A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema
Primary Purpose
Hereditary Angioedema Types I and II
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
C1-esterase inhibitor
Sponsored by
About this trial
This is an interventional prevention trial for Hereditary Angioedema Types I and II
Eligibility 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.
Sites / Locations
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Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
C1-INH - low-volume dose
C1-INH - medium-volume dose
Arm Description
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).
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).
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02316353
Brief Title
A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
December 31, 2014 (Actual)
Primary Completion Date
September 21, 2017 (Actual)
Study Completion Date
September 21, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
CSL Behring
4. Oversight
Data Monitoring Committee
No
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hereditary Angioedema Types I and II
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
126 (Actual)
8. Arms, Groups, and Interventions
Arm Title
C1-INH - low-volume dose
Arm Type
Experimental
Arm Description
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).
Arm Title
C1-INH - medium-volume dose
Arm Type
Experimental
Arm Description
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).
Intervention Type
Biological
Intervention Name(s)
C1-esterase inhibitor
Primary Outcome Measure Information:
Title
Person-time Incidence Rates (Subject Based)
Description
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.
Time Frame
Up to 146 weeks.
Title
The Person-time Incidence Rates (Event Based)
Description
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.
Time Frame
Up to 146 weeks.
Secondary Outcome Measure Information:
Title
Percentage of Subjects Who Have Solicited Adverse Events (AEs)
Description
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.
Time Frame
Up to 146 weeks
Title
Percentage of Injections Followed by At Least One Solicited Adverse Event
Description
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.
Time Frame
Up to 146 weeks
Title
Percentage of Subjects Who Become Seropositive for Human Immunodeficiency Virus (HIV-1/-2), Hepatitis B Virus, or Hepatitis C Virus.
Description
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.
Time Frame
Up to 146 weeks
Title
Percentage of Subjects Who Experience a Time-normalized HAE Attack Frequency of <1 HAE Attack Per 4-Week Period
Description
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.
Time Frame
Up to 146 weeks
Title
Percentage of Subjects Who Are Responders
Description
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.
Time Frame
Up to 146 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Global Clinical Program Director
Organizational Affiliation
CSL Behring
Official's Role
Study Director
Facility Information:
Facility Name
Study Site
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35209
Country
United States
Facility Name
Study Site
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85251
Country
United States
Facility Name
Study Site
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Facility Name
Study Site
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Study Site
City
Walnut Creek
State/Province
California
ZIP/Postal Code
94598
Country
United States
Facility Name
Study Site
City
Chevy Chase
State/Province
Maryland
ZIP/Postal Code
20815
Country
United States
Facility Name
Study Site
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45231
Country
United States
Facility Name
Study Site
City
Tulsa
State/Province
Oklahoma
ZIP/Postal Code
74136
Country
United States
Facility Name
Study Site
City
Portland
State/Province
Oregon
ZIP/Postal Code
97223
Country
United States
Facility Name
Study Site
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Facility Name
Study Site
City
Dallas
State/Province
Texas
ZIP/Postal Code
75231
Country
United States
Facility Name
Study Site
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
Study Site
City
Campbelltown
State/Province
New South Wales
ZIP/Postal Code
2560
Country
Australia
Facility Name
Study Site
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 3Z5
Country
Canada
Facility Name
Study Site
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1Y 4G2
Country
Canada
Facility Name
Study Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4V 1R2
Country
Canada
Facility Name
Study Site
City
Quebec
ZIP/Postal Code
G1V 4M6
Country
Canada
Facility Name
Study Site
City
Plzen
ZIP/Postal Code
30460
Country
Czechia
Facility Name
Study Site
City
Mörfelden-Walldorf
State/Province
Hesse
ZIP/Postal Code
64546
Country
Germany
Facility Name
Study Site
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
Study Site
City
Frankfurt
ZIP/Postal Code
60596
Country
Germany
Facility Name
Study Site
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Study Site
City
Budapest
ZIP/Postal Code
1125
Country
Hungary
Facility Name
Study Site
City
Tel Aviv
ZIP/Postal Code
64239
Country
Israel
Facility Name
Study Site
City
Tel Hashomer
ZIP/Postal Code
52621
Country
Israel
Facility Name
Study Site
City
Catania
ZIP/Postal Code
95123
Country
Italy
Facility Name
Study Site
City
Milano
ZIP/Postal Code
20157
Country
Italy
Facility Name
Study Site
City
Cluj Napoca
ZIP/Postal Code
400139
Country
Romania
Facility Name
Study Site
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Facility Name
Study Site
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Study Site
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Name
Study Site
City
London
ZIP/Postal Code
E1 2ES
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
36326435
Citation
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.
Results Reference
derived
PubMed Identifier
33588897
Citation
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.
Results Reference
derived
PubMed Identifier
32042283
Citation
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.
Results Reference
derived
PubMed Identifier
30772477
Citation
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.
Results Reference
derived
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A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema
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