Safety and Efficacy Study of CINRYZE for Prevention of Angioedema Attacks in Children Ages 6-11 With Hereditary Angioedema

A Phase 3, Multicenter, Randomized, Single-Blind, Dose-Ranging, Crossover Study to Evaluate the Safety and Efficacy of Intravenous Administration of CINRYZE® (C1 Esterase Inhibitor [Human]) for the Prevention of Angioedema Attacks in Children 6 to 11 Years of Age With Hereditary Angioedema

Primary Objective - To assess the relative efficacy of two dose levels of CINRYZE (500 Units and 1000 Units) administered by intravenous (IV) injection every 3 or 4 days to prevent angioedema attacks in children 6 to 11 years of age with hereditary angioedema (HAE).

Secondary Objectives - To assess the safety and tolerability, characterize the pharmacokinetics (PK) and pharmacodynamics (PD), and assess the immunogenicity of two dose levels of CINRYZE administered by IV injection in children 6 to 11 years of age with HAE.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema (HAE)
• Intervention / Treatment: Biological: CINRYZE 500; Biological: CINRYZE 1000

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Frankfurt, Germany, 60590
    • Klinikum der J.W. Goethe Universität
  • Mörfelden-Walldorf, Germany, 64546
    • HZRM Hämophilie Zentrum Rhein Main GmbH
• Israel
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
• Mexico
  • Mexico City, Mexico, 04530
    • Instituto Nacional de Pediatría
• Romania
  • Targu-Mures, Romania, 540072
    • Clinical County Hospital Mures
• United States
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Asthma and Allergy Associates, P.C
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Nevada Access to Research and Education Society
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Oregon Allergy Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 11 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of Type I or Type II HAE.
• History of angioedema attacks.

Exclusion Criteria:

• History of bleeding or clotting abnormality.
• Diagnosis of acquired angioedema or known to have C1 INH antibodies.
• History of allergic reaction to C1 esterase inhibitor or other blood products.
• Receipt of any experimental agents other than those required for prevention or treatment of angioedema attacks within 30 days prior to screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 500/1000; 500 Units of CINRYZE administered by IV injection twice per week for 12 weeks followed by 1000 Units of CINRYZE administered by IV injection twice per week for 12 weeks	Biological: CINRYZE 500; 500 Units of CINRYZE administered by IV injection; Biological: CINRYZE 1000; 1000 Units of CINRYZE administered by IV injection
Experimental: 1000/500; 1000 Units of CINRYZE administered by IV injection twice per week for 12 weeks followed by 500 Units of CINRYZE administered by IV injection twice per week for 12 weeks	Biological: CINRYZE 500; 500 Units of CINRYZE administered by IV injection; Biological: CINRYZE 1000; 1000 Units of CINRYZE administered by IV injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Normalized Number of Angioedema Attacks Per Month in a Treatment Period	Angioedema attack was defined as the participant-reported indication of symptoms or signs such as swelling or pain at any location following a report of no swelling or pain on the previous day. Manifestations of an attack that progress from one site to another, prior to complete resolution, was considered a single attack. Attacks that began to regress and then worsened before complete resolution was also considered one attack. Attacks that began then appeared to resolve and then reappeared without a symptom-free calendar day reported after the appearance of resolution were considered 1 attack. Any events of swelling due to trauma or symmetrical nonpainful swelling of the lower extremities were not considered an angioedema attack. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.	From start of treatment up to 12 weeks during each treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Attack-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period	Severity of the angioedema attack sign/symptom was characterized as None: no symptom; Mild: noticeable symptom but easily tolerated by the participant and did not interfere with routine activities; Moderate: symptom interfered with the participant's ability to attend school or participate in family life and social/recreational activities; Severe: symptom significantly limited the participant's ability to attend school or participate in family life and social/recreational activities. Symptom severity score was assigned as Mild = 1, Moderate = 2 and Severe = 3. Cumulative attack severity score was the sum of the maximum symptom severity scores recorded for each angioedema attack in a treatment period. Cumulative attack-severity score normalized per month [(raw score/number of days of participation in that treatment period)*30.4] was reported here. Cumulative attack-severity score normalized per month ranged from 0 to 10.4 and higher scores represent worse symptoms.	From start of treatment up to 12 weeks during each treatment period
Cumulative Daily-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period	Severity of the angioedema attack sign/symptom was characterized as None: no symptom; Mild: noticeable but easily tolerated by the participant and did not interfere with routine activities; Moderate: interfered with the participant's ability to attend school or participate in family life and social/recreational activities; Severe: significantly limited the participant's ability to attend school or participate in family life and social/recreational activities. Symptom severity score was assigned as Mild = 1, Moderate = 2 and Severe = 3. Cumulative daily-severity score was the sum of the severity scores recorded for every day of reported symptoms in a treatment period. Cumulative daily-severity score normalized per month [(raw score/number of days of participation in that treatment period)*30.4] was reported here. Cumulative daily-severity score normalized per month ranged from 0 to 15.6 and higher scores represent worse symptoms.	From start of treatment up to 12 weeks during each intervention period
Normalized Number of Angioedema Attacks Per Month Requiring Acute Treatment in a Treatment Period	Angioedema attack was defined as the participant-reported indication of symptoms or signs such as swelling or pain at any location following a report of no swelling or pain on the previous day. Manifestations of an attack that progress from one site to another, prior to complete resolution, was considered a single attack. Attacks that began to regress and then worsened before complete resolution was also considered one attack. Attacks that began then appeared to resolve and then reappeared without a symptom-free calendar day reported after the appearance of resolution were considered 1 attack. Any events of swelling due to trauma or symmetrical nonpainful swelling of the lower extremities were not considered an angioedema attack. The number of attacks requiring acute treatment was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.	From start of treatment up to 12 weeks during each intervention period
Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Dose Group	An adverse event (AE) was any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a participant participating in a clinical study with the sponsor's product, regardless of causal relationship. TEAEs were defined as events that started or worsened on or after the date and time of the first dose of investigational product and up to 7 days after the last dose of investigational product.	From start of study treatment up to 25 weeks
Plasma Concentration of C1 Esterase Inhibitor (C1 INH) Antigen	C1 INH antigen concentration in plasma was determined using an automated nephelometric assay.	Pre-dose and 1 hour (h) post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
C1 Esterase Inhibitor (C1 INH) Functional Activity in Plasma	The functional activity of C1 INH in plasma samples was determined by a chromogenic assay.	Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
Plasma Concentration of Complement C4	Concentration of Complement C4 in plasma was determined using an automated nephelometric assay.	Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
Number of Participants With C1 Esterase Inhibitor (C1 INH) Antibodies in Plasma	The presence of C1 INH antibodies in plasma samples was determined using a proprietary enzyme-linked-immunosorbent-assay. Number of participants with C1 INH Antibodies was reported.	Pre-dose, 1 week post treatment (Week 13, Week 25) and 1 month post treatment follow-up (Week 28)

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K. Interventions for the long-term prevention of hereditary angioedema attacks. Cochrane Database Syst Rev. 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2.
• Aygoren-Pursun E, Soteres D, Moldovan D, Christensen J, Van Leerberghe A, Hao J, Schranz J, Jacobson KW, Martinez-Saguer I. Preventing Hereditary Angioedema Attacks in Children Using Cinryze(R): Interim Efficacy and Safety Phase 3 Findings. Int Arch Allergy Immunol. 2017;173(2):114-119. doi: 10.1159/000477541. Epub 2017 Jun 30.
• Aygoren-Pursun E, Soteres DF, Nieto-Martinez SA, Christensen J, Jacobson KW, Moldovan D, Van Leerberghe A, Tang Y, Lu P, Vardi M, Schranz J, Martinez-Saguer I. A randomized trial of human C1 inhibitor prophylaxis in children with hereditary angioedema. Pediatr Allergy Immunol. 2019 Aug;30(5):553-561. doi: 10.1111/pai.13060. Epub 2019 May 29.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2014
• Primary Completion (Actual): May 4, 2017
• Study Completion (Actual): May 4, 2017

Study Registration Dates

• First Submitted: January 30, 2014
• First Submitted That Met QC Criteria: January 30, 2014
• First Posted (Estimate): January 31, 2014

Study Record Updates

• Last Update Posted (Actual): June 3, 2021
• Last Update Submitted That Met QC Criteria: May 11, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Pediatric; Prevention; HAE; C1 inhibitor; C1 INH; Cinryze
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein
• Other Study ID Numbers: 0624-301; 2013-002453-29 (EudraCT Number); SHP616-301 (Other Identifier: Shire)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)