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

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

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.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema Types I and II
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Study Site
  • Frankfurt, Germany, 60596
    • Study Site
  • Mainz, Germany, 55101
    • Study Site
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Study Site
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Study Site
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Study Site
    • Toledo, Ohio, United States, 43617
      • Study Site
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 19108
      • Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low, then medium, C1-esterase inhibitor dose	Biological: C1-esterase inhibitor - single intravenous dose; 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.; Biological: C1-esterase inhibitor - subcutaneous low dose; A low dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.; Biological: C1-esterase inhibitor - subcutaneous medium dose; A medium dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.
Experimental: Medium, then low, C1-esterase inhibitor dose	Biological: C1-esterase inhibitor - single intravenous dose; 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.; Biological: C1-esterase inhibitor - subcutaneous low dose; A low dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.; Biological: C1-esterase inhibitor - subcutaneous medium dose; A medium dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.
Experimental: Medium, then high, C1-esterase inhibitor dose	Biological: C1-esterase inhibitor - single intravenous dose; 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.; Biological: C1-esterase inhibitor - subcutaneous medium dose; A medium dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.; Biological: C1-esterase inhibitor - subcutaneous high dose; A high dose of C1-esterase inhibitor will administered subcutaneously twice a week for four weeks.
Experimental: Low, then high, C1-esterase inhibitor dose	Biological: C1-esterase inhibitor - single intravenous dose; 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.; Biological: C1-esterase inhibitor - subcutaneous low dose; A low dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.; Biological: C1-esterase inhibitor - subcutaneous high dose; A high dose of C1-esterase inhibitor will administered subcutaneously twice a week for four weeks.
Experimental: High, then low, C1-esterase inhibitor dose	Biological: C1-esterase inhibitor - single intravenous dose; 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.; Biological: C1-esterase inhibitor - subcutaneous low dose; A low dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.; Biological: C1-esterase inhibitor - subcutaneous high dose; A high dose of C1-esterase inhibitor will administered subcutaneously twice a week for four weeks.
Experimental: High, then medium, C1-esterase inhibitor dose	Biological: C1-esterase inhibitor - single intravenous dose; 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.; Biological: C1-esterase inhibitor - subcutaneous medium dose; A medium dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.; Biological: C1-esterase inhibitor - subcutaneous high dose; A high dose of C1-esterase inhibitor will administered subcutaneously twice a week for four weeks.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: CSL Behring
• Collaborators: Parexel

Publications and helpful links

General Publications

• Zuraw BL, Cicardi M, Longhurst HJ, Bernstein JA, Li HH, Magerl M, Martinez-Saguer I, Rehman SM, Staubach P, Feuersenger H, Parasrampuria R, Sidhu J, Edelman J, Craig T. Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate. Allergy. 2015 Oct;70(10):1319-28. doi: 10.1111/all.12658. Epub 2015 Aug 11.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: April 10, 2012
• First Submitted That Met QC Criteria: April 10, 2012
• First Posted (Estimate): April 12, 2012

Study Record Updates

• Last Update Posted (Actual): February 1, 2021
• Last Update Submitted That Met QC Criteria: January 29, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary; Hereditary Angioedema Types I and II; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Complement C1s
• Other Study ID Numbers: CSL830_2001; 2011-005013-36 (EudraCT Number)