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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hereditary Angioedema Types I and II

Intervention / Treatment
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* Biological: C1-esterase inhibitor


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C1-INH - low-volume dose<br>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<br> <br> |
| Experimental: C1-INH - medium-volume dose<br>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<br> <br> |

What is the study measuring?
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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 |