SAHARA.

Study characteristics
Methods	Design: multicentre, randomised, double‐blind, placebo‐controlled, partial cross‐over trial Exclusions postrandomisation: none reported Losses to follow‐up: reasons for study discontinuation included patient withdrawal (9), AEs (4), physician decision (1), lost to follow‐up (in 1 participant who completed treatment; 1), and other (2). 1 participant receiving pdC1‐INH liquid experienced 2 TEAEs that led to treatment withdrawal (nausea and headache). Both events were considered treatment related and occurred within 24 hours of administration. 2 participants receiving placebo experienced 2 TEAEs leading to withdrawal (1 had cardiac arrest and 1 had an HAE attack). Neither considered treatment related Duration of study: screening began 17 December 2015, and last participant completed treatment on 24 July 2017 Unit of randomisation: participant
Participants	Country: 33 sites in North America and Europe Setting: outpatient Number: 75 participants randomised (60 for cross‐over sequence (31 received pdC1‐INH liquid in period 1; 29 received placebo in period 1), and 15 for continuous pdC1‐INH liquid). 58 (77%) completed study Age (mean): 41.3 (SD 14.6) years Sex: 23 male (30.7%); 52 female (69.3%) Inclusion criteria: children and adults aged ≥ 12 years (≥ 18 years in Germany and Israel) with Type I or II HAE and functional C1‐INH level < 50% of normal; experienced ≥ 2 HAE attacks per month during 3 consecutive months. Exclusion criteria: adults receiving prophylactic intravenous C1‐INH at doses > 1000 IU every 3 or 4 days (or weekly dose > 2000 IU) or adolescents currently receiving C1‐INH for prophylaxis.
Interventions	pdC1‐INH 2000 IU: self‐administered, subcutaneous, fixed‐dose liquid twice‐weekly Placebo twice‐weekly Treatment duration: 2 × 14 weeks for cross‐over sequence or 1 × 28 week continuous treatment
Outcomes	Rate of HAE attacks, attack severity, AEs, SAEs, injection site reactions, pharmacokinetics, pharmacodynamics
Funding	Shire Human Genetic Therapies, Inc, a Takeda company
Declarations of interest	Quote: "W. R. Lumry has received consultant fees from Adverum, BioCryst, CSL Behring, Pharming, and Shire (a Takeda company); research grants from BioCryst, CSL Behring, Pharming, and Shire (a Takeda company); payments for lectures from CSL Behring, Pharming, and Shire (a Takeda company); and is a member of the Medical Advisory Board of the US Hereditary Angioedema Association. I. Martinez‐Saguer has received honoraria, research funding, and travel grants from BioCryst, CSL Behring, Pharming, and Shire (a Takeda company) and/or served as a consultant and/or participated in advisory boards for these companies. W. H. Yang is a consultant and member of the advisory board for CSL Behring and Shire (a Takeda company); has received unrestricted educational grants from AnaptysBio, BioCryst, CSL Behring, Novartis, and Shire (a Takeda company); and research grants from Aimmune, AstraZeneca, BioCryst, CSL Behring, DBV Technologies, Galderma, Genentech/Roche, GlaxoSmithKline, Merck, Pfizer, Pharming, Regeneron, Sanofi‐Genzyme, and Shire (a Takeda company). J. A. Bernstein has been a clinical investigator for BioCryst, CSL Behring, Pharming, and Shire (a Takeda company); a speaker for CSL Behring, Pharming, and Shire (a Takeda company); and a consultant for BioCryst, CSL Behring, Pharming, and Shire (a Takeda company). J. Jacobs has received research grants from 3M, Aimmune, AstraZeneca, CSL Behring, Genentech, Novartis, Sanofi, Shire (a Takeda company), and Teva; consulting fees from AstraZeneca, CSL Behring, Pharming, Regeneron, Shire (a Takeda company), and Teva; and speaker honoraria from Shire and Teva. D. Moldovan has served as clinical investigator for BioCryst, CSL Behring, Pharming, and Shire (a Takeda company); a consultant for CSL Behring, Octapharma, Pharming, and Shire (a Takeda company); and has received travel grants from CSL Behring, Pharming, Shire (a Takeda company), and Swedish Orphan Biovitrum. M. A. Riedl has received research grants from BioCryst, CSL Behring, Pharming, and Shire (a Takeda company); consulting fees from Adverum, Alnylam, BioCryst, CSL Behring, Ionis, Pharming, and Shire (a Takeda company); payments for lectures from CSL Behring, Pharming, and Shire (a Takeda company); and is a medical advisory board member of the US HAE Association. D. T. Johnston has served on advisory boards for CSL Behring, Pharming/Valeant, and Shire (a Takeda company); received speaker fees from Shire (a Takeda company); and has served as an investigator for BioCryst and Shire (a Takeda company). H. H. Li has been a clinical investigator and received grants and/or honoraria from BioCryst, CSL Behring, Pharming, and Shire (a Takeda company). Y. Tang and J. Schranz were full‐time employees of Shire (a Takeda company) at the time of this analysis. P. Lu and M. Vardi are full‐time employees of Shire (a Takeda company). H. Farkas has received honoraria and travel grants from BioCryst, CSL Behring, Pharming, Shire (a Takeda company), and Swedish Orphan Biovitrum and/or served as a consultant for these companies."
Notes	Funded by Shire Human Genetic Therapies, but study performed externally.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Interactive response technology used for randomisation.
Allocation concealment (selection bias)	Low risk	Allocation was concealed as interactive response technology used for randomisation.
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	High overall attrition (23%), but evenly spread and cross‐over design meant that the worst outcome had only 11.7% attrition.
Selective reporting (reporting bias)	Low risk	All outcomes listed in protocol were reported.
Other bias	Low risk	We identified no other sources of bias.

AAS: Angioedema Activity Score; AE‐QoL: Angioedema Quality of Life Questionnaire; AE: adverse event; C1‐INH: C1 esterase inhibitor; C1‐INH(SC): subcutaneous C1 esterase inhibitor; C4: complement component 4; EuroQol: instrument for measuring quality of life; HAE: hereditary angioedema; ITT: intention‐to‐treat; LLN: lower limit of normal; C1‐INH‐nf: nanofiltered C1 esterase inhibitor; NIH: National Institutes of Health; pdC1‐INH: plasma‐derived C1 esterase inhibitor; SAE: serious adverse event; SD: standard deviation; TEAE: treatment‐emergent adverse event.