COMPACT.

Study characteristics
Methods	Design: randomised, multinational, multicentre, double‐blind, placebo‐controlled, dose‐ranging cross‐over trial Exclusions postrandomisation: none reported Losses to follow‐up: 11 patients discontinued for various reasons. 3 AEs led to trial discontinuation: pulmonary embolism in 1 participant who received placebo, urticaria in 1 participant who received C1‐INH(SC) (CSL830) 60 IU, and an increase in liver aminotransferase levels in 1 participant who received C1‐INH(SC) 60 IU Duration of study: from December 2013 to October 2015 Unit of randomisation: participant
Participants	Country: international Setting: outpatient Number: children and adults aged ≥ 12 years with Type I or II HAE. 90 people with C1‐INH HAE were randomised to 1 of 4 treatment sequences with 2 doses: 40 IU/kg (45 participants), 60 IU/kg (45 participants). Of the 90 people who underwent randomisation, 79 completed trial Age (mean): 39 (SD 14.9) years Sex: 30 male (33%); 60 female (67%) Inclusion criteria: capable of providing written informed consent/assent and willing and able to adhere to all protocol requirements, or the subject's parent(s) or legal representative(s) capable of providing written informed consent; male or female, aged ≥ 12 years at time of providing written informed consent/assent (as appropriate), with clinical diagnosis of Type I or II HAE C1‐INH deficiency; experienced ≥ 4 HAE attacks (requiring acute treatment or medical attention or causing functional impairment over a consecutive 2‐month period within 3 months prior to screening) as documented in the person's medical records; patients who have used oral medication for prophylaxis against HAE attacks (i.e. androgens, tranexamic acid, progestins) within 3 months of the screening visit should have a stable regimen (dose and administration) during 3 months prior to screening; patients using oral medications for prophylaxis were expected to continue their stable regimen throughout the study period* (After amendment of the study protocol, the inclusion criterion in the original protocol read: willing to cease any pre‐existing HAE prophylaxis (e.g. C1‐INH, androgens, antifibrinolytics) after informed consent was obtained and patient was assessed by the investigator to be able to be adequately treated pharmacologically on acute treatments of HAE attacks alone); investigator believed person was willing and able to adhere to all protocol requirements; assessed by investigator as able to appropriately store study medication and capable of being trained to administer study medication (by participant or caregiver) outside study centre setting. Exclusion criteria: diagnosis of HAE with normal C1‐INH or features consistent with acquired C1‐INH deficiency; history of arterial or venous thrombosis requiring anticoagulant therapy or current, clinically significant prothrombotic risk; known incurable malignancy at the time of screening; bodyweight < 40 kg at screening visit; any clinical condition that is likely to interfere with the evaluation of C1‐INH(SC) or study conduct; use of intravenous C1‐INH for routine prophylaxis against HAE attacks (i.e. administered every 3 or 4 days) within 3 months of screening visit or plans to use C1‐INH for routine prophylaxis against attacks during study. Use of intravenous C1‐INH for preprocedure prevention of attacks was permitted, not exceeding 1 dose prior to each procedure; assessed by investigator as having HAE unable to be adequately managed pharmacologically with on‐demand treatment, administered either independently or with assistance; clinically significant history of poor response to C1‐INH therapy for management of HAE; female of childbearing potential not using or unwilling to use a reliable method of contraception or not sexually abstinent during study or not surgically sterile; females who started taking or changed dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e. oestrogen/progesterone‐containing products) within 3 months prior to screening visit; intention to become pregnant during study; pregnant or breastfeeding; participation in another interventional clinical study within 30 days prior to screening visit, or at any time during study; alcohol, drug or medication abuse within 1 year prior to screening visit; currently receiving a therapy not permitted in study; mental condition rendering the person (or their legally acceptable representative(s)) unable to understand the nature, scope, and possible consequences of the study; known or suspected hypersensitivity to investigational product or its excipients; previously randomly assigned to or participated in the run‐in period of current study; employee at study site or spouse/partner/relative of the investigator or subinvestigators; any issue that, in investigator's opinion, would render the person unsuitable for study participation.
Interventions	C1‐INH(SC) 40 IU/kg twice‐weekly C1‐INH(SC) 60 IU/kg twice‐weekly Placebo twice‐weekly Regimen: C1‐INH(SC) 40 IU/kg bodyweight self‐administered during first 16‐week treatment period followed by placebo for the second 16‐week treatment period or vice versa (i.e. placebo first and C1‐INH second); or C1‐INH 60 IU/kg followed by placebo or vice versa Treatment duration: 16 weeks per treatment or placebo period
Outcomes	Rate of HAE attacks, attack severity, HAE symptoms, rescue medication use, C1‐INH activity, AE, SAEs, withdrawals due to AEs, quality of life.
Funding	Supported by CSL Behring. Sponsor was involved in study design, data analysis and decisions concerning submission of data for publication.
Declarations of interest	Quote: "HHL received institutional support from CSL Behring for the conduct of this study, and travel expenses and/or consultancy fees and speaker’s honoraria from CSL Behring, Shire/Dyax/ViroPharma, and Salix/Pharming. TC is a speaker for CSL Behring, Grifols and Dyax/Shire. He performs research for BioCryst, Boehringer Ingelheim, CSL Behring, Genentech, GlaxoSmithKline, Grifols, Merck, Novartis, Pharming, Sanofi, and Shire. He has received consultancy fees and/or speaker’s honoraria from BioCryst, Bellrose, CSL Behring, Dyax, Merck, Novartis, Pharming Technologies, and Shire, and has received non‐financial support from CSL Behring, Shire, and Grifols. BZ reports grant support from the Department of Defense and consultancy fees from Alnylam, Arrowhead Pharmaceuticals, BioCryst Pharmaceuticals, Nektar, CSL Behring, and Shire, and led the Scientific Steering Committee for this study. HJL has received grant support from CSL Behring, consultancy fees, and speaker’s honoraria from CSL Behring, Pharming, and Shire, and travel support from CSL Behring. MC has received grants from Shire and personal fees from Alnylam, BioCryst Pharmaceuticals, CSL Behring, Dyax, KalVista Pharming Technologies, Shire, Sobi (Swedish Orphan Biovitrum), and ViroPharma. KB reports personal fees from CSL Behring and Shire, outside the submitted work. HB received consultancy fees and speaker’s honoraria from CSL Behring, Pharming, and Shire. WL reports grant support from BioCryst Pharmaceuticals, CSL Behring, and Shire/Viropharma/Dyax; consultancy fees paid to his institution from Adverum, BioCryst Pharmaceuticals, CSL Behring, Pharming Technologies, and Shire/Viropharma/Dyax; speaker’s fees from Pharming Technologies, Shire/Viropharma and CSL Behring; and non‐financial support from the US Hereditary Angioedema Association outside the submitted work. JB reports grant support and personal fees from BioCryst Pharmaceuticals, CSL Behring, and Shire, outside the submitted work. MM reports grant support and consultant/speaker’s fees from CSL Behring, Shire, Dyax, and Shire; and personal fees from Salix and Pharming Technologies, outside the submitted work. DL has served on the speaker’s bureau, as a consultant, on a steering committee, and as a clinical investigator for CSL Behring. MR has received research grants from BioCryst Pharmaceuticals, CSL Behring, Dyax, Pharming Technologies, and Shire; consultant fees from Adverum Biotechnologies, Alnylam Pharmaceuticals, BioCryst Pharmaceuticals, CSL Behring, Global Blood Therapeutics, Ionis Pharmaceuticals, KalVista Pharmaceuticals, Pharming Technologies, and Shire; speaker’s honoraria from CSL Behring, Shire, and Pharming; and is an uncompensated advisory board member for the US Hereditary Angioedema Association. TM, SP HF and IP are employees of CSL Behring."
Notes	Funded by CSL Behring but study performed externally.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation using an interactive response system.
Allocation concealment (selection bias)	Low risk	Interactive response system prevents knowledge of the next allocation.
Blinding of participants and personnel (performance bias)	Low risk	Participants were blinded to their allocation.
Blinding of outcome assessment (detection bias)	Unclear risk	Blinding of outcome assessors not stated.
Incomplete outcome data (attrition bias) All outcomes	Low risk	12% attrition but ITT analysis used.
Selective reporting (reporting bias)	Low risk	All outcomes in protocol were reported.
Other bias	Low risk	None.