Leissinger 2011.

Methods	Multicenter randomized cross‐over study conducted at 16 centres in Europe and USA
Participants	34 participants Inclusion criteria: severe hemophilia A and a history of a factor VIII inhibitor titre exceeding 5 BU, older than 2 years old, being treated with bypassing agents and had 6 or more episodes of bleeding requiring treatment in the 6 months before the study Exclusion criteria: receiving immune tolerance therapy, regular prophylaxis with any hemostatic agent, symptomatic liver disease, platelet count of less than 100,000 per μL, planned elective surgery within 12 months, used an investigational product within 1 month of study enrolment, planned to begin treatment with interferon or protease inhibitor
Interventions	Prophylaxis: AICC (FEIBA) administration at a target dose of 85 units/kg (+/‐ 15%) on 3 non‐consecutive days weekly On demand: AICC at a target dose of 85 units/kg (+/‐ 15%) for bleeding episode Duration of treatment: 6 months of prophylaxis, 3 months of washout period and 6 months of on‐demand therapy (prophylaxis first), 6 months of on‐demand therapy, 3 months of washout period and 6 months of prophylaxis (on‐demand therapy first)
Outcomes	Primary outcome: reduction of bleeding events during prophylaxis period compared with the on‐demand period Secondary outcomes: number of joint bleeding, number of target joint bleeding, HRQoL and safety
Notes	Study funded by Baxter Bioscience who provided AICC. Study investigators and a medical writer paid by Baxter Bioscience prepared the manuscript
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization conducted from a centralized call center (telephone randomization) – information from the online protocol
Allocation concealment (selection bias)	Low risk	Randomization conducted from a centralized call center (telephone randomization) – information from the online protocol
Blinding of participants and personnel (performance bias) All outcomes	High risk	For ethical and practical reasons, participants were aware of study assignments
Blinding of outcome assessment (detection bias) All outcomes	High risk	For ethical and practical reasons, participants were aware of study assignments
Incomplete outcome data (attrition bias) All outcomes	High risk	Per protocol results reported for efficacy outcomes (reduction in bleeding rates / joint bleeding rates), ITT approach for safety outcomes (monthly hemorrhage rates, adverse effects). Up to 24% of participants excluded from results: 1 patient withdrew consent before receiving study medication. The ITT group comprised 33 participants, of whom 7 did not complete the study: 1 withdrew because of an allergic reaction, 2 died, 1 was lost to follow‐up after Hurricane Katrina, and 3 withdrew consent (2 during the on‐demand period and 1 during the prophylaxis period)
Selective reporting (reporting bias)	Low risk	Online protocol available. All outcomes reported in protocol fully reported in the study, no evidence of selective reporting
Other bias	Low risk	None identified