PROPEL III 2020.

Study characteristics
Methods	Open‐label, phase 3, prospective, randomized, multi‐centre clinical study comparing the safety and efficacy of BAX 855 following PK‐guided prophylaxis targeting two different FVIII trough levels in subjects with severe haemophilia A. Trial conducted at 62 study sites in 19 countries from November 2015 to August 2018. Participants underwent a 72‐ to 96‐hour washout period followed by initial PK parameter evaluation. Blood samples were taken within 30 minutes before a single intravenous infusion of 60 ± 5 IU/kg rurioctocog alfa pegol and at 7 time points up to 96 ± 4 hours post‐infusion.
Participants	Participants 12 ‐ 65 years old with severe haemophilia A (FVIII level < 1%), and an ABR ≥2 during the 12 months before study entry; had either completed a previous rurioctocog alfa pegol study or were naïve to rurioctocog alfa pegol; and had received prophylaxis or on‐demand treatment (for breakthrough bleeds) with plasma‐derived or recombinant FVIII for ≥ 150 documented exposure days. Number randomised: 115
Interventions	PwHA were randomly assigned (1:1) to 12 months of PK‐guided prophylaxis with rurioctocog alfa pegol targeting FVIII troughs of either 1% ‐ 3% (reference arm) or ~10% (8% ‐ 12%). Targeting trough levels of 1% ‐ 3%; N = 57. Targeting trough levels of 8% ‐ 12%; N = 58.
Outcomes	1. Pharmacokinetic parameters 2. Hemostatic efficacy; Presence or absence of any bleeds in the second 6‐month study period reported as proportion of patients with zero total bleeds. Proportions of PwHA who achieved zero spontaneous bleeds and zero spontaneous joint bleeds during the second 6‐months. Total ABR, spontaneous ABR, spontaneous joint ABR, joint ABR, ABR in joints with ≥ 4 spontaneous bleeds in 6 consecutive months, and injury‐related ABR. Total ABR during the 12‐month trial period was compared with historical ABR during the 12 months before enrollment. Change from baseline in the number of joints with ≥ 4 spontaneous bleeds. 3. Adverse events (inhibitor development, immunogenicity).
Notes	ClinicalTrials.gov NCT02585960; EudraCT 2014‐005477‐37 Dates of study; November 2015 to August 2018 Source of funding: Baxalta US Inc., a Takeda company, and Baxalta Innovations GmBH, a Takeda company, Vienna, Austria.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was stratified according to pre‐study treatment regimen and ABR (prophylaxis with ABR < 5 vs prophylaxis with ABR ≥ 5 vs on‐demand) and was independent of the patient’s PK profile."
Allocation concealment (selection bias)	Unclear risk	"The investigator and patient chose the dosing interval and dose was selected from the sponsor’s dosing recommendation table."
Blinding (performance bias and detection bias) Clinical Joint Function	Unclear risk	Not assessed.
Blinding (performance bias and detection bias) Bleeding	High risk	An open‐label trial.
Blinding (performance bias and detection bias) Radiologic Joint Score	Unclear risk	Not assessed.
Blinding of outcome assessment (detection bias) Bleeding	High risk	Outcome assessment was by patient self‐report. "Each patient was provided with a diary in electronic/paper format to record details of their infusions, bleeds and response to treatment, physical activity, unexpected events, and patient reported outcomes."
Blinding of outcome assessment (detection bias) Clinical Joint Function	Unclear risk	Not assessed.
Blinding of outcome assessment (detection bias) Radiologic Joint Score	Unclear risk	Not assessed.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Reasons for dropouts were discussed and were likely not due to allocated treatment. Both intention‐to‐treat (full analysis set) and per protocol analysis done.
Selective reporting (reporting bias)	Low risk	While the original protocol was not assessed (authors provided a 3‐month time frame to make this assessible), all expected outcomes were reported in the trial results.
Other bias	Low risk	No other potential sources of bias identified.