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

Emel Aygören‐Pürsün,Inmaculada Martinez‐Saguer,Jim Christensen,Yongqiang Tang,Moshe Vardi,Dumitru Moldovan,Arthur Van Leerberghe,Daniel F Soteres,Peng Lu,Jennifer Schranz,Sandra A Nieto‐Martinez,Kraig W Jacobson

doi:10.1111/pai.13060

Abstract

BackgroundPatients 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.MethodsEligible 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).ResultsTwelve 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.ConclusionsC1‐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 registrationClinicalTrials.gov identifier NCT02052141.

Highlights

Hereditary angioedema with C1 inhibitor deficiency or dysfunc‐ tion (C1‐INH‐HAE) is a rare inherited disease with an estimated prevalence of 1:50 000,1 characterized by episodic swelling of the skin, abdomen, and larynx.[2,3,4,5]
In Europe and the United States, C1‐INH (Cinryze; Shire) was re‐ cently approved for routine prophylaxis in patients aged ≥6 years, but before this study was initiated, it was only approved for adult and adolescent patients
This study shows that patients aged 6‐11 years with recurrent and burdensome hereditary angioedema attacks would benefit from prophylaxis with twice‐weekly C1‐INH (500 or 1000 U) as it is efficacious and safe, and may lead to a meaningful improvement in health‐related quality of life

Summary

| INTRODUCTION

Hereditary angioedema with C1 inhibitor deficiency or dysfunc‐ tion (C1‐INH‐HAE) is a rare inherited disease with an estimated prevalence of 1:50 000,1 characterized by episodic swelling of the skin, abdomen, and larynx.[2,3,4,5] C1‐INH‐HAE's clinical manifes‐ tations including age of first symptoms, and attack location, fre‐ quency, and severity, are heterogeneous.[6,7,8] Approximately 50% of patients have potentially fatal laryngeal attacks.[9,10] In a European survey of patients aged ≥12 years, recurrent acute angioedema attacks impaired health‐related quality of life (HRQoL) to a similar extent to other serious chronic diseases.[11]. International World Allergy Organization/European Academy of Allergy and Clinical Immunology guidelines for managing C1‐ INH‐HAE recommend C1‐INH for first‐line long‐term prophylaxis.[14] pediatric patients were included in prior studies of C1‐ INH,[15] no dedicated randomized clinical trials assessed children aged ≥6 to

| METHODS

| DISCUSSION

Findings

CONFLICT OF INTEREST