CSL312 (Garadacimab) in the Prevention of Hereditary Angioedema Attacks

A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-arm Study to Investigate the Efficacy and Safety of Subcutaneous Administration of CSL312 (Garadacimab) in the Prophylactic Treatment of Hereditary Angioedema

This is a multicenter, double-blind, randomized, placebo-controlled, parallel-arm study to investigate the efficacy and safety of subcutaneous administration of CSL312 (garadacimab) in the prophylactic treatment of hereditary angioedema.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Biological: CSL312; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Québec, Canada, G1V 4W2
    • Clinique Spécialisée en Allergie de la Capitale
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta - Research Transition Facility
  • Ontario
    • Ottawa, Ontario, Canada, K1H 1E4
      • Ottawa Allergy Research Corp
    • Toronto, Ontario, Canada, M3B 3S6
      • Gordon Sussman Clinical Research Inc.
• Germany
  • Berlin, Germany, 10117
    • Charité Universitätsmedizin Berlin
  • Leipzig, Germany, 04103
    • Universitätsklinikum Leipzig
  • Mainz, Germany, 55131
    • CRC Clinical Research / Hautklinik und Poliklinik der Universitätsklinik Mainz
  • Mörfelden-Walldorf, Germany, 64546
    • HZRM Hämophilie Zentrum Rhein Main GmbH
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • Universitätsklinikum Frankfurt Goethe-Universität
• Hungary
  • Budapest, Hungary, 1088
    • Semmelweis University
• Israel
  • Ashkelon, Israel, 7830604
    • Barzilai University Medical Center
• Japan
  • Saitama, Japan, 340-0041
    • Saiyu Soka Hospital
  • Hiroshima
    • Hiroshima-shi, Hiroshima, Japan, 734-8551
      • Hiroshima University Hospital
  • Hyogo
    • Kobe-shi, Hyogo, Japan, '650-0017
      • Kobe University Hospital
  • Kanagawa
    • Kawasaki-shi, Kanagawa, Japan, 216-8511
      • St.Marianna University School of Medicine hospital
  • Kawagoe-shi
    • Saitama, Kawagoe-shi, Japan, 350-8550
      • Saitama Medical Center
  • Saga-shi
    • Saga, Saga-shi, Japan, '849-8501
      • Saga University Hospital
  • Shizuoka
    • Yaizu-shi, Shizuoka, Japan, 425-0088
      • Koga Community Hospital
  • Tokyo
    • Bunkyo, Tokyo, Japan, 113-8431
      • Juntendo University Hospital
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam UMC, location AMC
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Clinical Research Center of Alabama
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Medical Research of Arizona
  • California
    • Santa Monica, California, United States, 90404
      • Raffi Tachdjian MD, Inc.
    • Walnut Creek, California, United States, 94598
      • Allergy and Asthma Clinical Research
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Institute of Asthma and Allergy
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Bernstein Clinical Research Center LLC
  • 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: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female ≥ 12 years of age; diagnosed with clinically confirmed C1-INH hereditary angioedema; experience ≥ 3 attacks during the 3 months before screening.

Note: For subjects taking any prophylactic HAE therapy during the 3 months before Screening, ≥ 3 HAE attacks may be documented over 3 consecutive months before commencing the prophylactic therapy.

Exclusion Criteria:

• Concomitant diagnosis of another form of angioedema such as idiopathic or acquired angioedema, recurrent angioedema associated with urticarial or hereditary angioedema type 3

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CSL312; Participants received a CSL312 loading dose of 400 mg as two 200 mg SC injections in Month 1 along with CSL312 of 200 mg subcutaneous (SC) injections, once monthly from Months 2 to 6.	Biological: CSL312; Fully human immunoglobulin G subclass 4/lambda recombinant monoclonal antibody; Other Names: garadacimab; Factor XIIa inhibitor monoclonal antibody
Placebo Comparator: Placebo; Participants received a CSL312 matched loading dose of placebo as two SC injections in Month 1 along with CSL312 matched placebo SC injections, once monthly from Months 2 to 6.	Drug: Placebo; Buffer without active ingredient

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-Normalized Number of Hereditary Angioedema (HAE) Attacks Per Month During Treatment Period	Time-normalized number of HAE attacks per month during treatment was calculated per participant as: [number of HAE attacks / length of participant treatment in days] * 30.4375.	First injection up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in the Time-normalized Number of HAE Attacks Per Month During the Treatment Period Compared to the Run-in Period	Percentage change in the time-normalized number of HAE attacks was calculated within a participant as: 100 * [1 - (time-normalized number of HAE attacks per month during treatment period / time-normalized number of HAE attacks per month during run-in period)]. Time-normalized number of HAE attacks per month during treatment period was calculated per participant as: [number of HAE attacks / length of participant treatment in days] * 30.4375.	6 months, first 3-months and second 3-months of treatment period
Time-Normalized Number of HAE Attacks Per Month Requiring On-Demand Treatment	Time-normalized number of HAE attacks per month requiring on-demand treatment was calculated per participant as: [number of HAE attacks requiring on-demand treatment / length of participant in days] * 30.4375.	6 months, first 3-months and second 3-months of treatment period
Time-Normalized Number of Moderate or Severe HAE Attacks Per Month	Time-normalized number of moderate or severe HAE attacks per month during treatment period was calculated per participant as: [number of moderate or severe HAE attacks / length of participant treatment in days] * 30.4375.	6 months, first 3-months and second 3-months of treatment period
Time-normalized Number of HAE Attacks Per Month in the First 3-months and Second 3-months of Treatment Period	Time-normalized number of HAE attacks per month during treatment was calculated per participant as: [number of HAE attacks / length of participant treatment in days] * 30.4375.	First 3-months and second 3-months of treatment period
Relative Difference in Means in the Time-Normalized Number of HAE Attacks Per Month Between CSL312 to Placebo	Relative difference in means in the time-normalized number of HAE attacks per month CSL312 to Placebo was calculated as: 100 * [(mean time-normalized number of HAE attacks for CSL312 - mean time-normalized number of HAE attacks for placebo) / mean time-normalized number of HAE attacks for placebo]. Time-normalized number of HAE attacks per month during treatment was calculated per participant as: [number of HAE attacks / length of participant treatment in days] * 30.4375.	6 months, first 3-months and second 3-months of treatment period
Percentage of Participants With a Response to Subject's Global Assessment of Response to Therapy (SGART)	SGART is a self-assessment by the participant and measures the subject's overall treatment response to the investigational product using the following ratings: 0 (none: worse or no response at all, not acceptable), 1 (poor: very little response, not acceptable), 2 (fair: some response, acceptable but could be better), 3 (good: good response, acceptable), and 4 (excellent: excellent response, as good as can be imagined).	Up to 6 months
Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE), and AEs of Special Interest (AESI)	AE is any untoward medical occurrence in a participant administered with an investigational product which does not necessarily have a causal relationship with treatment, can be any unfavorable and unintended sign, symptom, or disease temporally associated with use of an investigational product, whether or not considered related to product. SAE is any untoward medical occurrence that results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, is a congenital anomaly or birth defect, or is a medically significant event. An AESI is an AE of scientific and medical concern specific to sponsor's product or program, for which ongoing monitoring and rapid communication by investigator to sponsor is appropriate.	From first dose of study drug up to 3 months after the last injection (approximately 8 months)
Number of Participants With CSL312-induced Anti-CSL312 Antibodies		Up to 8 months
Number of Participants With Clinically Significant Abnormalities in Laboratory Assessments Reported as Treatment Emergent Adverse Events (TEAEs)	Laboratory assessments included: Hematology, biochemistry, urinalysis, and coagulation parameters.	From first dose of study drug up to 3 months after the last injection (approximately 8 months)
Percentage of Participants With at Least One AE, SAE, and AESI	AE is any untoward medical occurrence in a participant administered with an investigational product which does not necessarily have a causal relationship with treatment, can be any unfavorable and unintended sign, symptom, or disease temporally associated with use of an investigational product, whether or not considered related to product. SAE is any untoward medical occurrence that results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, is a congenital anomaly or birth defect, or is a medically significant event. An AESI is an AE of scientific and medical concern specific to sponsor's product or program, for which ongoing monitoring and rapid communication by investigator to sponsor is appropriate.	From first dose of study drug up to 3 months after the last injection (approximately 8 months)
Percentage of Participants With CSL312-induced Anti-CSL312 Antibodies		Up to 6 months
Percentage of Participants With Clinically Significant Abnormalities in Laboratory Assessments Reported as TEAEs	Laboratory assessments included: Hematology, biochemistry, urinalysis, and coagulation parameters.	From first dose of study drug up to 3 months after the last injection (approximately 8 months)

Collaborators and Investigators

• Sponsor: CSL Behring
• Investigators: Study Director: Study Director, CSL Behring LLC

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.

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2021
• Primary Completion (Actual): June 7, 2022
• Study Completion (Actual): June 7, 2022

Study Registration Dates

• First Submitted: December 1, 2020
• First Submitted That Met QC Criteria: December 1, 2020
• First Posted (Actual): December 7, 2020

Study Record Updates

• Last Update Posted (Actual): June 29, 2023
• Last Update Submitted That Met QC Criteria: June 7, 2023
• Last Verified: June 1, 2023

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
• Other Study ID Numbers: CSL312_3001; 2020-000570-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

CSL will consider requests to share Individual Patient Data (IPD) from systematic review groups or bona-fide researchers. For information on the process and requirements for submitting a voluntary data sharing request for IPD, please contact CSL at clinicaltrials@cslbehring.com.

Applicable country specific privacy and other laws and regulations will be considered and may prevent sharing of IPD.

If the request is approved and the researcher has executed an appropriate data sharing agreement, IPD that has been appropriately anonymized will be available.

• IPD Sharing Time Frame: IPD requests may be submitted to CSL no earlier than 12 months after publication of the results of this study via an article made available on a public website.

IPD Sharing Access Criteria

Requests may only be made by systematic review groups or bona-fide researchers whose proposed use of the IPD is non-commercial in nature and has been approved by an internal review committee.

An IPD request will not be considered by CSL unless the proposed research question seeks to answer a significant and unknown medical science or patient care question as determined by CSL's internal review committee.

The requesting party must execute an appropriate data sharing agreement before IPD will be made available.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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