Nisbet‐Brown 2001.

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24 participants with transfusion‐dependent β‐thalassaemia (23 analysed, 3 replacements for participants who were withdrawn for serious AEs during the study) Age (median (range): placebo: 32 (22 ‐ 38) years; 10 mg/kg DFX: 28 (20 ‐ 39) years; 20 mg/kg DFX: 24 (18 ‐ 38); 40 mg DFX: 27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.