OPuS‐1.

Study characteristics
Methods	Design: binational, randomised, double‐blind, placebo‐controlled trial, cross‐over design Exclusions postrandomisation: 2 participants discontinued after randomisation but before first dose of study drug (1 withdrew consent and 1 was considered by investigator to be unable to meet visit schedule requirements) Losses to follow‐up: none reported Duration of study: November 2013 to May 2014 Unit of randomisation: participant
Participants	Country: Germany and the UK Setting: outpatient Number: 26 randomised (1 did not meet age eligibility criteria and 1 withdrew consent before randomisation). 24 completed study Age (mean): 42 (SD 11) years Sex: 9 male (37%); 15 female (63%) Inclusion criteria: men and non‐pregnant, non‐lactating women with HAE Type I or II; aged 18–65 years; body mass index 19–36 kg/m2; clinical diagnosis of HAE as documented by low C4 level and 1. low C1‐INH antigenic level, or 2. normal or increased C1‐INH antigenic level and a low C1‐INH functional level; able to provide documentation of a mean 1 HAE attack per week over ≥ 3 months demonstrated within past year. Exclusion criteria: use within the 7 days before screening or planned use through study of C1 inhibitor or tranexamic acid for prophylaxis of angioedema attacks; use within 30 days before screening or planned use through study of anabolic steroids for prophylaxis of angioedema attacks; concurrent use of anticoagulants, antiplatelet drugs, angiotensin‐converting enzyme inhibitors, oestrogen‐ or progestin‐containing contraceptive or non‐steroidal anti‐inflammatory drugs; prolonged activated partial thromboplastin time or prothrombin time at screening.
Interventions	Avoralstat 400 mg 3 times per day Placebo 3 times per day Treatment duration: 4 weeks for each period Washout period: 1 week
Outcomes	Rate of HAE attacks, AEs, AE‐QoL score
Funding	Supported by awards HL107188 and HL095021 from the National Heart, Lung, and Blood Institute, NIH
Declarations of interest	Quote: "E. Aygoren‐Pursun reports grants from Bio‐Cryst during the conduct of the study. J. Graff reports grants from BioCryst during the conduct of the study. I. Martinez‐Saguer reports grants from BioCryst during the conduct of the study and personal fees from CSL Behring, Shire, Viropharma, and SOBI Biovitrum outside the submitted work. W. Kreuz reports grants from BioCryst during the conduct of the study and personal fees from CSL Behring, Shire, Viropharma, and from SOBI Biovitrum outside the submitted work. H. Longhurst reports grants from BioCryst during the conduct of the study; grants, personal fees, and nonfinancial support from CSL Behring, Shire, and Viropharma; personal fees and nonfinancial support from SOBI Biovitrum; and personal fees from Dyax outside the submitted work. I. Nasr receives research funding from BioCryst. M. Bas reports grants from BioCryst during the conduct of the study and grants, personal fees, and nonfinancial support from CSL Behring, Shire, and Viropharma outside the submitted work. U. Straßen receives research funding from BioCryst. L. Fang receives research funding from BioCryst. M. Cornpropst, S. Dobo, and P. Collis report personal fees from BioCryst Pharmaceuticals during the conduct of the study and are employees of BioCryst. W. P. Sheridan reports personal fees from BioCryst Pharmaceuticals and is an employee of BioCryst. M. Maurer receives research support, honorarium, and travel support and serves as a consultant for BioCryst; serves as a consultant and receives payment for lectures from Shire and Viropharma; and reports grants from BioCryst during the conduct of the study, personal fees and nonfinancial support from Shire, CSL Behring, and Viropharma, and personal fees from SOBI Biovitrum outside the submitted work."
Notes	Funded by BioCryst, but study performed externally.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation not stated.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not stated.
Blinding of participants and personnel (performance bias)	Low risk	Participants and personnel were blinded.
Blinding of outcome assessment (detection bias)	Unclear risk	Blinding of outcome assessors not stated.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed the study.
Selective reporting (reporting bias)	High risk	2/4 stated outcomes in the protocol were not reported (AE‐QoL scores and AAS)
Other bias	Low risk	We identified no other sources of bias.