Methods

Study design: randomised controlled trial

Total duration of study: 24 weeks.

'Run‐in' period: 8 weeks. All participants received salmeterol/fluticasone propionate combination (SFC) at a dose of 50/250 μg twice daily.

Number of study centres and locations: 124 centres (no locations specified)

Study setting: not stated

Date of study: not stated

Participants

Enrolled (N): 603

Randomised (n): 475 (SFC 50/250, n = 159; SFC 50/100, n = 157; FP 250, n = 159)

Analysed (n): 464 (SFC 50/250, n = 154; SFC 50/100, n = 156; FP 250, n = 154)

Withdrawals (n): 63

Median age (range), years: SFC 50/250, 46.5 (18‐81); SFC 50/100, 43.0 (18‐75); FP 250 42.0 (18‐77)

Age range, years: 18‐81

Gender (% female): SFC 50/250, 48.1; SFC 50/100, 46.2; FP 250 51.3

Severity of condition: well controlled on step 2 or 3. Mean % predicted prebronchodilator FEV₁ (SD) as follows: SFC 50/250, 87.8 (18.2); SFC 50/100, 91.2 (17.8); FP 250, 90.8 (17.2)

Diagnostic criteria: Asthma control was assessed using the GOAL definitions of 'well controlled' and 'total control'.

Baseline lung function (mean morning PEF (SD), L/min): SFC 50/250, 465.6 (113.2); SFC 50/100, 467.9 (111.2); FP 250, 463.7 (105.1)

Smoking history, % smokers or ex‐smokers: SFC 50/250, 24.7; SFC 50/100, 21.3; FP 250, 16.2

Inclusion criteria: aged ≥18 years; documented history of asthma (≥ 6 months) well controlled with current treatment (ICS at a dose of CFC beclomethasone dipropionate or equivalent and a long‐acting beta₂‐agonist at recommended dose) at a stable dose for ≥ 4 weeks before initial clinic visit (V1); respiratory tract infection, with acute exacerbation requiring emergency department treatment/hospitalisation or use of oral/parenteral steroids, within 4 weeks of V1; any change in asthma maintenance treatment within 4 weeks

Exclusion criteria: smoking history ≥ 10 pack‐years; respiratory tract infection

Details of criteria for stepping down treatment: All participants received SFC 50/250 μg twice daily and were randomised to remain on SFC 50/250 or move to 1 of the 2 step‐down treatment arms if their asthma was assessed as 'well controlled' over the last 2 weeks of the run‐in period; asthma control was assessed according to GOAL definitions (see Bateman 2004).

Interventions

Intervention 1: SFC 50/100 μg twice daily

Intervention 2: FP 250 μg twice daily (not relevant to review)

Comparison: SFC 50/250 μg twice daily

Concomitant medications: Short‐acting bronchodilators (previously used as rescue medication) and antihistamines were permitted, provided they had been used for at least 4 weeks.

Excluded medications: All previous asthma medications were discontinued at entry into the run‐in period, except short‐acting bronchodilators (previously used as rescue medication) and antihistamines, provided they had been used for at least 4 weeks.

Outcomes

Primary outcomes: mean morning PEF over the first 12 weeks of randomised treatment

Secondary outcomes: mean morning PEF over the last 12 weeks of randomised treatment; daily symptoms; use of short‐acting bronchodilator as rescue medication; FEV₁; asthma control based on GOAL definitions of total control and 'well‐controlled' (see Bateman 2004)

Notes

Funding for trial: not stated

Notable conflicts of interest of trial authors: Three of the trial authors had received sponsorship and had attended advisory boards for various pharmaceutical companies, including AstraZeneca, GlaxoSmithKline and Boehringer‐Ingelheim; 3 authors are employees of GlaxoSmithKline.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information provided

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Study reported as double blind

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Study reported as double blind

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data provided for all randomised individuals. We note that study authors reported lung function results only for the per‐protocol population, whereas they reported all other outcomes for the intent‐to‐treat population.

Selective reporting (reporting bias)

High risk

Study authors reported the primary outcome for the per‐protocol data set on the basis that this is a non‐inferiority study. Furthermore, the primary outcome considers lung function only over the first 12 weeks of treatment; a secondary outcome assessed lung function in the full analysis set but considered only the second 12 weeks of treatment. All in all, findings were quite confusing and inconsistent. This trial was not reported as registered, and we cannot source a protocol.

Other bias

High risk

The protocol suggests that only participants whose condition was well controlled within the last 2 weeks of the run‐in period would go on to randomisation; however, it appears that a relatively high proportion of participants whose asthma was not controlled were included in the full analysis set. Results of this study are not well reported, and as the study does not appear to have been prospectively registered, and a protocol was not cited, it is difficult to ascertain whether selective outcome reporting occurred. Study sponsorship is not reported, although several authors worked for GSK. Key exclusion criteria of poor control according to ACQ were not defined or reported. A large proportion of poorly controlled randomised participants were not included in the primary outcome analysis (but were included in the secondary outcome analysis). Reporting was confusing.

Methods

Study design: randomised controlled trial, multi‐centre, open label

Total duration of study: 2‐week run‐in period; 12‐week treatment period

'Run‐in' period: 2‐week run in period, during which participants remained on their existing doses of ICS ('high‐dose' budesonide 400 μg twice daily, beclomethasone 400 μg twice daily or beclomethasone 500 μg twice daily via a pMDI with a spacer; or 'low‐dose' budesonide or beclomethasone 200 μg twice daily)

Number of study centres and locations: UK

Study setting: primary care

Withdrawals: 147/631 (23%) randomised participants withdrew during the treatment period

Date of study: not stated

Participants

N: 631 patients were randomised after a 2‐week run‐in period.

Mean age (range), years: budesonide OD: 44.1 (16.5‐80.2); budesonide BID: 45.7 (16.7‐77.0); no ICS dose change: 40.9 (16.2‐80.2)

Gender M/F, n: budesonide OD: 100/128; budesonide BID: 90/101; no ICS dose change: 100/112

Severity of condition: baseline mean morning PEFR (SD), L/min: controlled on step 2. Budesonide OD: 437.2 (106.5); budesonide BID: 447.4 (111.3); no ICS dose change: 445.8 (100.9)

Diagnostic criteria: mild, well controlled

Baseline lung function ‐ mean morning PEFR (SD), L/min: budesonide OD: 437.2 (106.5); budesonide BID: 447.4 (111.3); no ICS dose change: 445.8 (100.9)

Smoking history: not stated

Inclusion criteria: aged ≥ 16 years; documented diagnosis of asthma (currently stable); asthma considered by physician to be well controlled (as per BTS guidelines); receiving 200 μg twice daily (low dose) or 400/500 μg twice daily (high dose) budesonide or beclomethasone (via a pMDI ± spacer) for 6 months before entry; patients on the higher dose of steroid were required to have used a large volume spacer for a minimum of 4 weeks before entry

Exclusion criteria: pregnant, at risk of pregnancy, breast feeding, brittle asthma, night shift workers. Within 3 months: any increase in total daily inhaled steroid dose; exacerbation resulting in hospitalisation or requiring nebulisation, oral/injectable/rectal steroids, beta blockers, sodium cromoglycate, sodium nedocromil, any unlicensed medication or fluticasone propionate. Within 1 week before the study: Patients were not permitted to have taken theophylline (or derivatives), any long‐acting bronchodilators, ipratropium/oxitropium bromide or ketotifen.

Details of criteria for stepping‐down treatment: Participants were eligible for randomisation if their diary cards showed that they had no nocturnal wakening due to asthma in the previous 7 nights, and if they fulfilled 3 of the following criteria:

asthma symptoms of no more than mild severity experienced on 3 or fewer days of the previous 7 days; using ≤ 1 puff per day of inhaled bronchodilator on a maximum of 5 of the last 7 days; circadian variation in PEFR < 20% in the previous 7 days; morning PEFR ≥ 80% or predicted or best (if this value was greater than predicted) on 5 of the 7 previous days

Interventions

Intervention: Participants on an initial high dose of ICS (budesonide 400 μg twice daily or beclomethasone 400 μg twice daily or beclomethasone 500 μg twice daily delivered via a pMDI and a spacer device) were randomised to receive budesonide 200 μg twice daily via a turbuhaler or 400 μg once daily (i.e. both groups represent a halving of the initial ICS dose). Participants on an initial low dose of ICS (budesonide or beclomethasone 200 μg twice daily) were randomised to receive budesonide 100 μg twice daily via a turbuhaler or 200 μg once daily (i.e. both groups represent a halving of the initial ICS dose).

Comparison: No change in initial dose of budesonide or beclomethasone.

Concomitant medications: Each patient was given terbutaline (Bricanyl) turbuhaler 500 μg prn for rescue mediation during the run‐in and throughout the study.

Excluded medications: See exclusion criteria.

Outcomes

Primary outcomes: morning PEFR recorded by diary cards (recorded at baseline, and at 4, 8 and 12 weeks)

Secondary outcomes: evening PEFR, proportion of symptom‐free days/nights, proportion of beta₂‐agonist‐free days/nights, sleep disturbance (all recorded via diary cards) quality of life (Juniper Asthma Quality of Life Questionnaire (Juniper 1993); PEFR measured at clinic visits; asthma severity measured at clinic visits; asthma control)

Notes

Funding for trial: not stated; likely Astra Pharmaceuticals

Notable conflicts of interest of trial authors: not stated. One study author was an employee of Astra Pharmaceuticals.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information provided

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided

Blinding of participants and personnel (performance bias)
All outcomes

High risk

The study was open label.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The study was open label, and it does not appear that outcome assessors were blinded to treatment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Incomplete primary outcome data were reported, but the number of participants for whom data were missing was similar across OD/BD/pMDI groups.

Selective reporting (reporting bias)

High risk

No study protocol available. The data for high‐dose and low‐dose groups were pooled and were not presented individually. Study authors stated that separate data were not presented individually because no significant differences between the 2 dose groups were found for any of the analyses performed.

Other bias

Unclear risk

Unclear risk of bias: This is a complicated study, and some changes in inhaler device appear to have occurred at the same time as changes in dose. Participants entered the run‐in period on their existing dose of ICS ('high' or 'low') and were later randomised to remain on their existing dose, or step down to half the dose in 1 of 2 different formats (half the dose twice daily, or the same dose but only once daily). No data were reported for the run‐in period.

Unclear risk of bias: Funding for the study is not reported. The paper has industry authors, and the company manufactures products that seem to match the products reported upon. Funding for the study is not declared, but one study author is employed by Astra.

Methods

Study design: randomised controlled trial, double‐blind, parallel group

Total duration of study: 1 year

'Run‐in' period: 1 month

Number of study centres and locations: general practices in Western and Central Scotland

Study setting: primary care (general practice)

Withdrawals: 24/130 participants in the stepdown group and 22/129 in the control group discontinued the intervention. Analyses were performed on all randomised participants.

Date of study: The study was performed between May 1999 and October 2001.

Participants

N: 259 participants were randomised.

Mean age (SD), years: step‐down 52.8, (14.5); control 55 (15.2)

Age range: 18‐86 years

Gender (M/F), n: step‐down, 54/76; control, 54/75

Severity of condition: controlled on high‐dose ICS (at least 1000 μg BDP) plus possibly other drugs (steps 2‐4)

Baseline lung function ‐ % predicted pre‐salbutamol FEV₁ (SD), L/min: step‐down, 80.3 (19.2); control, 80.1 (18.6)

Smoking history ‐ current/former/never, n: step‐down, 16/44/70; control, 17/49/63

Inclusion criteria: aged ≥ 18 years; diagnosis of asthma ≥ 1 year; treated with ≥ 800 μg inhaled BDP (or budesonide or fluticasone propionate at equivalent dosage)

Exclusion criteria: required oral corticosteroids or attended general practice or hospital within 2 months; inability to use peak flow meter; treatment with immunosuppressive drugs; serious illness; alcohol, substance or drug misuse; pregnancy; participation in other research within the past 6 months

Details of criteria for stepping down treatment: stable asthma (i.e. good control) assessed at end of run‐in period and at 3, 6, 9 and 12 months. Good control was defined as an asthma morbidity score ≤ 2, no visits to general practice or hospital since previous visit and peak flow ≥ target flow on 8 of the previous 14 days; if peak flow data were missing, the first two criteria were used.

Interventions

Intervention: step‐down ‐ 50% reduction in ICS dose

Comparison: no change in ICS dose

Concomitant medications: Reliever inhalers were permitted. 36.9% of the step‐down group and 30.2% of the control group were receiving a concomitant LABA.

Excluded medications: immunosuppresive drugs

Outcomes

Primary outcomes: proportion of participants experiencing an asthma exacerbation, asthma control (short asthma morbidity score (Rimmington 1997); scores ranged from 0 (perfect control) to 8 (very poor control))

Secondary outcomes: adverse events, health‐related quality of life (EuroQoL and St George's Respiratory Questionnaire), annual corticosteroid dose

Notes

Funding for trial: NHS R&D Programme on Asthma Management

Notable conflicts of interest of trial authors: Study authors had received funding, and various pharmaceutical companies including GlaxoSmithKline provided the study inhalers.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Well‐described randomisation with computer‐generated randomisation stratified by centre

Allocation concealment (selection bias)

Low risk

Computer‐allocated randomisation sequence; randomisation code withheld from investigators until study completion

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and personnel were blinded to treatment allocation via use of identical inhaler packs.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Randomisation code was maintained blind until the end of the study.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Primary outcome data were reported for all participants as intention to treat. Some data for health status secondary outcome measures were missing (not explained), but the number of participants for whom data were missing was similar in both treatment groups. Lung function was not reported during or at the end of the treatment period.

Selective reporting (reporting bias)

High risk

Protocol was not available. It is not clear why study authors did not present lung function as, according to the Methods section, participants did monitor lung function for 2 weeks before each visit. Detailed adverse event data were not presented.

Other bias

Low risk

Study medication was provided by industry, but study was funded by NHS R&D programme on asthma development. No industry was involved in authorship of the paper.

Methods

Study design: randomised controlled trial, double‐blind, parallel group

Total duration of study: 3 months

'Run‐in' period: no run‐in (this is a follow‐up extension to a previous study)

Number of study centres and locations: Firestone Regional Chest and Allergy Clinic at St Joseph's Hospital and the McMaster University Medical Centre in Hamilton, Canada

Study setting: secondary care (asthma clinic)

Withdrawals: All 28 participants completed the study

Date of study: not reported

Participants

N: 28. A subgroup of 14 participants were relevant to this review.

Mean age: not reported. Mean age in parent study was ˜ 42 years (Juniper 1990).

Age range: not reported

Gender: not reported

Severity of condition: controlled on step 2 (mild to moderate: approximately half of participants were 'steroid dependent')

Baseline lung function: Individual participant data were reported. At entry to initial study, all participants had airway hyper‐responsiveness to methacholine (PC20 < 8.0 mg/mL) and symptomatic asthma.

Smoking history: not reported

Inclusion criteria and exclusion criteria: successful completion of previous study

Details of criteria for step‐down treatment: not reported

Interventions

Intervention: a halving of the budesonide dose in steroid‐dependent participants (n = 6)

Comparison: no change in budesonide dose among steroid‐dependent participants (n = 8)

Concomitant medications: Bronchodilator medication was permitted (long‐acting vs short‐acting not specified).

Excluded medications: not reported

Outcomes

Primary outcomes: airway responsiveness to methacholine (measured with a standardised tidal breathing protocol); clinical asthma severity (i.e. asthma control assessed via asthma severity questionnaire). The questionnaire comprised 6 items: awakened at night by symptoms; awakened in the morning by symptoms; limitation of normal daily activities; sputum; use of bronchodilator more than 4 times per day; FEV₁ prebronchodilator < 70% predicted (One point was scored for each of the first 5 items that had been positive on ≥ 1 day during the previous week; 1 point was scored for reduced spirometry; therefore, the maximum asthma severity score (i.e. worst control) was 6).

Secondary outcomes: bronchodilator use; allergen exposure score; upper respiratory tract infection score

Notes

Funding for trial: Funding was not reported.

Notable conflicts of interest of trial authors: Conflicts of interest were not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information provided

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The study was reported as double‐blind.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The study was reported as double‐blind.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All 28 randomised participants completed the study, and it appears that data were reported for all 28 participants.

Selective reporting (reporting bias)

High risk

Study authors state, "During analysis, it was found that all the outcomes in the two reduction groups were very similar, and also, the outcomes in the two groups in whom steroids were not reduced were very similar. Therefore, for simplicity, the data have been combined and are presented as two groups, reduced and maintained".

No protocol was available; no prespecified analysis plan was prepared. Group data were combined as described above.

Other bias

Low risk

None identified

Methods

Study design: randomised controlled, double‐blind, double‐dummy, parallel group

Total duration of study: 14 weeks

'Run‐in' period: 2 weeks

Number of study centres and locations: 16 centres (8 each in UK and Belgium)

Study setting: not stated

Withdrawals: 5 participants (CIC 160 μg, n = 4; FP 250 μg, n = 1)

Date of study: October 2004 to July 2005

Participants

N: 111 randomised

Mean age, years: CIC 160 μg OD: 43; FP 250 μg BID: 46

Age range, years: 18‐75

Gender M/F, n: CIC 160 μg OD: 28/30; FP 250 μg BID: 30/23

Severity of condition: controlled on step 2

Baseline lung function ‐ mean (SD) FEV₁, L: CIC 160 μg OD: 3.272 (0.869); FP 250 μg BID: 3.146 (0.823)

Smoking history ‐ non‐smoker/ex‐smoker/current smoker, n: CIC 160 μg OD: 38/18/2; FP 250 μg BID: 34/18/1

Inclusion criteria: male and female patients aged 17–75 years; diagnosis of asthma as defined by American Thoracic Society guidelines for at least 6 months, but otherwise in good health; FEV₁ ≥ 90% of predicted; maintained asthma control over previous 3 months using fluticasone propionate 250 μg twice daily, or equivalent, with short‐acting bronchodilator use as rescue medication only

Exclusion criteria: concomitant severe disease, such as a lower respiratory tract infection; chronic obstructive pulmonary disease or other relevant lung diseases; more than 1 emergency care visit or hospitalisation due to asthma exacerbations in the previous year; or clinically relevant abnormal laboratory values suggesting an
unknown disease. Other exclusion criteria were use of systemic glucocorticoids, long‐acting β₂‐agonists,
oral β₂‐agonists and sustained‐release xanthines within 3 months before study entry; pregnancy and breast‐feeding among
female patients; and ex‐smokers or current smokers with ≥ 10 pack‐years.

Details of criteria for step‐down treatment: Participants were randomised to step‐down (for eligibility, see inclusion and exclusion criteria).

Interventions

Intervention: ciclesonide 160 μg OD (i.e. ˜ 50% reduction according to GINA 2016)

Comparison: fluticasone propionate 250 μg BID (i.e. no change)

Concomitant medications: short‐acting bronchodilator used as rescue medication only

Excluded medications: See exclusion criteria.

Outcomes

Primary outcomes: efficacy ‐ percentage of days with asthma control (defined as days without asthma symptoms and without rescue medication use); asthma symptom‐free days; rescue medication‐free days; and nocturnal awakening‐free days. Safety ‐ adverse events

Secondary outcomes: efficacy ‐ FEV₁; forced vital capacity (FVC); PEF from spirometry; PEF from participant diaries measured on a Mini‐Wright PEF meter; asthma symptom scores from participant diaries (sum scores based on a 9‐point scale, with 0 indicating no symptoms); use of rescue medication; number of participants with an asthma exacerbation; and time to onset of the first asthma exacerbation. Safety ‐ vital signs (blood pressure and pulse rate); standard laboratory tests (including haematology, blood chemistry and urinalysis); and number of participants with oral candidiasis

Notes

Funding for trial: This study was funded and sponsored by ALTANA Pharma AG, a member of the Nycomed Group.

Notable conflicts of interest of trial authors: Editorial assistance for preparation of the manuscript was provided by Nathan Price‐Lloyd, PhD, Medicus International, which was funded by ALTANA Pharma AG, a member of the Nycomed Group. Study authors reported no conflicts of interest.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information provided

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The study was reported as double‐blind, double‐dummy.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The study was reported as double‐blind, double‐dummy.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention‐to‐treat analyses were performed for safety analyses and comprised all randomised participants. Some data for lung function analyses were missing, but only from 3 participants in the step‐down group.

Selective reporting (reporting bias)

Unclear risk

Protocol was not available; however, the range of outcomes seems fairly comprehensive.

Other bias

Low risk

None identified

Methods

Study design: randomised controlled, double‐blind, double‐dummy, parallel group

Total duration of study: 14 weeks

'Run‐in' period: 4 weeks

Number of study centres and locations: 18 pulmonology practices

Study setting: pulmonology outpatient practices

Withdrawals: none reported

Date of study: November 1996 to October 1997

Participants

N: 150

Mean (SD) age, years: 400 μg/day BDP: 43 (15); 1000 μg/day BDP: 42 (15)

Age range: not reported

Gender ‐ M/F, n: 400 μg/day BDP: 22/50; 1000 μg/day BDP: 30/48

Severity of condition: step 2

Baseline lung function ‐ mean (SE) FEV₁, L: 400 μg/day BDP: 2.77 (0.09); 1000 μg/day BDP: 2.85 (0.09)

Smoking history: not reported

Inclusion criteria and exclusion criteria, allowable range: age 18‐75 years; use of inhaled steroids for ≥ 3 months (BDP 1000 mg or BUD 800‐1000 mg); use of β₂‐agonists on demand (≥ 1 puffs/d); reversible airflow obstruction assessed within the last 2 years; change in FEV ≥ 12%; change in PEF ≥ 20%; bronchial hyper‐responsiveness to inhaled histamine (PC20 FEV₁ ≥ 4 mg/mL); baseline FEV₁ ≥ 60% of predicted; variability of baseline FEV₁ during run‐in period ≤ 15%

Details of criteria for step‐down treatment: Participants were randomised to step‐down (for eligibility, see inclusion and exclusion criteria).

Interventions

Intervention: hydrofluoroalkane beclomethasone 400 μg/day (i.e. < 50% dose reduction)

Comparison: chlorofluorocarbon beclomethasone 1000 μg/day.

Concomitant medications: not reported; likely that use of short‐acting bronchodilators as rescue medication was permitted

Excluded medications: none specified

Outcomes

Primary outcomes: Efficacy ‐ morning peak flow; Safety ‐ adverse events

Secondary outcomes: evening peak flow, FEV₁, concentration of inhaled histamine causing a 20% decline in FEV₁, frequency of β₂‐agonist use, daily asthma symptom score (0 represents no symptoms; 5 represents severe symptoms); and sleep disturbance score. Safety ‐ oropharyngeal candidiasis; reported hoarseness; clinical laboratory tests (i.e. haematology, serum chemistry, urine analysis); and vital signs (i.e. sitting pulse rate, blood pressure, ECG)

Notes

Funding for trial: 3M Medica (Borken, Germany)

Notable conflicts of interest of trial authors: not reported; however, several study authors were employees of 3M Medica

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information provided

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The study was reported as double‐blind.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The study was reported as double‐blind.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcome data appear complete. Data appear to be reported for all randomised participants.

Selective reporting (reporting bias)

High risk

Protocol was not available. Reporting of safety results appears to be fairly selective (SAEs not reported, details of individual AEs not reported).

Other bias

Low risk

None identified