OPuS‐2.

Study characteristics
Methods	Design: multicentre, randomised, double‐blind, placebo‐controlled parallel trial Exclusions postrandomisation: none reported Losses to follow‐up: 7 (6.4%) participants discontinued study drug prior to week 12. Reasons for study drug discontinuation included AEs (1 participant due to rash and 1 participant due to angioedema attack in avoralstat 500 mg group), lack of efficacy (1 participant each in the avoralstat 300 mg group and the placebo group), positive pregnancy test (1 participant in placebo group), protocol violation (1 participant in avoralstat 500 mg group), and study non‐compliance (1 participant in placebo group) Duration of study: December 2014 to January 2016 Unit of randomisation: participant
Participants	Country: 46 centres in North America and Europe Setting: outpatient Number: 110 people randomised: 38 received avoralstat (BCX4161) 500 mg, 36 received avoralstat 300 mg and 36 received placebo. 103 (93.6%) participants completed study Age (mean): 41.2 (SD 13.3) years Sex: 25 men (22.7%); 85 women (77.3%) Inclusion criteria: aged ≥ 18 years; clinical diagnosis of Type I or II C1‐INH HAE as documented by either a low C1‐INH antigenic level (Type I HAE) or a normal C1‐INH antigenic level and a low C1‐INH functional level (Type II HAE); documentation of minimum angioedema attack rate of 2 per month, either by audit of medical record (≥ 2 angioedema attacks per month for 3 consecutive months within 6 months prior to screening) or a participant diary record of ≥ 4 unique angioedema attacks collected in a run‐in period of ≤ 2 months, with ≥ 1 attack occurring each month. Exclusion criteria: use of C1‐INH or tranexamic acid within 7 days prior to screening visit or expected use at any time during study; use of androgens within 30 days unless the person was receiving a stable dose of androgens ≥ 90 days prior to screening visit, met required angioedema attack frequency while on stable dose, and planned to remain on current dose of androgens during study.
Interventions	Avoralstat 500 mg orally 3 times/day Avoralstat 300 mg orally 3 times/day Placebo orally 3 times/day Treatment duration: 12 weeks
Outcomes	Rate of HAE attacks, AE‐QoL, AAS
Funding	BioCryst Pharmaceuticals, Inc
Declarations of interest	Quote: "This study was sponsored by BioCryst Pharmaceuticals, Inc (BioCryst), Durham, NC. Dr. Riedl reports grants from BioCryst during the conduct of the study; grants and personal fees from BioCryst, CSL Behring, Shire, and Pharming; and personal fees from Adverum, Alnylam, Ionis, and Kalvista outside the submitted work. Dr. Aygören‑Pürsün reports grants from BioCryst during the conduct of the study; personal fees and nonfinancial support from BioCryst; grants, personal fees, and nonfinancial support from CSL Behring; grants, personal fees, and nonfinancial support from Shire; and personal fees from Pharming and Adverum outside the submitted work. Dr Baker reports grants from BioCryst during the course of the study. Dr. Farkas reports personal fees from BioCryst during the conduct of the study, and personal fees from CSL Behring, Pharming, and Shire outside the submitted work. Dr. Anderson reports other from BioCryst during the conduct of the study, and personal fees from Shire, CSL Behring, and Pharming outside the submitted work. Dr. Bernstein reports grants and personal fees from BioCryst, Shire, CSL Behring, and Pharming during the conduct of the study. Dr. Bouillet reports personal fees and nonfinancial support from Shire; grants, personal fees, and nonfinancial support from Behring; personal fees and nonfinancial support from Pharming; grants, personal fees, and nonfinancial support from Novartis; nonfinancial support from GSK, nonfinancial support from Pfizer, and grants and nonfinancial support from LFB outside the submitted work. Dr, Busse received personal fees from CSL Behring; grants, personal fees, and other from Shire; personal fees and other from Pharming; personal fees from Pearl Therapeutics; personal fees from Teva; other from Law Offices of Victoria Broussard; and personal fees from Global Life Sciences outside the submitted work. Dr. Manning reports grants from BioCryst during the conduct of the study; grants and personal fees from Shire and CSL Behring, and Dyax; and personal fees from Pharming outside the submitted work. Dr. Magerl reports personal fees and nonfinancial support from Shire, Viropharma, CSL Behring, and BioCryst, and personal fees from Sobi outside the submitted work. Dr. Gompels reports other from Allergy Therapeutics; other from Bristol Myers; personal fees from Advisory board for BioCryst; and other from Viiv, Gilead, BMS, and Janssen outside the submitted work. Dr. Huissoon reports nonfinancial support from CSL limited and Shire Limited outside the submitted work. Dr. Longhurst reports grants and personal fees from BioCryst during the conduct of the study; grants and personal fees from CSL Behring; personal fees from Kalvista; personal fees from Pharming; personal fees from Adverum; and grants and personal fees from Shire outside the submitted work. Dr. Lumry reports consultancy fees from BioCryst during the conduct of the study; nonfinancial support from Medical Advisory Board of US HAEA; other from Shire/Viropharma, Pharming, Adverum, and CSL Behring; research grants from Shire/Viropharma and CSL Behring; and speakers bureau honoraria and travel support from Shire/Viropharma, CSL Behring, and Pharming outside the submitted work. Dr Ritchie reports grants from Bio‐Cryst during the conduct of the study. Dr. Shapiro reports investigator and speaker; consultant fees from Shire; and investigator fees from GreenCross. Dr. Soteres reports other from BioCryst during the conduct of the study and other from BioCryst; personal fees and other from Shire; personal fees from CSL Behring; and personal fees from Pharming outside the submitted work. Dr. Banerji reports research grants and other from BioCryst during the conduct of the study; research grants and other from Shire; and other from CSL, Alnylam, and Pharming outside the submitted work. Dr Cancian reports grants from BioCryst during the conduct of the study. Dr. Johnston reports grants and personal fees from BioCryst, during the conduct of the study; personal fees from Shire; personal fees from CSL Behring; personal fees from BioCryst; and personal fees from Pharming outside the submitted work. Dr. Craig reports grants and other from BioCryst, during the conduct of the study; other from CSL Behring; other from Shire; other from Grifols; other from Pharming; and other from HAE Association, outside the submitted work. Dr. Launay reports grants from BioCryst Pharmaceuticals; grants from Shire; and grants from CSL Behring, during the conduct of the study. Dr Li reports grants and nonfinancial support from BioCryst during the conduct of the study, and grants, personal fees, and nonfinancial support from Shire, CSL Behring, and Pharming outside the submitted work. Drs. Nickel and Schrijvers report other from BioCryst during the conduct of the study. Drs Offenberger, Rae, Triggiani, and Wedner report grants from BioCryst during the conduct of the study. S. Dobo, M. Cornpropst, D. Clemons, P. Collis, and W. Sheridan are employees of BioCryst. L. Fang reports consultancy fees from Bio‐Cryst. Dr. Maurer reports grants and personal fees from BioCryst during the conduct of the study, and grants and personal fees from BioCryst, Shire, Pharming, and CSL Behring outside the submitted work. There is no further conflict of interests to declare. The sponsor provided research grant support to all investigators. All authors had access to all of the data in the study and approved the final published manuscript. The corresponding author had final responsibility for the decision to submit for publication."
Notes	Funded by BioCryst Pharmaceuticals but study performed externally.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation unclear.
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation unclear.
Blinding of participants and personnel (performance bias)	Low risk	Participants and personnel were blinded.
Blinding of outcome assessment (detection bias)	Low risk	Outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawal rates were low and evenly distributed, and ITT analysis was performed.
Selective reporting (reporting bias)	Low risk	Most outcomes in protocol were reported on. EuroQol was missing, but AE‐QoL was present.
Other bias	Low risk	We identified no other sources of bias.