APeX‐1.

Study characteristics
Methods	Design: dose‐ranging, placebo‐controlled, double‐blind, parallel, randomised trial Exclusions postrandomisation: none reported Losses to follow‐up: 2 participants never received a trial regimen or entered any diary data and 3 discontinued the trial regimen owing to an AE or laboratory abnormality Duration of study: 1 year (trial initiated in August 2016, the last participant observation in August 2017) Unit of randomisation: participant
Participants	Country: international (86 patients screened from 26 sites across Europe, Canada and Australia) Setting: outpatient Number: 77 participants underwent randomisation, 75 received berotralstat (BCX7353) or placebo, 72 completed the trial; 23 participants received placebo, 7 received berotralstat 62.5 mg, 14 received berotralstat 125 mg, 15 received berotralstat 250 mg, and 18 received berotralstat 350 mg Age (mean): 44.5 (SD 12.5) years Sex: male 29 (38.7%); female 46 (61.3%) Inclusion criteria: adults aged 18–70 years with Type I or II HAE with history of ≥ 2 angioedema attacks per month for 3 consecutive months within a 6‐month period Exclusion criteria: suspected to have C1 inhibitor resistance or using a C1 inhibitor, androgens, or tranexamic acid for prophylaxis of attacks within 7 days before screening
Interventions	Berotralstat 62.5 mg once daily Berotralstat 125 mg once daily Berotralstat 250 mg once daily Berotralstat 350 mg once daily Placebo once daily Treatment duration: 28 days
Outcomes	Number of attacks (overall, by location), change in AE‐QoL, AEs
Funding	Sponsored by BioCryst Pharmaceuticals.
Declarations of interest	Numerous conflicts of interest among study authors; see disclosure form at www.nejm.org/doi/suppl/10.1056/NEJMoa1716995/suppl_file/nejmoa1716995_disclosures.pdf
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	Double‐blind.
Blinding of outcome assessment (detection bias)	Unclear risk	Blinding of outcome assessment not stated.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed.
Selective reporting (reporting bias)	Low risk	All outcomes in protocol were reported on.
Other bias	Low risk	None.