Fernandes 2016.

Methods	Randomised controlled trial. Design: parallel group. Duration: 12 months. Location: multicentre in Brazil.
Participants	Inclusion criteria: people with thalassaemia major, at least 6 years of age, regular transfusions for 2 or more years (total lifetime red blood cell transfusions above 20 units). Exclusion criteria: change in chelation therapy expected or scheduled in the next 12 months, presence of advanced clinical heart failure or ejection fraction > 35%, presence of a contraindication to use of MRI. 62 participants were enrolled from a pool of 77 screened individuals. 1 participant from the placebo arm was excluded because of a diagnosis other than thalassaemia major and a second was lost to follow‐up. One patient was excluded from the amlodipine arm due to lack of follow‐up MRI examinations. This left 59 participants for analysis, 30 in the amlodipine arm and 29 in the placebo arm. Particpants were stratified into two subgroups based on their baseline myocardial T2* values: reduction group (T2* < 35 m/s) and prevention group (T2* > 35 m/s). Within the reduction subgroup, 15 participants were randomised to the amlodipine arm and 15 to the placebo arm. There were no statistically significant differences in baseline characteristics between these arms. Similarly, within the prevention subgroup, 15 participants were randomised to the amlodipine arm and 14 to the placebo arm. Again, there were no statistically significant differences in the baseline characteristics between these 2 arms. Total cohort N = 59, mean (SD) age 23.4 (9) years, 51% male. Intervention group n = 30, mean (SD) age 27.7 (7.7) years, 43% male. Mean (SD) baseline characteristics: haemoglobin 9.4 (1) g/dL; heart T2* 29.37 (12.81) m/s; MIC 1.48 (2.37) mg/g; LVEF 67.73 (5.46) %; serum ferritin 2682.34 (1908.64) ng/mL; liver T2* 5.11 (4.58) m/s; LIC 12.97 (10.29) mg/g. Control group n = 29, mean (SD) age 23.5 (10.2) years, 59 % male. Mean (SD) baseline characteristics: haemoglobin 9.5 (1) g/dL; heart T2* 31.24 (SD) 9.42 m/s; MIC 0.92 (0.88) mg/g; LVEF 67.07 (6.64) %; serum ferritin 2662.6 (2840.61) ng/mL; liver T2* 5.23 (4.7) m/s; LIC 10.53 (7.3) mg/g.
Interventions	Intervention group: oral amlodipine 5 mg once daily in addition to standard chelation therapy. Control group: placebo in addition to standard chelation therapy.
Outcomes	Primary outcome: change in MIC from baseline and a comparison of the effect of treatment between the prevention and reduction subgroups at 12 months. Secondary outcomes: assessment of MIC at 6 months, change in LIC at 12 months, serum ferritin, LVEF and incidence of adverse events at 6 and 12 months.
Notes	All outcomes were reported as median values in the published report. We obtained mean values from individual patient data provided by the principal investigator.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated sequence.
Allocation concealment (selection bias)	Low risk	Assignments made by central pharmacy.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participants and health personnel involved in diagnosis, exam interpretation, and treatment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	A central core lab concealed to treatment allocation and identity of the participant, performed interpretation of the all MRI images using a dedicated workstation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis performed; 1 participant excluded from the amlodipine arm due to lack of follow‐up MRIs; in the placebo arm, 1 participant lost to follow up and another excluded due to diagnosis other than thalassaemia major. Myocardial T2* values were not reported as the investigators uncovered a nonlinear relationship between MIC and myocardial T2*, and MIC was considered more clinically applicable. However, since we had access to the the individual patient data, we were able to obtain the heart T2* values.
Selective reporting (reporting bias)	Low risk	All intended primary and secondary outcome data were reported.
Other bias	Low risk	None identified.

LIC: liver iron concentration
 LVEF: left ventricular ejection fraction
 MIC: myocardial iron concentration
 MRI: magnetic resonance imaging
 SD: standard deviation