APeX‐J.

Study characteristics
Methods	Design: phase 3, randomised, double‐blind, placebo‐controlled, parallel group trial Exclusions postrandomisation: none reported Losses to follow‐up: 1 participant in the placebo group discontinued treatment early due to a TEAE of urticaria Duration of study: 24 weeks (quote: "This study remains ongoing and data presented herein summarize the results of the 24‐week placebo‐controlled period only") Unit of randomisation: participant; randomisation stratified by baseline expert‐confirmed attack rate (≥ 2 attacks/month vs < 2 attacks/month) at time of randomisation
Participants	Country: 11 sites in Japan Setting: outpatient Number: children or adults aged ≥ 12 years with Type I or II HAE. 19 people randomised to receive once‐daily treatment (6 received berotralstat 110 mg, 7 received berotralstat 150 mg and 6 received placebo) Age (mean): 42 (SD 13) years Sex: 3 male (16%); 16 female (84%) Inclusion criteria: aged ≥ 12 years with a clinical diagnosis of Type I or II HAE, defined as having a C1‐INH functional level < 50% and C4 level below the LLN reference range as assessed during screening period. Patients with C1‐INH functional level between 50% and the assay LLN (74%) or a C4 value above the LLN could qualify via alternative protocol‐specified criteria. Patients underwent a prospective run‐in period of 56 days to determine eligibility. Patients with ≥ 2 independent expert‐confirmed HAE attacks during the prospective run‐in period were eligible for enrolment. Exclusion criteria: used androgens or tranexamic acid for prophylaxis of angioedema attacks within the 28 days before the screening visit or had any planned initiation during study, or had used C1‐INH for prophylaxis of angioedema attacks within 14 days before screening or had any planned initiation during study.
Interventions	Berotralstat 110 mg once daily Berotralstat 150 mg once daily Placebo once daily Treatment duration: 24 weeks
Outcomes	Rate of HAE attacks, number of days with HAE symptoms, change in AE‐QoL, responders, AEs, SAEs
Funding	Funded by BioCryst Pharmaceuticals, Inc, Durham, North Carolina, USA
Declarations of interest	Quote: "DH reports speaker fees from CSL Behring, Kyowa Kirin, Otsuka, Shire, and Takeda outside the submitted work. GC, MC, SCM, SMD, EN, SVD, LR, JB, HI, PC, and WPS are employees of BioCryst Pharmaceuticals. GC, EN, LR, and WPS hold stock options in BioCryst Pharmaceuticals. MH reports personal fees from BioCryst Pharmaceuticals during the conduct of the study; personal fees from Shire/Takeda; and grants and personal fees from CSL Behring, outside the submitted work; and a grant of the Ministry of Health, Labour and Welfare of Japan. IO, YSuzuki, TF, KK, EM, SM, OI, YSasaki, and MT have nothing to disclose."
Notes	Funded by BioCryst, but study performed externally.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Eligible patients were randomized 1:1:1 to berotralstat 110 mg, berotralstat 150 mg, or placebo into part 1 of the study via an interactive response system."
Allocation concealment (selection bias)	Low risk	Allocation was blinded from investigators, staff and participants; interactive response system prevents knowledge of the next allocation.
Blinding of participants and personnel (performance bias)	Low risk	Allocation was blinded from investigators, staff and participants.
Blinding of outcome assessment (detection bias)	Low risk	Allocation was blinded from investigators, staff and participants.
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis.
Selective reporting (reporting bias)	Low risk	All outcomes in protocol were reported on.
Other bias	Low risk	None.