A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema

An Open-label, Randomized Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneous Administration of Human Plasma-derived C1-esterase Inhibitor in the Prophylactic Treatment of Hereditary Angioedema

The aim of this study is to assess the long-term safety of C1-esterase inhibitor (C1-INH) in preventing hereditary angioedema (HAE) attacks when it is administered under the skin of subjects with HAE. The safety of participating subjects will be assessed for up to 54 weeks. The long-term efficacy of C1-INH will also be assessed. Each eligible subject will enter the treatment phase, wherein subjects will be randomized to treatment with either low- or medium-volume C1-INH. Subjects who have an insufficient treatment response during the study will be given an opportunity to undergo a dose increase. The study aims to enroll eligible subjects who completed study CSL830_3001 (NCT01912456). Subjects who did not participate in study CSL830_3001 may also participate, if eligible and if space permits. Subjects from the United States (US) who complete Treatment Period 2 will be allowed to participate in an Extension Period. During the Extension Period participating US subjects will continue to receive treatment with open-label CSL830 for up to an additional 88 weeks.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema Types I and II
• Intervention / Treatment: Biological: C1-esterase inhibitor

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Campbelltown, New South Wales, Australia, 2560
      • Study Site
• Canada
  • Quebec, Canada, G1V 4M6
    • Study Site
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Study Site
    • Ottawa, Ontario, Canada, K1Y 4G2
      • Study Site
    • Toronto, Ontario, Canada, M4V 1R2
      • Study Site
• Czechia
  • Plzen, Czechia, 30460
    • Study Site
• Germany
  • Berlin, Germany, 10117
    • Study Site
  • Frankfurt, Germany, 60596
    • Study Site
  • Mainz, Germany, 55131
    • Study Site
  • Hesse
    • Mörfelden-Walldorf, Hesse, Germany, 64546
      • Study Site
• Hungary
  • Budapest, Hungary, 1125
    • Study Site
• Israel
  • Tel Aviv, Israel, 64239
    • Study Site
  • Tel Hashomer, Israel, 52621
    • Study Site
• Italy
  • Catania, Italy, 95123
    • Study Site
  • Milano, Italy, 20157
    • Study Site
• Romania
  • Cluj Napoca, Romania, 400139
    • Study Site
• Spain
  • Madrid, Spain, 28007
    • Study Site
  • Madrid, Spain, 28046
    • Study Site
  • Valencia, Spain, 46026
    • Study Site
• United Kingdom
  • London, United Kingdom, E1 2ES
    • Study Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Study Site
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Study Site
  • California
    • La Jolla, California, United States, 92037
      • Study Site
    • Orange, California, United States, 92868
      • Study Site
    • Walnut Creek, California, United States, 94598
      • Study Site
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Study Site
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Study Site
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Study Site
  • Oregon
    • Portland, Oregon, United States, 97223
      • Study Site
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Study Site
  • Texas
    • Dallas, Texas, United States, 75231
      • Study Site
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females aged 6 years or older.
• A confirmed diagnosis of HAE type I or II.
• HAE attacks over a consecutive 2-month period that required acute treatment, medical attention, or caused significant functional impairment.
• For subjects who have used oral therapy for prophylaxis against HAE attacks within 3 months of first study visit: use of a stable regimen within 3 months of the first study visit.

Exclusion Criteria:

• Incurable malignancies.
• Any clinical condition that will interfere with the evaluation of C1-INH therapy.
• Clinically significant history of poor response to C1-esterase therapy for the management of HAE.
• Suspected or confirmed diagnosis of acquired HAE or HAE with normal C1-INH.
• Inability to have HAE managed pharmacologically with on-demand treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: C1-INH - low-volume dose; A low-volume dose of C1-INH will be administered subcutaneously twice a week for up to 52 weeks (up to 146 weeks extension period).	Biological: C1-esterase inhibitor
Experimental: C1-INH - medium-volume dose; A medium-volume dose of C1-INH will be administered subcutaneously twice a week for up to 52 weeks (up to 146 weeks extension period).	Biological: C1-esterase inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Person-time Incidence Rates (Subject Based)	Subject-based Analysis for Person-Time Incidence Rate = (the total number of subjects who experienced the event during the respective treatment) / (the sum of the date each subject experienced the event - the subject's start date + 1 day) / (365.25 days). The analysis population for this endpoint was the Safety Population: the Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.	Up to 146 weeks.
The Person-time Incidence Rates (Event Based)	Event-based Analysis for Person-Time Incidence Rate = (the total number of events documented during the respective treatment) / (the sum of each subject's end date - the subject's start date + 1 day) / (365.25 days). The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.	Up to 146 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects Who Have Solicited Adverse Events (AEs)	The number of subjects having at least 1 solicited local AE during a treatment were divided by the number of subjects in the corresponding treatment. The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.	Up to 146 weeks
Percentage of Injections Followed by At Least One Solicited Adverse Event	The percent of injections followed by at least one solicited adverse event. The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830. This was assessed across all participants, calculated as total number of events following injections / total number of injections across all participants, in each Arm.	Up to 146 weeks
Percentage of Subjects Who Become Seropositive for Human Immunodeficiency Virus (HIV-1/-2), Hepatitis B Virus, or Hepatitis C Virus.	Blood samples to be tested for HIV-1/-2, HBV, and HCV. The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.	Up to 146 weeks
Percentage of Subjects Who Experience a Time-normalized HAE Attack Frequency of <1 HAE Attack Per 4-Week Period	The percentage of subjects with a time-normalized merged HAE attack frequency of <1 HAE attack per 4-week period. The analysis population for this endpoint was the Intent-to-Treat (ITT) Population: The ITT Population comprised all subjects who provided informed consent / assent and were randomized, regardless of whether or not they received CSL 830.	Up to 146 weeks
Percentage of Subjects Who Are Responders	A responder was defined as a subject with a ≥ 50% reduction in the time-normalized number of HAE attacks on CSL830 relative to the time-normalized number of HAE attacks used to qualify for participation in the current study. The analysis population for this endpoint was the Intent-to-Treat (ITT) Population: The ITT Population comprised all subjects who provided informed consent / assent and were randomized, regardless of whether or not they received CSL830. Not all subjects in the ITT were available for this outcome measure.	Up to 146 weeks

Collaborators and Investigators

• Sponsor: CSL Behring

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.
• Lumry WR, Zuraw B, Cicardi M, Craig T, Anderson J, Banerji A, Bernstein JA, Caballero T, Farkas H, Gower RG, Keith PK, Levy DS, Li HH, Magerl M, Manning M, Riedl MA, Lawo JP, Prusty S, Machnig T, Longhurst H; on behalf of the COMPACT Investigators. Long-term health-related quality of life in patients treated with subcutaneous C1-inhibitor replacement therapy for the prevention of hereditary angioedema attacks: findings from the COMPACT open-label extension study. Orphanet J Rare Dis. 2021 Feb 15;16(1):86. doi: 10.1186/s13023-020-01658-4. Erratum In: Orphanet J Rare Dis. 2021 Jul 28;16(1):329.
• Levy DS, Farkas H, Riedl MA, Hsu FI, Brooks JP, Cicardi M, Feuersenger H, Pragst I, Reshef A. Long-term efficacy and safety of subcutaneous C1-inhibitor in women with hereditary angioedema: subgroup analysis from an open-label extension of a phase 3 trial. Allergy Asthma Clin Immunol. 2020 Feb 4;16:8. doi: 10.1186/s13223-020-0409-3. eCollection 2020.
• Craig T, Zuraw B, Longhurst H, Cicardi M, Bork K, Grattan C, Katelaris C, Sussman G, Keith PK, Yang W, Hebert J, Hanzlikova J, Staubach-Renz P, Martinez-Saguer I, Magerl M, Aygoren-Pursun E, Farkas H, Reshef A, Kivity S, Neri S, Crisan I, Caballero T, Baeza ML, Hernandez MD, Li H, Lumry W, Bernstein JA, Hussain I, Anderson J, Schwartz LB, Jacobs J, Manning M, Levy D, Riedl M, Christiansen S, Feuersenger H, Pragst I, Mycroft S, Pawaskar D, Jacobs I; COMPACT Investigators. Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks. J Allergy Clin Immunol Pract. 2019 Jul-Aug;7(6):1793-1802.e2. doi: 10.1016/j.jaip.2019.01.054. Epub 2019 Feb 15.

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2014
• Primary Completion (Actual): September 21, 2017
• Study Completion (Actual): September 21, 2017

Study Registration Dates

• First Submitted: December 10, 2014
• First Submitted That Met QC Criteria: December 10, 2014
• First Posted (Estimate): December 12, 2014

Study Record Updates

• Last Update Posted (Actual): November 14, 2018
• Last Update Submitted That Met QC Criteria: October 17, 2018
• Last Verified: October 1, 2017

More Information

Terms related to this study

• 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; Hereditary Angioedema Types I and II; 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: CSL830_3002; 2014-001054-42 (EudraCT Number)