NCT02247739.

Study characteristics
Methods	Design: multicentre, randomised, double‐blind, placebo‐controlled, cross‐over trial Exclusions postrandomisation: none reported Losses to follow‐up: per‐protocol population comprised 23 participants after exclusion of 6 who withdrew during study, 2 patients who received plasma‐derived C1‐INH and 1 who received wrong treatment Duration of study: enroled between 28 December 2014 and 3 May 2016. Each treatment sequence consisted of 3 × 4‐week treatment periods separated by a 1‐week washout period before cross‐over Unit of randomisation: participant
Participants	Country: 10 centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the US Setting: outpatient Number: 32 people were randomised and 26 completed the study Age (mean): 45.9 (SD 14.5) years Sex: 6 male (19%); 26 female (81%) Inclusion criteria: aged ≥ 13 years with functional concentrations of C1 inhibitor < 50% of normal, and history of frequent attacks of HAE (≥ 4 attacks per month for ≥ 3 consecutive months before study initiation). Exclusion criteria: allergy to rabbits or a diagnosis of acquired angio‐oedema; pregnant or breastfeeding; receiving angiotensin‐converting enzyme inhibitors.
Interventions	Recombinant human C1‐INH 50 IU/kg twice per week Recombinant human C1‐INH 50 IU/kg once per week Placebo once per week Placebo twice per week Treatment duration: 4 weeks then crossing over to another treatment until all treatments were experienced
Outcomes	Rate of HAE attacks, functional C1‐INH concentrations in plasma, AEs, SAEs
Funding	Pharming Healthcare (Berkeley Heights, New Jersey, USA) and Salix Pharmaceuticals (Bridgewater, New Jersey, USA)
Declarations of interest	Quote: "MAR has received research grants from BioCryst Pharmaceuticals, CSL Behring, Ionis Pharmaceuticals, Pharming Technologies, and Shire; has served as a consultant for Adverum Biotechnologies, Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, BioCryst Pharmaceuticals, CSL Behring, Global Blood Therapeutics, Ionis Pharmaceuticals, KalVista Pharmaceuticals, Pharming Technologies, Salix Pharmaceuticals, and Shire; and has served on the speakers’ bureaus for CSL Behring, Pharming Technologies, Salix Pharmaceuticals, and Shire. VG‐P has served as principal investigator for clinical trials sponsored by Pharming Group. DM has received grants from Swedish Orphan Biovitrum, Pharming Technologies, Shire, and CSL Behring, and personal fees from Pharming Technologies, Shire, Swedish Orphan Biovitrum, and CSL Behring. JB is a researcher for BioCryst Pharmaceuticals, CSL Behring, Dyax, Pharming Technologies, and Shire; has served as a consultant for BioCryst Pharmaceuticals; and has served on the speakers’ bureau for Shire. WHY has served as a member of the national and international advisory boards for BioCryst Pharmaceuticals, CSL Behring, and Shire, and has received research or educational grants from BioCryst Pharmaceuticals, CSL Behring, Shire, and Pharming Technologies. BMG is an employee of Pharming Group. ARes has received research grants from Pharming Technologies. RH has received financial support and personal fees from Pharming Group. JRH and ARel are employees of Pharming Healthcare. MC has received grants from Shire and personal fees from Shire, CSL Behring, Pharming Technologies, BioCryst Pharmaceuticals, Alnylam, and KalVista. SA, RFL, and SK declare no competing interests."
Notes	Funded by Pharming Technologies, but study performed externally.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Interactive response technology system used for randomisation.
Allocation concealment (selection bias)	Low risk	Allocation could not be anticipated because of use of interactive response technology system.
Blinding of participants and personnel (performance bias)	Low risk	Participants and personnel were blinded.
Blinding of outcome assessment (detection bias)	Low risk	Outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	12.5% attrition but evenly spread and some ITT data available.
Selective reporting (reporting bias)	Low risk	All outcomes in protocol were reported.
Other bias	Low risk	We identified no other sources of bias.