Subcutaneous CINRYZE With Recombinant Human Hyaluronidase for Prevention of Angioedema Attacks

A Phase 2, Randomized, Double-Blind, Multicenter, Dose-Ranging, Crossover Study to Evaluate the Safety and Efficacy of Subcutaneous Administration of CINRYZE® (C1 Esterase Inhibitor [Human]) With Recombinant Human Hyaluronidase (rHuPH20) for the Prevention of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema

The primary objectives of the study are to evaluate the safety, tolerability, and efficacy of two doses of CINRYZE with recombinant human hyaluronidase (rHuPH20) administered by subcutaneous (SC) injection to prevent angioedema attacks.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema (HAE)
• Intervention / Treatment: Biological: CINRYZE with rHuPH20

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • ViroPharma Investigational Site
  • Essen, Germany
    • ViroPharma Investigational Site
  • Mainz, Germany
    • ViroPharma Investigational Site
  • Munchen, Germany
    • ViroPharma Investigational Site
• Spain
  • Barcelona, Spain
    • ViroPharma Investigational Site
• Sweden
  • Jonkoping, Sweden
    • ViroPharma Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • ViroPharma Investigational Site
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • ViroPharma Investigational Site
  • Arkansas
    • Bentonville, Arkansas, United States, 72712
      • ViroPharma Investigational Site
  • California
    • Walnut Creek, California, United States, 94598
      • ViroPharma Investigational Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • ViroPharma Investigational Site
  • Florida
    • Tampa, Florida, United States, 33613
      • ViroPharma Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • ViroPharma Investigational Site
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • ViroPharma Investigational Site
  • New York
    • Mineola, New York, United States, 11501
      • ViroPharma Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • ViroPharma Investigational Site
    • Columbus, Ohio, United States, 43235
      • ViroPharma Investigational Site
  • Oregon
    • Lake Oswego, Oregon, United States, 97035
      • ViroPharma Investigational Site
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • ViroPharma Investigational Site
    • Pittsburgh, Pennsylvania, United States, 15241
      • ViroPharma Investigational Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • ViroPharma Investigational Site
  • Texas
    • Dallas, Texas, United States, 75231
      • ViroPharma Investigational Site
  • Washington
    • Spokane, Washington, United States, 99204
      • ViroPharma Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Be ≥12 years of age.
• Have a confirmed diagnosis of Hereditary Angioedema.

Exclusion Criteria:

• Receipt of any C1 inhibitor (C1 INH) therapy or any blood products for treatment or prevention of an angioedema attack within 7 days before the first dose of study drug.
• Be receiving prophylactic intravenous CINRYZE that exceeds 1000 units every 3 or 4 days (maximum weekly dose 2000 units).
• Have received any androgen therapy (e.g., danazol, oxandrolone, stanozolol, testosterone) within 7 days prior to the first dose of study drug.
• If female, have started taking or changed the dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e., estrogen/progestin containing products) within 3 months prior to the first dose of study drug.
• History of allergic reaction to C1 INH products, including CINRYZE or other blood products.
• History of abnormal blood clotting.
• Have a known allergy to hyaluronidase or any other ingredient in the study formulation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: SC CINRYZE with rHuPH20 Dose Level 1 followed by Dose Level 2; SC CINRYZE with rHuPH20 Dose Level 1 twice weekly (every 3 or 4 days) for 8 weeks followed by SC CINRYZE with rHuPH20 Dose Level 2 twice weekly (every 3 or 4 days) for 8 weeks.	Biological: CINRYZE with rHuPH20; Other Names: C1 esterase inhibitor (human); Recombinant human hyaluronidase
EXPERIMENTAL: SC CINRYZE with rHuPH20 Dose Level 2 followed by Dose Level 1; SC CINRYZE with rHuPH20 Dose Level 2 twice weekly (every 3 or 4 days) for 8 weeks followed by SC CINRYZE with rHuPH20 Dose Level 1 twice weekly (every 3 or 4 days) for 8 weeks.	Biological: CINRYZE with rHuPH20; Other Names: C1 esterase inhibitor (human); Recombinant human hyaluronidase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Normalized Number of Angioedema Attacks During the 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. Participants who were dosed but did not have any attacks in the period were assigned a value of zero. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.	From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Attack-severity During the Treatment Period	Cumulative Attack-severity score was the sum of maximum symptom severity recorded for each angioedema attack, determined on the last day of symptoms and recorded as None=0, Mild=1, Moderate=2, and Severe=3 and summing over the unique attacks, yields a Cumulative Attack-severity score. None: no angioedema attack symptom; Mild: the angioedema attack symptom was noticeable to the participant but was easily tolerated and did not interfere with routine activities; Moderate: the angioedema attack symptom interfered with work/school or the ability to participate in family life and social activities; Severe: the angioedema attack symptom significantly limited the participant's ability to attend work/school or participate in family life and social activities. Cumulative attack-severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms.	From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Cumulative Daily-severity During the Treatment Period	Cumulative Daily-severity score was the sum of the severity scores recorded for every day of reported symptoms during the treatment period. Severity scores were recorded as None=0, Mild=1, Moderate=2, and Severe=3. None: no angioedema attack symptom; Mild: the angioedema attack symptom was noticeable to the participant but was easily tolerated and did not interfere with routine activities; Moderate: the angioedema attack symptom interfered with work/school or the ability to participate in family life and social activities; Severe: the angioedema attack symptom significantly limited the participant's ability to attend work/school or participate in family life and social activities. Cumulative daily severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms.	From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Cumulative Symptomatic Days During the Treatment Period	Cumulative symptomatic days was defined as the sum of the symptomatic days of each angioedema attack reported during the treatment period. Participants who were dosed but did not have any attacks in the period were assigned a value of zero. Cumulative symptomatic days was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.	From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Number of Angioedema Attacks Requiring Acute Treatment During the 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. Participants who were dosed but did not have any attacks in the period were assigned a value of zero. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.	From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Riedl MA, Lumry WR, Li HH, Banerji A, Bernstein JA, Ba M, Bjrkander J, Magerl M, Maurer M, Rockich K, Chen H, Schranz J. Subcutaneous administration of human C1 inhibitor with recombinant human hyaluronidase in patients with hereditary angioedema. Allergy Asthma Proc. 2016 Nov;37(6):489-500. doi: 10.2500/aap.2016.37.4006.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 4, 2013
• Primary Completion (ACTUAL): September 13, 2013
• Study Completion (ACTUAL): September 13, 2013

Study Registration Dates

• First Submitted: June 29, 2012
• First Submitted That Met QC Criteria: December 19, 2012
• First Posted (ESTIMATE): December 25, 2012

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: Crossover; Subcutaneous; Prevention; Hereditary Angioedema; C1 inhibitor; C1 esterase inhibitor; Recombinant human hyaluronidase
• 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; Complement C1 Inactivator Proteins; Complement C1s
• Other Study ID Numbers: 0624-206; 2012-000083-24 (EUDRACT_NUMBER)