A Study to Investigate CSL312 in Subjects With Hereditary Angioedema (HAE)

A Multicenter, Randomized, Placebo-controlled, Parallel-arm Study to Investigate the Efficacy, Pharmacokinetics, and Safety of CSL312 in Subjects With Hereditary Angioedema

This is a multicenter, randomized, placebo-controlled, parallel-arm, phase 2 study to investigate the clinical efficacy, pharmacokinetics, and safety of CSL312 as prophylaxis to prevent attacks in subjects with HAE.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Drug: Placebo; Biological: Factor XIIa antagonist monoclonal antibody

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Campbelltown, New South Wales, Australia, 2560
      • Campbelltown Hospital
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta
  • Ontario
    • Hamilton, Ontario, Canada, L8S 4K1
      • Allergy and Clinical Immunology McMaster University
    • Ottawa, Ontario, Canada, K1G 6C6
      • Ottawa Allergy Research Corp
• Germany
  • Berlin, Germany, 10117
    • Charite Universitatsmedizin Berlin
  • Frankfurt, Germany, 60590
    • Universitätsklinikum Frankfurt Goethe-Universität
  • Mainz, Germany, 55131
    • Hautklinik und Poliklinik der Universitätsklinik Mainz
  • Mörfelden-Walldorf, Germany, 64546
    • HZRM Hämophilie Zentrum Rhein Main GmbH
• Israel
  • Ashkelon, Israel, 7830604
    • Barzilai University Medical Center
• United States
  • California
    • Orange, California, United States, 92868
      • Donald S. Levy
    • Walnut Creek, California, United States, 94598
      • Allergy & Asthma Clinical Research
  • Colorado
    • Centennial, Colorado, United States, 80112
      • Immunoe Health Centers
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Institute for Asthma and Allergy
  • New York
    • New York, New York, United States, 10029
      • The Mount Sinai Hospital
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Pennsylvania State University
  • Texas
    • Dallas, Texas, United States, 75231
      • AARA Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female
• Aged ≥ 18 to ≤ 65 years
• A diagnosis of C1-INH HAE or FXII/PLG HAE;
• For subjects with C1-INH HAE: ≥ 4 HAE attacks over a consecutive 2-month period during the 3 months before Screening, as documented in the subject's medical record.

Exclusion Criteria:

• History of clinically significant arterial or venous thrombosis, or current clinically significant prothrombotic risk
• History of an uncontrolled, abnormal bleeding event due to a coagulopathy, or a current clinically significant coagulopathy or clinically significant risks for bleeding events
• Known incurable malignancies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subjects with C1-INH HAE receiving buffer only	Drug: Placebo; Buffer without active ingredient
Active Comparator: CSL312 (low); Subjects with C1-INH HAE receiving low dose CSL312	Biological: Factor XIIa antagonist monoclonal antibody; Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use; Other Names: CSL312
Active Comparator: CSL312 (med); Subjects with C1-INH HAE receiving medium dose CSL312	Biological: Factor XIIa antagonist monoclonal antibody; Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use; Other Names: CSL312
Active Comparator: CSL312 (high); Subjects with C1-INH HAE receiving high dose CSL312	Biological: Factor XIIa antagonist monoclonal antibody; Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use; Other Names: CSL312
Active Comparator: CSL312 (med/high); Subjects with C1-INH HAE receiving medium/high dose CSL312	Biological: Factor XIIa antagonist monoclonal antibody; Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use; Other Names: CSL312

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Mean Time Normalized Number of HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1	The time-normalized number of HAE attacks per month during Treatment Period 1 for a subject was calculated as the (number of HAE attacks / length of subject's evaluation period in days) * 30.4375	13 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Responder Subjects With C1-INH HAE During Treatment Period 1	Response is defined as a ≥ 50% relative reduction in the time-normalized number of HAE attacks (per month) during Treatment Period 1 compared to each subject's time-normalized number of HAE attacks (per month) during the Run-in Period	13 weeks
The Percentage of Responder Subjects With C1-INH HAE During Treatment Period 1	Response is defined as a ≥ 50% relative reduction in the time-normalized number of HAE attacks (per month) during Treatment Period 1 compared to each subject's time-normalized number of HAE attacks (per month) during the Run-in Period.	13 weeks
The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1		13 weeks
The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1		13 weeks
The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1	The time-normalized number of HAE attacks per month during Treatment Period 1 for a subject was calculated as the (number of HAE attacks / length of subject's evaluation period in days) * 30.4375	13 weeks
The Number of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
The Percentage of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
Maximum Concentration (Cmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
Area Under the Concentration-time Curve in 1 Dosing Interval (AUC0-tau) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
Time of Maximum Concentration (Tmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
Terminal Elimination Half-life (T1/2) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
Clearance (CL/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
Volume of Distribution During the Elimination Phase (Vz/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1		13 weeks
The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1	Adverse events of special interest is defined as anaphylaxis, thromboembolic events, and bleeding events.	13 weeks

Collaborators and Investigators

• Sponsor: CSL Behring

Publications and helpful links

General Publications

• 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.
• Craig T, Magerl M, Levy DS, Reshef A, Lumry WR, Martinez-Saguer I, Jacobs JS, Yang WH, Ritchie B, Aygoren-Pursun E, Keith PK, Busse P, Feuersenger H, Pawaskar D, Jacobs I, Pragst I, Doyle MK. Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2022 Mar 5;399(10328):945-955. doi: 10.1016/S0140-6736(21)02225-X. Epub 2022 Feb 24.

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2018
• Primary Completion (Actual): October 15, 2021
• Study Completion (Actual): October 15, 2021

Study Registration Dates

• First Submitted: October 17, 2018
• First Submitted That Met QC Criteria: October 17, 2018
• First Posted (Actual): October 19, 2018

Study Record Updates

• Last Update Posted (Actual): November 8, 2022
• Last Update Submitted That Met QC Criteria: October 13, 2022
• Last Verified: October 1, 2022

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; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Antibodies, Monoclonal
• Other Study ID Numbers: CSL312_2001; 2018-000605-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No