A Study to Evaluate the Clinical Efficacy and Safety 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 efficacy of C1-esterase inhibitor in preventing hereditary angioedema attacks when it is administered under the skin of subjects with hereditary angioedema. The safety of C1-esterase inhibitor will also be assessed. Each subject will enter a run-in period of up to 8-weeks. Subjects who complete the run-in period and who are eligible will then enter the treatment phase which comprises two sequential treatment periods. In the treatment phase, subjects will be randomized to one of four arms consisting of treatment with low- or higher-volume C1-esterase inhibitor in one treatment period and treatment with low- or higher-volume placebo in the other treatment period. The study will measure the number of hereditary angioedema attacks that subjects experience while receiving each treatment.

Official Title
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A Double-blind, Randomized, Placebo-controlled, Cross-over Study to Evaluate the Clinical Efficacy and Safety 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: Low-volume C1-esterase inhibitor
* Biological: Higher-volume C1-esterase inhibitor
* Biological: Low-volume placebo
* Biological: Higher-volume placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Run-In Period Inclusion Criteria: Males or females aged 12 years or older. A clinical diagnosis of hereditary angioedema type I or II. Hereditary angioedema 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 Screening: use of a stable regimen within 3 months of Screening, with no plans to change. Eligibility Criteria for Entering Treatment Period 1: Laboratory confirmation of type I or type II hereditary angioedema, including C1-esterase inhibitor functional activity less than 50% AND C4 antigen level below the laboratory reference range. No clinically significant abnormalities as assessed using laboratory parameters. During participation in the run-in period, subjects must have experienced hereditary angioedema attacks that required acute treatment, required medical attention, or caused significant functional impairment. Exclusion Criteria: Run-In Period Exclusion Criteria: History of clinical significant arterial or venous thrombosis, or current history of a clinically significant prothrombotic risk. Incurable malignancies at screening. Any clinical condition that will interfere with the evaluation of C1-esterase inhibitor therapy. Clinically significant history of poor response to C1-esterase therapy for the management of hereditary angioedema. Receiving therapy prohibited by the protocol, including medications for hereditary angioedema prophylaxis. Female subjects who started taking or changed dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e., estrogen/progesterone-containing products) within 3 months prior to the screening visit.

Ages Eligible for Study
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Minimum Age: 12 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Higher-volume placebo, then low-volume C1-esterase inhibitor<br>A higher-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | Biological: Low-volume C1-esterase inhibitor<br> <br> Biological: Higher-volume placebo<br> <br> |
| Experimental: Low-volume C1-esterase inhibitor, then higher-volume placebo<br>A low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then a higher-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | Biological: Low-volume C1-esterase inhibitor<br> <br> Biological: Higher-volume placebo<br> <br> |
| Experimental: Low-volume placebo, then higher-volume C1-esterase inhibitor<br>A low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks then a higher-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | Biological: Higher-volume C1-esterase inhibitor<br> <br> Biological: Low-volume placebo<br> <br> |
| Experimental: Higher-volume C1-esterase inhibitor, then low-volume placebo<br>A higher-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | Biological: Higher-volume C1-esterase inhibitor<br> <br> Biological: Low-volume placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time-normalized Number of Hereditary Angioedema Attacks | The time normalized number of HAE attacks as reported by the investigator per subject was calculated as: The total number of HAE attacks per subject and per treatment period / length of stay of subject in treatment period (days), Where length of stay of subject in treatment period was calculated as: Date of last day of subject in treatment period - date of first day of Week 3 of subject in treatment period + 1. | During the treatment phase, up to 28 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With a ≥ 50% Reduction in the Number of Hereditary Angioedema Attacks by CSL830 Treatment | The percentage reduction (%) in the time normalized number of HAE attacks was calculated as: 100 x [1 - (the time normalized number of HAE attacks when treated with CSL830) / (the time normalized number of HAE attacks when treated with placebo)]. A subject is classed as a responder if the percentage reduction is >= 50%. | During the treatment phase, up to 28 weeks. | 
| Time-Normalized Number of Uses of Rescue Medication | The time-normalized number of uses of rescue medication during treatment with C1-esterase inhibitor or placebo | During the treatment phase, up to 28 weeks. | 
| Percentage of Subjects With Adverse Events (AEs) Within 24 Hours of C1-esterase Inhibitor or Placebo Administration |  | Within 24 hours of C1-esterase inhibitor or placebo administration. | 
| Percentage of Subjects With AEs or Other Specified Safety Events. | The percentage of subjects experiencing the following during treatment with CSL830 and placebo: unsolicited AEs, serious AEs, suspected adverse drug reactions, increased risk scores for deep vein thrombosis and pulmonary embolism, thromboembolic events, inhibitory anti C1 INH antibodies, or clinically significant abnormalities in laboratory assessments. | During the treatment phase, up to 32 weeks. | 
| Percentage of Subjects Experiencing Solicited AEs (Injection Site Reactions) | The percentage of subjects experiencing solicited local AEs (discomfort [eg, pain, burning], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo. | During the treatment phase, up to 32 weeks. | 
| Injections Resulting in Solicited AEs (Injection Site Reactions) | The rate/injection of injections of C1-esterase inhibitor or placebo that were followed by solicited local AEs (discomfort [eg, pain, burning], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo. Rate/Injection = Number of events/number of injections. | During the treatment phase, up to 32 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hereditary Angioedema