NCT01005888.

Study characteristics
Methods	Design: randomised, double‐blind, placebo‐controlled, cross‐over trial Exclusions postrandomisation: after completion of treatment, 3 participants (1 in C1‐INH group and 2 in placebo group) were judged by an independent, blinded expert to have had episodes that were not true attacks of HAE. Participants were then excluded from efficacy analysis Losses to follow‐up: during first period, 1 participants from each group withdrew, leaving 22 participants (11 in each group) who completed first period and then crossed over to other treatment for second period Duration of study: 2 × 12 weeks Unit of randomisation: participant
Participants	Country: US Setting: outpatient Number: acute attack treatment trial: 68 participants (35 in C1‐INH group and 33 in placebo group); prophylaxis trial (11 in placebo with cross‐over to C1‐INH group and 11 in C1‐INH with cross‐over to placebo) Age (mean): 36.5 (SD 15.9) years Sex: 15 male (22.1%); 53 female (77.9%) Inclusion criteria: aged ≥ 6 years with confirmed diagnosis of HAE, including a low C4, normal C1q and a low antigenic or functional C1‐INH level or a mutation in the C1‐INH gene known to cause HAE. Exclusion criteria: low C1q level, history of a B‐cell cancer, presence of anti‐C1 inhibitor antibody, history of allergic reaction to C1‐INH or other blood or plasma products, pregnancy, and narcotic addiction.
Interventions	C1‐INH‐nf 1000 IU twice‐weekly Placebo (saline) twice‐weekly Treatment duration: 12 weeks then crossing over to other treatment
Outcomes	Rate of HAE attacks, attack severity, attack duration, use of rescue medication, functional C1 inhibitor, AEs
Funding	Lev Pharmaceuticals (now owned by ViroPharma Biologics)
Declarations of interest	Quote: "Dr. Zuraw reports receiving consulting fees from Lev Pharmaceuticals, CSL Behring, Jerini (now Shire), and Dyax; reimbursements for travel or accommodation expenses from Lev Pharmaceuticals, Shire, and Dyax; fees for serving on the speakers bureau of the Robert Michael Educational Institute; grant support from Lev Pharmaceuticals, Pharming, and Shire; and fees for providing expert testimony for Lev Pharmaceuticals; Dr. Busse, receiving consulting fees and reimbursements for travel or accommodation expenses from Lev Pharmaceuticals; grant support from Lev Pharmaceuticals and Shire Pharmaceuticals; fees for reviewing a patient file from Eichorn and Eichorn; payment for manuscript preparation from Innovative Strategic Communications; and fees for serving on the speakers bureaus of ViroPharma and the Robert Michael Educational Institute; Dr. White, receiving consulting fees from Lev Pharmaceuticals and Dyax; reimbursements for travel or accommodation expenses from Dyax; honoraria from Dyax; grant support from Lev Pharmaceuticals, Dyax, Shire, ViroPharma, and Pharming; and fees for serving on the speakers bureau of ViroPharma; Dr. Jacobs, receiving consulting fees from ViroPharma; reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and ViroPharma; honoraria from ViroPharma; grant support from Lev Pharmaceuticals; and fees for serving on the speakers bureaus of ViroPharma and Lev Pharmaceuticals; Dr. Lumry, receiving consulting fees and honoraria from ViroPharma; consulting fees from Dyax and Shire; reimbursements for travel or accommodation expenses from ViroPharma, Dyax, and Shire; grant support from Lev Pharmaceuticals, Dyax, and Shire; and payment for development of educational presentations from Dyax; Dr. Baker, receiving grant support from Lev Pharmaceuticals, Shire, Dyax, and Pharming; Dr. Craig, receiving consulting fees from ViroPharma, Dyax, and CSL Behring; fees for participation in review activities and reimbursements for travel or accommodation expenses from ViroPharma; honoraria from ViroPharma, Dyax, and CSL Behring; grant support from Lev Pharmaceuticals, ViroPharma, Dyax, CSL Behring, Pharming, and Shire; and payment for development of educational presentations from Dyax, CSL Behring, and ViroPharma; Dr. Grant, receiving reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and Dyax and grant support from Lev Pharmaceuticals, Dyax, and Shire; Dr. Hurewitz, receiving consulting fees from Shire; reimbursements for travel or accommodation expenses from ViroPharma, Shire, Dyax, and CSL Behring; honoraria from Shire; and grant support from Lev Pharmaceuticals, ViroPharma, Shire, Dyax, and CSL Behring; Dr. Bielory, receiving reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and grant support from Lev Pharmaceuticals and STARx Clinical Research Center; Dr. Cartwright, receiving grant support and consulting fees or honoraria from Lev Pharmaceuticals and ViroPharma; Dr. Koleilat, receiving grant support from Lev Pharmaceuticals; Dr. Ryan, receiving grant support from Lev Pharmaceuticals; Dr. Schaefer, receiving grant support from Lev Pharmaceuticals and reimbursements for travel or accommodation expenses from ViroPharma; Dr. Manning, receiving reimbursements for travel or accommodation expenses and grant support from Lev Pharmaceuticals and ViroPharma; honoraria from ViroPharma; and payment for development of educational presentations from ViroPharma; Dr. Patel, receiving grant support from Lev Pharmaceuticals; Dr. Bernstein, receiving consulting fees from Dynova, Lantheus, and Flint Hills Resources; honoraria from AstraZeneca, Alcon Labs, Dyax, ViroPharma, and CSL Behring; fees for providing expert testimony on environmental and drug reaction cases; and grant support from Lev Pharmaceuticals, Dyax, ViroPharma, CSL Behring, Shire, Pharming, Dynova, and Flint Hills Resources; and being listed as a patent holder on a patent held by the University of Cincinnati for a biosensor to detect airborne chemicals from Biosensors; Dr. Friedman, receiving reimbursements for travel or accommodation expenses from ViroPharma and grant support from Lev Pharmaceuticals; Dr. Wilkinson, receiving fees for study visits from Lev Pharmaceuticals and grant support from Dyax; Dr. Tanner, receiving grant support from Lev Pharmaceuticals; Dr. Gunther, receiving grant support from Lev Pharmaceuticals; Dr. Levy, receiving grant support from Lev Pharmaceuticals and ViroPharma; consulting fees from CSL Behring, Alcon Labs, Dyax, Jerini, and Sepracor; reimbursements for travel or accommodation expenses from CSL Behring and Dyax; and payment for manuscript preparation from Cadent Communications; Dr. McClellan, receiving a grant from Lev Pharmaceuticals; Dr. Redhead, receiving a grant from Lev Pharmaceuticals; Dr. Guss, receiving grant support from Lev Pharmaceuticals; Dr. Heyman, receiving consulting fees from Lev Pharmaceuticals; Dr. Blumenstein, receiving consulting fees and reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and ViroPharma; Dr. Kalfus, receiving consulting fees and reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and ViroPharma; payment for development of educational presentations from ViroPharma; and stocks and stock options from Lev Pharmaceuticals; and being previously employed as vice president of medical affairs at Lev Pharmaceuticals; and Dr. Frank, receiving consulting fees from ViroPharma, CSL Behring, Shire, Dyax, and Pharming; fees for providing expert testimony for Lev Pharmaceuticals, Jerini, and CSL Behring; reimbursements for travel or accommodation expenses from ViroPharma; and grant support from Lev Pharmaceuticals and CSL Behring. No other potential conflict of interest relevant to this article was reported."
Notes	Funded by Lev Pharmaceuticals 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	Concealment of allocation not stated.
Blinding of participants and personnel (performance bias)	Low risk	Participants and personnel were blinded.
Blinding of outcome assessment (detection bias)	Unclear risk	Unclear if outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	8% attrition, but evenly distributed and ITT analysis used.
Selective reporting (reporting bias)	Low risk	All outcomes in protocol were reported on.
Other bias	Low risk	We identified no other sources of bias.