Leaute‐Labreze 2015.

Methods	Design: parallel, 4 arms Country: France Method of randomisation: interactive voice‐response system, with the use of block randomisation stratified according to age group (35 to 90 days vs 91 to 150 days) and haemangioma location (facial vs non‐facial). Page 736 Blinding: participants, outcome evaluators Location: Unité de Dermatologie Pédiatrique, Hôpital Pellegrin‐ Enfants, Pl. Amélie Raba Léon, Bordeaux, France Length of follow‐up: 24 weeks (first measurement). Last follow‐up was performed at week 96.
Participants	Diagnosis: proliferating infantile haemangioma requiring systemic therapy (i.e. an evaluated lesion with a minimal diameter of 1.5 cm) Sex: male: 131; female: 325 Age: between 35 to 150 days of age Inclusion criteria: a proliferating IH (target haemangioma) requiring systemic therapy present anywhere on the child's body except on the diaper area, with largest diameter of at least 1.5 cm; written informed consent; 35 to 150 days old Exclusion criteria: congenital haemangioma; Kasabach‐Merritt syndrome; bronchial asthma; bronchospasm; hypoglycaemia (< 40 mg/dL or at risk); untreated phaeochromocytoma; hypotension (< 50/30 mmHg); second‐ or third‐degree heart block; cardiogenic shock; metabolic acidosis; bradycardia (< 80 beats per minute); severe peripheral arterial circulatory disturbances; Raynaud’s phenomenon; sick sinus syndrome; uncontrolled heart failure or Prinzmetal’s angina; documented PHACE syndrome with central nervous system involvement; previously been treated for IH; child’s mother had been breastfeeding the child while she was also being treated with beta blockers; known to have a hypersensitivity to propranolol and/or any other beta blockers; life‐threatening IH; function‐threatening IH (e.g. those causing impairment of vision, or respiratory compromise caused by airway lesions); ulcerated IH (whatever the localisation) with pain and lack of response to simple wound care measures; born prematurely and had not yet reached his/her term‐equivalent age; left ventricular systolic function ≤ 40% and/or cardiomyopathy and/or hereditary arrhythmia disorder Number of randomised children: 460
Interventions	Intervention A (number of children: 98): propranolol at 1 mg per kilogram per day for 3 months Intervention B (number of children: 102): propranolol at 1 mg per kilogram per day for 6 months Intervention C (number of children: 100): propranolol at 3 mg per kilogram per day for 3 months Intervention D (number of children: 101): propranolol at 3 mg per kilogram per day for 6 months Intervention E (number of children: 55): placebo at 3 mg per kilogram per day for 6 months
Outcomes	Primary Complete or nearly complete resolution of the target haemangioma (with nearly complete resolution defined as a minimal degree of telangiectasis, erythema, skin thickening, soft‐tissue swelling, and distortion of anatomical landmarks), haemangioma evolution (improvement, stabilisation, or worsening), and change in haemangioma size and colour were assessed centrally. Secondary Centralised assessments of the target IH Investigator on‐site qualitative assessments of the target IH at each postbaseline visit vs baseline Investigator on‐site qualitative assessments of the target IH at paired consecutive patient visits (each scheduled postbaseline visit compared to the previous scheduled visit) Other investigator on‐site qualitative assessments at each scheduled postbaseline visit Parent(s) or guardian(s) on‐site qualitative assessments of the target IH at each scheduled postbaseline visit compared to the previous scheduled visit Intake of IH treatment (outside that assigned in the trial) during follow‐up (systemic/local beta blockers, systemic/local corticoids, and laser)
Notes	Trial registration: NCT01056341 Funder: Pierre Fabre Dermatologie Role of funder: involved in study design, analysis, and manuscript production A priori sample size estimation: yes (page 737) Conducted: February 2010 to November 2011 Declared conflicts of interest: stated in full text (supplementary appendix)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Patients were assigned to treatment through an interactive voice‐response system, with the use of block randomisation stratified according to age group (35 to 90 days vs. 91 to 150 days) and hemangioma location (facial vs. non‐facial) and applied in a 2:2:2:2:1 ratio (propranolol at 1 mg per kilogram per day for 3 months, propranolol at 1 mg per kilogram per day for 6 months, propranolol at 3 mg per kilogram per day for 3 months, propranolol at 3 mg per kilogram per day for 6 months, and placebo, respectively).” Page 736 Comment: Authors reported information about adequate random sequence generation.
Allocation concealment (selection bias)	Low risk	Quote: “Patients were assigned to treatment through an interactive voice‐response system, with the use of block randomisation stratified according to age group (35 to 90 days vs. 91 to 150 days) and hemangioma location (facial vs. non‐facial) and applied in a 2:2:2:2:1 ratio (propranolol at 1 mg per kilogram per day for 3 months, propranolol at 1 mg per kilogram per day for 6 months, propranolol at 3 mg per kilogram per day for 3 months, propranolol at 3 mg per kilogram per day for 6 months, and placebo, respectively).” Page 736 Comment: Authors reported information about adequate allocation concealment.
Blinding of participants (Performance bias)	Low risk	Quote: “Different concentrations of propranolol were used (1.25, 2.50, or 3.75 mg per millilitre) in order to administer the same volume to each patient and thereby maintain blinding; patients assigned to 3‐month propranolol regimens received placebo for the second 3 months.” Page 737 Comment: Authors reported information about adequate blinding of participants.
Blinding of personnel (performance bias)	Unclear risk	There was insufficient information to assess this item as low or high.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Primary efficacy was assessed by centralized evaluation of standardized digital photographs (taken by investigators at each visit) by two independent, trained, validated readers who were unaware of the study‐group assignments, with adjudication for discrepancies; inter‐reader and intra‐reader reliability were assessed.” Page 737 Comment: Authors reported information about adequate blinding of outcome assessment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The percentage lost at follow‐up was between 1% and 4%, respectively (intention‐to‐treat analysis with overrun).
Selective reporting (reporting bias)	Low risk	All outcomes were predefined and reported.
Other bias	Unclear risk	Quote: “The sponsor (Pierre Fabre Dermatologie) was involved in the study design in collaboration with three of the academic authors and was responsible for trial management, analysis and interpretation of data, and the decision to submit the manuscript for publication.” Page 736 Comment: The industry sponsor was involved in the analysis and interpretation of the data, as well as the decision to submit the manuscript for publication. It is unclear what effect this may have on the study results.