A Study to Evaluate the Clinical Pharmacology and Safety of C1-esterase Inhibitor Administered by the Subcutaneous Route

Study Overview
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Brief Summary
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The aim of the study is to assess what happens to C1-esterase inhibitor that is administered under the skin of subjects with hereditary angioedema. Three different dosing regimens of C1-esterase inhibitor will be assessed. Each subject will be assigned to receive 2 of the 3 dosing regimens, each for 4 weeks. The activity and concentration of C1-esterase inhibitor in the blood will be measured during each 4-week period. The study will also examine how well C1-esterase inhibitor administered under the skin is tolerated by the subjects.

Official Title
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An Open-label, Cross-over, Dose-ranging Study to Evaluate the Pharmacokinetics, Pharmacodynamics and Safety of the Subcutaneous Administration of a Human Plasma-derived C1-esterase Inhibitor in Subjects With Hereditary Angioedema

Conditions
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Hereditary Angioedema Types I and II

Intervention / Treatment
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* Biological: C1-esterase inhibitor - single intravenous dose
* Biological: C1-esterase inhibitor - subcutaneous low dose
* Biological: C1-esterase inhibitor - subcutaneous medium dose
* Biological: C1-esterase inhibitor - subcutaneous high dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged 18 years or older. Laboratory-confirmed hereditary angioedema type I or II. Less than two hereditary angioedema attacks per month in the last three months. Body weight of 50.0 kg to 110.0 kg. Exclusion Criteria: Receiving prophylactic C1-esterase inhibitor therapy. Received C1-esterase inhibitor, ecallantide, icatibant or any blood products for the prevention or treatment of hereditary angioedema within 7 days before the screening visit. Intends to use recombinant C1-esterase inhibitor or fresh frozen plasma for the acute treatment of hereditary angioedema during the study. Received androgen therapy (e.g., danazol, oxandrolone, stanozolol, testosterone) within 30 days before the screening visit. 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. Known or suspected hypersensitivity to the study product, or to any excipients of the study product. Pregnancy or lactation.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low, then medium, C1-esterase inhibitor dose<br> | Biological: C1-esterase inhibitor - single intravenous dose<br>* A single intravenous dose of C1-esterase inhibitor (Berinert) at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor.<br>Biological: C1-esterase inhibitor - subcutaneous low dose<br>* A low dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.<br>Biological: C1-esterase inhibitor - subcutaneous medium dose<br>* A medium dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.<br>|
| Experimental: Medium, then low, C1-esterase inhibitor dose<br> | Biological: C1-esterase inhibitor - single intravenous dose<br>* A single intravenous dose of C1-esterase inhibitor (Berinert) at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor.<br>Biological: C1-esterase inhibitor - subcutaneous low dose<br>* A low dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.<br>Biological: C1-esterase inhibitor - subcutaneous medium dose<br>* A medium dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.<br>|
| Experimental: Medium, then high, C1-esterase inhibitor dose<br> | Biological: C1-esterase inhibitor - single intravenous dose<br>* A single intravenous dose of C1-esterase inhibitor (Berinert) at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor.<br>Biological: C1-esterase inhibitor - subcutaneous medium dose<br>* A medium dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.<br>Biological: C1-esterase inhibitor - subcutaneous high dose<br>* A high dose of C1-esterase inhibitor will administered subcutaneously twice a week for four weeks.<br>|
| Experimental: Low, then high, C1-esterase inhibitor dose<br> | Biological: C1-esterase inhibitor - single intravenous dose<br>* A single intravenous dose of C1-esterase inhibitor (Berinert) at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor.<br>Biological: C1-esterase inhibitor - subcutaneous low dose<br>* A low dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.<br>Biological: C1-esterase inhibitor - subcutaneous high dose<br>* A high dose of C1-esterase inhibitor will administered subcutaneously twice a week for four weeks.<br>|
| Experimental: High, then low, C1-esterase inhibitor dose<br> | Biological: C1-esterase inhibitor - single intravenous dose<br>* A single intravenous dose of C1-esterase inhibitor (Berinert) at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor.<br>Biological: C1-esterase inhibitor - subcutaneous low dose<br>* A low dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.<br>Biological: C1-esterase inhibitor - subcutaneous high dose<br>* A high dose of C1-esterase inhibitor will administered subcutaneously twice a week for four weeks.<br>|
| Experimental: High, then medium, C1-esterase inhibitor dose<br> | Biological: C1-esterase inhibitor - single intravenous dose<br>* A single intravenous dose of C1-esterase inhibitor (Berinert) at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor.<br>Biological: C1-esterase inhibitor - subcutaneous medium dose<br>* A medium dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.<br>Biological: C1-esterase inhibitor - subcutaneous high dose<br>* A high dose of C1-esterase inhibitor will administered subcutaneously twice a week for four weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modeled C1-esterase Inhibitor Functional Activity Trough Level | Mean trough C1-esterase inhibitor functional activity of the low, medium and high subcutaneous dose regimens, based on modeling and simulation | at the fourth week of each dosing regimen | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| As-observed C1-esterase Inhibitor Functional Activity Trough Level | Mean trough C1-esterase inhibitor functional activity of the low, medium and high subcutaneous dose regimens | during the last week of 4-week dose regimen | 
| C1-esterase Inhibitor Concentration Trough Level | Mean trough C1-esterase inhibitor concentration of the low, medium and high subcutaneous dose regimens | during the last week of 4-week dose regimen | 
| C4 Concentration Trough Level | Mean trough C4 concentration of the low, medium and high subcutaneous dose regimens | during the last week of 4-week dose regimen | 
| Change From Baseline in C1-esterase Inhibitor Functional Activity | Mean change from baseline of C1-esterase inhibitor functional activity of the low, medium and high subcutaneous dose regimens | Baseline and during the last week of 4-week dose regimen | 
| Change From Baseline in C1-esterase Inhibitor Concentration | Mean change from baseline of C1-esterase inhibitor concentration of the low, medium and high subcutaneous dose regimens | Baseline and during the last week of 4-week dose regimen | 
| Change From Baseline in C4 Concentration | Mean change from baseline of C4 concentration of the low, medium and high subcutaneous dose regimens | Baseline and during the last week of 4-week dose regimen |