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

• ClinicalTrials.gov Identifier: NCT03712228
• Recruitment Status: Completed
• First Posted: October 19, 2018
• Results First Posted: November 8, 2022
• Last Update Posted: November 8, 2022
• Sponsor: CSL Behring
• Information provided by (Responsible Party): CSL Behring

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hereditary Angioedema	Biological: Factor XIIa antagonist monoclonal antibody; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects are assigned to 1 of 2 or more groups in parallel for the duration of the study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double blind
• Primary Purpose: Prevention
• Official Title: A Multicenter, Randomized, Placebo-controlled, Parallel-arm Study to Investigate the Efficacy, Pharmacokinetics, and Safety of CSL312 in Subjects With Hereditary Angioedema
• Actual Study Start Date: October 29, 2018
• Actual Primary Completion Date: October 15, 2021
• Actual Study Completion Date: October 15, 2021

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: CSL312

Outcome Measures

Primary Outcome Measures :

1. The Mean Time Normalized Number of HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
   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

Secondary Outcome Measures :

1. The Number of Responder Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
   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
2. The Percentage of Responder Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
   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.
3. The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
4. The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
5. The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
6. The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
7. The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
   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
8. 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 [ Time Frame: 13 weeks ]
9. 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 [ Time Frame: 13 weeks ]
10. Maximum Concentration (Cmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
11. Area Under the Concentration-time Curve in 1 Dosing Interval (AUC0-tau) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
12. Time of Maximum Concentration (Tmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
13. Terminal Elimination Half-life (T1/2) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
14. Clearance (CL/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
15. Volume of Distribution During the Elimination Phase (Vz/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
16. 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 [ Time Frame: 13 weeks ]
    Adverse events of special interest is defined as anaphylaxis, thromboembolic events, and bleeding events.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Donald S. Levy

Orange, California, United States, 92868

Allergy & Asthma Clinical Research

Walnut Creek, California, United States, 94598

United States, Colorado

Immunoe Health Centers

Centennial, Colorado, United States, 80112

United States, Maryland

Institute for Asthma and Allergy

Chevy Chase, Maryland, United States, 20815

United States, New York

The Mount Sinai Hospital

New York, New York, United States, 10029

United States, Pennsylvania

Pennsylvania State University

Hershey, Pennsylvania, United States, 17033

United States, Texas

AARA Research Center

Dallas, Texas, United States, 75231

Australia, New South Wales

Campbelltown Hospital

Campbelltown, New South Wales, Australia, 2560

Canada, Alberta

University of Alberta

Edmonton, Alberta, Canada, T6G 2B7

Canada, Ontario

Allergy and Clinical Immunology McMaster University

Hamilton, Ontario, Canada, L8S 4K1

Ottawa Allergy Research Corp

Ottawa, Ontario, Canada, K1G 6C6

Germany

Charité Universitätsmedizin Berlin

Berlin, Germany, 10117

Universitätsklinikum Frankfurt Goethe-Universität

Frankfurt, Germany, 60590

Hautklinik und Poliklinik der Universitätsklinik Mainz

Mainz, Germany, 55131

HZRM Hämophilie Zentrum Rhein Main GmbH

Mörfelden-Walldorf, Germany, 64546

Israel

Barzilai University Medical Center

Ashkelon, Israel, 7830604

Sponsors and Collaborators

CSL Behring

Investigators

• Study Director: Study Director; CSL Behring LLC

  Study Documents (Full-Text)

Documents provided by CSL Behring:

Study Protocol  [PDF] March 20, 2020

Statistical Analysis Plan  [PDF] June 19, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: CSL Behring
• ClinicalTrials.gov Identifier: NCT03712228
• Other Study ID Numbers: CSL312_2001; 2018-000605-24 ( EudraCT Number )
• First Posted: October 19, 2018
• Results First Posted: November 8, 2022
• Last Update Posted: November 8, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Angioedema; Angioedemas, Hereditary; Vascular Diseases; Cardiovascular Diseases; Urticaria; Skin Diseases, Vascular; Skin Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Immunologic Deficiency Syndromes; Antibodies; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs