Methods

Open‐label, multinational, multicentre, randomised, phase III, non‐inferiority study.

Participants

586 β‐thalassaemia individuals

Age (mean (SD)): DFX: 17 (9.47) years; DFO: 17.3 (9.96) years

Gender (male/female): DFX: 140/156 DFO: 142/148

Setting and country: 65 centres (mentioned in full text publication) in 12 countries: Argentina, Belgium, Brazil, Canada, France, Germany, Greece, Italy, Tunisia, Turkey, UK, USA

Inclusion criteria

• ≥ 2 years

• β‐thalassaemia and chronic iron overload from blood transfusions

• LIC ≥ 2 mg/g dry weight

• ≥ 8 blood transfusions/year

• Female participants: required to use double‐barrier contraception

Exclusion criteria

• ALT > 250 U/L during year prior to enrolment

• Chronic hepatitis B infection

• Active hepatitis C infection

• History of a positive HIV test

• Serum creatinine above the ULN

• Urinary protein/creatinine ratio > 0.5 mg/mg

• Nephrotic syndrome

• Uncontrolled systemic hypertension

• Prolonged corrected QT interval

• Systemic infection within the 10 days prior to entry

• GI conditions preventing absorption of oral medication

• Concomitant conditions preventing therapy with deferasirox or DFO

• History of ocular toxicity related to iron chelation therapy

• A poor response to DFO

• Noncompliance with prescribed therapy

Follow‐up: 1 year

Interventions

2 groups

• DFX (n = 296): once‐daily at the assigned dose as a suspension in water half an hour prior to breakfast 7 days a week

Protocol assigned dose, mg/kg, Average daily dose, mg/kg/day (mean (SD)):

‐ LIC ≤ 3 mg Fe/g dry weight: 5; 6.2 (1.6)

‐ LIC > 3 mg Fe/g dry weight ‐ 7 mg Fe/g dry weight: 10; 10.2 (1.2)

‐ LIC > 7 mg Fe/g dry weight ‐ 14 mg Fe/g dry weight: 20; 19.4 (1.7)

‐ LIC > 14 mg Fe/g dry weight: 30; 28.2 (3.5)

• DFO (n = 290): Slow subcutaneous infusion using electronic infusion pumps over 8 ‐ 12 hours, 5 days a week

Protocol assigned dose, mg/kg, Average daily dose, mg/kg/day (mean (SD)):

‐ LIC ≤ 3 mg Fe/g dry weight: 20 ‐ 30; 33.9 (9.9)

‐ LIC > 3 mg Fe/g dry weight ‐ 7 mg Fe/g dry weight: 25 ‐ 35; 36.7 (9.2)

‐ LIC > 7 mg Fe/g dry weight ‐ 14 mg Fe/g dry weight: 35 ‐ 50; 42.4 (6.6)

‐ LIC > 14 mg Fe/g dry weight: ≥ 50; 51.6 (5.8)

‐ Exceptions were permitted to the number of days of administration (ranged 3 ‐ 7 days)

‐ DFO doses reported are normalized to administration for 5 days a week

Outcomes

• Primary response criterion: maintenance or reduction of LIC:

Success criteria:

LIC at baseline (mg Fe/g dry weight): success, LIC value after 1 year (mg Fe/g dry weight); failure, LIC value after 1 year (mg Fe/g dry weight)

2 to less than 7: 1 to less than 7, less than 1 or at least 7

7 to less than 10: 1 to less than 7, less than 1 or at least 7

10 or more: decrease in LIC of at least 3, decrease in LIC below 3

• CBC/differential

• Electrolytes

• Liver function tests

• Trace element analysis

• Urinary protein/creatinine

• Serum ferritin

• Fe

• Transferrin

• ECGs

• Ophthalmologic and auditory examinations

• Individuals < 16 years of age: assessment of growth rate (growth velocity) and sexual development

• LIC (liver biopsy or SQUID)

• Iron excretion‐intake ratio

Furthermore, mortality, discontinuations, willingness to continue treatment, time lost from normal activities due to treatment, satisfaction with treatment, dose adjustments and dose interruptions, convenience and AEs were reported.

Notes

Funding and conflict of interests

Study was supported in part by research funding from Novartis Pharma to some of the authors. Two authors have declared a financial interest in a company whose product was studied in the present work. Several of the authors are employed by Novartis Pharma.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details given with regard to sequence generation.

"Randomisation was stratified by age groups: 2 to younger than 12 years, 12 to younger than 18 years, and 18 years or older. After randomization, patients were assigned by the investigator to a dose dependent on their baseline LIC according to the algorithm noted in Table 2."

Allocation concealment (selection bias)

Unclear risk

No details given with regard to concealment of allocation.

"Randomisation was stratified by age groups: 2 to younger than 12 years, 12 to younger than 18 years, and 18 years or older. After randomisation, patients were assigned by the investigator to a dose dependent on their baseline LIC according to the algorithm noted in Table 2."

Blinding (performance bias and detection bias)
All outcomes

High risk

This was an open‐label study.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No flowchart according to CONSORT available.

586 individuals were randomised of which 29 discontinued and 4 died. The primary efficacy population consists of 553 individuals. However, it is stated that 541 participants completed one year of therapy. It remains unclear, what happened to the remaining 12 participants.

"Most patients completed 1 year of therapy on this study: 541 (92.3%) of 586 underwent both baseline and 1‐year LIC assessments. Discontinuations were relatively similar in the groups receiving deferasirox (n = 17) and deferoxamine (n = 12)."

"The primary efficacy population in this study consisted of 553 patients with LIC evaluations at baseline and after 52 weeks and those who discontinued due to safety reasons (AE, abnormal laboratory value or test procedure result, or iron overload–related death)."

Selective reporting (reporting bias)

Unclear risk

See also "Outcomes" in "Characteristics of included studies" table Cappellini 2005b above. Not all time points nor all parameters (secondary: e.g. trace elements) reported. However, EOS primary results are reported and secondary as outlined in methods section. However, it remains unclear whether any others were measured.

Other bias

Low risk

No other risk of bias detected.

Methods

Prospective study with randomised groups in the last 2 years of study period.

Participants

72 β‐thalassaemia participants: 21 non‐transfusion‐dependent thalassaemia participants, 51 transfusion‐dependent thalassaemia participants

Randomised in the last 2 years of study: n = 37

Age (mean (SD)): DFO : 30.2 (7.3) years; DFP: 28.8 (8.9) years; DFX: 31.4 (7.4) years

Gender: not mentioned

Setting: Thalassaemia Unit, Department of Pediatrics, University of Messina

Country: Italy

Inclusion criteria: not mentioned

Exclusion criteria:

• βT minor

• Acute illness

• Severe renal and liver disease

• Heart failure or cardiomyopathy

• Endocrine complications (e.g. diabetes mellitus, thyroid dysfunction or assuming hormonal therapy)

Follow‐up: whole study: 8 years; randomised phase: 2 years

Interventions

All participants received DFO monotherapy for 4 years or until the appearance of thyreopathy. Afterwards, individuals with thyreopathy received DFO (20 ‐ 40 mg/kg, 8 ‐ 12 hours, 2 ‐ 6 days/week) and DFP (daily oral administration 75 ‐ 100 mg/kg/day in 3 divided doses). Individuals without thyreopathy continued with DFO. After the end of 2 years, participants with a new diagnosis of thyreopathy started combined chelation therapy, whereas those without thyroid dysfunction were randomised in 3 arms for further 2 years.

• DFX (Exjade) (n = 12)

• DFP (n = 12)

• DFO (n = 13)

Only results of participants randomised to the 3 monotherapy groups in the last phase of the study were included in this systematic review.

All transfusion‐dependent thalassaemia participants followed a standard treatment protocol and were regularly transfused with packed red cells every 3 weeks, with the aim of maintaining pre‐transfusion haemoglobin levels above 9 g/dL.

Outcomes

• Thyroid disease

• Serum ferritin

Furthermore, FT₃, FT₄, TSH, TGA, TPO, thyroid dysfunction (overt hypothyroidism: low FT₄ and/or FT₃, increased TSH levels; subclinical hypothyroidism: normal FT₄, FT₃ and increased TSH concentration (> 5 TSH ɥIU/mL)); central hypothyroidism (inappropriately low serum TSH concentration in the presence of subnormal serum T₄ and T₃ concentrations), thyroid volumes, lipid profile, blood pressure and metabolic parameters (in particular insulin resistance) were measured.

Notes

The authors declare that they have no conflict of interest.

The authors state that this research did not receive any specific grant from any funding agency in the public, commercial or not‐for‐profit sector.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"This latter group was randomised into three arms, based on the type of iron chelation [...]"

Not mentioned how random sequence was generated.

Allocation concealment (selection bias)

Unclear risk

Not details given with regard to allocation concealment.

Blinding (performance bias and detection bias)
All outcomes

High risk

"The patients, physicians, laboratory staff and the epidemiologist who analysed the data were not aware of the intervention of each group"

No placebo treatment is mentioned, so blinding of participants and physicians is unlikely due to different administration routes and frequencies of application.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Results of all randomised participants at end of study are reported.

Selective reporting (reporting bias)

High risk

No results reported for TSH, FT₃, FT₄, but likely included in definition for thyroid dysfunction.

No results reported for TGA, TPO, thyroid volumes, insulin resistance, lipid profile, blood pressure at the end of the randomised phase.

Other bias

Unclear risk

Baseline data for randomised patients not reported apart from serum ferritin, age, splenectomy rate and haemoglobin before transfusion.

Methods

Randomised, prospective study.

Participants

180 people with β‐thalassaemia major

Age: ≤ 18 years

Gender: not mentioned

Setting: regular attendants of the Hematology Clinic, Pediatric Hospital, Ain Shams University

Country: Egypt

Inclusion criteria

• Moderately iron‐overloaded people with β‐thalassaemia major without clinical symptoms of cardiac dysfunction

• Vitamin C deficiency

• Serum ferritin > 1000 ‐ 2500 ng/mL

• Cardiac T2* > 10 ms calculated as geometric mean

• Ejection fraction > 56%

Exclusion criteria

• Insulin‐dependent diabetes

• LVEF ≤ 56%

• Active hepatitis (serum transaminases > 5 times above ULN)

• Renal impairment (serum creatinine > 2 times ULN),

• Sepsis or active infection

• Participation in a previous investigational drug study within the 30 days preceding screening

• Patients with a known allergy to DFX, DFP, and DFO

Follow up: 1 year

Interventions

3 groups:

• DFX (n = 60): 25 mg/kg/day

• DFO (n = 60): subcutaneous 40 mg/kg/day (5 days a week)

• DFP (n = 60): 75 mg/kg/day

‐ Each chelation group were further randomly divided into two subgroups according to vitamin C supplementation (n = 30 in each group): Oral vitamin C in the morning 100 mg daily

‐ Previous chelation therapy was withdrawn for 2 weeks before randomisation

‐ Patients consumed a low‐iron diet (11 ‐ 15 mg of iron/day) and standard vitamin C diet during the study

Outcomes

• Serum ferritin

• LIC

• Cardiac MRI

• AEs

Furthermore: transfusion index, haemoglobin, iron, total iron binding capacity, transferrin saturation, vitamin C, compliance.

Notes

The authors declare that they have no conflict of interests.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Drug administration was according to a predetermined schedule generated from random numbers in a 1:1:1 manner based on a computer‐generated randomisation sequence maintained within the investigational drug pharmacy[...]".

Allocation concealment (selection bias)

Low risk

"[...] with allocation concealment by opaque sequentially numbered sealed envelope".

Blinding (performance bias and detection bias)
All outcomes

High risk

No details given with regard to blinding. No placebo treatment is mentioned. Due to different administration routes, blinding is not likely.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Five patients in DFO subgroup did not continue till the end of study because of poor compliance [...]"

No ITT analysis performed, but proportion of missing outcome data was regarded as too low to have a large impact on effect size.

Selective reporting (reporting bias)

High risk

"The same improvement was found when each chelation subgroup receiving vitamin C supplementation was compared separately with the subgroup without vitamin C (data not shown)".

Only summarized data for patients with vitamin C supplementation versus patients without vitamin C supplementation and data for all chelation groups with vitamin C supplementation were reported.

The outcome "occurrence of AE" is mentioned, but only serious AE related to iron chelators are reported.

Serum ferritin is reported as median and IQR, but no reason for this reporting style is mentioned.

Other bias

Unclear risk

Baseline data are not given for all treatment groups

Methods

Interventional prospective randomised open‐labelled study with blinded data management and data analyses.

Participants

96 people with β‐thalassaemia major were randomised.

Age (mean (SD)): DFX + DFP : 14.05 (2.21), DFP + DFO: 15.25 (2.31)

Gender (male/female): 62/34

Setting: Thalassemia Centers of Ain Shams University, Egypt and Sultan Qaboos University Hospital, Oman

Countries: Egypt and Oman

Inclusion criteria

• β‐transfusion‐dependent thalassaemia

• Aged 10 ‐ 18 years

• Serum ferritin > 2500 µg/L on maximum tolerated dose of a single iron chelator with uptrend of serum ferritin over the last 12 months prior to the study

• Participants with LIC more than 7 mg/g by MRI R2* and mean cardiac T2* less than 20 and more than 6 ms calculated as geometric mean without clinical symptoms of cardiac dysfunction (shortness of breath at rest of exertion, orthopnoea, exercise intolerance, lower extremity edema, arrhythmias). Adequacy of prior chelation was defined as taking > 75% of the calculated dose/month on maximum tolerated dose with upward ferritin trend. For DFX, this should be 40 mg/kg/day, for DFP 100 mg/kg/day and for DFO at least 40 ‐ 50 mg/kg.

Exclusion criteria

• History of agranulocytosis

• Clinically significant GI or renal disease

• Clinical cardiac disease, or with LEVF < 50% on baseline echocardiography

• Evidence of active hepatitis

• Serum transaminase > 3 times above ULN

• Renal impairment (serum creatinine > ULN)

• Participation in a previous investigational drug study within the 30 d preceding screening

• Individuals with a known allergy to DFX, DFP and DFO

Follow‐up: 1 year

Interventions

2 groups:

• DFX + DFP (n = 48): DFP 75 mg/kg/day, divided into 2 doses taken orally at 8 a.m. and 3 p.m. combined with DFX 30 mg/kg/day taken orally at 10 p.m. for 7 days a week

• DFP + DFO (n = 48): DFP 75 mg/kg/day divided into 2 doses taken orally at 8 a.m. and 3 p.m, for 7 days (with 6 ‐ 8 hour interval between the 2 doses) combined with DFO 40 mg/kg/day by subcutaneous infusion over 10 hours starting at 10 p.m. for 6 days a week

‐ Chelation therapy was withdrawn for 2 weeks before randomisation

‐ The patients consumed a low‐iron diet (11 ‐ 15 mg of iron per day) during the study

‐ The transfusion regimen aimed to maintain the patients pre‐transfusion haemoglobin ≥ 8.0 g/dL by receiving approximately 15 mL/kg packed red blood cells every 3 ‐ 4 week

Outcomes

• Serum ferritin

• LIC

• Cardiac MRI

• SAE

• AE

• Adherence

• Satisfaction

• QoL

• Self‐reported adherence

• Proportion of participants who never thought about stopping iron‐chelating therapy

Notes

The authors state that they have nothing to declare

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The randomisation sequence was based on a computer randomised list in permuted blocks of 10 with a 1:1 ratio, generated at both University of Ain Shams and Sultan Qaboos".

Allocation concealment (selection bias)

Low risk

"To ensure no allocation bias, treatment group was assigned by telephone contact from the coordinating centre in Ain Shams".

Blinding (performance bias and detection bias)
All outcomes

High risk

"[...] open‐labelled study with blinded data management and data analyses"

High risk of bias in particular of performance bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

" [...] all the included patients continued till the end of study with no patients were lost follow‐up".

Selective reporting (reporting bias)

High risk

Patient‐reported satisfaction, percentage of patient's with self reported adherence, proportion of patients who never thought about stopping iron‐chelating therapy and 18‐months‐follow‐up results were reported incompletely so that they cannot be entered in a meta‐analysis.

Serum creatinine, liver function, audiometric and ophthalmological assessment were conducted as described in a conference abstract, but no or only incomplete results are published.

Although not pre‐defined as an outcome, the authors describe that "change in mean LVEF after 1 yr was not different between the two treatment groups (data not shown)."

On clinicaltrials.gov, only change in serum ferritin and the number of patients developing adverse reactions are predefined as outcomes.

Other bias

Low risk

No other bias detected.

Methods

2‐period, randomised, double‐blind, placebo‐controlled, sequential parallel‐group design.

Participants

25 people with transfusion‐dependent β‐thalassaemia were randomised

Age (mean (SD)): 21.6 (3.3) years

Gender (male/female): 25/0

Setting and country: 2 centers in Italy

Country: Italy

Inclusion criteria:

• White males

• Age ≥ 18 years

• Transfusion‐dependent β‐thalassaemia

• Participants had serum ferritin values between ≥ 1500 ng/mL and ≤ 5000 ng/mL, as well as post‐transfusion haemoglobin levels of at least 13 ± 0.5 g/ dL

• All patients had previously been treated with a mean daily dose of 20 to 50 mg/kg/day DFO for at least 4 weeks before screening.

Exclusion criteria:

• History of systemic reactions to treatment with DFO

• History of systemic disease

• Any medical condition that might have significantly altered the absorption, distribution, metabolism, or excretion of the study drug

Follow‐up: safety: Up to 10 days post dose

Interventions

"Following a 16‐day run‐in period, 24 patients were allocated to one of three study groups, with each group consisting of 8 patients. Each group was administered two single oral doses of ICL670 at an interval of at least 7 weeks, first a lower dose and later a higher dose. Group 1 received 2.5 and 20 mg/kg, group 2 received 5 and 40 mg/kg, and group 3 received 10 and 80 mg/kg ICL670, in all cases given as an oral suspension of 100 mL prepared from dispersible tablets. Before proceeding to a higher dose, the safety and tolerability of the preceding dose had to be assessed as satisfactory. In each treatment period, 2 of 8 patients received placebo in such a way that a given patient did not receive placebo more than once. Patients went back to their usual deferoxamine therapy and transfusion scheme in the interval between study periods."

Outcomes

• Urinary iron excretion

• Serum iron

• Transferrin

• Safety assessment: physical examination, vital signs, ECG, audiometry, clinical laboratory evaluations, and AE monitoring.

• Safety laboratory evaluations: hematology (including transferrin and serum iron), biochemistry (including routine renal and liver function parameters, zinc, copper, and vitamin C), special kidney function parameters (α‐glutathione‐S‐transferase, N‐acetyl‐β‐Dglucosaminidase, β2‐microglobulin, and retinol‐binding protein), urinalysis

Notes

Novartis involved in trial. No details given and no information available with regard to potential conflicts of interest.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details given with regard to sequence generation. From information given in paper, unclear, whether randomisation took place both in group assignment and in allocating patients to placebo. Author confirmed that randomisation was used to allocate placebo.

"Randomization was used to assign both drug (all treatment groups) and placebo. Hope to have clarified."

Allocation concealment (selection bias)

Unclear risk

No details given with regards to concealment of allocation.

Blinding (performance bias and detection bias)
All outcomes

Low risk

"The study employed a two‐period, randomised, double‐blind, placebo‐controlled, sequential parallel group design."

However, no definition of double‐blind. Unclear whether, e.g. outcome assessors and data analysts were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Not applicable. Data from all participants are presented.

Selective reporting (reporting bias)

Unclear risk

Only general information with regard to safety issues. No clear‐cut comparison of placebo vs verum groups. Unclear, whether other parameters were evaluated than those reported.

Other bias

Low risk

No other risk of bias detected.

Methods

Randomised clinical study

Participants

30 people with thalassaemia major

Age: not mentioned

Gender: not mentioned

Setting: Bahonar hospital of Karaj

Country: Iran

Inclusion criteria: not mentioned

Exclusion criteria: not mentioned

Follow‐up: 1 year

Interventions

2 groups:

• DFX

• DFO

Outcomes

Serum ferritin

Notes

The study was only reported in a conference abstract

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"In this randomized clinical trial [...]"

Not mentioned how random sequence generation was generated.

Allocation concealment (selection bias)

Unclear risk

No details given with regard to concealment of allocation.

Blinding (performance bias and detection bias)
All outcomes

High risk

No details given with regard to blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not reported how many patients reached end of study.

Selective reporting (reporting bias)

High risk

No results were reported.

Other bias

Unclear risk

No baseline characteristics were reported.

Methods

Prospective randomised study

Participants

60 β‐thalassemia major participants

Age (mean (SD)): DFX group: 8.9 (2.2), DFO group: 9.7 (1.9)

Gender: 19 male, 41 female

Setting: Out‐patient paediatric hematology clinic of Al‐Hussein University Hospital, Al‐Azhar University, Cairo

Country: Egypt

Inclusion criteria:

• ≥ 6 years

• Serum ferritin > 1500 µg/L

• Irregular subcutaneous DFO chelation therapy

Exclusion criteria:

• Serum creatinine above the upper age‐related normal range

• Significant proteinuria (urinary protein/creatinine ratio > 1.0 in a non‐first‐void urine sample at baseline)

• Elevated ALT more than 3‐fold of the ULN

• GI diseases,

• Clinically relevant auditory or ocular toxicity (or both) related to iron chelation therapy

• Cardiac disease

• Serious AEs with DFO or DFX

• Absolute neutrophilic count < 1500/mm³

• Platelet count < 100,000/mm³

Follow‐up: 1 year

Interventions

Two groups:

• DFX (n = 30): Orally single daily dose of 20 ‐ 40 mg/kg/day on an empty stomach after dissolution in water, apple juice, or orange juice; Starting dose of DFX was individualized based on the frequency of blood transfusions

• DFO (n = 30): 20 ‐ 50 mg/kg/day via subcutaneous infusion over 8 ‐ 10 hours, 5 days per week

Outcomes

• Serum ferritin < 1500 µg/L

• Safety

Furthermore, serum ferritin, ALT, AST, blood urea, serum creatinine, neutrophilic and platelet counts and some AEs were reported

Notes

The authors state that there is no conflict of interest to be declared.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"[...] the patients were randomized in a 1:1 ratio based on permuted blocks [...]"

Not mentioned how random sequence generation was generated.

Allocation concealment (selection bias)

Unclear risk

No details given with regard to concealment of allocation.

Blinding (performance bias and detection bias)
All outcomes

High risk

No details given with regard to blinding.

Due to different administration routes, blinding is not likely.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"[...] no discontinuation of drugs or drop‐out of follow‐up occurred."

Selective reporting (reporting bias)

Low risk

No protocol available. All predefined outcomes in the method section were reported.

Other bias

Low risk

No other bias detected.

Methods

Randomised controlled study.

Participants

40 thalassaemia major participants

Age: 5 ‐ 18 years

Gender: not mentioned

Setting: unclear

Country: unclear

Inclusion criteria: not mentioned

Exclusion criteria: not mentioned

Follow‐up: not mentioned

Interventions

Three groups:

• DFP (n = 10): 75 ‐ 100 mg/kg/day

• DFX (n = 10): 30 ‐ 40 mg/kg/day

• Both drugs administered sequentially every alternate week (n = 20)

Outcomes

• Cardiac MRI T2*

• Liver MRI T2*

• Serum ferritin

• CBC

• Liver enzymes

• Renal function tests

Notes

The study was only reported in a conference abstract.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"[...] were randomised to three groups [...]"

Not mentioned how random sequence generation was generated.

Allocation concealment (selection bias)

Unclear risk

No details given with regard to concealment of allocation.

Blinding (performance bias and detection bias)
All outcomes

High risk

No placebo treatment mentioned. High risk of bias in particular of performance bias and outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not reported how many patients reached end of study.

Selective reporting (reporting bias)

High risk

Regarding cardiac MRI T2*, only baseline data and P value for DFP vs DFP+DFX at the end of the study was reported. For liver MRI T2* it is unclear whether values given are baseline or end of study data. Missing data for serum ferritin. CBC, liver enzymes and renal function tests. Only untoward side‐effects reported and only for group receiving combination therapy.

Other bias

Unclear risk

No baseline data reported.

Methods

Randomised controlled open‐label study.

Participants

138 patients with β‐thalassemia major (n = 122) and thalassaemia intermedia (n = 16)

Age (mean (SD)): 13.59 (6.81) (range: 4 ‐ 27 years)

Gender (male/female): 62/76

Setting: Bandar Abbas Pediatric Hematology Clinic

Country: Iran

Inclusion criteria

• major/intermedia thalassaemia

• > 2 years

• Serum ferritin > 1000 ng/mL

• Normal creatinine

• Acceptable CBC

• Negative PCR in terms of HCV, negative HBV and HIV

• Absence of heart disease and cardiac drugs

• EF> 55%

• Absence of proteinuria

Exclusion criteria

• Serum creatinine increased by more than 33% compared to baseline

• Vision and hearing problems

• Hyperemesis

• Lack of response to anti‐nausea medication and fluids therapy

• Severe and rapidly progressive skin rash

• Increase in liver enzymes more than 5 times normal

• Platelets < 150 000

• Neutrophils < 1500

Follow‐up: 8 months

Interventions

2 groups:

• DFX (n = 69): 20 mg/kg/day oral, once a day on an empty stomach at least half an hour before a meal

• DFO (n = 69): 40 ‐ 50 mg/kg subcutaneous for 6 nights a week

Outcomes

• CBC

• ALT, AST

• Ferritin

• Creatinine

• Urinalysis

Furthermore, patients were visited weekly on the base of drug tolerance and side effects.

Notes

No funding or conflict of interest mentioned.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were assigned randomly in two groups"

No details given with regard to sequence generation.

Allocation concealment (selection bias)

Unclear risk

No details given with regard to concealment of allocation.

Blinding (performance bias and detection bias)
All outcomes

High risk

No placebo treatment mentioned. Due to different administration routes, blinding is not likely.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Although number of patients who reached end of study was not clearly stated, we concluded from given means, SDs and P values, that 69 participants were included in the results.

Selective reporting (reporting bias)

High risk

ALT, AST, creatinine evaluated at EOS, but only baseline values given

Only ferritin level, haemoglobin level and drug side effects predefined as outcomes on clinicaltrials.gov

Exclusion criteria were stated as, among others, “vision and hearing problems”, “severe skin rash”: implies that AEs were known for DFX/DFO and these data were collected; however they were not reported;

Only AEs reported: leukopenia, thrombocytopenia, although patients were visited weekly for drug tolerance and side effects.

Other bias

Low risk

No other bias detected.

Methods

Randomised clinical study.

Participants

100 children with thalassaemia major were selected, 94 participants entered study

Age (mean (SD)):12.23 (4.09) years (range: 2 ‐ 15 years)

Gender (male/female): 44/48

Setting: Thalassemia medical centre of Bandar Abbas

Country: Iran

Inclusion criteria:

• Age: 2 ‐ 15 years

• Serum ferritin > 2000 ng/mL despite the treatment with DFO (50 mg/kg 3 times a week)

Exclusion criteria: not mentioned

Follow‐up: 12 months

Interventions

Two groups:

• DFO (n = 48): 50 mg/kg transfused 3 times a week

• DFO and DFX (n = 46): DFX 20‐40 mg/kg (in case there was no desirable response, the dosage was altered to 20 mg/kg, and when no consequences were observed, it was increased to 40 mg/kg)

Outcomes

• Serum ferritin

• Neutrophil, ALT, AST, ALP

• Creatinine

• Hemoglobin

Notes

Conflict of interest not mentioned.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly and in the order of visiting the centre, they were divided in two 50‐member groups"

No details given on how random sequence was generated.

Allocation concealment (selection bias)

Unclear risk

No details mentioned with regard to concealment of allocation.

Blinding (performance bias and detection bias)
All outcomes

High risk

No placebo treatment in the Desferal monotherapy group is mentioned, so blinding is not likely in particular of performance bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

It remains unclear wether six patients were excluded due to exclusion criteria before or after randomisation; small number doesn't seem to affect results.

Selective reporting (reporting bias)

High risk

Level of creatinine was measured, but results were not reported.

Other bias

Low risk

No other bias detected.

Methods

Randomised, double‐blind, placebo‐controlled dose‐escalation study.

Participants

24 participants with transfusion‐dependent β‐thalassaemia (23 analysed, 3 replacements for participants who were withdrawn for serious AEs during the study)

Age (median (range): placebo: 32 (22 ‐ 38) years; 10 mg/kg DFX: 28 (20 ‐ 39) years; 20 mg/kg DFX: 24 (18 ‐ 38); 40 mg DFX: 27 (19 ‐ 34)

Gender (male/female): 11/12

Setting: Children's Hospital, Boston; Weill Medical College, New York; Toronto General Hospital, Toronto

Country: USA (2 centres) and Canda (1 centre)

Participant characteristics:

• Transfusion‐dependent β‐thalassaemia

• ≥ 16 years

• Serum ferritin values:1000 ‐ 8000 ng/mL

• Liver biopsies done in the previous 3 months with ≥ 3.5 mg Fe/g dry weight

• All participants required treatment with DFO at 20 mg/kg/day (mean daily dose) for at least 4 weeks before screening and a post transfusion haemoglobin concentration of at least 130 g/L

Follow‐up: 12 days

Interventions

Four groups:

• DFX (n = 5): 10 mg/kg

• DFX (n = 6): 20 mg/kg

• DFX (n = 7): 40 mg/kg

• Placebo (n = 5)

Outcomes

• Dietary, urine and faecal iron measured by atomic absorption spectrometry

• Net faecal iron excretion calculated by individual iron content in faeces minus individual iron content in the diet (the net iron excretion for each participant in mg Fe kg–1 day–1 was derived from the sum of the daily measurements of net faecal iron excretion and urinary iron excretion)

• UIBC calculated from serum iron concentration and total iron binding capacity

Notes

Conflict of interest and funding:

Novartis was involved in design and monitoring of the study.Study was financial supported by Novartis Pharmaceuticals Corporation.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Details of sequence generation process not stated.

"The randomisation sequence was generated by Novartis Pharmaceuticals and delivered to the research pharmacy in duplicate sealed envelopes."

Allocation concealment (selection bias)

Unclear risk

Sealed envelopes were used. However, unclear whether opaque and numbered.

"The randomisation sequence was generated by Novartis Pharmaceuticals and delivered to the research pharmacy in duplicate sealed envelopes."

Blinding (performance bias and detection bias)
All outcomes

Low risk

This was a placebo‐controlled study, in which investigators and those responsible for administering study drug were blinded with regard to treatment allocation. However, it remains unclear whether outcome assessors and data analysts were blinded as well.

"The investigators and those responsible for administering study drug were unaware of treatment allocation."

"Placebo and ICL670 were prepared as dispersible tablets with standard excipients. Tablets were suspended in water, and patients ingested the drug or placebo on an empty stomach."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Therefore, all patients who began either placebo or drug were included in the data analysis, whether they completed the 12‐day course or withdrew prematurely."

Selective reporting (reporting bias)

Unclear risk

"We did clinical, laboratory, and other safety assessments regularly throughout the study."

However, only a limited amount of data are presented in the publication.

Other bias

Low risk

No other bias detected.

Methods

Randomised controlled study.

Participants

26 individuals were recruited, who were diagnosed as β‐severe thalassaemia by gene screening, 2 met exclusion criteria

24 participants were randomised

Gender: 13 male, 11 female

Age (mean (SD) (range)): (14 (3) (11 ‐ 26)) years

Setting: First Affiliated Hospital, Guangxi Medical University, Nanning

Country: China

Inclusion criteria:

• Age ≥ 10 years

• History of 50 unit red blood cell transfusion (1 unit = 200 mL red blood cell) at least

• Receiving red blood cell transfusion (≥ 10 unit per year)

Exclusion criteria:

• T_2* ≥ 6.3 ms at first MRI screening or LIC ≤ 2 mg/g (1 mg/g = 17.9 mmoL/kg)

• Dysfunction of liver and kidney

• Contraindication of MR screening or disagreement doing the screening

Follow up: 12 months

Interventions

Two groups:

• DFX (n = 12): 40 mg/kg daily before breakfast

• DFO (n = 12): 50 mg/kg, diluted by 10% solution, subcutaneous injection 8 ‐ 12 hours continuously per day, at least 5 days every week

‐ Parameters of the body of patient, LIC, serum ferritin, serum creatinine, liver function and toxicity of the drugs are regarded as standards to adjust the dose or discontinue the therapy

‐ Meanwhile, the patients still receive the former transfusion program (red blood cell transfusion ≥ 10 units per year) to maintain the haemoglobin > 90 g/L

‐ 5‐day washout period without chelation therapz before treatment

Outcomes

• Serum ferritin

• Liver R₂^*

• Severity of iron deposition in liver

Notes

Study funding sources: National Natural Science Foundation of China, the Natural Science Foundation of Guangxi, China

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"[...] 24 iron‐overloaded patients were randomly divided into 2 groups [...]"

No details given with regard to sequence generation.

Allocation concealment (selection bias)

Unclear risk

No details given with regard to concealment of allocation.

Blinding (performance bias and detection bias)
All outcomes

High risk

No details given with regard to blinding.

Due to different administration routes, blinding is not likely.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There were no missing outcome data.

Selective reporting (reporting bias)

High risk

Side effects were not reported.

Other bias

Low risk

No other bias detected.

Methods

Prospective, multinational, randomised, open‐label, parallel‐group, phase 2 study; Non‐inferiority study.

Participants

197 participants were randomised

160 participants completed one year of treatment

Age (mean (SD)): 19.8 (6.4) years (range: 10 ‐ 40 years)

Gender (male/female): 115/82

Setting and countries: 22 centres across 11 countries

Inclusion criteria:

• People with β‐thalassaemia major, Diamond‐Blackfan anaemia, low/intermediate 1 myelodysplastic syndromes, or sideroblastic anaemia

• Aged ≥ 10 years

• Myocardial T2* 6 to 20 ms without clinical symptoms of cardiac dysfunction (shortness of breath at rest or exertion, orthopnoea, exercise intolerance, lower‐extremity edema, arrhythmias)

• LVEF ≥ 56%,

• R2 magnetic resonance imaging LIC ≥ 3 mg Fe/g dry weight

• Lifetime history of ≥ 50 U red blood cell transfusions

• Receiving ≥ 10 U/y of red blood cell transfusion

• Only people with β‐thalassaemia major fulfilled the inclusion criteria and were enrolled in the study

Exclusion criteria:

• Serum creatinine above the ULN

• Significant proteinuria (urinary protein/creatinine ratio ≥ 1.0 mg/mg in a non‐first‐void urine sample at baseline)

• ALT > 5 times the ULN only if their LIC was < 10 mg Fe/g dry weight

• Considerable impaired GI function or GI disease

• History of clinically relevant ocular and/or auditory toxicity related to iron chelation therapy

• History of HIV seropositivity or malignancy within the past 5 years

Follow‐up: 12 months

Interventions

Two groups:

• DFX (n = 96): Once‐daily starting dose was 20 mg/kg per day for 2 weeks, followed by 30 mg/kg per day for 1 week, and then continued with 40 mg/kg per day

• DFO (n = 91): 50 to 60 mg/kg per day via subcutaneous infusion over 8 to 12 hours, 5 to 7 days a week; dose adjustment recommendations were provided based on continuous assessment of efficacy and safety markers

Outcomes

• Ratio of geometric mean myocardial T2* with DFX divided by the ratio of geometric mean for DFO

• LVEF

• LIC

• Serum ferritin

Furthermore, safety, compliance, dose interruptions/reductions and laboratory parameters (serum creatinine, blood creatinine, ALT) were measured.

Notes

Study was sponsored by Novartis Pharma AG. Novartis Pharma AG was involved in design of the study, conducted the statistical analysis and paid a medical writer who assisted with writing the article. Some of the authors received research grant funding, honoraria or lecture fees from Novartis Pharmaceuticals and/or other pharmaceutical companies.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"[...]patients were randomised in a 1:1 ratio [...]"

"Randomization was based on permuted blocks; stratification by centre was not conducted."

Allocation concealment (selection bias)

Unclear risk

No details given with regard to concealment of allocation.

Blinding (performance bias and detection bias)
All outcomes

High risk

"Core laboratories were blinded to treatment allocation."

"In order to eliminate potential unrecognised biases, the core clinical trial team was blinded to the treatment assignment prior to the database lock for the primary analysis."

"Open‐label trial"

No placebo treatment mentioned. Due to different administration routes, blinding is not likely in particular of performance bias.

Incomplete outcome data (attrition bias)
All outcomes

High risk

ITT was done regarding myocardial T2*, but the number of included patients (n=180) was lower than the number of randomised patients (n=197)

Apart from that, per‐protocol analysis was done for the other outcomes.

Selective reporting (reporting bias)

High risk

Only most common AE (≥ 5%) and drug related AE ≥ 2 participants were reported

Other bias

Low risk

No other bias detected.

Methods

Open label, randomised, multicenter, phase II study.

Participants

71 people with thalassaemia and transfusional iron overload: 69 people with β‐thalassemia major, 2 people with β‐thalassemia intermedia

Age mean (range): DFX 10 mg/kg/day: 23.7 years (17 ‐ 33 years); DFX 20 mg/kg/day: 25.6 years (19 ‐ 50 years); DFO: 22.7 (18 ‐ 29 years)

Gender (male/female): 26/45

Setting and country: 4 centres in Italy

Inclusion criteria:

• Should have been regularly transfused

• Should have received a mean daily dose of DFO ≥ 30 mg/kg for 5 days/week for at least 4 weeks prior to entering the screening period

• Serum ferritin between 2000 ‐ 8000 ng/mL on at least two evaluations in the last 12 months or

• LIC of 5 ‐ 15 mg Fe/g dry weight measured in the last 12 months by SQUID

• Average post‐transfusion haemoglobin level between 10.5 ‐ 13.5 g/dL during last 12 months

Exclusion criteria:

• AST or ALT > 250 U/L

• Creatinine clearance < 80 mL/minute

• People with hypertension

• People with any degree of A‐V block, clinically relevant QT prolongation

• Treatment with digoxin or any other drug that could induce prolongation of A‐V conduction

• People with diagnosis of cataract or a previous history of clinically relevant ocular toxicity related to iron chelation

Follow‐up: 48 weeks

Interventions

3 groups:

• DFX (n = 24): 10 mg/kg once‐daily using 250 mg tables which were divisible into four parts. The correct number of tablets was dispersed in a glass of non‐carbonated mineral water, stirred and ingested 30 minutes before breakfast

• DFX (n = 24): 20 mg/kg once daily using 250 mg tables which were divisible into four parts. The correct number of tablets was dispersed in a glass of non‐carbonated mineral water, stirred and ingested 30 minutes before breakfast

• DFO (n = 23): 40 mg/kg on 5 consecutive days per week. Doses were prepared as a 10% solution using commercially available vials of 500 or 2000 mg dry powder. Subcutaneous infusion was performed using a pump over 8 ‐ 12 hours.

‐ During the 14‐day run‐in period, eligible patients had their usual DFO therapy adjusted to 40 mg/kg given on 5 consecutive days each week

‐ The study protocol allowed for dose adjustment within the range of 5 ‐ 40 mg/kg/day in the DFX groups and 20 ‐ 50 mg/kg in the DFO group

‐ Depending on response, assessed primarily using the change in LIC at 3 consecutive determinations, dose increases or decreases were made by ±5 or ±10 mg/kg in the DFX groups and by ± 10 mg/kg in the DFO group

‐ Dose reductions were performed if the decrease in LIC was extrapolated to fall below 2 mg Fe/g dry weight within the next 12 weeks and dose increases were prescribed if an increasing trend in LIC was noted

‐ Dose adjustments were decided on a case‐by‐case basis in joint consultation between the Study Monitoring Committee and the sponsor

‐ On day ‐5, participants were admitted to the study site to receive a blood transfusion to achieve a target haemoglobin level of ≥ 13g/dL prior to commencing study treatment followed by a DFO washout period of 5 days

Outcomes

• Mortality

• LIC (SQUID)

• Serum ferritin

• Serum iron

• Serum transferrin

• Transferrin saturation

• Blood indices

• Liver and renal function

• Serum electrolytes

• Copper and zinc

• Second void urine samples with measurement of N‐acetyl‐beta‐glucosaminidase and beta2‐miroglobulin

• Ophthalmological examination including slit lamp examination of the lens and retinal fundoscopy

• Audiometry, ECG and liver ultrasonography

Notes

Study was supported by Novartis Pharma AG. Some of the authors are employed by Novartis Pharma or received lecture fees from the manufacturer.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomization was performed using a validated system that generates an automated random assignment of numbers to treatment groups."

We expect that using this system resulted in an adequate sequence generation.

Allocation concealment (selection bias)

Unclear risk

"Randomization was performed using a validated system that generates an automated random assignment of numbers to treatment groups."

No information is given with regard to allocation concealment.

Blinding (performance bias and detection bias)
All outcomes

High risk

It is classified as an open‐label study. There is no mentioning of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants are included in safety analysis (primary objective). Few patients only are not included in efficacy analysis (secondary objective).

Selective reporting (reporting bias)

Unclear risk

"Laboratory tests, including evaluation of blood indices, liver and renal function, serum electrolytes, copper and zinc, were performed at baseline and at 2‐weekly intervals throughout the study. All laboratory parameters were measured at a central laboratory (EXACTA Clinical Trials Services, Verona, Italy). Second void urine samples were collected for measurement of N‐acetyl‐b‐glucosaminidase and an aliquot of urine was alkalinized for measurement of b‐2 microglobulin. An ophthalmology examination, including a slit lamp examination of the lens and retinal fundoscopy, was performed every 2 weeks. Audiometry, ECG and liver ultrasonography were carried out every 3 months. Adverse events were recorded at each study visit and the severity of each adverse event was graded as mild, moderate or severe. A serious adverse event was defined as a medically significant event that was either fatal or life threatening, required surgical intervention, prolonged hospitalization or resulted in persistent disability. All adverse events and serious adverse events were assessed by the investigator for a possible relationship to the study drug. Adverse events were ranked according to incidence in the deferasirox 20 mg/kg/day treatment group."

"All biomagnetic liver susceptometry evaluations were performed at the Ospedale Regina Margherita, University of Turin, Italy. LIC was determined at screening and then every 12 weeks during treatment and at the end of the study...... During the study, markers of iron metabolism (serum ferritin, serum iron, serum transferrin and transferrin saturation) were analyzed by a central laboratory (EXACTA Clinical Trials Services, Verona, Italy). The transferrin saturation was calculated from the serum iron and the transferrin concentrations. Urinary iron excretion was determined in 24‐hour urine collections in ten patients taking deferasirox (five in each dose group) who also underwent blood sampling for pharmacokinetic analyses. Urinary iron excretion was measured using atomic absorption spectrometry."

Only selected parameters at selected time points are reported.

Other bias

Low risk

No other bias detected.

Methods

Prospective randomised comparative study.

Participants

41 participants were randomised

38 participants reached end of study

Age (mean (SD)): DFX (n = 19): 5.23 (2.76) years; DFP (n = 19): 7.26 (2.42) years

Gender (male/female): 22/16

Setting: Thalassemia day care centre of Indira Gandhi Institute of child health, Bengaluru

Country: India

Inclusion criteria

• Thalassemia diagnosis and regular blood transfusion

• Serum ferritin > 1000 ng/mL

• No chelation therapy

Exclusion criteria

• Already on chelation therapy

• Chronic liver or renal disease

Follow‐up: 12 months

Interventions

2 groups:

• DFX (n = 19): dose of 20 mg/kg/day, once a day

• DFP (n = 22): 75 mg/kg/day in 3 divided doses

Outcomes

• Serum ferritin

• WBC

• Platelet count

• Blood urea

• Serum creatinine

• Serum enzymes (AST, ALT)

• Side effects

Notes

No funding or conflict of interest mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"These children were randomly divided into two groups as group 1 and group 2 by computer generated randomisation."

Allocation concealment (selection bias)

Unclear risk

No details mentioned with regard to concealment of allocation.

Blinding (performance bias and detection bias)
All outcomes

High risk

No details given with regard to blinding.

Due to different application frequencies, blinding is not likely, in particular regarding performance bias.

Incomplete outcome data (attrition bias)
All outcomes

High risk

3 dropouts due to AEs in deferiprone group, per protocol analysis.

Selective reporting (reporting bias)

High risk

Measurements other than serum ferritin and AEs only given for 9 months (and only in the thesis document), but not for end of study (unsure whether not measured or not reported), although the author report measurements every 3 months.

In the thesis document, fundoscopy, growth harm and hearing were part of the evaluation sheet at 12‐month follow‐up, but no results were reported.

Other bias

Low risk

No other bias detected.

Methods

Multinational, prospective, randomised, double‐blind, placebo‐controlled phase 2 study.

Participants

166 participants were randomised.

95 non‐transfusion‐dependent β‐thalassaemia, 22 α‐thalassaemia, 49 HbE/β‐thalassaemia

148 participants completed 1 year of the study.

Inclusion criteria

• ≥ 10 years of age with

• Non‐transfusion‐dependent β‐thalassaemia

• Iron overload (R2‐MRI‐measured LIC ≥ 5 mg Fe/g dry weight)

• Serum ferritin > 300 ng/mL at screening based on 2 consecutive values ≥ 14 days apart were eligible

• Participants were required to have not received transfusions within 6 months or chelation therapy within 1 month before study entry

Exclusion criteria

• People with previous exposure to DFX

• Anticipated regular transfusions; unplanned transfusions during the study were allowed

• HbS variants of thalassaemia syndromes

• Active hepatitis B (positive hepatitis B surface antigen with negative hepatitis B surface Ab) or hepatitis C (positive hepatitis C virus Ab and detectable hepatitis C virus RNA with alanine aminotransferase [ALT] above the normal range)

• Cirrhosis

• Levels of ALT > 5 x ULN

• Serum creatinine > ULN or creatinine clearance ≤ 60 mL/min on 2 measurements

• Significant proteinuria (urine protein/urine creatinine ratio > 1.0 mg/mg) on 2 measurements

Follow‐up: 1 year

Interventions

4 groups:

• DFX (n = 55): 5 mg/kg/day

• DFX (n = 55): 10 mg/kg/day

• Placebo (n = 28): 5 mg/kg/day

• Placebo (n = 28): 10 mg/kg/day

‐ Doses were doubled at 24 weeks for patients with LIC > 7 mg Fe/g dry weight and LIC reduction < 15% from baseline

‐ Dose adjustment recommendations were also provided based on continuous safety assessments

‐ If serum ferritin was <100 ng/mL or LIC was <3 mg Fe/g dry weight at any visit, treatment was to be suspended until LIC increased to ≥ 5 mg Fe/g dry weight and serum ferritin to > 300 ng/m

Outcomes

• LIC

• Number and proportion of patients with a LIC decrease of ≥ 3 mg Fe/g dry weight, those with ≥ 30% reduction in LIC, and those with LIC ≤ 7, ≤ 5, and ≤ 3 mg Fe/g dry weight

• Serum ferritin

• Correlation of serum ferritin and LIC

• AEs

• Serious AEs

• Adherence

Notes

Study was sponsored by Novartis Pharma AG. Novartis was involved in design and statistical analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"[...] patients were block randomised [...]".

No details given on how random sequence was generated.

Allocation concealment (selection bias)

Low risk

"[...] patients were block randomised using an interactive voice response system. After confirming that the patient fulfilled the inclusion/exclusion criteria, the investigator contacted the interactive voice response system to obtain a randomisation number linking the patient to a treatment arm."

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"Because blinding of dose was not possible, blinding was only applied to the treatment received. All persons were blinded to the treatment from the time of randomisation until database lock."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Attrition was 12.7%, 10.9% and 8.9% for the DFX 5 mg, DFX 10 mg and the placebo group, respectively

In the journal publication, the authors state that "efficacy was assessed for the full analysis set (all randomised patients).[...] If there was no LIC measurement available at week 52, the last available post‐baseline LIC measurement was carried forward."

Number of participants analysed on clinicaltrials.gov doesn't include all randomised patients for continuous outcomes.

Selective reporting (reporting bias)

High risk

Extensive data set available on ClinicalTrials.gov (along with prespecified protocol), but AEs and SAEs were not reported separately for the core phase

In the journal publication AEs and drug‐related AEs were not reported completely

Other bias

Low risk

No other bias detected.