequence generation, allocation concealment, incomplete outcome data, selective reporting, and other bias. High risk of bias was present in less than 20% of the trials for these components. The trials were weakest on blinding, with low risk of bias in less than 25% for blinding of participants and personnel, and less than 50% of trials for blinding of outcome assessment. The highest risk of bias (30% of trials) was for blinding of participants and personnel. A relatively high proportion of trials (particularly older trials) did not report sufficient information to clarify the risk of bias, especially for blinding and allocation concealment (≥ 30% of trials).

Pukrittayakamee 2004 excluded G6PD-deficient people from the PQ group post-randomization. We had no reason to suppose it biased the primary outcomes but it could have affected assessment of adverse effects.

Effects of interventions

See: Summary of findings for the main comparison Single dose primaquine at 0.2 to 0.25 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission; Summary of findings 2 Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission; Summary of findings 3 Single dose primaquine at 0.75 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission; Summary of findings 4 Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with non-artemisinin partner, for reducing P. falciparum transmission; Summary of findings 5 Single dose primaquine at 0.75 mg/kg compared to no primaquine, with non-artemisinin partner, for reducing P. falciparum transmission

We subgrouped the data by whether or not the malaria treatment was artemisinin-based, and by the gametocyte detection method. We included only one measure of gametocyte prevalence by PCR data if two different methods of PCR were reported, to avoid duplicate reporting of the same participants (Gonçalves 2016b).

Results were stratified by two time points of follow-up, with the exact day depending on what was reported. The goal was reporting at day 4 and 8, but this was varied to day 3 or 5 and day 8 in some trials. Results at these time points were included only if they were after the administration of PQ. For day 3 outcomes, we excluded Sutanto 2013 since PQ was given on that day. We excluded the QN comparison of Kamtekar 2004 because PQ was not given until day 8, but included all other trials with gametocyte outcomes at day 8 (all trials except Khoo 1981, Pukrittayakamee 2004, and Wang 2006).

Where reported, summary estimates of effects on gametocyte clearance time over the whole period of follow-up are reported.

The day on which PQ was given varied, and is presented for each trial in Table 1 and in the footnotes to each analysis.

Results on infections acquired by mosquitoes are reported in tables only because we were not able to account for the bias due to varying numbers of mosquitoes dissected per individual.

1. PQ as part of artemisinin-based treatment regimens

Follow-up at day 3 or 4

Infectiousness of people to mosquitoes

Four trials assessed proportion of participants infectious to mosquitoes on day 3 or 4 after first treatment on day 1. Results were stratified by dose. Only one trial out of three in the low dose (0.2 to 0.25 mg/kg) group had any events (infectious people) at day 3-4 (Analysis 1.1). The proportion of people infectious to mosquitoes was reduced by 88% (95% CI 12% to 98%, 105 participants). In the moderate dose group, again only one trial had any events. The proportion of people infectious was reduced by 87% (95% CI 6% to 98%, 129 participants). At the high dose of 0.75 mg/kg (one trial), the reduction in one trial was 80% but the 95% CI was very wide and overlapped 100% (2% to 168%, 51 participants).

Infections acquired by mosquitoes

Results were also expressed as the proportion of mosquitoes infected. At baseline, before treatment with the low dose, the groups were not well matched in one trial (Dicko 2016), with 29% more mosquitoes infected in the PQ group (Table 2). With the low dose and the moderate dose, on day 3 or 4, there was a slight decrease in the proportion of mosquitoes infected (Table 3) with data available for only one trial out of three in each of the low- and moderate-dose groups. In the 0.75 mg/kg dose group, the one trial showed a slight increase in percentage of mosquitoes infected in the group without PQ.

Table 2. Infectivity to mosquitoes baseline
  1. Abbreviations: PQ: primaquine.

DoseStudyWith PQWithout PQAbsolute difference (reduction or increase) in % of mosquitoes infected in PQ groupAverage number of mosquitoes dissected per participant (both arms combined)
Total number
of participants
Number of infectious
people
Average % of mosquitoes infectedTotal number of
participants
Number of infectious
people
Average %
of mosquitoes
infected
0.25 mg/kgDicko 2016151435.514106.7+28.8143.1
Gonçalves 2016b2784.5321514.8−10.344.0
0.4 to 0.5 mg/kgDicko 2016141211.014106.7+4.3136.6
Gonçalves 2016b2078.9321514.8−5.844.3
0.75 mg/kgLin 20175011.45165.3−3.950
Table 3. Infectivity to mosquitoes day 3-4
  1. Abbreviations: PQ: primaquine.

DoseStudyWith PQWithout PQAbsolute difference (reduction or increase) in % of mosquitoes infected in PQ groupAverage number of mosquitoes
dissected per participant
(both arms combined)
Total number
of participants
Number of infectious
people
Average % of
mosquitoes infected
Total number of
participants
Number of infectious
people
Average %
of mosquitoes
infected
0.25 mg/kgDicko 20161510.61378.1−7.571.6
Gonçalves 2016a2700.03200.00.026.9
Gonçalves 2016b2300.01900.00.045.6
0.4 to 0.5 mg/kgDicko 20161410.31378.1−7.870.2
Gonçalves 2016a2000.03200.00.033.4
Gonçalves 2016b2800.01900.00.045.6
0.75 mg/kgLin 20175011.45156.6-5.250
Gametocyte prevalence by PCR

At day 3 or 4 after treatment, there was no effect at any dose on the proportion of persons with gametocytes detected by PCR (Analysis 1.2). The risk ratios (RRs) (fixed effect) were 1.02 (95% CI 0.87 to 1.21; 3 trials, 414 participants) for low dose; 1.09 (95% CI 0.93 to 1.28; 3 trials, 418 participants) for moderate dose, and 0.92 (95% CI 0.75 to 1.13; 3 trials, 394 participants) for high dose.

Gametocyte prevalence by microscopy

At day 3 or 4 after treatment, there was no reduction in proportion of persons with gametocytes detected by microscopy for the low and moderate doses (Analysis 1.3). The RRs were 0.73 (95% CI 0.21 to 2.50; 3 trials, 490 participants) for low dose, and 0.86 (95% CI 0.33 to 2.25; 2 trials, 225 participants) for moderate dose. Due to heterogeneity, a random effects RR was estimated. At the high dose, reduction of 58% was observed (RR 0.42, 95% CI 0.20 to 0.85; 3 trials, 248 participants).

Follow-up at day 8

Infectiousness of people to mosquitoes

Four trials assessed proportion of participants infectious on day 8 after first treatment on day 1. Results were stratified by dose. Three trials out of four using a low dose had events (infectious people) at day 8 (Analysis 1.4). The proportion of people infectious to mosquitoes was not significantly reduced at this time point (RR 0.34, 95% CI 0.07 to 1.58; 4 trials, 243 participants). In the moderate dose group, three of the four trials had any events. The reduction in proportion of people infectious was similar to the low dose group (RR 0.33, 0.07 to 1.57; 4 trials, 246 participants). At the high 0.75 mg/kg dose there were two trials, both with infectious events in the non-PQ group (RR 0.18, 95% CI 0.02 to 1.41; 2 trials, 181 participants). Thus the reduction in infectiousness was large but the 95% CI was very wide and overlapped one.

Infections acquired by mosquitoes

With the low and moderate dose, data on the proportion of mosquitoes infected were available for three out of four trials in each dose group (Table 4). One trial of the four in the low dose group had 29% more mosquitoes infected in the PQ than the non-PQ group (arising from one infectious individual). Otherwise, there was very little difference between PQ and no-PQ groups in the proportion of mosquitoes infected at day 8 in either the moderate dose group (four trials) or the high dose group (two trials).

Table 4. Infectivity to mosquitoes day 8
  1. ¹Okebe 2016 reported the median number of mosquitoes per person.

    Abbreviations: PQ: primaquine.

DoseStudyWith PQWithout PQAbsolute difference (reduction or increase) in % of mosquitoes infected in PQ groupAverage number of mosquitoes dissected per participant (both arms combined)
Total number of
participants
Number of infectious
people
Average %
of mosquitoes
infected
Total number of
participants
Number of infectious peopleAverage %
of mosquitoes
infected
0.2 to 0.25 mg/kgDicko 20161500.01333.7−3.772.8
Gonçalves 2016a2700.03200.00.026.6
Gonçalves 2016b4900.04910.2−0.243.7
Okebe 2016¹44129.24611.3+27.980
0.4 to 0.5 mg/kgDicko 20161410.11333.7−3.671
Gonçalves 2016a2000.03200.00.031.4
Gonçalves 2016b4600.04910.2−0.243.4
Okebe 20164200.04611.3−1.380
0.75 mg/kgLin 20174800.04846.9−6.950
Okebe 2016¹3900.04611.3−1.380
Gametocyte prevalence by PCR

At day 8 after first treatment, reductions were observed in the proportion of persons with gametocytes detected by PCR (Analysis 1.5). The RRs (fixed effects) were 0.52 (95% CI 0.41 to 0.65; 4 trials, 532 participants) for low dose; 0.37 (95% CI 0.28 to 0.48; 4 trials, 758 participants) for moderate dose, and 0.31 (0.23 to 0.43; 5 trials, 793 participants) for high dose.

Gametocyte prevalence by microscopy

At day 8 after treatment, there was also a reduction in the proportion of people with gametocytes detected by microscopy for all dose groups (Analysis 1.6). The RRs (fixed effects) were 0.35 (95% CI 0.16 to 0.78; 3 trials, 491 participants) for low dose; 0.25 (95% CI 0.08 to 0.75; 2 trials, 225 participants for moderate dose, and 0.27 (95% CI 0.19 to 0.37; 6 trials (10 arms), 1433 participants) for high dose. There was moderate heterogeneity at the high dose, but not at low and moderate doses.

Additional summary measures of gametocyte persistence

Gametocyte clearance time or duration of gametocyte carriage (the length of time each person has gametocytes)

Seven trial authors presented gametocyte clearance time (the number of hours or days until gametocytes disappear, sometimes described as "duration of gametocyte carriage"). Pukrittayakamee 2004 makes a distinction between these two parameters, with gametocyte carriage adjusting for intermittent periods of time without gametocytes.

Using microscopy, at low dose, Tine 2017 reported that duration of gametocyte carriage was reduced from average of 1.08 days in the ACT only group to 0.29 days in the ACT plus PQ group. In Lin 2017 (high dose), median time to clearance was reduced from 12 days in non PQ group to 1 day in the PQ group.

At low and moderate doses, Gonçalves 2016b showed that mean gametocyte clearance time (by PCR) was reduced on average by 12 days (95% CI −12.83 to −11.17) in the low dose group and by 11.5 days (−12.33 to -10.67) in the moderate dose group (Analysis 1.7).

In Eziefula 2013, also by PCR, the gametocyte clearance time was not significantly longer in the 0.4 mg/kg group (6.3 days, 95% CI 5.1 to 7.5) than the 0.75 mg/kg group (6.6 days, 95% CI 5.3 to 7.8). However the 0.75 mg/kg group had significantly shorter gametocyte clearance time than the placebo group (12.4 days, 95% CI 9.9 to 15.0).

Two other trials reported results for the 0.75 mg/kg dose. Gametocyte clearance time in days was presented in Shekalaghe 2007 and was significantly shorter (by PCR) in the PQ group (6.3 days, 95% CI 4.7 to 8.5) than in the non-PQ group (28.6 days, 95% CI 17.0 to 48.0, P < 0.001). Smithuis 2010, using microscopy, also reported significantly shorter gametocyte clearance time in the PQ groups, reported as person-gametocytaemia-weeks standardized per 1000 person-weeks of follow-up. This was 5.5 weeks in the ACT+PQ groups versus 65.5 weeks in the non-PQ groups (RR 11.9, 95% CI 7.4 to 20.5, P < 0.001) and the difference was very large for each individual malaria treatment regimen (five different ACTs or formulations were tested). Although the duration of gametocyte carriage (without PQ) was significantly longer for AS+AQ, AL and DHAP than for AS+MQ, there was no difference in length of gametocyte carriage between the ACT groups when PQ was added (Smithuis 2010).

Pukrittayakamee 2004 reported reduction in median gametocyte clearance time from 138 (range 12 to 264) hours with artesunate alone to 73 (range 6 to 145) hours with artesunate and 7 days of PQ (0.5 mg/kg).

Gametocyte circulation time

Another outcome related to gametocytes estimated by PCR in Eziefula 2013 and Shekalaghe 2007 was the mean life (circulation time) of gametocytes (this is reported per gametocyte rather than per person as for gametocyte clearance time above). In Eziefula 2013 the circulation time per gametocyte was significantly longer in the placebo group (1.97 days, 95% CI 1.64 to 2.31). than in the other two groups (0.95 and 0.98 days in the 0.4 and 0.75 mg/kg groups respectively). In Shekalaghe 2007, the mean gametocyte circulation time was reduced from 4.6 days (95% CI 2.9 to 7.3) after AS+SP alone to 0.5 days (95% CI 0.2 to 1.2) after AS+SP plus 0.75 mg/kg PQ (P < 0.001).

Area under curve of gametocyte density over time

Area under curve combines measures of density over time. Trials varied in the follow-up time completed. Using microscopy, Tine 2017 observed reduction of AUC (follow-up to day 29) from 106.7 in the ACT+PQ group to 29.5 in the ACT only group.

Gametocyte density by PCR over time was reported in four trials. For low and moderate dose, Gonçalves 2016b reported a reduction of the mean AUC (up to day 15) of −9.20 (−10.79 to −7.61) for low dose and −9.10 (−10.50 to −7.70) for moderate dose (Analysis 1.8). Eziefula 2013 also used a duration of 15 days to estimate AUC using PCR and found that the log(10)AUC in each intervention group was not significantly different from placebo. It was 3.8 (95% CI 1.7 to 8.2) gametocytes per μL per day in the placebo group, 2.1 (1.0 to 4.5) in the 0.4 mg/kg group, and 2.0 (0.9 to 4.3) in the 0.75 mg/kg group.

Using PCR-detected gametocyte density estimates, Shekalaghe 2007 provided geometric mean and interquartile range (IQR) values on days 1, 4, 8, 15, 29, and 43. Mean density was consistently lower in the 0.75 mg/kg PQ than the non-PQ group, for days when gametocytes were detected (with PQ: 5.8, IQR 0.8 to 55.1; without PQ: 15.8, IQR 4.1 to 85.8). Shekalaghe 2007 also presented a statistical comparison of AUC of gametocyte density (by PCR) over a 43-day period, with a 95% CI derived from generalized estimation equations. There was a significant reduction in AUC in the 0.75 mg/kg PQ groups over 43 days after treatment, reported as mean of 1.5 (IQR 0.3 to 8.8) in the PQ group versus 11.1 (IQR 2.2 to 53.8) in the non-PQ group (P < 0.001).

Haemolytic adverse effects

Severe haemolysis

At the low dose, four trials evaluated severe haemolysis defined as drop of ≥ 25% (Dicko 2016; Mwaiswelo 2016), or ≥ 2 g in haemoglobin (Gonçalves 2016b; Tine 2017) over the course of follow-up; only three of these trials had such events (Analysis 1.9). The results given for Gonçalves 2016b included combined data from Gonçalves 2016a as they were not reported separately. Dicko 2016 and Gonçalves 2016b excluded G6PD deficient individuals identified by fluorescent spot test (FST) or the rapid test; Mwaiswelo 2016 and Tine 2017 screened participants but did not exclude those with G6PD deficiency. Severe haemolysis as defined above was no different in frequency between the PQ group (12.3% of 381 participants) than the control group (13.2% of 371 participants).

Mwaiswelo 2016 (low dose) also reported an outcome of "acute haemolytic anaemia", experienced by 2.8% of participants in both PQ and control groups (109 participants and 108 participants respectively).

Severe haemolysis was reported for the moderate dose for two trials (Dicko 2016; Gonçalves 2016b), of which only the latter had any events (Analysis 1.9) . No difference was observed in the proportion of participants with this outcome between the PQ group (3.7% of 136 participants) and the control group (2.4% of 124 participants).

At high dose, Smithuis 2010 stated that there were no cases of severe anaemia (< 5 g/dL) or blackwater fever in any ACT or control group. Shekalaghe 2007 stated that eight of 52 children in the PQ group had a 20% reduction in haemoglobin by day 8, compared to 0 of 53 children in the control group. However, Shekalaghe 2007 also stated that no child developed clinical symptoms related to anaemia or a haemoglobin below 5 g/dL.

Other measures of anaemia or haemoglobin
Measures of haemoglobin or PCV at day 8

No trials at low or moderate dose reported these outcomes. At high dose Shekalaghe 2007 and Sutanto 2013 found no difference between groups in mean haemoglobin at day 8. Also using high dose, El-Sayed 2007 showed that there was no difference in PCV between groups at day 8: 34.2% (15% to 44%) versus 36.2% (26% to 42%).

Maximum change in haemoglobin concentration

The maximum change in haemoglobin concentration (over all days of follow-up) was measured in three trials, two of which reported results separately by G6PD status (Eziefula 2013; Mwaiswelo 2016), while the other did not (Okebe 2016). In general, change in haemoglobin was less in the control than PQ groups (Analysis 1.10), but results were heterogenous especially at the low dose where the mean difference was 0.13 (−0.07 to 0.33) g of haemoglobin (random-effects model). The change in haemoglobin by day 8 (rather than any day) was reported in Tine 2017 and is included in Analysis 1.10. In the moderate and high dose groups, the mean difference was 0.18 (−0.08 to 0.44) and 0.05 (−0.04 to 0.14), respectively.

Percentage change in haemoglobin by day 8

Using percentage change by day 8 (rather than absolute haemoglobin concentration at that time), the low, moderate, and high dose PQ groups were not different from the control groups (Analysis 1.11), but heterogeneity was high, especially at low dose. Some trials reported this outcome separately by G6PD status, and if so, the results were presented separately (see footnotes).

Maximum percent change in haemoglobin

The maximum percent decrease in haemoglobin (by any day of follow-up) was also reported in three trials, one in each dose category (Analysis 1.12). In low and moderate dose, the maximum percent decrease was larger in the PQ group than control, but the opposite was seen for high dose.

Haemoglobinuria or dark urine

The presence of haemoglobinuria/dark urine was reported by Dicko 2016 (low and moderate dose, but with no events in the latter), Mwaiswelo 2016 (low dose), and Tine 2017 (low dose) and is shown in Analysis 1.13. These adverse effects were more than three times more likely in the PQ group (RR 3.40, 95% CI 2.15 to 5.38; 3 trials (4 arms), 527 participants) than the control group.

Other adverse effects

These outcomes were not classified by dose. Frequencies of headache, fatigue, nausea, vomiting, abdominal pain, diarrhoea, pruritis, paraesthesia, fever, cough, runny nose, muscle ache/pain, dizziness, upper respiratory infections, back pain, burning or pain with urination, bronchitis, rhinitis/rhino bronchitis, shortness of breath, whitlow, leg osteoarthritis, malaria, otitis, epistaxis, dental pain, high transaminase, palpebral inflammation, foot trauma or inflammation, skin infection or rash, pallor, pneumonia, meningitis, blurred vision, cold sore, weakness/asthenia, palpitations, cyanosis, insomnia, or unspecified other event were not increased in the PQ groups (Analysis 1.14; Analysis 1.15; Analysis 1.16; Analysis 1.17; Analysis 1.18) as reported in Wang 2006; Smithuis 2010; Dicko 2016; Gonçalves 2016a; Gonçalves 2016b; Mwaiswelo 2016; Okebe 2016; and Tine 2017, with one to 11 trial arms per event type reported. Small differences in frequencies between PQ and control groups are noted for anorexia (increased in PQ group) and wound/trauma (decreased in PQ group).

2. Comparison of low and moderate doses (artemisinin partner only)

Given the importance of confirming effectiveness of the low dose, and that fact that four trials included groups randomized to low and moderate doses, we compared these two doses directly.

Follow-up at day 3 or 4

Infectiousness of people to mosquitoes

Only one of three trials had any infectious events: one infectious person in each of the PQ and non-PQ groups, total 116 participants (Analysis 2.1). The RR was 0.93 (95% CI 0.06 to 13.54; 3 trials, 116 participants).

Gametocyte prevalence by PCR

Comparing the low and moderate groups, there was no difference in the proportion of participants with gametocytes by PCR (RR 0.93, 95% CI 0.80 to 1.09; 3 trials, 424 participants (Analysis 2.2).

Gametocyte prevalence by microscopy

In two trials (both in same location) that reported this outcome, there was also no difference in the proportion of participants with gametocytes detected by microscopy (RR 1.23, 95% CI 0.68 to 2.20; 2 trials, 231 participants; Analysis 2.3).

Follow-up at day 8

Infectiousness of people to mosquitoes

In four trials, two of which had infectious events, there was no evidence of any difference in effect on proportion of participants infectious between low and moderate doses (RR 0.95, 95% CI 0.14 to 6.48; 4 trials, 237 participants; Analysis 2.4).

Gametocyte prevalence by PCR

There were four trials reporting gametocyte prevalence by PCR at day 8. The evidence suggested the effect tended to be greater at moderate than low dose (RR 1.33, 95% CI 0.97 to 1.82; 4 trials, 559 participants; Analysis 2.5).

Gametocyte prevalence by microscopy

Two trials, both in the same site, showed the same trend as for PCR but no greater effect of moderate dose at day 8 (RR 1.80, 95% CI 0.51 to 6.38; 2 trials, 235 participants; Analysis 2.6).

3. PQ as part of non-artemisinin-based treatment regimens

Eleven trials contributed comparisons to this analysis, of which one trial tested both low dose and moderate dose PQ regimens over seven days (Pukrittayakamee 2004), and one trial (two comparisons) tested moderate dose PQ (Kolaczinski 2012). The remainder were high dose.

We could not use data from one trial with non-artemisinin partner CQ because it did not distinguish between patients with P. falciparum and P. vivax and their respective treatments (Khoo 1981). There was a much higher risk of adverse haemolytic events in those who received PQ in the Khoo 1981 trial (OR 22.27 for both haemolysis and need for blood transfusion), but we could not include the results because the groups combined participants receiving a short course (three days) of PQ with those receiving a 14-day regimen. The most unusual aspect of the trial, however, is that it included only individuals with G6PD deficiency.

Follow-up at day 5

Infectiousness of people to mosquitoes

No trials tested the low or moderate dose for effect on infectiousness with non-artemisinin partners.

Using high dose, two small trials in China (Chen 1993a; Chen 1994), with only six and nine participants per group, respectively, directly tested the impact of PQ added to MQ on infectiousness to mosquitoes. The proportion of people infectious was reduced to 0% in the PQ group when measured on day 5, compared to 66.7% in the control group (RR 0.09 (95% CI 0.01 to 0.62; 2 trials, 30 participants; Analysis 3.1).

Infections acquired by mosquitoes

Chen 1994 reported the number of mosquitoes infected after feeding on trial participants. None of the mosquitoes feeding on people receiving PQ were infected, with over 64% infected at day 5 after feeding on the group not receiving PQ,

Gametocyte prevalence by PCR

No trials with non-artemisinin partners assessed gametocyte prevalence by PCR.

Gametocyte prevalence by microscopy

Two trials each at the moderate and high doses showed no difference in the gametocyte prevalence at day 4-5 (Analysis 3.2); RR 0.83 (95% CI 0.62 to 0.13; one trial (two arms), 221 participants) for moderate dose and RR 0.85 (95% CI 0.48 to 1.50; 2 trials, 52 participants) for the high dose.

Follow-up at day 8

Infectiousness of people to mosquitoes

The two Chinese trials with MQ partner using high dose showed a similar effect at day 8 as at day 5 above: the proportion of infectious people was 93% in control group and 0% in the PQ group. (Analysis 3.3). RR 0.07 (95% CI 0.01 to 0.45; 2 trials, 30 participants).

Infections acquired by mosquitoes

Chen 1994 reported the number of mosquitoes infected after feeding on trial participants. None of the mosquitoes feeding on people receiving PQ were infected, with 54% infected at day 8 after feeding on the group not receiving PQ.

Gametocyte prevalence by PCR

No trials with non-artemisinin partners assessed gametocyte prevalence by PCR.

Gametocyte prevalence by microscopy

At day 8 one trial (two arms) reported gametocyte prevalence at moderate dose (reduction of 40%); RR 0.60 (95% CI 0.49 to 0.75; 216 participants) and four trials (five arms) at the high dose (reduction of 61%) (RR 0.39, 95% CI 0.25 to 0.62; 4 trials, 186 participants; Analysis 3.4).

Additional summary measures of gametocyte persistence

Gametocyte clearance time or duration of gametocyte carriage (the average number of days each person has gametocytes)

The median gametocyte clearance time was reduced in Pukrittayakamee 2004 (two comparisons; partner QN) from 48 (range: six to 324) hours with low dose PQ, and from 216 (range: six to 624) hours with quinine only to 87 (range: five to 207 hours) hours with moderate dose PQ. There was no difference between the median clearance time in the two PQ arms (P = 0.45).

Using high dose, gametocyte clearance time (in days) was significantly reduced in the PQ group in Singhasivanon 1994 (which had MQ+SP partner) with a mean difference of −14.90 days (95% CI −18.18 to −11.62; Analysis 3.5).

Adverse events

The trials with non-artemisinin partner regimens did not report adverse effects well or consistently. None of these trials reported on haemolysis, other haematological measures, or severe adverse events.

Singhasivanon 1994 using high dose found no difference in frequency of reported adverse effects (nausea, vomiting or dizziness) over 28 days follow-up (Analysis 3.6).

4. Comparison of different 8AQ

Follow-up at day 8

Two small trials compared the effect of bulaquine and PQ (0.75 mg/kg) on gametocyte prevalence at day 8 (Gogtay 2004; Gogtay 2006). Both trials suggested a greater reduction of gametocytes by bulaquine (RR 0.41, 95% CI 0.26 to 0.66; 2 trials, 112 participants; Analysis 4.1). Neither trial concealed allocation.

Discussion

Summary of main results

We included 24 RCTs and one quasi-RCT. Sixteen trials included study arms with artemisinin-based treatments, 11 trials included study arms with non-artemisinin-based treatments, and two trials included both types of partner arms. Fifteen trials tested for G6PD status: ten then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and four included all irrespective of status. The remaining 10 trials either did not report on whether they tested (eight trials), or reported that they did not test (two trials). No trials evaluated community effects on malaria transmission.

With artemisinin combination treatment

See Summary of findings for the main comparison, Summary of findings 2 and Summary of findings 3 for low, moderate, and high dose with artemisinin partner drugs, respectively.

Low-dose PQ

Infectiousness to mosquitoes was reduced (Iow certainty evidence). For gametocytes detected by PCR, there was little or no effect of PQ at day 3 or 4 (moderate certainty evidence) with clear reduction at day 8 (high certainty evidence). Low-dose PQ probably has little or no effect on severe haemolysis (moderate certainty evidence).

Moderate-dose PQ

Infectiousness to mosquitoes was reduced (low certainty evidence). The pattern and level of certainty of evidence with gametocytes detected by PCR was the same as low dose (moderate and high at days 3 or 4 and 8 respectively, and severe haemolysis was infrequent in both groups (low certainty evidence).

High dose PQ

Infectiousness to mosquitoes was reduced (low certainty evidence). The effects on gametocyte prevalence showed a similar pattern to moderate and low dose PQ (low and high certainty at days 3 or 4 and 8 respectively). Evidence of haemolysis was not systematically sought in this dose group.

With non-artemisinin treatment

See Summary of findings 4 and Summary of findings 5 for moderate and high dose with non-artemisinin partner drugs respectively.

Trials have been conducted only in the moderate- and high-dose PQ categories. Two small trials from the same laboratory in China evaluated infectiousness to mosquitoes with high dose PQ, reporting that infectiousness was reduced markedly on day 5 and on day 8 (very low certainty evidence).

Reduction in gametocytes, detected in this case by microscopy, showed similar patterns to the artemisinin-based treatments. For moderate dose, there was little or no effect at day 4 or 5 (moderate certainty evidence), and larger effect by day 8 (moderate certainty evidence). At high dose, findings were similar but certainly of evidence was low at day 4 to 5. No trials with non-artemisinin partners systematically sought evidence of severe haemolysis.

Two small trials comparing bulaquine with PQ suggest bulaquine may have larger effects on gametocytes (by microscopy) on day 8.

Overall completeness and applicability of evidence

What is known

This review update adds recently available evidence on infectiousness of people with falciparum malaria treated with low and moderate PQ doses in addition to primary treatment. It also includes additional evidence on the effect of PQ at different doses on gametocyte prevalence at two time points after treatment. Previously only indirect evidence was available (for example, Bunnag 1980, with no difference in gametocyte outcomes between 15 mg PQ for five days in children, and single doses of 30 mg or 45 mg PQ in adults), in narrative summaries and analyses that have proposed widespread programmatic implementation of PQ (White 2012; White 2013).

Adding PQ at around 0.25 mg/kg to treatment using artemisinin-based combination therapies reduces infectiousness to mosquitoes at day 3 to 5 and at day 8 after treatment. These data come from four trials conducted in Burkina Faso (with AL partner) (Gonçalves 2016a; Gonçalves 2016b) Gambia (DHAP) (Okebe 2016), and Mali (DHAP) (Dicko 2016). One other trial using high dose also reported on infectiousness in Cambodia with DHAP partner (Lin 2017). Two of these trials included only gametocyte carriers at screening (Dicko 2016; Gonçalves 2016b). Due to relatively low proportion of infectious individuals among treated malaria patients (even those with gametocytes), the absolute reduction in proportion of people infectious is not large. The absolute reduction in proportion of mosquitoes infected was also low.

The effect on infectiousness was more marked at day 3 or 4 than day 8, which reflects the declining infectiousness in the non-PQ control groups by this time. Unlike the pattern seen in reducing infectiousness, there was little reduction by PQ with artemisinin partners in gametocyte prevalence at day 3 or 4 with the low or moderate dose. By day 8, large effects of PQ on gametocyte prevalence were seen. Reductions in gametocyte clearance time were also dramatic. The results come from trials in different epidemiological settings and with a variety of artemisinin-based treatments (Burkina Faso: AL (Gonçalves 2016a; Gonçalves 2016b); Cambodia: DHAP (Lin 2017); Colombia: AS+MQ (Vásquez 2009; Arango 2012); Gambia: DHAP (Okebe 2016); Senegal: DHAP, AL, and ASAQ (Tine 2017); Indonesia: DHAP (Sutanto 2013); Mali: DHAP (Dicko 2016); Myanmar: AS+MQ, DHAP, AL and ASAQ (Smithuis 2010); Sudan: AS+SP (El-Sayed 2007); Tanzania: AS+SP (Shekalaghe 2007); Thailand: AS (Pukrittayakamee 2004); and Uganda: AL (Eziefula 2013)).

In terms of safety, adverse effects of PQ in people with G6PD deficiency are less common with lower doses of PQ (Olalekan 2017), although direct comparisons are few and sample sizes small. Most trials included in this review excluded individuals with G6PD deficiency, but some included them, did not test for it or did not state whether they tested; thus some trials included some G6PD deficient participants. However, few severe haematological effects were reported (Shekalaghe 2007; Dicko 2016; Gonçalves 2016b; Mwaiswelo 2016; Tine 2017).

What is unknown

While reducing infectiousness to mosquitoes and the duration and density of gametocytaemia can be assumed to reduce transmission to mosquitoes at the level of the individual, it remains unclear whether it will impact materially on community level transmission, as reliable trials have never evaluated this. We excluded from this review several older trials, which are often cited as proof of an effect on community transmission, because either: i) they lacked an adequate control group with partner drug but without PQ (Clyde 1962); ii) they did not apply the interventions equally in intervention and control groups or had no ‘before' data (Doi 1989; Kaneko 1989); iii) they administered PQ alongside vector control co-interventions, which may equally be responsible for any effect seen (Hii 1987; Kaneko 2000); or iv) they administered PQ or 8AQ alone and not alongside treatment regimens (which is the policy currently recommended) (Barber 1932).

Many gametocyte carriers are asymptomatic and unlikely to seek treatment, at least in areas of moderate to high transmission where most adults have a level of acquired immunity that reduces the probability that parasitaemia will cause clinical symptoms. Therefore, since a minority of infected persons seek treatment, it is unclear whether a policy of adding PQ to malaria treatment regimens will reduce malaria transmission at a community level. Johnston 2014 modelled the effect of treatment, and concluded that the most important factor predicting success is the percentage of infected individuals treated with an ACT, and that adding PQ is of negligible benefit. Johnston and colleagues estimated that "it would require switching 180 people from ACTs to ACTs plus PQ to achieve the same transmission reduction as switching a single individual from untreated to treated with ACTs".

The relative contribution of symptomatic and asymptomatic gametocyte carriers to the infectious reservoir in the population, as well of the relative infectiousness of gametocytes detected by microscopy and PCR, are areas of active research (Stone 2015). The proportion of asymptomatic carriers varies according to the level of transmission, with low density infections comprising a large proportion of infections in low transmission areas (Gerardin 2015a). If most infectious individuals are not among the care-seeking population, they can only be reached by proactive strategies such as ‘mass screen and treat' or mass treatment programmes.

Mass treatment programmes (where everyone in the community is treated at specified intervals until transmission is stopped) are a potential strategy to reach asymptomatic gametocyte carriers (von Seidlein 2003; GMAP 2008; Mendis 2009; Sturrock 2013). However, in theory, mass treatment consisting only of primary treatment (an ACT alone) could interrupt transmission, and the additional effects of adding PQ (interrupting transmission more quickly, or at a lower coverage levels) have not been demonstrated (Poirot 2013). Gerardin 2015b modelled the impact of adding PQ to either AL or DHAP in mass treatment programs. and concluded that it would be most effective in combination with a long acting partner such as DHAP and where most of the population is protected against reinfection; otherwise, if transmission is high, the effect of adding PQ would be ‘negligible'. A similar conclusion was reached by the WHO Malaria Policy Advisory Committee (MPAC) through consensus modelling (WHO 2015c).

Infectiousness of a population to mosquitoes comprises two elements: the proportion of people who are infectious, and the proportion of mosquitoes infected after feeding on an infectious person. The two factors can be multiplied together to arrive at a combined ‘mosquito infection probability' (Graves 1990; Stone 2015), representing the likelihood of a mosquito acquiring infection after feeding on a member of the population. Considering only reduction in the proportion of infectious individuals may underestimate the impact of PQ, although evidence from the trials included here does not suggest large reduction in the proportion of mosquitoes infected by persons remaining infectious after treatment (Table 2; Table 3; Table 4). Larger sample sizes of infectious people are required.

The relative effect of PQ on infectiousness when added to different artemisinin drugs is not well understood and needs to be empirically studied further, since it known that there is variation between them in gametocytocidal activity (WWARN 2016). Two studies included here compared multiple ACTs (AL, AS+MQ, ASAQ, and DHAP) (Smithuis 2010; Tine 2017), but no infectiousness data were included.

The ability to metabolize PQ to active ingredients (dependent on human cytochrome P-450 enzyme (CYP2D6)) may also affect its impact, since alleles conferring low and intermediate metabolizer phenotypes are unable to reap the benefits of PQ (Bennett 2013; Meltzer 2014). In this review, Eziefula 2013 reported on the CYP2D6 phenotypes of participants. Since this may be a factor in heterogeneity of effects observed, further study of geographical distribution of these variant phenotypes affecting ability to utilize PQ is needed to determine their impact on the effectiveness of PQ on gametocytes and for reducing transmission.

The trials included in this review do not mention PQ resistance as a potential threat. PQ clearly should be used where it is of clinical importance, especially for P. vivax and P. ovale. Its effectiveness against those parasites could be compromised by resistance if used at low doses in populations where P. falciparum, P. vivax, and P. ovale coexist. As for all antimalarial drugs, there is a global responsibility to maintain the effectiveness of PQ for as long as possible without withholding it when needed. In this case, that translates into using it to reduce transmission only if there is reasonable evidence that it actually has that effect. Otherwise, it will be used to little or no effect but its value for radical cure may be diminished by the development of resistant Plasmodium parasites.

Quality of the evidence

In our hierarchy of study types, the strongest, most direct evidence for an effect of PQ on falciparum malaria transmission would come from trials that randomize entire communities to treatment with and without PQ and then monitor malaria prevalence over a period of years. No such trials—at any dose or with any partner drug—met the inclusion criteria. The evidence is, therefore, all indirect, requiring some untested assumptions in evaluating an effect of single dose PQ on malaria transmission.

The evidence is also predominantly for higher PQ doses than the 0.25 mg/kg currently recommended by the WHO. Out of 40 total trial arms that met the inclusion criteria and reported gametocyte outcomes, only five used a low dose (0.20 to 0.25 mg/kg). The remaining arms provide evidence, but the exact dose-response relationship that would apply to single dose PQ is not known, so again, some assumptions are needed to evaluate the relevance of this information.

Second in our evidence hierarchy were trials of the infectiousness of treated individuals to mosquitoes, of which there were four at the low dose of PQ. However, all four trials did not report all key data. Summing up, the infectiousness results for the low dose are based mainly on the results from only one trial (Dicko 2016), which observed one versus seven infectious events at day 3, and 0 versus 3 events at day 8 in the PQ and non-PQ groups respectively. Thus, despite the inclusion of several new trials with infectiousness data in this update, the evidence for reduction is inconsistent and based on a very small number of trials and events. The three infectiousness trials at higher PQ doses reported significant declines, but once again, the relevance to lower doses is uncertain.

Most of the included trials were on the next rung of the hierarchy: the effect of PQ on circulating gametocytes in people treated with and without PQ (potential infectiousness). The included trial arms span decades of research, including many conducted before the artemisinin era. Out of 40 arms, 16 were with non-artemisinin partners (which also used higher PQ doses). Artemisinin drugs themselves have some impact on gametocytes, so how well the earlier evidence reflects the impact of an artemisinin derivative plus PQ is also unknown. Nonetheless, results of these trials were generally consistent. Differences in gametocyte detection method (microscopy or PCR) made synthesis somewhat difficult, but potential infectiousness is the most convincing and robust evidence for a possible effect on transmission, under the right conditions.

The included trials do not provide sufficient evidence to evaluate the safety of this intervention. Many trials did not test for G6PD deficiency, and of those that did, most excluded deficient individuals. The trials were, by and large, not designed for safety evaluations.

Overall, the evidence of efficacy is limited in both quality and quantity, and it is all indirect, to varying degrees.

Potential biases in the review process

We have identified three potential biases or deficiencies in the search and review processes.

First, three trials could not be located. Two were earlier trials (publication dates 1993 and 2006) in Chinese; one was a conference abstract from 2009. Second, we restricted follow-up only to day 8 because most persons were non-infectious by then. Third, we stratified by artemisinin/non-artemisinin drugs, since the former are the recommended treatments in the majority of malaria-endemic areas. We believe these decisions should have no material impact on the results, but could be challenged.

Agreements and disagreements with other studies or reviews

A historical review of patients treated at clinics in India with either AS+SP+PQ (single dose 0.75 mg/kg on the third treatment day, nine sites) or AS+SP alone (12 sites) observed that PQ reduced the gametocyte clearance time by 45% and the AUC of gametocyte density over time (up to 28 days) by about the same proportion (Shah 2013). They expressed the reduction as a hazard ratio with PQ increasing the rate of gametocyte clearance by 1.9 (95% CI 1.1 to 1.3). These results are consistent with our findings. A paper whose title implies it was a systematic review of the impact of artemisinin derivatives and PQ on infectiousness, Abay 2013, included only two before-and-after trials using PQ with small numbers of patients. Neither of these studies met our inclusion criteria (Rieckmann 1968; Clyde 1971).

In a Cochrane Review of MDA (Poirot 2013), the authors found no studies directly comparing MDA regimens that included 8AQs with regimens that did not. In a secondary analysis, the authors then subgrouped the included non-RCTs by regimens with and without 8AQs. In high endemicity areas, two studies included PQ, and one study did not. During multiple MDA rounds, there were substantial drops in parasitaemia regardless of whether PQ was included. At one to three months, the studies without PQ showed larger impact than the one study that did, but this single observation from a non-randomized comparison cannot be relied upon. In a second similar subgroup analysis of four before-and-after studies, the stratified analysis was uninformative.

In an opinion piece in the Lancet, the possibility that doses lower than 0.5 to 0.75 mg/kg might still be very effective in blocking transmission is raised (White 2013). Based on the current review, it appears that the effect on infectiousness and gametocytes is preserved at lower doses of 0.2 to 0.25 mg/kg.

A review in the Malaria Journal provides an analysis of published and unpublished data on 158 subjects with different drug exposures spanning 80 years (White 2012). The methods, sources of data and comparisons are not clearly specified, but the authors argue this provides evidence that PQ decreases infectivity much faster than the effect on gametocytes would suggest. The current review supports this view that the effect of PQ on infectiousness appears earlier (day 3-5) than the effect on gametocyte presence, at least for artemisinin partners. However the effect on infectiousness wanes by day 8 due to declining infectiousness in both PQ and control groups.

Also in the Malaria Journal, White 2014 urged stratification of trials by dose, which has now been further accomplished with the newly included trials at lower doses. The overall conclusion of White 2014 endorses the conclusions of all earlier editions of this Cochrane Review: there is a need for more mosquito-feeding studies for "the assessment of transmission-blocking, dose-response relationships". This updated review now includes several trials that report reduction in infectiousness soon after treatment, and hence improve on earlier recommendations based only on indirect measures. However, although there were five new trials aiming to study infectiousness included here, all trials except two had no or very few infection events. Overall infectiousness of patients attending for malaria treatment is very low and wanes quickly, despite a large proportion having PCR detectable gametocytes.

In relation to current WHO guidelines, evidence is available from this systematic review to support the currently recommended 0.25 mg/kg dose as 1) effective in potentially reducing transmission from individuals to mosquitoes and 2) probably safer than higher doses for those without G6PD deficiency and possibly for those with the deficiency. This review of all available evidence sheds minimal light on the question of whether PQ at any dose will materially affect transmission in communities (WHO 2012b; WHO 2015b). The amount of evidence on infectiousness of treated malaria patients to mosquitoes remains low, and evidence of the impact of treating malaria patients on transmission at a community level completely absent.

Authors' conclusions

Implications for practice

Current policy recommendations are that 0.25 mg/kg PQ should be added as a single dose to primary treatment for P. falciparum malaria in areas of low transmission to reduce infectiousness of treated individuals to mosquitoes, under the assumption that this will contribute to reducing malaria prevalence.

This Cochrane Review of all reliable data supports the idea of reducing infectiousness of people to mosquitoes, but provides very little evidence on the question of whether this reduction is of any material value in reducing community prevalence. It is consistent with the recommendation that PQ not be used in high endemicity areas, where the dilutional effects of a large part of the population carrying asymptomatic infections would likely outweigh a potential benefit. In a low endemicity area, what might be important is whether most people with parasitaemia are likely to be treated. If PQ is used systematically, monitoring malaria prevalence in a well-designed programme might provide useful information on its effectiveness.

If PQ is to be used, then it should be implemented as early as possible during treatment as the effects on infectivity appear to be maximal early in the treatment course.

Risk of harm at the currently recommended dose of 0.25 mg/kg was low in the study participants, relatively few of whom were G6PD-deficient. However, the emphasis in the included trials, hence in this systematic review, is on the efficacy of PQ, and evidence from these sources is insufficient to comment definitively on safety in all affected populations.

Implications for research

The totality of the evidence from the trials included in this review does not provide a clear answer about whether, or under what circumstances, low-dose PQ could materially reduce the community malaria burden. We do not envision direct evidence being generated that will fill this high-level gap; to do so would require many large cluster-randomized trials at different endemicity levels, conducted over many years. A realistic approach would combine evidence from randomized trials and possibly some observational data in robust mathematical models to predict the impact of PQ on malaria transmission at the community level across the range of endemicity levels. This Cochrane Review is the first step toward determining whether the existing information is sufficient to inform modelling studies and, if not, what specific questions must be addressed in further field or laboratory research to generate evidence that can be used for sound future recommendations.

A next step could be the collaborative evaluation of current evidence by recent randomized trialists, mathematical modelers who are working on this question, and others involved with malaria control policy. It would be important to examine key parameter estimates (and the relevant variability in those parameter estimates) in relation to the question of whether low-dose PQ should be implemented in combination with antimalarial treatment of acute episodes of malaria illness and, if yes, when and under what circumstances. A consensus could be reached about whether results from additional trials would provide missing information. This determination would guide decisions on the need for further trials and if needed, precisely what endpoints should be sought.

Acknowledgements

We thank the trial authors of Shekalaghe 2007, Vásquez 2009, Smithuis 2010, Kolaczinski 2012, and Sutanto 2013 for providing unpublished data for this review. Dr Isabela Ribeiro assisted with assessing trials in Portuguese for inclusion. Dr Adam Ye, Dr Qian Xu, Qiang Long, and Annabelle Yuet Chun Lee helped with translation of Chinese trials, and Prof Nick White provided links to Chinese trials and useful feedback on an earlier version of the review.

The academic editor of this review is Lawrence Mbuagbaw.

We are grateful to our affiliated institutions and organizations, and thank the referees and editors for their comments and encouragement. The editorial base for the Cochrane Infectious Disease Group is funded by the Department for International Development (DFID), UK, for the benefit of low- and middle-income countries (Grant: 5242).

Data and analyses

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Comparison 1. Artemisinin treatment regimen: PQ versus no PQ
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Participants infectious, day 3 or 4, by dose4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 0.2 to 0.25 mg/kg3105Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.02, 0.88]
1.2 0.4 to 0.5 mg/kg3109Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.02, 0.94]
1.3 0.75 mg/kg1101Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.02, 1.68]
2 Participants with gametocytes (PCR), day 3 or 4, by dose4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 0.2 to 0.25 mg/kg3414Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.87, 1.21]
2.2 0.4 to 0.5 mg/kg3418Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.93, 1.28]
2.3 0.75 mg/kg2394Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.75, 1.13]
3 Participants with gametocytes (microscopy), day 3 or 4, by dose6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 0.2 to 0.25 mg/kg3490Risk Ratio (M-H, Random, 95% CI)0.73 [0.21, 2.50]
3.2 0.4 to 0.5 mg/kg2225Risk Ratio (M-H, Random, 95% CI)0.86 [0.33, 2.25]
3.3 0.75 mg/kg3248Risk Ratio (M-H, Random, 95% CI)0.42 [0.20, 0.85]
4 Participants infectious, day 8, by dose5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 0.2 to 0.25 mg/kg4243Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.07, 1.58]
4.2 0.4 to 0.5 mg/kg4246Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.07, 1.57]
4.3 0.75 mg/kg2181Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.02, 1.41]
5 Participants with gametocytes (PCR), day 8, by dose8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 0.2 to 0.25 mg/kg PQ4532Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.41, 0.65]
5.2 0.4 to 0.5 mg/kg PQ5758Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.29, 0.48]
5.3 0.75 mg/kg PQ5793Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.23, 0.43]
6 Participants with gametocytes (microscopy), day 8, by dose9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 0.2 to 0.25 mg/kg3491Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.16, 0.78]
6.2 0.4 to 0.5 mg/kg2225Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.08, 0.75]
6.3 0.75 mg/kg61443Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.19, 0.37]
7 Gametocyte clearance time (PCR), by dose1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 0.2 to 0.25 mg/kg1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 0.4 to 0.5 mg/kg1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Area under curve of gametocytes (PCR), days 1 to 15, by dose1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 0.2 to 0.25 mg/kg1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8.2 0.4 to 0.5 mg/kg1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Participants with severe haemolysis, by dose5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
9.1 0.2 to 0.25 mg/kg4752Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.69, 1.39]
9.2 0.4 to 0.5 mg/kg2260Risk Ratio (M-H, Fixed, 95% CI)1.54 [0.38, 6.30]
9.3 0.75 mg/kg1102Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Mean max change in haemoglobin concentration, by dose4 Mean Difference (IV, Random, 95% CI)Subtotals only
10.1 0.2 to 0.25 mg/kg2435Mean Difference (IV, Random, 95% CI)0.13 [-0.07, 0.33]
10.2 0.4 to 0.5 mg/kg2475Mean Difference (IV, Random, 95% CI)0.18 [-0.08, 0.44]
10.3 0.75 mg/kg3538Mean Difference (IV, Random, 95% CI)0.05 [-0.04, 0.14]
11 Percent change in haemoglobin, day 8, by dose4 Mean Difference (IV, Random, 95% CI)Subtotals only
11.1 0.2 to 0.25 mg/kg2492Mean Difference (IV, Random, 95% CI)0.25 [-0.99, 1.50]
11.2 0.4 to 0.5 mg/kg1230Mean Difference (IV, Random, 95% CI)0.43 [-3.40, 4.26]
11.3 0.75 mg/kg2334Mean Difference (IV, Random, 95% CI)1.46 [-1.70, 4.63]
12 Max percent change in haemoglobin, by dose2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
12.1 0.2 to 0.25 mg/kg1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12.2 0.4 to 0.5 mg/kg1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12.3 0.75 mg/kg1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
13 Haemoglobinuria/dark urine3527Odds Ratio (M-H, Fixed, 95% CI)3.40 [2.15, 5.38]
14 Other adverse effects (CNS symptoms)6 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
14.1 Headache51706Odds Ratio (M-H, Fixed, 95% CI)0.95 [0.66, 1.36]
14.2 Paresthesia1331Odds Ratio (M-H, Fixed, 95% CI)0.95 [0.13, 6.80]
14.3 Dizziness41335Odds Ratio (M-H, Fixed, 95% CI)0.95 [0.74, 1.23]
14.4 Meningitis1441Odds Ratio (M-H, Fixed, 95% CI)0.08 [0.00, 2.13]
14.5 Blurred vision1217Odds Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.12]
14.6 Insomnia1808Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.64, 1.47]
15 Other adverse effects (systemic)64142Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.74, 1.24]
15.1 Fatigue2236Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.46, 2.19]
15.2 Pruritis1347Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
15.3 Fever41056Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.65, 1.55]
15.4 Muscle ache/pain2398Odds Ratio (M-H, Fixed, 95% CI)0.66 [0.12, 3.55]
15.5 Skin rash3921Odds Ratio (M-H, Fixed, 95% CI)1.51 [0.46, 5.01]
15.6 Pallor2704Odds Ratio (M-H, Fixed, 95% CI)0.95 [0.59, 1.54]
15.7 Weakness/asthenia2480Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.43, 1.49]
16 Other adverse effects (respiratory symptoms)5 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
16.1 Cough2488Odds Ratio (M-H, Fixed, 95% CI)1.39 [0.77, 2.54]
16.2 Runny nose147Odds Ratio (M-H, Fixed, 95% CI)0.49 [0.07, 3.61]
16.3 URTI/respiratory infection2488Odds Ratio (M-H, Fixed, 95% CI)2.57 [0.68, 9.72]
16.4 Bronchitis1351Odds Ratio (M-H, Fixed, 95% CI)2.34 [0.50, 10.87]
16.5 Rhinitis/rhinobronchitis2398Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.10, 5.83]
16.6 Shortness of breath147Odds Ratio (M-H, Fixed, 95% CI)0.16 [0.01, 4.45]
16.7 Otitis1351Odds Ratio (M-H, Fixed, 95% CI)2.36 [0.11, 50.02]
16.8 Epistaxis1351Odds Ratio (M-H, Fixed, 95% CI)1.41 [0.06, 35.04]
16.9 Pneumonia1441Odds Ratio (M-H, Fixed, 95% CI)0.32 [0.05, 2.24]
16.10 Cold sores1217Odds Ratio (M-H, Fixed, 95% CI)1.33 [0.29, 6.10]
16.11 Cyanosis1263Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
17 Other adverse effects (gastrointestinal symptoms)7 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
17.1 Nausea51624Odds Ratio (M-H, Fixed, 95% CI)1.20 [0.88, 1.64]
17.2 Vomiting72459Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.65, 1.56]
17.3 Abdominal pain72453Odds Ratio (M-H, Fixed, 95% CI)1.14 [0.86, 1.51]
17.4 Diarrhoea/dysentery/stooling72462Odds Ratio (M-H, Fixed, 95% CI)0.74 [0.50, 1.10]
17.5 Anorexia/loss of appetite31296Odds Ratio (M-H, Fixed, 95% CI)0.66 [0.45, 0.95]
18 Other adverse effects (Miscellaneous)5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
18.1 Back pain147Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.04, 2.05]
18.2 Burning with urination147Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.06, 29.31]
18.3 Pain with urination147Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.06, 29.31]
18.4 Whitlow147Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.06, 29.31]
18.5 Leg osteoarthritis147Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.01, 4.14]
18.6 Uncomplicated malaria1351Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.12, 4.04]
18.7 Dental pain1351Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 3.67]
18.8 High transaminase1351Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 3.67]
18.9 Palpebral inflammation1351Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 3.67]
18.10 Wound/trauma2792Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.12, 0.97]
18.11 Foot trauma1351Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.06, 33.01]
18.12 Foot inflammation1351Risk Ratio (M-H, Fixed, 95% CI)1.4 [0.06, 33.83]
18.13 Skin infection1441Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.30, 2.29]
18.14 Palpitations1808Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.80, 1.37]
18.15 Unspecified2655Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.46, 1.96]
Analysis 1.1.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 1 Participants infectious, day 3 or 4, by dose.

Analysis 1.2.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 2 Participants with gametocytes (PCR), day 3 or 4, by dose.

Analysis 1.3.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 3 Participants with gametocytes (microscopy), day 3 or 4, by dose.

Analysis 1.4.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 4 Participants infectious, day 8, by dose.

Analysis 1.5.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 5 Participants with gametocytes (PCR), day 8, by dose.

Analysis 1.6.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 6 Participants with gametocytes (microscopy), day 8, by dose.

Analysis 1.7.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 7 Gametocyte clearance time (PCR), by dose.

Analysis 1.8.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 8 Area under curve of gametocytes (PCR), days 1 to 15, by dose.

Analysis 1.9.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 9 Participants with severe haemolysis, by dose.

Analysis 1.10.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 10 Mean max change in haemoglobin concentration, by dose.

Analysis 1.11.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 11 Percent change in haemoglobin, day 8, by dose.

Analysis 1.12.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 12 Max percent change in haemoglobin, by dose.

Analysis 1.13.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 13 Haemoglobinuria/dark urine.

Analysis 1.14.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 14 Other adverse effects (CNS symptoms).

Analysis 1.15.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 15 Other adverse effects (systemic).

Analysis 1.16.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 16 Other adverse effects (respiratory symptoms).

Analysis 1.17.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 17 Other adverse effects (gastrointestinal symptoms).

Analysis 1.18.

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 18 Other adverse effects (Miscellaneous).

Comparison 2. Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Participants infectious, day 3 to 43116Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.06, 13.54]
2 Participants with gametocytes (PCR), day 3 to 43424Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.80, 1.09]
3 Participants with gametocytes (microscopy), day 3 to 42231Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.68, 2.20]
4 Participants infectious, day 84237Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.14, 6.48]
5 Participants with gametocytes (PCR), day 84559Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.97, 1.82]
6 Participants with gametocytes (microscopy), day 82235Risk Ratio (M-H, Fixed, 95% CI)1.80 [0.51, 6.38]
Analysis 2.1.

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 1 Participants infectious, day 3 to 4.

Analysis 2.2.

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 2 Participants with gametocytes (PCR), day 3 to 4.

Analysis 2.3.

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 3 Participants with gametocytes (microscopy), day 3 to 4.

Analysis 2.4.

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 4 Participants infectious, day 8.

Analysis 2.5.

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 5 Participants with gametocytes (PCR), day 8.

Analysis 2.6.

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 6 Participants with gametocytes (microscopy), day 8.

Comparison 3. Non-artemisinin treatment regimen: PQ versus no PQ
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Participants infectious, day 5, by dose2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 0.75 mg/kg230Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 0.62]
2 Participants with gametocytes (microscopy), day 4 to 5, by dose3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 0.4 to 0.5 mg/kg1221Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.62, 1.13]
2.2 0.75 mg/kg252Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.48, 1.50]
3 Participants infectious, day 8, by dose2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 0.75 mg/kg PQ230Risk Ratio (M-H, Fixed, 95% CI)0.07 [0.01, 0.45]
4 Participants with gametocytes (microscopy), day 8, by dose5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 0.4 to 0.5 mg/kg PQ1216Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.49, 0.75]
4.2 0.75 mg/kg PQ4186Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.25, 0.62]
5 Gametocyte clearance time1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6 Adverse effects1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
6.1 Nausea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 Vomiting1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 Dizziness1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6.4 Any adverse effect1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Non-artemisinin treatment regimen: PQ versus no PQ, Outcome 1 Participants infectious, day 5, by dose.

Analysis 3.2.

Comparison 3 Non-artemisinin treatment regimen: PQ versus no PQ, Outcome 2 Participants with gametocytes (microscopy), day 4 to 5, by dose.

Analysis 3.3.

Comparison 3 Non-artemisinin treatment regimen: PQ versus no PQ, Outcome 3 Participants infectious, day 8, by dose.

Analysis 3.4.

Comparison 3 Non-artemisinin treatment regimen: PQ versus no PQ, Outcome 4 Participants with gametocytes (microscopy), day 8, by dose.

Analysis 3.5.

Comparison 3 Non-artemisinin treatment regimen: PQ versus no PQ, Outcome 5 Gametocyte clearance time.

Analysis 3.6.

Comparison 3 Non-artemisinin treatment regimen: PQ versus no PQ, Outcome 6 Adverse effects.

Comparison 4. PQ versus other 8AQ
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Participants with gametocytes (microscopy), day 82112Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.26, 0.66]
Analysis 4.1.

Comparison 4 PQ versus other 8AQ, Outcome 1 Participants with gametocytes (microscopy), day 8.

Appendices

Appendix 1. Search strategy

Search setCIDG SR1CENTRAL MEDLINE2EMBASE2LILACS2
1malaria

MALARIA, FALCIPARUM/

DRUG THERAPY

MALARIA, FALCIPARUM/

DRUG THERAPY

MALARIA FALCIPARUM/DRUG THERAPYMalaria AND falciparum
2primaquine OR pamaquine OR plasmoquine OR plasmochin OR plasmocide OR rhodoquine OR plasmocid OR quinocine OR pentaquine OR isopentaquine OR bulaquine OR tafenoquine OR 8-aminoquinoline*     Malaria AND falciparum ti, abMalaria AND falciparum ti, abMalaria AND falciparum ti, abprimaquine OR pamaquine OR plasmoquine OR plasmochin OR plasmocide OR rhodoquine OR plasmocid OR quinocine OR pentaquine OR isopentaquine OR bulaquine OR tafenoquine OR 8-aminoquinoline$   
31 and 21 or 21 or 21 or 21 and 2
4 -

PRIMAQUINE/

ADMINISTRATION AND DOSAGE/ THERAPEUTIC USE

PRIMAQUINE/

ADMINISTRATION AND DOSAGE/ THERAPEUTIC USE

PRIMAQUINE -
5 -primaquine OR pamaquine OR plasmoquine OR plasmochin OR plasmocide OR rhodoquine OR plasmocid OR quinocine OR pentaquine OR isopentaquine OR bulaquine OR tafenoquine OR 8-aminoquinoline*   ti, abprimaquine OR pamaquine OR plasmoquine OR plasmochin OR plasmocide OR rhodoquine OR plasmocid OR quinocine OR pentaquine OR isopentaquine OR bulaquine OR tafenoquine OR 8-aminoquinoline*   ti, abprimaquine OR pamaquine OR plasmoquine OR plasmochin OR plasmocide OR rhodoquine OR plasmocid OR quinocine OR pentaquine OR isopentaquine OR bulaquine OR tafenoquine OR 8-aminoquinoline*   ti, ab -
6 -4 or 54 or 54 or 5 -
7 -3 and 63 and 63 and 6 -
8 - -Limit 7 to HumansLimit 7 to Human -

1Cochrane Infectious Diseases Group Specialized Register.
2Search terms used in combination with the search strategy for retrieving trials developed by the Cochrane Collaboration (Lefebvre 2011); Upper case: MeSH or EMTREE heading; Lower case: free text term.

What's new

DateEventDescription
9 February 2018AmendedPLS title corrected to 'A single dose of primaquine added to malaria treatment to prevent malaria transmission'

History

Protocol first published: Issue 4, 2009
Review first published: Issue 9, 2012

DateEventDescription
1 February 2018New search has been performedSearch updated to 21 July 2017. We included seven new trials (Dicko 2016; Gonçalves 2016a; Gonçalves 2016b; Mwaiswelo 2016; Okebe 2016; Lin 2017; Tine 2017) and four additional publications from a previously included trial (Eziefula 2013).The new trials included direct measures of infectiousness of people to mosquitoes and these data were included.
1 February 2018New citation required and conclusions have changedThis is an update of a review last updated in 2015.
4 February 2015New citation required but conclusions have not changedNew citation.
4 February 2015New search has been performedSearch updated to 5 January 2015. No new trials were included. We simplified the text. We corrected data extraction errors in one study and corrected the results and 'Summary of findings' table. We adjusted the wording around "evidence of no effect". We took into account comments and criticisms received. These criticisms were also published in the Malaria Journal in 2014, so this revision corrects the minor data extraction errors pointed out in this article. The conclusions are not changed.
24 June 2014New citation required and conclusions have changedWe stratified the analysis by dose of primaquine and added new studies. We clarified the excluded studies and adjusted the conclusions.
24 June 2014New search has been performedNew studies added.

Contributions of authors

2018 update

PMG and HG screened the abstracts, added the new studies, and extracted the data. LC and PG revised the GRADE analysis and ‘Summary of findings' tables. All authors contributed to interpretation of results and rewriting the review.

Graves 2015: PMG, HG, and PG contributed to adjusting the data and updating the text.

Graves 2014: PMG and HG added the new studies. PG helped rewrite the review. All review authors contributed to the interpretation of the results and the conclusions drawn.

Graves 2012: two review authors (PMG and HG) independently screened all abstracts, applied inclusion criteria and extracted data. PG helped structure the review and contributed to the logic framework of the ‘Summary of findings' tables. All review authors contributed to the writing of the review, the interpretation of the results, and the conclusions drawn.

Declarations of interest

We have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of the review (for example, employment, consultancy, stock ownership, honoraria, or expert testimony).

This review and the salary of PG is supported by a DFID grant aimed at ensuring the best possible systematic reviews, particularly Cochrane Reviews, are completed on topics relevant to the poor in low- and middle-income countries. DFID does not participate in the selection of topics, in the conduct of the review or in the interpretation of findings. PG is a member of the WHO Guidelines for the Treatment of Malaria Group that made the recommendation for PQ to reduce P. falciparum malaria transmission.

PMG was a member from 2012 to 2016 of the WHO Malaria Policy Advisory Committee, which provides independent strategic advice in forming WHO policies in malaria.

HG and LC have no known conflicts of interest.

None of the review authors are investigators on any of the included trials.

Sources of support

Internal sources

  • Liverpool School of Tropical Medicine, UK.

External sources

  • Department for International Development, UK.

    Grant: 5242

Differences between protocol and review

2012 version

1. After reading the trials, we added several new outcomes and modified some outcomes; we deleted two outcomes.

Changes to primary outcomes:

  • Proportion of participants with gametocytes: we added: by microscopy and PCR;

  • We added: Proportion of participants infectious;

  • We included: Gametocyte density (by microscopy and PCR);

  • We added: Gametocyte clearance time and duration of gametocyte carriage.

We arranged the primary outcomes to capture the three categories: transmission intensity, infectiousness and potential infectiousness.

Changes to secondary outcomes:

  • We deleted AUC of asexual parasite density over time. We did not identify any relevant data;

  • We added asexual clearance time.

Changes to adverse events:

  • We deleted: all adverse events (data reported was minimal and not in a form that was easily summarized. The main question is whether there are serious adverse events);

  • We modified haemolysis or drop in haemoglobin or PCV (as assessed/defined in each trial) by deleting reference to G6PD since these outcomes occur in non-G6PD people too. We also added PCV since this was used in some trials as a measure of anaemia.

2. In the first version of the review, we deleted the objective: "To compare the effects of different doses and schedules of PQ given to reduce infectiousness" and we modified the definition of control in comparisons accordingly. We only included controls without PQ. We deleted the comparison of different doses of PQ with identical other treatment regimens since it does not answer the important question of whether adding PQ is effective. We included one trial with two arms using different doses of PQ with same other treatment regimens as two separate arms within the same comparison.

2014 version

In the June 2014 update, we reversed this decision. We planned to use the following comparisons described in the protocol:

  • CQ (with and without PQ, or with different doses of PQ);

  • SP (with and without PQ, or with different doses of PQ);

  • CQ plus sulphadoxine + pyrimethamine (with and without PQ, or with different doses of PQ);

  • Artemisinin derivatives (with and without PQ, or with different doses of PQ);

  • Other drugs (with and without PQ, or with different doses of PQ).

In the review, we changed the groups, added some, and combined some for the following reasons:

a. some trials combined two types of malaria treatment regimens, not distinguishing the patients who received each one (for example, CQ or CQ plus SP);

b. there were many different artemisinin derivatives and combinations tested, with few trials of each, so these were grouped within the same comparison. We also grouped combinations of an artemisinin derivative with SP here.

3. There were no eligible cluster-RCTs so we deleted how we would manage them from the Methods section. If we include any cluster-RCTs in future editions, we will check that trials have correctly adjusted for clustering and, if not, attempt to make this adjustment. When the analyses have not adjusted for clustering, we will attempt to adjust the results for clustering by multiplying the standard errors of the estimates by the square root of the design effect, where the design effect is calculated as DEff=1+(m-1)*ICC. This assumes that the necessary information is reported, the average cluster size (m) and the intra-cluster correlation coefficient (ICC). 

4. We intended a sensitivity analysis to investigate the robustness of the results to the quality (risk of bias) components, but were unable to do so as there were insufficient trials. If appropriate and necessary, we will conduct sensitivity analysis on cluster-RCTs using a range of estimates for the ICC to see if clustering could influence the individual trial's result.

2015 version

5. Comments on the review were addressed (see below). An updated search did not identify any new trials for inclusion.

2018 version

6. In 2018 we removed some secondary outcomes including our AUC calculations, asexual stage outcomes, and gametocyte prevalence outcomes at time periods after day 8, given new higher priority evidence and comparisons. AUC if reported by trials is still included. We removed the following secondary outcomes that were in the 2015 version:

  • Presence of asexual stage parasites (may be reported as treatment failure rate);

  • Asexual parasite clearance time (duration of asexual carriage).

We also restricted infectiousness and gametocyte prevalence outcomes to day 8 of follow-up. We excluded any trial arms with < 0.2 mg/kg PQ (three arms). We converted analysis figures of infections acquired by mosquitoes to tables.

Notes

We received comments from Professor Nick White, who has published extensively on using PQ to prevent transmission. Professor White sent some helpful comments on the use of the data and its interpretation. These were considered by the authorship team and disaggregated into key points that needed to be addressed by the review. The Cochrane Contact Editor moderated the process. The main points raised and addressed were:

  1. The lack of effect in low dose categories of PQ does not mean there is no effect and the data suggests a dose response relationship. Response: we have adjusted the wording within the review.

  2. Data from Pukrittayakamee 2004 has been incorrectly extracted/interpreted. Response: Two review authors working independently assumed "after treatment" meant after the seven day course, and it was helpful to have it clarified that this was not the case. Therefore we excluded the data for day 8 gametocyte prevalence from this analysis. We inserted additional text on the gametocyte clearance time and duration of gametocyte carriage to the Results section.

Professor White's comments subsequently appeared in a publication about the topic (White 2014). We corrected all points of factual detail in the 2015 review version.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Arango 2012

MethodsQuasi-RCT: alternate allocation to AQ+SP and AQ+SP+PQ, then MQ+AS and MQ+AS+PQ
Participants

Inclusion criteria

  • Uncomplicated malaria.

  • P. falciparum only.

  • Not pregnant.

  • Voluntary consent.

Colombia

82 participants, aged one to 75 years (mean age ranged from 24 to 35 years in four groups)

Gametocytes in 23/82 (28%)

Interventions

All loose combinations

  • AQ+SP.

  • AQ+SP+PQ.

  • MQ+AS.

  • MQ+AS+PQ.

AQ: 25 mg/kg total dose divided into 10 mg/kg on day 1 and 7.5 mg/kg on days 2 and 3

SP: 25 mg/kg/1.25 mg/kg single dose on day 1

MQ: 25 mg/kg total dose, divided into 8.3 mg/kg per day for 3 days

AS: 4 mg/kg per day for 3 days

PQ: 0.75 mg/kg, total single dose on day 2

Outcomes

Day 1 (pretreatment with schizonticide), 4 and 8

Asexual and gametocyte counts in thick smears

Gametocyte prevalence

Gametocyte density

NotesNo mention of G6PD status
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAlternate allocation.
Allocation concealment (selection bias)Unclear riskNot discussed.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence of incomplete data.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasUnclear riskNo information given.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot discussed.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot discussed.

Chen 1993a

MethodsRCT
Participants

18 participants, healthy adults with P. falciparum and positive for gametocytes

Setting: China

Interventions

A: MQ 750 mg.

B: MQ 750 mg + SP (1500 mg/75 mg).

C: MQ 750 mg + PQ 45 mg.

Follow-up: 28 days for gametocytes and 21 days for infectiousness

Outcomes

Gametocyte prevalence at days 3, 8, 14, and 21

Infectiousness to An. dirus

Sporozoite infections in mosquitoes

Infectivity of sporozoite-infected mosquitoes to subsequent patients

Notes

Only abstract available.

Mosquitoes fed on the patients were allowed to develop sporozoites which were then fed on uninfected people. One of the MQ + PQ group passed the infection to a new person.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskTrial authors stated it was randomized in abstract but no details given in the text.
Allocation concealment (selection bias)Low riskSupervisor who oversaw patients taking the drug opened a sealed envelope then saying what drug it was.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants were followed up.
Selective reporting (reporting bias)Unclear riskNo information in the text.
Other biasUnclear riskNo information given
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated to be double blind in the text.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information in the text.

Chen 1994

Methods

Possibly individually RCT (stated to be randomized but no information given).

Dates of trial not reported.

Participants

27 participants with slide positive P. falciparum including both asexual stages and gametocytes. No information given on age or sex. All dosages appear to be adult dosages.

Site: malaria-endemic Hainan Island, China.

Exclusion criteria: history of antimalarial treatment for present attack.

Interventions
  • Artemisinin: 1200 mg per day for 5 days (not included in review).

  • MQ 750 mg single dose day 1 (reported as day 0).

  • MQ 750 mg single dose + PQ 45 mg single dose day 1 (reported as day 0).

Outcomes
  • Gametocyte density: days 5, 8, 15, 22, and 29 (reported in paper as days 4, 7, 14, 21, and 28 since first day was day 0). Given as % of initial density on chart only.

  • Percentage of participants infectious to An. dirus: days 5, 8, 15, and 22 (reported as days 4, 7, 14, and 21).

  • Percentage of mosquitoes infected: days 5, 8, 15, and 22 (reported as days 4, 7, 14, and 21).

NotesFor gametocyte density, graph only of percentages; no raw numbers given except range of asexual and gametocyte numbers reported for each group on day 1 (reported as day 0).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information on sequence generation. Trial authors described process as participants "divided into groups A, B, and C". Equal number in each group and lack of detail suggests randomization not done adequately.
Allocation concealment (selection bias)High riskNo data to suggest any measures to conceal allocation.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing participants in intervention groups 2 and 3.
Selective reporting (reporting bias)Low riskNo obvious selective reporting.
Other biasLow riskNo indication of other bias.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Dicko 2016

MethodsIndividually RCT
Participants

81 men aged 5 to 50 years

All gametocyte carriers by microscopy (≥ 32 gametocytes/µL) - at least 2 gametocytes/500 wbcs on thick film

Hb ≥ 8 g/dL

Normal G6PD by colorimetric classification

Oulessbougoue, near MRTC Mali

Exclusion criteria

  • Malaria drugs in last 7 days.

  • Known allergies to study drugs.

  • Serious or chronic illness.

  • Diagnosed cardiac arrhythmias.

Interventions

DHAP daily for 3 days, by weight to closest whole tablet; tablets were 320 mg DHA and 40 mg piperaquine.

13 kg to < 24 kg: 1 tablet; 24 kg to < 36 kg: 2 tablets; 36 kg to < 75 kg: 3 tablets; 75 to 100 kg: 4 tablets.

DHAP plus PQ on day 1 at 0.125 and 0.5 mg/kg in Phase 1

DHAP plus PQ on day 1 at 0.065 and 0.25 mg/kg in Phase 2

PQ dissolved in water and given orally, observed.

Outcomes

People infective to mosquitoes on day 1 (pretreatment), 2, 3, and 8

Mosquitoes infected on day 1 (pretreatment), 2, 3, and 8 by membrane feeding

Mean within-person change in mosquito infectivity (in all participants, and only those who were infectious on day 1)

Hb on day 1, 2, 3, 4, 8, 15, 29

Mean within-person change in Hb after treatment on day 1, 2, 3, 4, 8, 15, 29

Adverse events (mild, moderate, severe) on day 2, 3, 4, 8, 15, 29

Gametocyte prevalence and density by microscopy day 1 (pretreatment), 2 hours, 6 hours, 12 hours, and days 2, 3, 4, 8, 15, 29

Gametocyte prevalence and density by qRT-PCR, same time points

CYP2D^ genotype and metabolizers phenotype

AUC gametocyte density (qt-PCR) over time to day 29

NotesStudy was halted after 8 participants enrolled in phase 1, due to low infection rate in mosquitoes before treatment. Protocols were optimized and the study restarted 6 months later.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStudy was in two phases: phase 1 was RCT (in blocks of 6) and phase 2 was not randomized (alternate allocation?).
Allocation concealment (selection bias)High riskSealed opaque envelopes in phase 1. In phase 2 "participants were enrolled first into 0.25 mg/kg group and then 0.0625 mg/kg group when full".
Incomplete outcome data (attrition bias)
All outcomes
Low risk79/81 (97.5%) had at least one follow-up visit; 68/81 (84%) completed all follow-up to day 29.
Selective reporting (reporting bias)Unclear riskGametocyte density by microscopy is not reported except at baseline and in summary form for intervention and control groups combined at day 3 and 8 in the discussion.
Other biasLow riskNone known.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStudy participants were allowed to ask which group they were in. PQ taste is distinctive. Unlikely that participants knowledge of their status could influence infectivity or gametocyte prevalence.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskInvestigators and outcome assessors were blinded.

El-Sayed 2007

Methods

Individually RCT

Dates of trial: randomization June 2004; trial done 17 August 2004 to 3 September 2004.

Participants

104 people with asymptomatic P. falciparum positive by slide and positive for gametocytes by PCR. No information given on age and sex.

Site: 2 villages in East Sudan where there is seasonal malaria, mainly P. falciparum, during October to December.

Exclusion criteria: pregnancy, history of sulfa allergy, fever or other symptoms, Plasmodium spp other than P. falciparum present.

Interventions
  • AS: children < 50 kg: 4 mg/kg; all > 50 kg: 200 mg (two 100 mg tabs) days 1, 2, and 3 (reported as days 0, 1, and 2). SP: children < 50 kg: 25 mg/kg S + 1.25 mg/kg P; All > 50 kg: 3 tablets of 500 mg S + 25 mg P.

  • As for 1. above plus PQ 0.75 mg/kg day 4 (reported as day 3).

Outcomes
  • Proportion of people with P. falciparum parasites by PCR days 4, 8 and 15 (reported as days 3, 7, and 14).

  • Proportion of people with gametocytes by RT-PCR days 8 and 15 (reported as days 7 and 14).

  • Adverse events days 2, 3, 4, 8 and 15 (reported as days 1, 2, 3, 7, and 14).

  • Packed cell volume days 1, 8 and 15 (reported as days 0, 7, and 14).

NotesThe trial was conducted about two months after the initial screening for positives (asymptomatic carriers).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The list of carriers was sorted according to village and age to ensure that the treatment groups were balanced with respect to these two variables. The random allocation of this ordered list into the treatment arms was then created using restricted randomization with a block size of 12 in STATA v7".
Allocation concealment (selection bias)Unclear riskNo information given.
Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly 3/104 participants did not complete follow-up.
Selective reporting (reporting bias)Low riskNo obvious selective reporting.
Other biasLow riskNo indication of other bias.
Blinding of participants and personnel (performance bias)
All outcomes
High riskPatients and health staff were not blinded.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskLaboratory staff doing PCR were blinded.

Eziefula 2013

MethodsIndividually randomized placebo-controlled, double blind trial conducted December 2011 to March 2013
Participants

468 randomized, aged one to 10 years old, male and female

Setting: Uganda

Inclusion criteria

  • P. falciparum mono infection with parasite density lower than 500,000 parasites/μL

  • Normal G6PD enzyme function

  • Fever or history of fever in past 24 hours

Exclusion criteria

  • Signs of severity.

  • Haemoglobin concentration < 80 g/L.

  • Known allergy to the trial drugs.

  • Antimalarials taken within the past 2 days.

  • PQ taken within the past 4 weeks.

  • Blood transfusion within the past 90 days.

Interventions
  • AL standard three day (twice per day) course + placebo (given with 5th AL dose, that is, with 1st dose on 3rd day of treatment).

  • AL + 0.1 mg/kg PQ.

  • AL + 0.4 mg/kg PQ.

  • AL + 0.75 mg/kg PQ (reference).

Outcomes

Primary efficacy: mean duration of gametocyte carriage

Secondary efficacy: point prevalence of gametocytes on days 7, 10 and 14; gametocyte circulation time (days), AUC of gametocyte density

Primary safety: arithmetic mean maximum decrease in haemoglobin concentration from enrolment to day 28

Secondary safety: day of haemoglobin nadir, maximum percentage decrease in haemoglobin, percentage of participants with haemoglobin concentration lower than 50 g/L, requirement for blood transfusion, evidence of black urine, and frequency of severe adverse events.

Mean absolute and relative change in Hb on day 3, 7, 10 stratified by G6PD status

Gametocyte prevalence on day 7 stratified by CYP2D6 metabolism status.

NotesG6PD enzyme function based on a fluorescence spot test (R&D Diagnostics, Aghia Paraskevi, Greece) and on genotyping of G6PD A-; 202A and 376G. CYP2D6 genotyped by QuantSudio 12K Flex system and 32SNP Open Array and Copy number variation assays (N = 247)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated 4-digit treatment assignment codes and allocated these to random dose groups in block sizes of 16.
Allocation concealment (selection bias)Low riskOnly the pharmacist was aware of allocation.
Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly 8% of participants were lost to follow-up. No group significantly different from others.
Selective reporting (reporting bias)Low riskNone detected or suspected.
Other biasLow riskNone detected or suspected.
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Masking syrup" added to all treatments to mask taste of drug.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessors were blinded.

Gogtay 2004

MethodsAllocated by "simple, computer-generated randomization code"
Participants

Twenty-two patients in Mumbai, India

Inclusion criteria

  • > 18 years.

  • Normal G6PD.

  • > 55 P. falciparum gametocytes/μL on admission.

Exclusion criteria

  • Complicated malaria.

Interventions
  • Quinine days 1 to 7: 30 mg/kg/day + PQ (45 mg).

  • Quinine days 1 to 7: 30 mg/kg/day + bulaquine (approximately 75 mg base).

Outcomes

Asexual and gametocyte counts on days 1, 4, 8, 15, 22, and 29

Adverse events

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomization.
Allocation concealment (selection bias)Unclear riskNot reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence of incomplete data.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasHigh riskUnbalanced allocation (9 versus 13) and small number of participants.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskLaboratory technician reading blood smears was blinded.

Gogtay 2006

MethodsRandomized (computer-generated) to PQ or bulaquine (1:2 ratio) after primary treatment with quinine + doxycycline
Participants

93 participants in India

Inclusion criteria

  • > 16 years.

  • Male.

  • Uncomplicated P. falciparum only.

  • > 55 P. falciparum gametocytes/μL on admission.

Exclusion criteria

  • Antimalarial treatment in previous two weeks.

  • Allergy to trial drug.

  • G6PD deficient.

Interventions

All patients: quinine days 1 to 7: 30 mg/kg/day (10 mg/kg/day three times per day) + 100 mg doxycycline

Randomization and treatment on day 4

  • PQ.

  • Bulaquine.

Outcomes

Gametocyte prevalence, density and viability on days 1, 4, 15, 22, and 29

Adverse events

NotesGametocyte viability assessed by Shute's technique (ex flagellation)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomization.
Allocation concealment (selection bias)Unclear riskNot reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence of incomplete data. Three participants (2 bulaquine, 1 PQ) did not return for follow-up.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNone noted.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskSlide readers were blinded.

Gonçalves 2016a

MethodsIndividually RCT. This is Phase 1 of the trial.
Participants

Children aged 2 to 15 years

Asymptomatic

Normal G6PD by BinaxNOW RDT

Carrying patent P. falciparum asexual parasites or gametocytes (1000 to 200,000 parasites/µl)

Weigh ≥ 10 kg

Living in Balonghin, Sapone, Burkina Faso, an area of seasonal malaria transmission

Exclusion criteria: Hb < 8 g/dL, fever or history or fever in last 24 hours, antimalarials in last 48 hours, PQ use in last 4 weeks, blood transfusion in last 90 days, non-P. falciparum infection at screening.

Interventions

AL: half a tablet (20 mg artemether and 120 mg of lumfantrine) per 5 kg body weight in 6 doses over 3 days + placebo

AL+PQ: 0.25 and 0.4 mg/kg given on day 3 with the 5th dose of AL

Outcomes

Gametocyte clearance time

Gametocyte prevalence by microscopy days 4, 8, 11, and 15

Proportion of mosquitoes infected

Oocyst counts

Max fall in Hb during follow-up (to day 15)

Number of participants needing blood transfusion

Max % decrease in Hb

Proportion of participants with Hb below 5 g/dL

Serious adverse events

Notes

Phase 1: children who are asymptomatic P. falciparum carriers (Gonçalves 2016a): N = 210

Phase 1: children who infect mosquitoes: no baseline feeding experiments.

Confirmed P. falciparum gametocyte carriers in Phase 2 (Gonçalves 2016b): N = 150

Phase 2: children who infected mosquitoes: 30/79 38%)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRCT stratified by gender and blocks of 6 (3 study arms and two feeding schedules).
Allocation concealment (selection bias)Low riskSealed envelopes.
Incomplete outcome data (attrition bias)
All outcomes
Low riskPhase 1: 205/210 (97.6%) completed follow-up to day 14.
Selective reporting (reporting bias)Low riskAll prespecified outcomes appear to have been reported.
Other biasLow riskNone noted.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo controlled; syrup was added to mask taste of PQ.
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Participants, investigators and staff were blinded to study arm allocation".

Gonçalves 2016b

MethodsIndividually RCT. This is Phase 2 of the trial where inclusion criteria were modified to increase probability of infecting mosquitoes
Participants

Children aged 2 to 15 years

Asymptomatic

Normal G6PD by BinaxNOW RDT

Carrying patent P.falciparum gametocytes (1000 to 200,000 parasites/µl)

Weigh ≥ 10 kg

Living in Balonghin, Sapone, Burkina Faso, an area of seasonal malaria transmission

Exclusion criteria: Hb < 8 g/dL, fever or history or fever in last 24 hours, antimalarials in last 48 hours, PQ use in last 4 weeks, blood transfusion in last 90 days, non-P. falciparum infection at screening.

Interventions

AL: half a tablet (20 mg artemether and 120 mg of lumfantrine) per 5 kg body weight in 6 doses over 3 days + placebo

AL+PQ: 0.25 and 0.4 mg/kg given on day 3 with the 5th dose of AL

Outcomes

Gametocyte clearance time

Gametocyte prevalence by microscopy days 4, 8, 11, and 15

Proportion of mosquitoes infected

Oocyst counts

Max fall in Hb during follow-up (to day 15)

Number of participants needing blood transfusion

Max % decrease in Hb

Proportion of participants with Hb below 5 g/dL

Serious adverse events

Notes

Asymptomatic P. falciparum carriers in Phase 1 (Gonçalves 2016a): N = 210

Confirmed P. falciparum gametocyte carriers in Phase 2 (Gonçalves 2016b): N = 150

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRCT stratified by gender and blocks of 6 (3 study arms and two feeding schedules).
Allocation concealment (selection bias)Low riskSealed envelopes.
Incomplete outcome data (attrition bias)
All outcomes
Low riskPhase 2: 146/150 (97.3%) completed follow-up to day 14.
Selective reporting (reporting bias)Low riskAll prespecified outcomes appear to have been reported.
Other biasLow riskNone noted.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo controlled; syrup was added to mask taste of PQ.
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Participants, investigators and staff were blinded to study arm allocation".

Kamtekar 2004

Methods

Individually RCT, comprising two distinct comparisons a: (CQ or [CQ+SP]) with and without PQ and b: QN with and without PQ.

Dates of trial: not given.

Participants

57 people aged ≥ 16 years with symptomatic uncomplicated and 46 with severe (WHO criteria) P. falciparum malaria, diagnosed by thick and thin blood slides. Gametocytaemic within first 72 hrs with > 55 P. falciparum gametocytes/μL

Site: urban areas of Mumbai, India.

Exclusion criteria: pregnant or lactating, treatment for malaria within last 2 weeks, co-infection with P. vivax, history of PQ allergy.

Interventions

Comparison a: for uncomplicated malaria

All received CQ (some also got SP)

Day 4: randomized to PQ or placebo (45 mg)

Comparison b: for severe malaria

All received quinine

Day 8: randomized to PQ or placebo (dose 45 mg)

Doses background drugs: CQ 10 mg/kg on days 1 and 2; 5 mg/kg on day 3; SP 1500 mg; quinine dose 10 mg/kg every 8 hrs for 24 to 48 hrs and orally for total of 7 days

Outcomes
  • Proportion of people with gametocytes, days 1, 4, 8, 15, 22, and 29.

  • Proportion of people with viable gametocytes (exflagellation), days 1, 4, 8, 15, 22, and 29.

  • Gametocyte density (given as range) days 1, 4, 8, 15, 22, and 29.

NotesNo screening for G6PD deficiency. It is not stated how many got SP in addition to CQ or why.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk

"simple computer generated randomization code".

Not all patients had gametocytes on day 1. Inclusion criteria were that the person had to have gametocytes in the first 72 hours (from day 1?). This suggests some post randomization inclusions or exclusions.

Allocation concealment (selection bias)Unclear riskNo information.
Incomplete outcome data (attrition bias)
All outcomes
High risk

Originally there were 57 people included in uncomplicated comparison (a), of whom 2 were lost to follow-up and 9 were not evaluated as they showed CQ resistance.

There were 46 in severe comparison (b), of whom 3 were lost to follow-up.

The final numbers evaluated in each group were (a) 22 and 24 (b) 22 and 21.

Selective reporting (reporting bias)Unclear riskNo obvious selective reporting.
Other biasHigh riskIt was not clear why some patients got SP and others did not, and the numbers in each group are not given.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskTrial used a placebo for PQ. Patients and health workers were blinded.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskSlide readers were blinded.

Khoo 1981

Methods

Individually RCT

Dates of trial: between June 1976 and March 1978.

Participants

69 people (adults and children of both sexes, no ages specified) with G6PD deficiency (full or partial by Brewer's methaemoglobin reduction test) who were slide positive for malaria (P. falciparum, P. vivax or mixed).

Site: Sabah, Malaysia.

Exclusion criteria: other associated clinical conditions.

Interventions
  • CQ: 1.5 g CQ over 3 days for P. falciparum, P. vivax or mixed, less for children.

  • CQ + PQ: CQ as above plus 75 mg PQ over 3 days for P. falciparum; 210 mg PQ over 14 days for P. vivax and mixed infections; less for children.

  • SP (not included in this review): 1.5 g S and 75 mg P, single dose.

Outcomes
  • Haemolysis.

  • Proportion cleared parasites by 72 hours.

  • Need for blood transfusion.

  • Renal failure.

NotesThe participants are not divided by P. falciparum, P. vivax, or mixed, so it is not possible to use the data.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"those found G6PD deficient were randomly assigned".
Allocation concealment (selection bias)Unclear riskNo information given.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information given.
Selective reporting (reporting bias)Low riskNo apparent selective reporting.
Other biasLow riskNo indication of other bias.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Kolaczinski 2012

Methods

Individually RCT

Dates of trial: between July and January, from 2000 to 2003.

Participants

237 individuals aged from 3 to 70 years, in 5 villages for Afghan refugees in Pakistan.

Inclusion: > 2 years of age, P. falciparum mono-infection, confirmed by slide, will be resident during entire follow-up period.

Exclusions: pregnancy, signs of severe malaria, report of antimalarial drug in past 21 days, other serious disease

Interventions
  • CQ: 3 days 25 mg/kg.

  • CQ+PQ: CQ as in 1; PQ on day 3 (0.5 mg/kg).

  • SP: 25(S)/1.25(P) mg/kg in single dose.

  • SP+PQ: SP as in 3; PQ on same day (0.5 mg/kg).

Outcomes
  • Clinical treatment failure (PCR non-adjusted and adjusted).

  • Gametocytes on day 8.

  • Gametocyte density on days 1 to 8 of follow-up.

  • Genotyping of resistant strains for CQ and SP-specific mutations.

NotesAlso included CQ + AS and SP + AS arms, compared with CQ ± PQ and SP ± PQ arms, respectively.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPatients numbered sequentially at enrolment. Random numbers with treatment assignment from Excel-generated lists, then paired with patient numbers.
Allocation concealment (selection bias)Low riskPatient number concealed until after enrolment.
Incomplete outcome data (attrition bias)
All outcomes
Low risk209 of 237 randomized completed treatment and at least one follow-up test. 47 (13%) of those randomized did not contribute data. Variable numbers tested during follow-up (see analyses).
Selective reporting (reporting bias)Low riskNone detected.
Other biasLow riskNone noted.
Blinding of participants and personnel (performance bias)
All outcomes
High riskIdentified in report as "single-blind". Manager (gave Rx) not blinded; patients, microscopists and health workers "partially blinded" due to different drug appearance and times of follow-up. No placebos used, but vitamin given to those in non-PQ arms.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskImplied only.

Lederman 2006

Methods

Individually RCT

Date of trial: July to Oct 2001.

Participants

117 malaria cases with P. falciparum ≥ 400 asexual stages/μL (thick film) recruited by mass blood survey and passive case detection. Symptoms not required.

Age: ≥ 15 years

Site: Central Java, Indonesia, an area with high CQ resistance and resurgent malaria approximately equal P. falciparum and P. vivax.

Exclusion criteria: Pregnancy, breast feeding, body weight < 40 kg, G6PD deficiency, history of antimalarial or antibiotic in last 7 days, severe or complicated malaria, history or allergy or adverse reaction to trial medications, P. vivax or mixed infection.

Interventions
  • CQ only (not included in this review).

  • CQ+SP: CQ 150 mg base, 10, 10 and 5 mg/kg on days 1, 2, 3 (reported as days 0, 1, 2). SP 500 mg S 25 mg P on day 1 (reported as day 0).

  • CQ+SP as for group 2 above plus PQ 45 mg on day 1 (reported as day 0).

  • CQ+SP as for group 2 above plus PQ 45 mg on day 3 (reported as day 2).

Outcomes
  • Parasite clearance time assessed at days 1, 3, 8, 15, 22, 29 or day of recurrent parasitaemia (reported as days 0, 2, 7, 14, 21, 28)

  • Fever clearance time at days 2, 3, 4, 5, 8, 12, 15, 19, 22, 29

  • Proportion of people with gametocytes (from chart) days 1 to 29

  • Adverse events

NotesSome comparisons in the results reported include the CQ only group.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTrial subject codes were assigned to treatment arms by a random process (not specified).
Allocation concealment (selection bias)High riskEligibles were assigned a sequential participant number by the screening physician. Pre-packaged treatment but not stated whether allocation was concealed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk7% of participants withdrew before day 28.
Selective reporting (reporting bias)Unclear riskAbstract states that drugs were well tolerated and safe but no evidence is given in report.
Other biasLow riskNo indication of other bias.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding was implied only.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding was implied only.

Lin 2017

MethodsIndividually RCT
Participants

101 adults aged 18 to 65 years, 97% male presenting or referred with uncomplicated P. falciparum or mixed P. falciparum/P. vivax infection diagnosed with microscopy and confirmed with qPCR, had mild or moderate G6PD deficiency.

Setting: Cambodia

Interventions

DHAP: daily for 3 days; tablets containing 40mg DHA and 320 mg piperaquine each

PQ: single dose 45mg at day 3

Outcomes

The proportion of individuals infecting at least 1 mosquito out of 50, at 1 and 2 weeks post-treatment in the 2 arms.

The effect of the 2 treatment regimens on the risk of gametocyte carriage as measured by microscopy and RT-PCR. This was done by comparing gametocyte prevalence at weekly timepoints post-treatment and the time to gametocyte clearance in the 2 arms.

The number of infected mosquitos per treatment arm, the relationship of gametocytaemia to mosquito infectivity, and within-person changes in haemoglobin 4 days post-PQ treatment among volunteers with G6PD-deficiency

NotesBaseline infectivity of participants (day 0): DHAP 6/51 (12%); DHAP+PQ 1/51 (2%).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock size 2, randomization scheme and codes prepared in advance.
Allocation concealment (selection bias)Low riskSealed envelopes offered to patients to choose from.
Incomplete outcome data (attrition bias)
All outcomes
Low riskless than 10% loss to follow-up by day 8; >10% at day 15.
Selective reporting (reporting bias)Low riskNot detected.
Other biasUnclear riskBaseline infectivity between the groups probably chance.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.

Mwaiswelo 2016

MethodsIndividually RCT
Participants

Yombo primary health facility, Bagamoyo town, an area of high year round transmission in Tanzania with two seasonal peaks.

220 participants

Inclusion criteria

  • Gender: both.

  • Age of 1 year and above and neither pregnant nor breast feeding.

  • Weight over 10 kg.

  • Body temperature = 37.5°C or history of fever in the last 24 hours.

  • P. falciparum mono-infection.

Exclusion criteria

  • Evidence of severe illness malaria or danger signs.

  • Known allergy to study medications.

  • Haemoglobin < 8 g/dL.

  • Antimalarials taken within last 2 weeks.

  • Blood transfusion within last 90 days and evidence of recent use (within 14 days) of or will be taking other drugs known to cause haemolysis in G6PD-deficient subjects.

Interventions

AL standard doses by weight, six doses over 3 days. Placebo given with dose 1

AL+PQ (0.25 mg/kg) with dose 1, thereafter AL only.

Outcomes

No gametocyte outcomes were reported. Original planned outcomes:

Primary outcome planned: number of days per treatment arm for gametocytes to become undetectable using quantitative nucleic acid sequence based assay (QT-NASBA) (time frame: 14 days)

Secondary outcome: mean maximal fall in haemoglobin (g/dL) from enrolment to day 28 of follow-up defined as mean greatest negative difference in haemoglobin per treatment arm (time frame: 28 days)

Actually reported: PCR-adjusted asexual parasite outcomes (parasitological cure)

Mean relative reduction in Hb between day 1 and 8

Notes

ClinicalTrials.gov identifier: NCT02090036

Primary sponsor: Muhimbili University of Health and Allied Sciences

Secondary sponsor: Karolinska Institutet

Patients were admitted during treatment

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSex-stratified block randomization with 4 blocks, 2 per treatment arm using Research Randomizer v4.
Allocation concealment (selection bias)Low riskOpaque envelopes with pre-determined treatment codes.
Incomplete outcome data (attrition bias)
All outcomes
Low risk211 out of 220 (95.9%) completed the follow-up.
Selective reporting (reporting bias)High riskTrial was designed to look at gametocyte clearance but this was not reported because only one enrolled patient had gametocytes at baseline.
Other biasLow riskNone known.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskSingle blind. Nurses giving treatment opened the envelopes. Patients were blinded but could have noticed extra tablet. Glucose syrup masked the taste.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated.

Okebe 2016

MethodsIndividual RCT
Participants

694 asymptomatic malaria-infected (RDT, then microscopy, > 20 parasites/µl) G6PD normal individuals aged ≥ 1 year

Upper and Central River Regions, The Gambia, in an area with seasonal transmission peaking between Sept and Nov.

Age ≥ 1 year and weight > 10 kg

G6PD normal

Hb > 8 g/dL

No known allergy to study drugs

Not pregnant or breastfeeding

No malaria treatment in last 2 weeks

No blood transfusion in last 3 months

No history of sickle cell anaemia

No chronic or acute conditions that might interfere with the study

170 participants in membrane feeding studies.

Interventions
  • DHAP only.

  • DHAP 3 days + 0.2 mg/kg PQ on day 3 (reported as 2).

  • DHAP 3 days + 0.4 mg/kg PQ on day 3 (reported as 2).

  • DHAP 3 days + 0.75 mg/kg PQ on day 3 (reported as 2).

Outcomes

Participants with gametocytes on day 1, 4, 8, 11, 15 (reported as 0, 3, 7, 10, 14) by QT-NASBA

Participants infectious to mosquitoes on day 8 (reported as 7)

Mosquitoes infected on day 8 (reported as 7)

Adverse events

Clinical follow-up to day 43

NotesClinicalTrials.gov NCT01838902
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization list generated by the trial statistician using STATA 13. 1:1:1:1 ratio using blocks of varying size to ensure a balance between the 4 groups. A separate randomization sequence was used to select participants for membrane feeding.
Allocation concealment (selection bias)Low riskSequentially numbered opaque envelopes prepared from randomization list by non-study physician.
Incomplete outcome data (attrition bias)
All outcomes
Low risk647/694 (93.2%) of participants completed follow-up.
Selective reporting (reporting bias)Low riskNot detected.
Other biasLow riskNot detected.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label: staff involved in clinical care including the trial drugs were aware of assigned groups.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskThose involved in sample processing and data analysis are blinded.

Pukrittayakamee 2004

Methods

Individually RCT

Dates of trial not stated.

Participants

176 patients with acute uncomplicated P. falciparum. After exclusion of QN+tetracycline group: 146.

Age 14 to 62.

All male.

Site: Hospital for Tropical Diseases, Bangkok, Thailand.

Exclusion criteria: severe malaria, mixed malaria infection, history of drug hypersensitivity, any antimalarial within last 48 hrs, urine positive for sulfonamide or 4AQ.

People with G6PD deficient phenotype were excluded from receiving PQ.

Interventions
  • QN: QN sulfate (300 mg salt/tab) at 10 mg salt/kg, three times per day for 7 days.

  • QN+tetracycline (excluded from this review).

  • QN+PQ low dose: QN as above in 1 plus PQ 15 mg base/tab, 0.25 mg/kg base (adult dose 15 mg base) daily for 7 days.

  • QN+PQ high dose: QN as above in 1 plus PQ 0.50 mg/kg base (adult dose 30 mg base) daily for 7 days.

  • AS: AS 50 mg salt/tab 3.3 mg/kg (adult dose 200 mg) on day 1 and 1.65 mg/kg (adult dose 100 mg) daily on days 2 to 7.

  • AS+PQ (high dose): AS as above plus PQ 0.5 mg/kg base daily on days 1 to 7.

Outcomes
  • Parasite clearance time: measured at 12 hrs until clearance.

  • Gametocyte clearance time: median, 12 hrs until clearance.

  • Fever clearance time (measured every 4 hr at first and then every 6 to 12 hrs until resolution of fever).

  • Parasite reduction ratio at 48 hrs.

  • Reappearance of infection P. falciparum/P. vivax up to 28 days.

  • Prevalence of gametocytes on admission/after treatment/total.

  • Gametocyte carriage: total number of hours for which gametocytes were detectable.

NotesPatients with recrudescence of P. falciparum or relapse of P. vivax were re-treated with 7 day QN+tetracycline or ‘standard doses' of CQ+PQ respectively; not clear if they were excluded from further trial.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskMethod not stated. Patients with G6PD deficiency were excluded from getting PQ which suggests randomization was biased.
Allocation concealment (selection bias)Unclear riskNo information given.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk122/142 of the original participants in the 5 groups studied here completed follow-up. Patients with recrudescences of P. falciparum or relapse of P. vivax were re-treated with QN+tetracycline or CQ+PQ respectively; not clear if they were excluded from further trial.
Selective reporting (reporting bias)Unclear riskNot detected.
Other biasUnclear riskThose who were unable to stay in hospital until clearance of both fever and parasites were excluded from trial of fever clearance time.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Shekalaghe 2007

Methods

Individually RCT

Dates of trial: June to Sept 2006.

Participants

108 children with fever > 37.5°C or history of fever in last 48 hours and P. falciparum mono-infection 500 to 100,000/μL.

Age three to 15 years.

Both sexes.

Site: Mynuzi health centre, North-Eastern Tanzania, a hyperendemic area with rainy seasons in March to June and October to December

Exclusion criteria: Hb < 8, inability to take drugs orally, known hypersensitivity to meds, reported anti-malarial treatment in last 2 weeks, evidence of chronic disease or acute infection other than malaria, domicile outside trial area, signs of severe malaria, eligible for other malaria studies.

Interventions
  • AS+SP: AS: 4 mg/kg once daily for 3 days; SP: S 25 mg/kg and P: 1.125 mg/kg.

  • AS+SP+PQ: As above for AS and SP plus PQ base 0.75 mg/kg on the third day.

Outcomes
  • Proportion of people with gametocytes (by microscopy) days 1, 4, 8, 15, 29 and 43 (reported as 0, 3, 7, 14, 28, and 42).

  • Proportion with gametocytes (by PCR), same time points.

  • Gametocyte density by PCR.

  • AUC for gametocyte presence.

  • Adverse events.

  • Adequate clinical and parasitological response.

  • Haemoglobin.

NotesHb outcome assessed with respect to G6PD variant.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskGenerated in STATA 8.0 using restricted randomization with block size of 20.
Allocation concealment (selection bias)Low riskPre-prepared envelopes (but person who opened envelope administered treatment).
Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly 2 out of 108 failed to complete follow-up.
Selective reporting (reporting bias)Low riskNo information given.
Other biasLow riskNo indication of other bias.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskTrial physician evaluated patients, opened envelopes, and administered treatment. Other staff were blinded. Not clear if participants were blinded.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated.

Singhasivanon 1994

Methods

Individual RCT

Dates of trial: not stated.

Participants

23 people with uncomplicated P. falciparum malaria, parasitaemia between 1 to 5 per 1000 RBC.

Age 5 to 12 years, sex not stated.

Exclusion criteria: antimalarial drugs, urine with quinoline and sulfonamide drugs, other diseases, hematocrit ≤ 20%, inability to take oral medication.

Interventions
  • MSP: MQ 20 mg/kg; S 40 mg base/kg; P 2 mg/kg; single dose.

  • MSP + PQ: As above plus PQ 0.75 mg/kg single dose. MSP+PQ crushed and mixed with 30 mL syrup (83% dextrose).

Outcomes
  • Gametocyte clearance time (days) (assessed twice daily until negative, then once daily, by blood slide).

  • Adverse drug reactions, assessed once daily in first week then once a week.

  • Parasite clearance time (hrs).

  • Fever clearance time (hrs).

  • Cure rate.

NotesThose who vomited within 3 hours of Rx were excluded - this is a post-randomization exclusion.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Unclear riskNo information given.
Incomplete outcome data (attrition bias)
All outcomes
High riskOutcomes only reported for 18 of the 23 participants.
Selective reporting (reporting bias)Unclear riskNo information given.
Other biasHigh riskThose who vomited within 3 hours of Rx were excluded; this is a post-randomization exclusion.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated.

Smithuis 2010

Methods

Individually RCT (5 comparisons, 10 arms).

Follow-up: patients were asked to return weekly for 9 weeks for assessment and at any other time they were unwell.

Dates: December 2008 to March 2009.

Participants

Number: 808 people attending clinics in Myanmar.

Inclusion criteria: age > 6 months, weight > 5 kg, P. falciparum mono-infection 500 to 200,000 parasites/µL or co-infection with P. vivax, informed consent.

Exclusion criteria: pregnancy, signs of severe malaria, severe malnutrition, history of hypersensitivity to any of the trial drugs, severe malnutrition, concomitant febrile illness, history of psychiatric disorder, a full course of MQ in the previous 9 weeks or any other antimalarial in the previous 48 hrs.

Interventions

Each of the five trial arms was divided into two where one half also received a one-off dose of 0.75 mg/kg PQ on day 1.

Groups:

1+2. AS plus amodiaquine, fixed-dose combination: 25 mg/67.5 mg or 50 mg/135 mg or 100 mg/270 mg tablets.

  • AS 4 mg/kg once daily for 3 days

  • AQ 10.8 mg base/kg once daily for 3 days

3+4. AL, fixed-dose combination: 20 mg/120 mg tablets.

  • A 3.3 mg/kg in two divided doses each day for 3 days

  • L 19.8 mg/kg in two divided doses each day for 3 days

  • Advised to consume fatty food or breast feed before each dose

5+6. AS plus MQ, fixed-dose combination: 25 mg/55 mg or 100 mg/220 mg tablets (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days

  • MQ 8.8 mg/kg once daily for 3 days

7+8. Artesunate plus MQ, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days

  • MQ 25 mg base/kg as a single dose on day 1 (reported as day 0)

9+10. DHAP, fixed-dose combination: 40 mg/320 mg or 20 mg/160 mg tablets (Artekin: Holleykin)

  • DHA 2.5 mg/kg once daily for 3 days

  • P 20 mg/kg once daily for 3 days

First dose supervised, all others unsupervised.

Outcomes
  • Recurrent parasitaemia at day 15, 29, 43 and 64 (reported as days 14, 28, 42, and 63).

  • Treatment failure due to P. falciparum.

  • Gametocytaemia prevalence.

  • Person-gametocyte weeks.

  • Haemoglobin on days 1 and 64.

  • Adverse events (monitoring not described).

NotesFunding: Médecins sans Frontières (Holland).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"After patients were screened and enrolled in the study, they were stratified prospectively into three age groups (1 to 4 years, 5 to 14 years and older than 14 years). Patients were randomly assigned in equal numbers to receive one of the five different treatments. They were then randomly assigned either a single dose of PQ ...or not".
Allocation concealment (selection bias)Low risk"Treatment allocations were put in sealed envelopes in blocks of 50 for each age group, and random assignment was achieved by patients drawing an envelope from a box after enrolment. When the box was empty, another 50 envelopes were added".
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition is low in absolute numbers and unlikely to have introduced significant bias.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo indication of other bias.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label trial for patients and medical staff.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskMicroscopists were blinded.

Sutanto 2013

Methods

Two-arm open-label RCT

Follow-up: days 1, 2, 3, 7, 14, 21, 28, 35, and 42, and any other day in between if they felt ill. Thin and thick blood smears and dried blood spot for genotyping

Dates of randomization: December 2008 to March 2010

Participants

188 (178 left on day 3) + 186 (171 day 3). Analysis based on those still present on day 3

Setting: Hanura Primary Health Center, Padang Cermin district, Lampung province located at the southern end of Sumatra.

Endemicity: low malaria endemicity with a malaria prevalence of 1.8% across all age groups. Seasonal transmission.

Inclusion criteria

  • Parasite density ≥ 1000 parasites/μL.

  • Age ≥ 5 years.

  • Normal glucose-6-phosphate dehydrogenase (G6PD) enzyme levels based on a qualitative test.

  • Haemoglobin level ≥ 8 g/dL.

  • Negative pregnancy test (assessed by human chorionic gonadotropin urine test) or not breastfeeding.

  • No signs of severe malnutrition.

  • No other chronic diseases.

  • No history of allergy to the trial drugs.

  • Ability to return for 42 days of follow-up.

Interventions
  • Standard 3-day DHAP (fixed-dose tablets of 40 mg dihydroartemisinin and 320 mg piperaquine; D-ARTEPP, Guilin Pharmaceutical Co, Ltd).

  • DHAP as in intervention 1; PQ: Day 3, single dose of 0.75 mg/kg, rounded to the nearest half tablet. Mean dose was 0.74 mg/kg (range, 0.5 to 0.94 mg/kg).

Outcomes
  • Gametocyte prevalence-days 7, 14, 21, 28, 35, and 42.

  • Gametocyte clearance rates by day 42 in patients with gametocytes on day 3.

  • Recurrence of asexual stages of P. falciparum, PCR adjusted and unadjusted for reinfections.

  • Gametocyte development by day 42 in patients who were gametocyte free on day 3.

  • Gametocyte densities between days 3 and 42 inclusive.

  • Asexual infection recurrence by PCR.

  • Haemoglobin on days 7, 42.

  • Adverse events.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated sequences in blocks of 4.
Allocation concealment (selection bias)Low riskOpaque envelopes used in order at the health centre.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence of differential attrition.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNone detected.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding, no PQ placebo.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information.

Tine 2017

MethodsIndividually RCT
Participants

Adult patients > 18 years of age presenting with falciparum malaria with a parasite density of 1000 to 100,000 trophozoites/μL

Setting: Senegal, Deggo health post, Pikine, Dakar

Number of participants: 274 randomized (over two transmission seasons)

Exclusion criteria

  • Pregnant (confirmed by urine testing).

  • Breastfeeding.

  • History of hypersensitivity to any of the study drugs.

  • Severe malaria.

  • Moderately severe anaemia (haemoglobin < 8 g/dL).

  • Had a chronic illness.

Interventions
  • AL: twice daily; tablets containing 20 mg artemether and 120 mg lumefantrine.

  • DHAP: daily for 3 days; tablets containing 40 mg DHA and 320 mg piperaquine.

  • ASAQ: daily for 3 days, 2 tablets containing 100 mg artesunate plus 270 mg amodiaquine.

  • PQ: single dose 15mg given on the first day of treatment with the ACT in the intervention arm.

  • PQ +AL was given with biscuits.

Outcomes
  • Change in Hb from day 0 to day 7.

  • Change in Hb by day 3, day 14, day 21, and day 28.

  • Anaemia (Hb < 11 g/dL) at any time up to day 28.

  • Clinical adverse events up to day 28.

  • Prevalence and density of gametocyte carriage during follow-up.

NotesPatients were withdrawn from the study and treated with quinine if they vomited for a second time within 30 minutes of taking each treatment dose
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomization of 18, to 6 treatment groups.
Allocation concealment (selection bias)Low riskNumbered sealed opaque envelopes opened by study pharmacist at time of treatment.
Incomplete outcome data (attrition bias)
All outcomes
Low risk4% loss to follow-up.
Selective reporting (reporting bias)Low riskNone detected.
Other biasLow riskNone detected.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskTrial assessors not blinded, although microscopists and laboratory technicians were not aware of allocation.

Vásquez 2009

Methods

Individually RCT

Dates of trial: April 2007 to Feb 2008.

Participants

50 people with uncomplicated P. falciparum diagnosis by thick blood slide, 150 to 50,000 parasites/μL

Age 1 year and over, both sexes.

Exclusion criteria: pregnant, mixed infection, danger signs and complications, allergy to antimalarials, serious illness at time or presentation, antimalarial treatment in last 72 hrs, MQ in last 4 weeks.

Setting: Colombia

Interventions

1. AS+MQ

Age 1 to 6: AS 50 mg on days 1, 2, 3 (reported as 0, 1, 2); MQ 250 mg on day 2.

Age 7 to 13: AS 100 mg on days 1, 2, 3; MQ 250 mg on days 1, 2, 3.

Age > 13: AS 200 mg on days 1, 2, 3; MQ 500 mg on days 1, 2, 3.

2. AS+MQ+PQ

As above plus PQ:

Age 1 to 6: 0.3 to 0.6 mg/kg day 3 (reported as day 2).

Age 7 to 13: 22.5 mg/kg day 3.

Age > 13: 45 mg day 3.

Outcomes

Assessed on days 2, 3, 4, 8, 15, 22, 29, 36, and 43.

  • Clinical recurrence.

  • Parasitemia prevalence.

  • Parasite density.

  • Fever resolution.

  • Prevalence of gametocytes.

  • Density of gametocytes.

  • Adverse effects.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskSeems to be alternate allocation following order of arrival ("segun el orden de llegada").
Allocation concealment (selection bias)Unclear riskNot clear.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts noted.
Selective reporting (reporting bias)Low riskNo evidence of bias.
Other biasLow riskNo suggestion of other bias.
Blinding of participants and personnel (performance bias)
All outcomes
High riskDoes not seem to be blinded ("con determination no ciega del efecto en grupos iguales").
Blinding of outcome assessment (detection bias)
All outcomes
High riskDoes not seem to be blinded ("con determination no ciega del efecto en grupos iguales").

Wang 2006

  1. a

    Abbreviations: AL = artemether-lumefantrine; AQ = amodiaquine; AS = artesunate; CQ = chloroquine; DHAP = dihydroartemisinin-piperaquine; G6PD = glucose-6-phosphate dehydrogenase; IM = intramuscular; MQ = mefloquine; PCR = polymerase chain reaction; PQ = primaquine; QN = quinine; RCT = randomized controlled trial; SP = sulfadoxine-pyrimethamine.

MethodsIndividually RCT
Participants

Number of participants: 214 (no dropouts mentioned)

Gabon International Tropical Medicine Institute

Age range: 6 to 60

All had P. falciparum malaria clinical symptoms and blood smear positive.

  • Trial group: 108, male 50, female 58, age 16.4 ± 10.5.

  • Control group: 106, male 52, female 54, age 18.2 ± 9.4.

Exclusion criteria: N/A

Interventions
  • Artesunate IM injection, daily for 5 days, 1.2 mg/kg each dose, first dose double. PQ 3 tablets (base 7.5 mg/tablet, children use half) once a day, for 5 days.

  • Only artesunate IM injection daily for 5 days, 1.2 mg/kg each dose, the first dose double total 5 days.

Outcomes
  • Fever clearance time: (hrs) below 37°C continuously measured 4 times.

  • Clinical cure rate at day 7.

  • Adverse events (not specified).

  • Recrudescence rate: symptoms appeared again after clinical cure; parasite appeared in blood smear by 28 days.

Follow-up: 28 days

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskStated to be randomized, and the fact that numbers per group are not equal supports this contention.
Allocation concealment (selection bias)Unclear riskNo information given.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated.
Selective reporting (reporting bias)Unclear riskNot stated.
Other biasUnclear riskNot stated.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated to be blinded.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated to be blinded.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    Abbreviations: 8AQ = 8-aminoquinoline; AS = artesunate; CQ = chloroquine; CV8 = combination of dihydroartiemisin, piperaquine, trimethoprim, and PQ; G6PD = glucose-6-phosphate dehydrogenase; ITN = insecticide treated net; MDA= mass drug administration; MQ = mefloquine; PQ = primaquine; QN = quinine; RCT = randomized controlled trial; SP = sulfadoxine-pyrimethamine.

Baird 2002Outcome is cure of asexual infection. No gametocyte outcomes.
Barber 1929Not a RCT or quasi-RCT. No controls.
Barber 1932MDA with PQ; no other drug.
Brueckner 1998Participants were not infected. Safety only trial.
Bunnag 1980Comparison of SP plus either five day PQ 15 mg, single dose PQ 30 mg or single dose PQ 45 mg in patients with and without gametocytes at presentation. No regimen without PQ. Not a RCT or quasi-RCT. Authors state they will do further studies, including transmission. No difference in gametocyte outcomes between regimens, and gametocytes persisted for up to 21 days.
Burgess 1961Comparison of 15 mg, 30 mg and 45 mg dose of PQ. Outcomes were gametocyte prevalence, density, percent of mosquitoes infected and mean oocysts per mosquito up to eight days. Not a RCT or quasi-RCT. No other drug. Although this trial used different doses by group (12 participants total), they were assigned to participants based on age or body size, and therefore it was not a valid comparison of different doses.
Cai 1985Not a RCT.
Carter 2011No 8AQ in trial.
Che 1987No mention of randomization. No valid comparison group (pyronaridine phosphate plus sulfadoxine plus PQ versus pyronaridine phosphate only).
Che 1990No appropriate control group.
Chevalley 2010In vitro studies only. Not a RCT.
Clyde 1962All patients got PQ.
Clyde 1970Individual before-and-after study, but small number of participants and not controlled.
Clyde 1971Individual before-and-after study, but small number of participants and not controlled.
da Silva 1984Trial of treatment regimens, some including PQ, for P. vivax and P. falciparum.
Degowin 1966No 8AQ in trial.
Doi 1989Community observational study. Except for a small pilot study, everyone in the intervention villages got PQ. There no ‘before' data from these villages. In the control site, some children received treatment.
Giao 2004No appropriate control group (trial of CV8 (contains PQ) versus atovaquone-proguanil).
Gogtay 1999Compares QN+PQ against QN+bulaquine. Not a relevant comparison.
Gunders 1961Before-and-after studies of gametocytes and mosquito feeds on people with gametocytes given pyrimethamine and PQ in doses ranging from 10 mg to 40 mg base. No group without other drug.
Hii 1987Controlled before-and-after study comparing SP+PQ+ITN versus SP+PQ only. Only one cluster per arm and no group without PQ.
Huang 1993Not a RCT. Unbalanced groups.
Huang 1996PQ given to both intervention groups in same regimen. Malaria treatment regimen was varied (low and higher dose pyronardine/SP).
Huang 2001No gametocyte outcomes.
Jeffery 1956Non-randomized comparison of gametocytes and infectivity of artificially infected patients treated with CQ or CQ+PQ.
Jeffery 1963Observational study of gametocytes and infectivity of two patients given PQ.
Jerace 1933Case series studying gametocytes and infectivity of patients given PQ.
Kaneko 1989Non-randomized community trial comparing SP+PQ in one village with SP only in another. Only one cluster per arm. The trial was predominantly mass fever test and treat but 75% of people in the intervention village were treated versus 18% in the control village.
Karbwang 1991Not randomized, no gametocyte outcomes.
Karbwang 1992Pharmacokinetic study; no gametocyte outcomes or control group.
Kyaw 1994No control group. All patients got PQ.
Li 2007No gametocyte outcomes.
Li 2010No gametocyte outcomes.
Lin 2004All patients got PQ.
Mackerras 1949No other malaria treatment; one patient fed on before and after PQ.
Mapanawang 2016Pharmacokinetic study of PQ in 12 patients. Not randomized and no gametocyte measures.
Rieckmann 1968Two patients given 45 mg PQ only and fed on by mosquitoes before and after. No other malaria treatment or control group.
Rieckmann 196918 patients given CQ alone (N = 2), CQ plus 45 mg PQ (N = 3), or PQ alone in doses ranging from 15 to 45 mg, at either single dose or at one to two week intervals, and fed on before and after one of the doses of PQ. Non-randomized or quasi-randomized.
Santana 2007Study of 14 day regimen of 15 mg PQ. Some P. falciparum cases were included but study did not distinguish between the patients with P. falciparum and P. vivax. Study was a comparison of association between methaemoglobinaemia after 14 day PQ in people with and without G6PD deficiency.
Shah 2013Review of 21 trials from national drug resistance monitoring system of India. Compares 9 sites where AS+SP+PQ was used with 12 sites where it was not.
Shekalaghe 2010Randomized comparison of anaemia after SP+AS+PQ versus placebo. Children with haemoglobin < 8 g were excluded from receiving PQ.
Shekalaghe 2011Trial was a comparison of SP+AS+PQ versus placebo. No comparison of groups with and without PQ.
Sun 2011AS + PQ versus Quinimax only. No appropriate control group.
Suputtamongkol 2003Comparison of MQ+AS versus MQ + PQ. No appropriate control group.
Tangpukdee 2008Comparison of Artequick (contains PQ) with MQ+AS. No appropriate control group and no gametocyte outcomes.
Yang 1989All patients got PQ, though different doses of PQ and other malaria treatments.
Yeramian 2005PQ given only to P. vivax patients for 14 days.
Young 1959No other malaria treatment; case series of PQ given either daily, twice a week or weekly to P. falciparum patients.

Characteristics of studies awaiting assessment [ordered by study ID]

Chen 1993b

Methods 
Participants 
Interventions 
Outcomes 
NotesStudy not yet located

Ishii 2009

MethodsUnclear
ParticipantsResidents of trial villages in Solomon Islands (number not given)
InterventionsTesting of clinical malaria patients for G6PD and addition of single dose PQ to other malaria treatment if appropriate
OutcomesVillage prevalence of malaria
NotesAbstract only with no results

Li 2006

  1. a

    Abbreviations: G6PD = glucose-6-phosphate dehydrogenase; PQ = primaquine.

Methods 
Participants 
Interventions 
Outcomes 
NotesStudy not yet located

Characteristics of ongoing studies [ordered by study ID]

ISRCTN11594437

Trial name or titleAssessing the tolerability and safety of single low dose primaquine in African children with acute uncomplicated falciparum malaria and glucose 6 phosphate dehydrogenase deficiency in Africa. Primaquine in African Children (PAC study)
MethodsMulti-centre double blind open randomised parallel safety trial (Treatment)
Participants

Democratic Republic of Congo and Uganda

Inclusion criteria:

  • Aged six months to 11 years old

  • Clinically uncomplicated disease

  • Fever (= 37.5°C aural) or history of fever within the previous 72 hours

  • Positive malaria RDT (Uganda only)

  • Positive malaria slide for P. falciparum (mono or mixed infection) of any parasitaemia (Kinshasa only)

  • Informed consent provided by patient or relative/legal guardian

Exclusion criteria:

  • Malaria danger signs, sign(s) of severe malaria, or decompensated anaemia, including: an inability to take or retain fluids or oral medications, confusion, prostration, convulsions, respiratory distress, passing of red or cola-coloured urine (putative “blackwater fever”)

  • Severe anaemia (Hb < 6 g/dL)

  • Comorbid illness that requires treatment in hospital (physician’s judgement)

  • Patients on drugs known to cause haemolysis in G6PDd e.g. dapsone, nalidixic acid

  • Known to be allergic to PQ, AL, or DHAPP

  • Previous enrolment in the current trial or current enrolment in another trial

Interventions

Participants are allocated to either the G6PDd group or the G6PD normal group based on their the results of a G6PD rapid diagnostic test (RDT).

Participants are then randomly allocated as to which dosing group they receive using a computer generated randomisation list generated for each site. Treatment allocation is placed in a sealed envelope which is opened once participants receive their study number. The treatment allocation described the Artemisinin based combination treatment (ACT) to be given and the number of PQ/placebo pack.

The four dosing groups are the following:

  • Artemether lumefantrine (AL) + single low-dose primaquine (SLDPQ)

  • AL + SLDPQ placebo

  • Dihydroartemisinin-piperaquine (DHAPP) + single low-dose primaquine (SLDPQ)

  • DHAPP + SLDPQ placebo

The dosages for primaquine depends vary with age and the dosing for AL vary with weight (in kg). DHAPP+SLDPQ dosages are given daily for three days and vary with body weight (in kg). Those who receive the primaquine/placebo receive it once only at baseline. Follow up continues until day 42.

Outcomes

Primary outcomes

  • Profound anaemia (Hb concentration < 4 g/dL) is measured using the HemoCue machine during the first days 21 days of follow-up

  • Severe anaemia (Hb < 5 g/dL) with clinical features of severe malaria is measured using the HemoCue machine during the first 21 days of follow-up

Starting date01/09/2017
Contact informationBob Taylor, Mahidol Oxford Tropical Medicine Clinical Research Unit (MORU) Mahidol University 420/6 Rajvithi Road Rajthevee 10400 Bangkok Thailand
Noteshttp://isrctn.com/ISRCTN11594437

NCT01906788

Trial name or titleThe optimal timing of primaquine to prevent malaria transmission after artemisinin-combination therapy
MethodsRandomized, open label
Participants

250 male and female participants

Inclusion criteria:

  • Age 3 years to 17 years

  • Residents of research area

  • Willingness to come for complete scheduled follow-up

  • Uncomplicated malaria with P. falciparum mono-infection

  • Axillary temperature > 37.5°C and < 39.5°C, or history of fever in previous 48 hours

  • No history of adverse reactions to trial medication

  • Understanding of the trial procedures by parent or guardian and willing to participate by signing written informed consent forms

Exclusion criteria:

  • Haemoglobin below 9 g/dL

  • Inability to take drugs orally

  • Known hypersensitivity to any of the drugs given

  • Reported treatment with antimalarial chemotherapy in the past two weeks

  • Evidence of chronic disease or acute infection other than malaria

  • Domicile outside the trial area

  • Signs of severe malaria (such as respiratory distress, altered consciousness deep breathing, anaemia)

  • Participating in other malaria studies conducted in the region

  • Mixed malaria parasite species infection

  • Positive pregnant test by urine (UPT) if participant is female aged above 12 years

  • G6PD deficient using the fluorescence spot test

Interventions

Group 1: AL 6 dose regime orally

Group 2: AL 6 dose regime plus single dose PQ (0.75/kg) on day 0

Group 3: AL 6 dose regimen plus single dose PQ (0.75/kg) on day 2

Outcomes

Primary: Gametocyte prevalence and density by microscopy and QT-NASBA on day 14

Secondary:

  • Haemoglobin level on days 3, 7, 10 and 14

  • Proportion of infected mosquitoes on day 7 after initiation of treatment and the intensity of infection (oocyst burden) by membrane feeding assay

Starting dateMay 2013; October 2013 (final data collection date for primary outcome measure)
Contact informationSeif Shekalaghe, MD, PhD sshekalaghe@ihi.or.tz +255 755 470472
Notes

ClinicalTrials.gov identifier: NCT01906788

Tanzania KCMC and Ifakara

NCT02259426

Trial name or titleA double blind randomized controlled trial of dihydroartemisinin-piperaquine alone and in combination with single dose primaquine to reduce post-treatment malaria transmission
MethodsPhase 3 randomized, safety/efficacy study, parallel assignment, double blind (subject, caregiver, investigator, outcomes assessor)
Participants

120 participants will be recruited in Kenya

Inclusion criteria

  • Microscopically detectableP. falciparum gametocyte carriage

  • Age 5 years to 15 years

  • Gender: both

Exclusion criteria

  • Age < 5 years or > 15 years

  • Non-falciparum malaria co-infection

  • Malaria parasite density = 200,000 parasites/µL

  • Clinical symptoms indicating severe malaria

  • Axillary temperature = 39°C

  • Body Mass Index (BMI) below 16 or above 32 kg/m²

  • Haemoglobin concentration below 9.5 g/dL

  • Antimalarials taken in last 2 days

  • For women: pregnancy (assessed by clinical examination and urine pregnancy test) or lactation

  • Known hypersensitivity to DP or PQ

  • History or symptoms, or both indicating chronic illness

  • Current use of tuberculosis or anti-retroviral medication

  • Unable to give written informed consent

  • Unwillingness to participate in two membrane feeding assays

  • Travel history to Angola, Cameroon, Chad, Central African Republic, Congo, DR Congo, Equatorial Guinea, Ethiopia, Gabon, Nigeria and Sudan

  • Family history of congenital prolongation of the QTc interval or sudden death or with any other clinical condition known to prolong the QTc interval such as history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease

  • Taking drugs that are known to influence cardiac function and to prolong QTc interval, such as class IA and III: neuroleptics, antidepressant agents, certain antibiotics including some agents of the following classes - macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics (terfenadine, astemizole) and cisapride

  • Known disturbances of electrolyte balance, for example, hypokalaemia or hypomagnesaemia

  • Taking drugs which may be metabolized by cytochrome enzyme CYP2D6 (for example, flecainide, metoprolol, imipramine, amitriptyline, clomipramine)

  • Blood transfusion within last 90 days

Interventions

Control: DHAP (Artekin) combination alone

Experimental: DHAP (Artekin) combination alone plus single-dose 0.25 mg/kg PQ

Outcomes

Primary outcome

  • Gametocyte prevalence on day 7 after initiation of treatment (time frame: day 7 of follow-up)

Secondary outcomes

  • Gametocyte carriage during follow-up (time frame: 14 days during follow-up)

  • Gametocyte sex-ratio (time frame: 14 days of follow-up)

  • Haematological recovery (time frame: 14 days during follow-up)

  • Transmission to An. gambiae mosquitoes (time frame: day 3 and 7 during follow-up)

Starting dateRegistration date 29 September 2014; first enrolment October 2014
Contact information

psawa@icipe.org +254 59 22620 (Patrick Sawa MD, ICIPE)

teun.bousema@lshtm.ac.uk +31243617574 (Teun J Bousema, PhD)

Notes

ClinicalTrials.gov identifier: NCT02259426

Primary sponsor: London School of Hygiene and Tropical Medicine

NCT02431650

Trial name or titleEffectiveness of OZ439 as a gametocytocidal and transmission blocking agent (OZGAM)
Methods

Allocation: randomized

Intervention model: parallel assignment

Masking: no masking

Primary purpose: treatment

Each participant in the cohort will be inoculated on Day 0 with ˜2800 viable parasites of P. falciparum-infected human erythrocytes (BSPC) administered intravenously. when PCR quantification of all participants is ≥ 5000 parasites/mL, they will receive a single dose of 480 mg of piperaquine phosphate to clear blood stage parasitaemia. When gametocytaemia is at the peak (approximately 15 days after administration of piperaquine), participants will be randomized to receive either OZ439 or a control group (PQ treatment).

Participants12 adults aged 18 to 55 years
Interventions

Experimental: OZ439

Active Comparator: PQ

Outcomes

Primary outcome

  • Infection success of vector mosquitoes (time frame: from day 10 to 21 post-piperaquine dosing) assessing the transmissibility by oocyst detection in mosquito midgut preparations following direct and membrane (indirect) feeding.

Starting dateApril 2015
Contact information

Q-Pharm Clinics Herston, Queensland, Australia, 4006

Prof James McCarthy

QIMR Berghofer Medical Research Institute

Notes 

NCT02434952

Trial name or titleThe tolerability and safety of low dose PQ for transmission blocking in symptomatic falciparum infected Cambodians
Methods

Allocation: randomized

Intervention model: parallel assignment

Masking: open label

Primary purpose: treatment

Participants

Cambodia

Inclusion criteria:

  • Age ≥ 1 year

  • Presentation with a confirmed fever (≥ 38⁰C axilla or ≥ 37.5°C aural) or history of fever in previous 48 hours ± other clinical features of uncomplicated malaria

  • P. falciparum monoinfection ≥ 1 asexual form / 500 white blood cells

  • Informed consent (written/verbal) provided by patient or relative/legal guardian

  • Signed assent form for children aged 12 to < 18 years

Exclusion criteria:

  • Clinical signs of severe malaria or danger signs

  • Pregnant or breast feeding

  • Unable or unwilling to take a pregnancy test (for women of child-bearing age)

  • Women intending to become pregnant in the next 3 months

  • Allergic to PQ or DHA PP

  • Patients taking drugs known to cause acute intravascular haemolytic anaemia (AIHA) in G6PD deficiency e.g. dapsone, nalidixic acid

  • Patients on treatment for a significant illness e.g. HIV, tuberculosis (TB) treatment, steroids

  • On drugs that could interfere with anti-malarial pharmacokinetics like antiretrovirals, cimetidine, ketoconazole, antiepileptic drugs, rifampicin

Interventions

Experimental: DHA PP plus PQ, G6PD deficiency

Active comparator: DHA PP plus PQ, G6PD normal

Active comparator: DHA PP alone, G6PD deficiency

Active comparator: DHA PP alone, G6PD normal

Outcomes

Primary outcomes:

  • Haemoglobin concentration [Time Frame: Day 7] Compare haemoglobin concentrations in g/dL between the G6PD deficient arm given DHA PP plus PQ, and the G6PD normal arm receiving the same regimen

Starting dateOctober 2014
Contact informationDysoley Lek, MD, National Centre for Parasitology, Entomology and Malaria Control, Cambodia
Noteshttps://clinicaltrials.gov/ct2/show/NCT02434952

NCT02831023

Trial name or titlePhase 2 efficacy study of primaquine and methylene blue: efficacy, safety, and pharmacokinetics of sulphadoxine-pyrimethamine-amodiaquine (SP-AQ), SP-AQ plus primaquine, dihydroartemisinin-piperaquine (DP), DP plus methylene blue for preventing transmission of P. falciparum gametocytes in Mali
Methods

Interventional

Allocation: randomized; endpoint classification: safety/efficacy study; intervention model: parallel assignment; masking: single blind (outcomes assessor), primary purpose: treatment

Phase 2

Participants

Mali

Inclusion criteria:

  • Glucose-6-phosphate dehydrogenase (G6PD) normal defined by CareStart™ G6PD rapid diagnostic test (RDT) or the OSMMR2000 G6PD semi-qualitative test

  • Absence of symptomatic falciparum malaria, defined by fever upon enrolment

  • Presence of P. falciparum gametocytes on thick blood film at a density > 30 gametocytes/µL (i.e. = 2 gametocytes recorded in the thick film against 500 white blood cells)

  • No allergies to study drugs

  • No self-reported use of antimalarial drugs over the past 7 days (as reported by the participant)

  • Haemoglobin = 10 g/dL

  • Individuals weighing < 80 kg

  • No evidence of severe or chronic disease

  • Written, informed consent

Exclusion criteria:

  • Age < 5 years or > 50 years

  • Female gender

  • Blood thick film negative for sexual stages of malaria

  • Previous reaction to study drugs/known allergy to study drugs

  • Signs of severe malaria, including hyperparasitaemia, defined as asexual parasitemia >100,000 parasites/µL)

  • Signs of acute or chronic illness, including hepatitis

  • Use of other medications (with the exception of paracetamol and/or aspirin) - Consent not given

Age minimum: 5 Years
Age maximum: 50 Years
Gender: Male

Interventions

Drug: 0.25 mg/kg PQ

Drug: Amodiaquine

Drug: Dihydroartemisinin-piperaquine

Drug: Methylene blue

Drug: Sulphadoxine-pyrimethamine

Outcomes

Primary:

Mosquito infectivity assessed through membrane feeding assays (time frame: 7 day)

Starting dateJuly 2016
Contact informationAlassane Dicko, MD adicko@icermali.org; Ingrid Chen, PhD ingrid.chen@ucsf.edu
Noteshttps://clinicaltrials.gov/show/NCT02831023

NCT02851108

Trial name or title

Methylene blue against falciparum malaria in Burkina Faso BlueACTn

Safety of artesunate-amodiaquine combined with methylene blue or PQ for falciparum malaria treatment in African children: a randomised controlled trial

Methods

Interventional

Allocation: randomized; endpoint classification: safety/efficacy study; intervention model: parallel assignment; masking: open label; primary purpose: treatment

Phase 2

Participants

Burkina Faso

Inclusion criteria:

  • Weight = 6 kg

  • Uncomplicated malaria caused by P. falciparum

  • Asexual parasites = 2 000/µL and = 100,000/µL

  • Axillary temperature = 37.5°C or a history of fever during the last 24 hours

  • Burkinabe nationality

  • Permanent residence in the study area with no intention of leaving during the surveillance period

  • Written informed consent of parents or care takers

Exclusion criteria:

  • Severe malaria

  • Mixed malaria infection

  • Vomiting (> 2 times within 24 hours before the visit)

  • Any apparent significant disease, including severe malnutrition

  • A history of a previous, significant adverse reaction or known allergy to one or more of the study drugs

  • Anaemia (haemoglobin < 7 g/dL)

  • Treated in the same trial before

  • All modern antimalarial treatment prior to inclusion (last 7 days)

  • Therapy with serotonin reuptake inhibitors (e.g. citalopram, escitalopram, fluoxetine, Paroxetine, Sertraline)

  • Simultaneous participation in another investigational study

  • Patients with known HIV/AIDS disease

  • Therapy with drugs known to inhibit the liver enzymes cytochrome 2A6 (e.g. methoxsalen, pilocarpine, tranylcypromine) and/or cytochrome 2C8 (e.g. trimethoprim,

  • ketoconazole, ritonavir, saquinavir, lopinavir, gemfibrozil, montelukast)

Age minimum: 6 months
Age maximum: 59 months
Gender: Both

Interventions

Drug: methylene blue

Drug: PQ

OutcomesPrimary: Change in haemoglobin compared to the baseline (time frame: 7 days)
Starting dateOctober 2016
Contact informationOlaf Müller, Prof. Dr. olaf.mueller@urz.uni-heidelberg.de
Noteshttps://clinicaltrials.gov/show/NCT02851108

PACTR201611001859416

  1. a

    Abbreviations: AL = artemether-lumefantrine; BSPC = blood stage Plasmodium falciparum challenge; DHA = dihydroartemisinin; DHAP = dihydroartemisinin-piperaquine; DHAPP = Dihydroartemisinin-piperaquine; DP = dihydroartemisinin-piperaquine; G6PD = glucose-6-phosphate dehydrogenase; Hb = haemoglobin; PCR = polymerase chain reaction; PP = piperaquine phosphate; PQ = primaquine; QT-NASBA = real-time quantitative nucleic acid sequence-based amplification; RT-PCR = real time PCR; SLDPQ = single low-dose primaquine; SP-AQ = sulphadoxine-pyrimethamine-amodiaquine.

Trial name or titleAddition of low dose primaquine to artemether-lumefantrine for the treatment of uncomplicated malaria
Methods

RCT

Parallel: different groups receive different interventions at same time during study,
Randomized
Random number generation, stratified by clinic, prepared by an independent statistician using a valid system,
Sealed opaque envelopes,

Participants

South Africa

Inclusion criteria:

  • P. falciparum positive by RDT

  • Age b 2 years

  • Weight over 10 kg

  • Prescribed artemether-lumefantrine according to standard practice

  • Informed consent (by legally acceptable representative if under 18 years of age)

  • Assent in children aged 7 and above

  • Intention to remain in the study area for the duration of the follow-up period

Exclusion criteria:

  • Evidence of severe illness/danger signs

  • Known allergy to study medications

  • Medical history of haemolysis, rheumatoid arthritis, lupus erythematosus or cardiac disease

  • In patients receiving concurrently other drugs that are cause haemolysis, bone marrow suppression, or QTc interval prolongation

  • Hb 7 g/dL

  • A decrease in Hb of b 2 g/dL between day 0 and day 3 prior to PQ dose

  • Currently menstruating

  • Pregnant or breastfeeding

  • History of any antimalarials (including PQ) taken within the last 4 weeks

  • Blood transfusion within the last 90 days

Age minimum: 2 years
Age maximum: 100 years
Gender: both

Interventions

PQ plus standard of care (AL)

Standard of care (AL)

Outcomes

Primary:

Change in mean haemoglobin (Hb) as measured by HemoCue on day 3

Changes in gametocyte prevalence on days 7 and 14 using RT-PCR

Starting date2016-11-18
Contact informationJaishee Raman, jaishreer@nucd.ac.za ; Karen Barnes karen.barnes@uct.ac.za
Noteswww.pactr.org/ATMWeb/appmanager/atm/atmregistry?dar=true&tNo=PACTR201611001859416

Ancillary