Piga 2002.

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.