NCT02052141.

Study characteristics
Methods	Design: randomised, single‐blind, cross‐over trial Exclusions postrandomisation: none Losses to follow‐up: none Duration of study: after 12‐week baseline observation period, participants received C1‐INH 500 U or 1000 U, twice‐weekly, for 12 weeks before crossing over to alternate dose for 12 weeks Unit of randomisation: participant
Participants	Country: 10 sites in the US, EU, Mexico and Israel Setting: outpatient Number: children aged 6–11 years with Type I or II HAE. 12 children randomised and completed study. 5 to the C1‐INH‐nf 500/1000 IU treatment sequence and 7 to C1‐INH‐nf 1000/500 IU sequence Age (mean): 10 (SD not reported) years Sex: 5 boys (41.7%); 7 girls (58.3%) Inclusion criteria: aged ≥ 6 to < 12 years with confirmed HAE type I or II diagnosis, functional C1‐INH level < 50% of normal, mean ≥ 1.0 (≥ 2.0 in Germany) attacks/month of moderate or severe intensity or requiring acute treatment. Exclusion criteria: not provided.
Interventions	C1‐INH‐nf 500 IU twice‐weekly C1‐INH‐nf 1000 IU twice‐weekly Treatment duration: 12 weeks then crossing over to other treatment
Outcomes	Number of HAE attacks, attack severity, EuroQol 5‐dimensional descriptive system (youth version)
Funding	Shire HGT, a Takeda company
Declarations of interest	Quote: "Emel Aygören‐Pürsün has received honoraria, research funding, and/or travel grants from, and/or served as a consultant for, Adverum, BioCryst, CSL Behring, Pharming Technologies, KalVista Pharmaceuticals, and Shire. Daniel F. Soteres is a speaker and has participated in advisory boards for Shire. Sandra A. Nieto‐Martinez is a speaker for, has received honoraria from, and has participated in advisory boards for Shire, and has received travel grants from CSL Behring, Pharming Technologies, and Shire. Kraig W. Jacobson has participated in clinical trials for Shire. Dumitru Moldovan received research funding and travel grants from CSL Behring, Pharming Technologies, and Shire HGT and unrestricted educational grants from CSL Behring, Pharming Technologies, Shire HGT, and Swedish Orphan Biovitrum and served as a consultant for Pharming Technologies and Swedish Orphan Biovitrum. Inmaculada Martinez‐Saguer has received honoraria, research funding, and travel grants from BioCryst, CSL Behring, Pharming Technologies, and Shire and/or served as a consultant for these companies. Arthur Van Leerberghe, Yongqiang Tang, Peng Lu, and Moshe Vardi are fulltime employees of Shire, a Takeda company (Lexington, MA, USA). Jennifer Schranz was a full‐time employee of Shire, a Takeda company (Lexington, MA, USA), at the time of this study. Jim Christensen has indicated that he has no potential conflicts of interest to disclose."
Notes	Funded by Shire HGT, 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	Method of allocation concealment not stated.
Blinding of participants and personnel (performance bias)	Low risk	Quote: "Only patients and parents/caregivers were blinded to treatment sequence and dose."
Blinding of outcome assessment (detection bias)	High risk	Staff and investigators were not blinded to allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed the study.
Selective reporting (reporting bias)	Low risk	All outcomes in protocol were reported.
Other bias	Low risk	We identified no other sources of bias.