Kaspers 2013.

Methods	Block randomisation (block size 4) with a central interactive computerized system (stratified by study group and time to relapse on a 1:1 basis)
Participants	394 children (age 0‐19 years; 231 boys and 163 girls) with acute myeloid leukaemia (non‐FAB type M3; stage nm; first relapse or primary refractory disease). Prior treatment yes (heterogenous first‐line treatment, but all groups applied cytarabine‐based treatment combined with an anthracycline and allogeneic stem cell transplant was used in a limited number of patients; no further information provided) No prior cardiac dysfunction (patients with symptomatic cardiac disease and/or left ventricular shortening fraction < 29% were excluded)
Interventions	Re‐induction chemotherapy without daunoxome (=liposomally entrapped daunorubicin; N = 197) versus chemotherapy including daunoxome (N = 197) Cumulative daunoxome dose nm (according to protocol 180 mg/m2); peak dose (i.e. the maximal dose received in one week) 180 mg/m2; infusion duration nm Cranial irradiation was not recommended No surgery No cardioprotective interventions
Outcomes	Overall survival (defined as time from study enrolment untill last follow‐up or death from any cause) Tumour response (complete response (after 2 courses) defined as 5% or less leukemic blasts in bone marrow with signs of normal haematopoiesis and of regeneration of normal peripheral blood cell production (platelets > 50x109/L without transfusions, neutrophils > 1.0x109/L) and no leukaemic cells in the peripheral blood or anywhere else) Cardiotoxicity (grade 3 or 4 acute toxicity according to National Cancer Institute Common Toxicity Criteria version 2)
Notes	Median length of follow‐up 4 years Age in treatment group ranged from 0 to 19 years (median 10 years); age in the control group ranged from 0 to 19 years (median 9 years) Re‐induction chemotherapy was followed by allogeneic stem cell transplant if available (different conditioning regimens); otherwise patients received consolidation chemotherapy (different schedules). An inclusion criterium for this systematic review was that therapy other than anthracyclines should have been the same in both treatment groups; timing of different aspects of the treatment could differ between the treatment groups, but the cumulative doses of therapy other than anthracyclines should not differ more than 25% between the treatment groups. Although this was not completely clear for this study, it was stated that treatment was well‐balanced between the treatment groups and therefore we gave this study the benefit of the doubt and judged it to be eligible for inclusion.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation was performed using a central interactive computerised system
Allocation concealment (selection bias)	Low risk	Block randomisation was performed using a central interactive computerised system
Blinding of participants and personnel (performance bias)	High risk	It was an open label study
Blinding of outcome assessment (detection bias): overall survival	Low risk	Since this was an open label study, outcome assessors were not blinded. However, blinding of outcome assessors is not applicable for overall survival, so we judged this as a low risk of bias
Blinding of outcome assessment (detection bias): outcomes other than overall survival	High risk	It was an open label study
Incomplete outcome data (attrition bias): overall survival	Low risk	Intention‐to‐treat analyses were performed
Incomplete outcome data (attrition bias): tumour response	Low risk	Intention‐to‐treat analyses were performed
Incomplete outcome data (attrition bias): anthracycline‐induced cardiotoxicity	High risk	7% of participants lost to follow‐up
Selective reporting (reporting bias)	Low risk	There was no protocol mentioned in the manuscript (and we did not search for it), but all expected outcomes were reported
Other bias	High risk	Block randomisation in unblinded trials: yes (see information provided at earlier associated risk of bias items) Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex and/or prior cardiac dysfunction): unclear (age and sex were balanced between treatment arms; no prior cardiac dysfunction; unclear if prior cardiotoxic treatment was balaned between the treatment arms) Difference in length of follow‐up between treatment arms: unclear (not reported) Inappropriate influence of funders: unclear (there was no outside funding for the trial and daunoxome was not provided free of charge, but two authors had a consultant/advisory role at the pharmaceutical company which delivered daunoxome and where compensated for this)