A randomized trial of human C1 inhibitor prophylaxis in children with hereditary angioedema

Abstract

Background: Patients with hereditary angioedema with C1 inhibitor deficiency or dysfunction have burdensome recurrent angioedema attacks. The safety, efficacy, and health-related quality of life (HRQoL) outcomes of C1 inhibitor (C1-INH) prophylaxis (intravenously administered) in patients aged 6-11 years were investigated.

Methods: Eligible patients were enrolled in a randomized, single-blind, crossover, phase 3 trial. After a 12-week baseline observation period (BOP), patients received 500 or 1000 U C1-INH, twice weekly, for 12 weeks before crossing over to the alternate dose for 12 weeks. The primary efficacy end-point was the monthly normalized number of angioedema attacks (NNA). HRQoL was assessed using the EuroQoL 5-dimensional descriptive system youth version and visual analog scale (EQ-VAS).

Results: Twelve randomized patients had a median (range) age of 10.0 (7-11) years. Mean (SD) percentage reduction in monthly NNA from BOP was 71.1% (27.1%) with 500 U and 84.5% (20.0%) with 1000 U C1-INH. Mean (SD) within-patient difference (-0.4 [0.58]) for monthly NNA with both doses was significant (P = 0.035 [90% CI, -0.706 to -0.102]). Cumulative attack severity, cumulative daily severity, and number of acute attacks treated were reduced. No serious adverse events or discontinuations occurred. Mean EQ-VAS change from BOP to week 9 of treatment (500 U C1-INH, 10.4; 1000 U C1-INH, 21.6) was greater than the minimal important difference, indicating a meaningful HRQoL change.

Conclusions: C1-INH prophylaxis was effective, safe, and well tolerated in children aged 6-11 years experiencing recurrent angioedema attacks. A post hoc analysis indicated a meaningful improvement in HRQoL with C1-INH.

Trial registration: ClinicalTrials.gov identifier NCT02052141.

Keywords: C1 esterase inhibitor (human); efficacy; health-related quality of life; hereditary angioedema; pediatric patients; phase 3 study; prophylaxis; safety.

Conflict of interest statement

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 full‐time 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.

© 2019 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.

Figures

Figure 1

A, Total number of HAE attacks. B, Cumulative attack severity. C, Cumulative daily severity. D, Number of attacks needing acute treatment. Data (n = 12) normalized per month. Mean (SD) values shown at top of each bar. Minimum/maximum values shown in square brackets. Mean difference (MD) between baseline and treatment period shown

Figure 2

A, Clinical response rate. Proportion of patients achieving at least 50%, 70%, or 90% reduction relative to baseline in NNA. B, Angioedema attack and severity profile of patients during baseline observation period and during treatment with 500 and 1000 U C1‐INH. Data for full analysis set shown (n = 12)

Figure 3

Proportion of patients by attack severity during baseline observation period and during treatment with 500 and 1000 U C1‐INH. Data for full analysis set shown (n = 12)

Figure 4

A, Proportion of patients who responded “no problems” to EQ‐5D‐Y questionnaire at scheduled week 9 visit. B, Mean EQ‐VAS scores at baseline and week 9 of treatment. Data shown for patients in full analysis set with valid non‐missing result at time point and dimension. EQ‐VAS score change ≥7 considered MID. Δ: change