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

• ClinicalTrials.gov Identifier: NCT02316353
• Recruitment Status: Completed
• First Posted: December 12, 2014
• Results First Posted: November 14, 2018
• Last Update Posted: November 14, 2018
• Sponsor: CSL Behring
• Information provided by (Responsible Party): CSL Behring

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hereditary Angioedema Types I and II	Biological: C1-esterase inhibitor	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 126 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: December 31, 2014
• Actual Primary Completion Date: September 21, 2017
• Actual Study Completion Date: September 21, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Person-time Incidence Rates (Subject Based) [ Time Frame: Up to 146 weeks. ]
   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.
2. The Person-time Incidence Rates (Event Based) [ Time Frame: Up to 146 weeks. ]
   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.

Secondary Outcome Measures :

1. Percentage of Subjects Who Have Solicited Adverse Events (AEs) [ Time Frame: Up to 146 weeks ]
   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.
2. Percentage of Injections Followed by At Least One Solicited Adverse Event [ Time Frame: Up to 146 weeks ]
   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.
3. Percentage of Subjects Who Become Seropositive for Human Immunodeficiency Virus (HIV-1/-2), Hepatitis B Virus, or Hepatitis C Virus. [ Time Frame: Up to 146 weeks ]
   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.
4. Percentage of Subjects Who Experience a Time-normalized HAE Attack Frequency of <1 HAE Attack Per 4-Week Period [ Time Frame: Up to 146 weeks ]
   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.
5. Percentage of Subjects Who Are Responders [ Time Frame: Up to 146 weeks ]
   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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

Study Site

Birmingham, Alabama, United States, 35209

United States, Arizona

Study Site

Scottsdale, Arizona, United States, 85251

United States, California

Study Site

La Jolla, California, United States, 92037

Study Site

Orange, California, United States, 92868

Study Site

Walnut Creek, California, United States, 94598

United States, Maryland

Study Site

Chevy Chase, Maryland, United States, 20815

United States, Ohio

Study Site

Cincinnati, Ohio, United States, 45231

United States, Oklahoma

Study Site

Tulsa, Oklahoma, United States, 74136

United States, Oregon

Study Site

Portland, Oregon, United States, 97223

United States, Pennsylvania

Study Site

Hershey, Pennsylvania, United States, 17033

United States, Texas

Study Site

Dallas, Texas, United States, 75231

United States, Virginia

Study Site

Richmond, Virginia, United States, 23298

Australia, New South Wales

Study Site

Campbelltown, New South Wales, Australia, 2560

Canada, Ontario

Study Site

Hamilton, Ontario, Canada, L8N 3Z5

Study Site

Ottawa, Ontario, Canada, K1Y 4G2

Study Site

Toronto, Ontario, Canada, M4V 1R2

Canada

Study Site

Quebec, Canada, G1V 4M6

Czechia

Study Site

Plzen, Czechia, 30460

Germany

Study Site

Mörfelden-Walldorf, Hesse, Germany, 64546

Study Site

Berlin, Germany, 10117

Study Site

Frankfurt, Germany, 60596

Study Site

Mainz, Germany, 55131

Hungary

Study Site

Budapest, Hungary, 1125

Israel

Study Site

Tel Aviv, Israel, 64239

Study Site

Tel Hashomer, Israel, 52621

Italy

Study Site

Catania, Italy, 95123

Study Site

Milano, Italy, 20157

Romania

Study Site

Cluj Napoca, Romania, 400139

Spain

Study Site

Madrid, Spain, 28007

Study Site

Madrid, Spain, 28046

Study Site

Valencia, Spain, 46026

United Kingdom

Study Site

London, United Kingdom, E1 2ES

Sponsors and Collaborators

CSL Behring

Investigators

• Study Director: Global Clinical Program Director; CSL Behring

  Study Documents (Full-Text)

Documents provided by CSL Behring:

Study Protocol  [PDF] July 10, 2015

Statistical Analysis Plan  [PDF] September 12, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: CSL Behring
• ClinicalTrials.gov Identifier: NCT02316353
• Other Study ID Numbers: CSL830_3002; 2014-001054-42 ( EudraCT Number )
• First Posted: December 12, 2014
• Results First Posted: November 14, 2018
• Last Update Posted: November 14, 2018
• Last Verified: October 2017

Additional relevant MeSH terms:

Angioedema; Angioedemas, Hereditary; Hereditary Angioedema Types I and II; Vascular Diseases; Cardiovascular Diseases; Urticaria; Skin Diseases, Vascular; Skin Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Immunologic Deficiency Syndromes; Complement C1s; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Immunologic Factors; Physiological Effects of Drugs; Complement Inactivating Agents; Immunosuppressive Agents