APeX‐2.

Study characteristics
Methods	Design: phase 3, randomised, double‐blind, placebo‐controlled parallel‐group multicentre study Exclusions postrandomisation: none reported Losses to follow‐up: 12 participants discontinued treatment early (4 receiving berotralstat 110 mg; 3 receiving berotralstat 150 mg and 5 receiving placebo). In addition, 5 participants discontinued treatment because of a laboratory result abnormality or AE (3 receiving berotralstat 110 mg; 1 receiving berotralstat 150 mg and 1 receiving placebo), 4 discontinued treatment due to perceived lack of efficacy (1 receiving berotralstat 110 mg; 1 receiving berotralstat 150 mg and 2 receiving placebo), 2 withdrew consent (1 receiving berotralstat 150 mg and 2 receiving placebo), and 1 withdrew consent for other reasons (1 receiving placebo) Duration of study: 24 weeks Unit of randomisation: participant
Participants	Country: 40 sites in 11 countries, including the US, Canada and Europe Setting: outpatient Number: children or adults aged ≥ 12 years with Type I or II HAE. 121 people were randomised; 120 received ≥ 1 dose of treatment (41 received berotralstat 110 mg, 40 received berotralstat 150 mg, and 39 received placebo) Age (mean): 41.6 (SD 15.2) years Sex: female 80 (66.1%); male 41 (33.9%) Inclusion criteria: people with HAE aged ≥ 12 years if living in the US and Canada and ≥ 18 years if living in Europe. People with a C1‐INH functional level between 50% and the assay LLN (74%) or a C4 value greater than the LLN could qualify for inclusion under additional alternative protocol‐specified criteria. Used a prospective run‐in period of up to 70 days to determine baseline attack rate. Patients with ≥ 2 distinct investigator‐confirmed HAE attacks requiring treatment or causing functional impairment in first 56 days of prospective run‐in period were eligible for enrolment. Exclusion criteria: used androgen or tranexamic acid prophylaxis within 28 days of screening or C1‐INH prophylaxis within 14 days of screening.
Interventions	Berotralstat 110 mg once daily Berotralstat 150 mg once daily Placebo once daily Treatment duration: 24 weeks
Outcomes	Rate of HAE attacks, AE‐QoL, days with HAE symptoms, responders, rescue medication use, treatment satisfaction
Funding	Funded by BioCryst Pharmaceuticals.
Declarations of interest	Quote: "B. Zuraw reports personal fees from Adverum Biotechnologies, Attune Pharmaceuticals, BioCryst Pharmaceuticals, CSL Behring, Intellia Therapeutics, Pharming, and Shire/Takeda; research grants and travel support from the United States Hereditary Angioedema Association; and a laboratory service agreement from Ionis Pharmaceuticals outside the submitted work. B. Zuraw also has a TSKA patent pending (licensee, US Hereditary Angioedema Association [US HAEA]). W. R. Lumry reports grants from BioCryst Pharmaceuticals during the conduct of the study; in addition, he is a member of the US HAEA Medical Advisory Board, and he reports the following: grants and personal fees from CSL Behring and Shire/Takeda; grants from Ionis Pharmaceuticals and KalVista; and personal fees from Adverum Biotechnologies, Intellia, and Pharming outside the submitted work. D. Johnston reports personal fees from BioCryst Pharmaceuticals, CSL Behring, Pharming, Regenxbio, and Takeda outside the submitted work. E. Aygören‐Pürsün reports grants and personal fees from BioCryst Pharmaceuticals and grants from CSL Behring and Shire during the conduct of the study. In addition, E. Aygören‐Pürsün reports grants and personal fees from BioCryst Pharmaceuticals, CSL Behring, and Shire/Takeda; grants from KalVista; and personal fees from Pharming outside the submitted work. A. Banerji reports grants from BioCryst Pharmaceuticals, as well as personal fees and advisory board fees from BioCryst Pharmaceuticals, CSL Behring, KalVista, Pharming, Pharvaris, and Takeda outside the submitted work. J. Best reports grants and personal fees from BioCryst Pharmaceuticals, CSL Behring, Ionis Pharmaceuticals, KalVista, Pharming, and Shire/Takeda; in addition, she is a member of the US HAEA Medical Advisory Board, and she reports grants and personal fees from AstraZeneca, Genentech, Novartis, and Sanofi Regeneron outside the submitted work. S. Christiansen reports personal fees from BioCryst Pharmaceuticals, CSL Behring, and Takeda advisory boards outside the submitted work. J. S. Jacobs reports contracted research support from BioCryst Pharmaceuticals during the conduct of the study, and personal fees from Pharming and personal fees and contracted research support from CSL Behring and Takeda outside the submitted work. K. V. Sitz reports personal fees and grants from BioCryst Pharmaceuticals during the conduct of the study, as well as grants from 3M, AstraZeneca, GlaxoSmithKline, Novartis, Pearl, and Watson outside the submitted work. R. Gower reports clinical research and advisory board payments from BioCryst Pharmaceuticals during the conduct of the study, as well as speaker, advisory board, and clinical research trial payments and consultant fees from CSL Behring and Shire/Takeda outside the submitted work; in addition, R. Gower reports advisory board and clinical research trial payments, as well as consultant fees from Pharming outside the submitted work. T. Kinaciyan reports clinical study conducting fees from BioCryst Pharmaceuticals during the conduct of the study, personal fees and clinical study conducting fees from Shire/Takeda, expert meetings fees from CSL Behring, and clinical study conducting fees from KalVista outside the submitted work. J. Hanzlíková reports clinical study conducting fees from and cooperation with BioCryst Pharmaceuticals, CSL Behring, and Takeda. J. T. Anderson reports personal fees and other support from BioCryst Pharmaceuticals during conduct of the study, reports personal fees, clinical research, and advisory board fees from BioCryst Pharmaceuticals during the conduct of the study, and clinical research fees, speaker fees, and advisory board fees from CSL Behring, Pharming, and Shire/Takeda outside the submitted work. W. Yang is a member of advisory boards for BioCryst Pharmaceuticals, CSL Behring, Merck, Novartis, Sanofi, and Shire/Takeda; in addition, he has received speaker fees for AstraZeneca, Merck, Novartis, and Shire/Takeda and has received research grants from Aimmune Therapeutics, ALK, AnaptysBio, AstraZeneca, BioCryst Pharmaceuticals, CSL Behring, DBV Technologies, Dermira, Genentech, GlaxoSmithKline, Glenmark, Pharming, Regeneron, Roche, Sanofi, and Shire/Takeda. R. Tachdjian reports speaker and advisory board fees from CSL Behring, Pharming, and Takeda, as well as research support from Ionis Pharmaceuticals. P. Busse reports grants and personal fees from BioCryst Pharmaceuticals, CSL Behring, Novartis, Pharming, ResTORbio, and Shire/Takeda; she also reports personal fees from AstraZeneca, CVS Health, Fresenius, GlaxoSmithKline; the Law Offices of Levin, Riback, Adelman, and Flangel; and Pearl Therapeutics and Vedderprice. In addition, she has received nonfinancial support from the US HAEA and the American Academy of Allergy, Asthma & Immunology outside the submitted work. T. Craig reports past research, consultant, and speaker fees from CSL Behring and Takeda; speaker and consultant fees from Pharming; and research and consultant fees from BioCryst Pharmaceuticals; in addition, he is a member of the US HAEA Medical Advisory Board. H. H. Li reports grants from BioCryst Pharmaceuticals during the conduct of the study and grants and personal fees from CSL Behring, Pharming, and Shire/Takeda outside the submitted work. H. Farkas reports grants and personal fees from CSL Behring, Pharming, and Shire/Takeda, as well as personal fees from BioCryst Pharmaceuticals and KalVista outside the submitted work. J. M. Best, D. Clemons, M. Cornpropst, S. Dobos, H. A. Iocca, D. Kargl, E. Nagy, S. Murray, P. Collis, and W. P. Sheridan are employees of BioCryst Pharmaceuticals. M. Maurer reports grants and personal fees from BioCryst Pharmaceuticals during the conduct of the study; grants and personal fees from CSL Behring, KalVista, Moxie, and Shire/Takeda; grants from Pharming; and personal fees from Pharvaris outside the submitted work. M. Riedl reports grants and personal fees from BioCryst Pharmaceuticals during the conduct of the study; grants and personal fees from CSL Behring, Pharming, and Shire/Takeda; grants from Ionis Pharmaceuticals; and personal fees from Adverum Biotechnologies, Attune, KalVista, and Pharvaris outside the submitted work; in addition, he is a member of the US HAEA Medical Advisory Board. The rest of the authors declare that they have no relevant conflicts of interest."
Notes	Funded by BioCryst, but study performed externally.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation.
Allocation concealment (selection bias)	Low risk	Quote: "All patients, investigators, and site and sponsor personnel were blinded to treatment group allocation, except for sponsor or vendor staff responsible for the management of study drug supplies." Computer generation of randomisation prevented anticipation of allocation.
Blinding of participants and personnel (performance bias)	Low risk	Quote: "All patients, investigators, and site and sponsor personnel were blinded to treatment group allocation, except for sponsor or vendor staff responsible for the management of study drug supplies."
Blinding of outcome assessment (detection bias)	Low risk	Quote: "All patients, investigators, and site and sponsor personnel were blinded to treatment group allocation, except for sponsor or vendor staff responsible for the management of study drug supplies."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Analysis was ITT.
Selective reporting (reporting bias)	Low risk	All outcomes in protocol were reported on.
Other bias	Low risk	None.