COMPACT extension.

Study characteristics
Methods	Design: multicentre, randomised, parallel, open‐label extension of COMPACT trial Exclusions postrandomisation: none reported Losses to follow‐up: of 15 (11.9%) participants who discontinued treatment before week 53, 9 (7.1%) discontinued during treatment period 1 (4/63 (6.3%) in C1‐INH(SC) 60 IU/kg group and 5/63 (7.9%) in C1‐INH(SC) 40 IU/kg group) and 6 (4.8%) participants discontinued during treatment period 2 (3 in each group). In addition, 1 (1.6%) participant from C1‐INH(SC) 60 IU/kg group discontinued during extension period. 4 AEs led to study discontinuation, including the unrelated SAE of myocardial infarction. 4 (3.2%) participants discontinued treatment because of pregnancy, having received a total exposure of 15–85 doses of C1‐INH(SC), inclusive of administrations throughout the first trimester until pregnancy was detected. Duration of study: treatment period 1: 24 weeks; treatment period 2: 28 weeks Unit of randomisation: participant
Participants	Country: 32 hospitals across 11 countries (Australia, Canada, Czech Republic, Germany, Hungary, Israel, Italy, Romania, Spain, the UK, and the US) Setting: outpatient Number: 63 participants received C1‐INH(SC) 40 IU/kg and 63 participants received C1‐INH(SC) 60 IU/kg Age (mean): 40.5 (SD 15.6) years Sex: 50 male (40%); 76 female (60%) Inclusion criteria: participants who completed COMPACT and study treatment‐naive patients were eligible to enrol into the COMPACT extension study to receive ≥ 52 weeks of continuous therapy with C1‐INH(SC); aged ≥ 6 years with biochemically confirmed diagnosis of Type I (C1‐INH deficiency) or Type II (C1‐INH dysfunction) HAE, with C1‐INH functional levels < 50%; people with a history of experiencing frequent attacks (≥ 4 attacks within 2 consecutive months) before enrolment into the COMPACT programme were eligible; people using oral prophylactic medication were required to be on a stable regimen and willing to continue this regimen for the study duration. Exclusion criteria: any clinical conditions likely to interfere with evaluation of study drug, clinical history of poor response to C1‐INH therapy, and any patient whose HAE could not be adequately managed by on‐demand pharmacological treatment as assessed by investigator.
Interventions	C1‐INH 40 IU/kg self‐administered twice‐weekly C1‐INH 60 IU/kg self‐administered twice‐weekly Treatment duration: 1.5–2 years
Outcomes	Long‐term safety: serious adverse events, withdrawals due to adverse events, thromboembolic events, anaphylaxis, HAE attacks requiring hospitalisation, injection site reactions, other adverse events, rate of HAE attacks, rescue medication use, duration of attacks, number of symptomatic days.
Funding	CSL Behring (Marburg, Germany)
Declarations of interest	Quote: "T. Craig reports grant support from CSL Behring during the conduct of the study; is a speaker for CSL Behring, Dyax, Grifols, Pharming, and Shire; reports grant support from AstraZeneca, BioCryst, Boehringer Ingelheim, CSL Behring, Dyax, Genentech, GlaxoSmithKline, Grifols, Merck, Novartis, Pharming, Sanofi, and Shire; has received consultancy fees and/or speaker’s honoraria from BioCryst, Bellrose, CSL Behring, Dyax, Grifols, Merck, Novartis, Pharming Technologies, and Shire; has received travel support from CSL Behring, Pharming, and Shire; and has received nonfinancial support from CSL Behring, Shire, and Grifols. B. Zuraw reports grant support from the Department of Defense; reports consultancy fees from Adverum, Alnylam, Arrowhead Pharmaceuticals, BioCryst, Nektar, CSL Behring, and Shire; and has led the Scientific Steering Committee for this study. H. Longhurst has received grant support, personal fees, and nonfinancial support from CSL Behring during the conduct of the study; grant support from BioCryst and Shire; personal fees from Adverum, BioCryst, Pharming, and Shire; and travel support from CSL Behring and nonfinancial support from Pharming and Shire. M. Cicardi has received grants from Shire and personal fees from Alnylam, BioCryst, CSL Behring, Dyax, KalVista, Pharming Technologies, Shire, Sobi (Swedish Orphan Biovitrum), and ViroPharma. K. Bork reports speaker fees from CSL Behring and Shire, outside the submitted work. C. Grattan reports personal fees as chair of the COMPACT Data Safety Monitoring Board (DSMB) from CSL Behring during the conduct of the study. C. Katelaris has received honoraria as a speaker and advisory board chair for Novartis, Shire, and Sequirus; has received travel support from Shire; and is a Principal Investigator for trials conducted by CSL Behring. G. Sussman has received grant support and personal fees from Novartis and personal fees from Merck, CSL Behring, and Pfizer, outside the submitted work. P. K. Keith has received grant support from CSL Behring and Shire during the conduct of the study, and consulting and speaker’s honoraria from CSL Behring and Shire, outside the submitted work. W. Yang has served as an advisory board member for BioCryst Pharmaceuticals, CSL Behring, and Shire, and has received research and/or educational grants from BioCryst Pharmaceuticals, CSL Behring, Shire, and Pharming, outside of the submitted work. J. Hébert has been a Principal Investigator for CSL Behring clinical trials. P. Staubach‐Renz has been a clinical trial investigator for CSL Behring and has received grants and/or speaker/ consultant fees from AbbVie, Astellas, Celgene, CSL Behring, Genentech, Janssen, Karrer, LEO, Leti, Lilly, MSD, Novartis, Pfizer, Shire, Sobi (Swedish Orphan Biovitrum), UCB, and ViroPharma, outside the submitted work. I. Martinez‐Saguer has received grants and speaker/consultant fees and been a clinical trial investigator for BioCryst, CSL Behring, Sobi (Swedish Orphan Biovitrum), Shire, and ViroPharma. M. Magerl has received financial compensation from CSL Behring for the conduct of the study and has also received speaker/consultant fees from BioCryst, CSL Behring, Novartis, Shire, and Pharming Technologies. E. Aygören‐Pürsün has received grant support as a clinical trial investigator for this study and has received honoraria as a speaker/advisor and/or grant support/clinical trial investigator support from BioCryst, CSL Behring, KalVista, Pharming Technologies, Shire, and ViroPharma. H. Farkas received institutional support for a clinical trial for this study from CSL Behring; advisory board/consultancy fees and/or speaker’s honoraria from BioCryst, CSL Behring, Shire, and Sobi (Swedish Orphan Biovitrum); and travel support from CSL Behring. S. Neri reports educational grants and honoraria for advisory boards and symposia from CSL Behring, Shire, and ViroPharma and other support from Pharming, outside of the submitted work. A. Reshef reports grant support from CSL Behring during the conduct of the study and has received grant support from Pharming. I. Crisan reports institutional support from CSL Behring during the conduct of the study. T. Caballero reports institutional support from CSL Behring during the conduct of the study; personal fees from BioCryst, CSL Behring, GlaxoSmithKline, MSD, and Sobi; personal fees and other support from CSL Behring, Novartis, and Shire HGT; and research funding from the IdiPaz Program for Promoting Research Activities, outside the submitted work. M. L. Baeza reports institutional support from CSL Behring during the conduct of the study. H. Li received institutional support from CSL Behring for the conduct of this study; travel expenses and/or consultancy fees and speaker’s honoraria from BioCryst, CSL Behring, Shire, and Salix/Pharming; and institutional support for clinical trials from BioCryst, Pharming, and Shire. W. Lumry reports grant support from CSL Behring, Pharming, and Shire/Viropharma; consultancy fees/honorarium paid to his institution from Adverum, BioCryst Pharmaceuticals, CSL Behring, and Shire/Viropharma; travel support paid to his institution from CSL Behring and the US Hereditary Angioedema Association; and fees for participation in review activities paid to his institution from BioCryst during the conduct of the study. J. A. Bernstein reports grant support and personal fees from BioCryst, CSL Behring, and Shire, outside the submitted work. I. Hussain reports institutional support from CSL Behring during the conduct of the study. J. Anderson reports personal fees as a consultant and for speaker’s bureau participation from CSL Behring, Pharming, and Shire; and other clinical research support from BioCryst, CSL Behring, Dyax, and Shire, outside the submitted work. L. B. Schwartz reports grant support from CSL Behring during the conduct of the study and grant support from Dyax outside the submitted work. J. Jacobs reports grant support from CSL Behring during the conduct of the study; grant support from BioCryst, Dyax Corp, and Shire PLC; and honoraria and advisory fees from CSL Behring, Dyax Corp, Shire, Pharming, and Shire PLC, outside the submitted work. M. Manning reports grant support from BioCryst, CSL Behring, Dyax, and Shire; and personal fees from CSL Behring, Dyax, Pharming Technologies, Salix, and Shire, outside the submitted work. D. Levy has served on the speaker’s bureau, as a consultant, on a steering committee, and as a clinical investigator for CSL Behring. M. Riedl reports grant support from CSL Behring during the conduct of the study and has received research grants from BioCryst, CSL Behring, Dyax, Ionis Pharmaceuticals, Pharming Technologies, and Shire; has served as a consultant and/or speaker for Adverum Biotechnologies, Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, BioCryst, CSL Behring, Dyax, Global Blood Therapeutics, Ionis Pharmaceuticals, KalVista Pharmaceuticals, Pharming Technologies, Salix Pharmaceuticals, and Shire; and is an uncompensated advisory board member for the US Hereditary Angioedema Association, outside the submitted work. S. Christiansen reports receiving personal fees as an advisory board member from Bio‐Cryst, CSL Behring, and Shire, outside of the submitted work. H. Feuersenger, I. Pragst, S. Mycroft, D. Pawaskar, and I. Jacobs are employees of CSL Behring. I. Pragst has patents WO 2016/131958 A1 and WO 2018/037046 pending. D. Pawaskar has a patent pending. The rest of the authors declare that they have no relevant conflicts of interests."
Notes	Funded by CSL Behring 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	Unclear if allocation was concealed.
Blinding of participants and personnel (performance bias)	High risk	Open‐label extension.
Blinding of outcome assessment (detection bias)	High risk	Open‐label extension.
Incomplete outcome data (attrition bias) All outcomes	Low risk	13% attrition but evenly distributed and ITT analysis used.
Selective reporting (reporting bias)	Low risk	All outcomes in protocol were reported.
Other bias	Low risk	We identified no other sources of bias.