Long-term Safety and Efficacy of CSL312 (Garadacimab) in the Prophylactic Treatment of Hereditary Angioedema Attacks

An Open-label Study to Evaluate the Long-term Safety and Efficacy of CSL312 (Garadacimab) in the Prophylactic Treatment of Hereditary Angioedema

This phase 3b study will evaluate long-term safety and efficacy of CSL312 (also known as garadacimab) when administered subcutaneously (SC)

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 171
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Campbelltown, New South Wales, Australia, 2560
      • Campbelltown Hospital / Western Sydney University
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital, Department of Clinical Immunology
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta - Research Transition Facility
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University
    • Ottawa, Ontario, Canada, K1H 1E4
      • Ottawa Allergy Research Corp
    • Toronto, Ontario, Canada, M3B 3S6
      • Gordon Sussman Clinical Research
  • Quebec
    • Montreal, Quebec, Canada, H2W 1R7
      • Montreal Clinical Research Institute
• Czechia
  • Brno, Czechia, 65691
    • University hospital St. Anna Ustav klinicke imunologie a alergologie, Fakultní nemocnice u sv. Anny v Brně
  • Prague, Czechia, 150 06
    • University Hospital Motol
• Germany
  • Berlin, Germany, 10117
    • Charité - Universitätsmedizin Berlin
  • Frankfurt, Germany, 60590
    • Universitätsklinikum Frankfurt
  • Mainz, Germany, 55131
    • Johannes Gutenberg-Universität KöR, Hautklinik und Poliklinik der Universitätsmedizin, Clinical Research Center
  • Mörfelden-Walldorf, Germany, 64546
    • HZRM Haemophilie Zentrum Rhein Main GmbH
• Hong Kong
  • Hong Kong, Hong Kong
    • The University of Hong Kong, Queen Mary Hospital
• Hungary
  • Budapest, Hungary, 1088
    • Semmelweis Egyetem Altalanos Orvostudományi Kar Belgyógyászati és Hematológiai Klinika
• Israel
  • Ashkelon, Israel, 7830604
    • Barzilai University Medical Center
• Japan
  • Daikakuji Yaizu-shi
    • Shizuoka, Daikakuji Yaizu-shi, Japan, 425-0088
      • Koga Community Hospital
  • Edobashi, Tsu-shi
    • Mie, Edobashi, Tsu-shi, Japan, Edobashi, Tsu-shi
      • Mie University Hospital
  • Hongo Bunkyo-ku
    • Tokyo, Hongo Bunkyo-ku, Japan, 113-8431
      • Juntendo University Hospital
  • Kamoda Kawagoe-shi
    • Saitama, Kamoda Kawagoe-shi, Japan, 350-8550
      • Saitama Medical Center
  • Kawasaki-shi
    • Kanagawa, Kawasaki-shi, Japan, 216-8511
      • St. Marianna University School of Medicine Hospital
  • Kugenumaishigami, Fujisawa-shi
    • Kanagawa, Kugenumaishigami, Fujisawa-shi, Japan, 251-0025
      • Clover Hospital
  • Matsubara Soka-shi
    • Saitama, Matsubara Soka-shi, Japan, 340-0041
      • Saiyu Soka Hospital
  • Midoricho, Tachikawa-shi
    • Tokyo, Midoricho, Tachikawa-shi, Japan, 190-0014
      • National Hospital Organization Disaster Medical Center
  • Nebeshima, Saga-shi
    • Saga, Nebeshima, Saga-shi, Japan, 849-8501
      • Saga University Hospital
  • Osaka-shi
    • Miyakojima-ku, Osaka-shi, Japan, 534-0021
      • Local Incorporated Administrative Agency Osaka City Hospital Organization Osaka City General Hospital
• Netherlands
  • Amsterdam, Netherlands, 1105
    • Amsterdam UMC, location AMC
• New Zealand
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Auckland City Hospital
• Russia
  • Moscow, Russia, 115522
    • NRC Institute of Immunology FMBA Russia
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitari General de La Vall d'Hebron
  • Madrid, Spain, 28007
    • Hospital Gregorio Marañón, Servicio de Alergia
• Taiwan
  • Taichung, Taiwan, 407
    • Taichung Veterans General Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Clinical Research Center of Alabama
  • Arizona
    • Litchfield Park, Arizona, United States, 85340
      • Research Solutions of Arizona
    • Scottsdale, Arizona, United States, 85251
      • Medical Research of Arizona
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Little Rock Allergy & Asthma Clinic
  • California
    • Orange, California, United States, 92868
      • Donald S. Levy M.D.
    • Santa Monica, California, United States, 90404
      • Raffi Tachdjian MD, Inc.
    • Walnut Creek, California, United States, 94598
      • Allergy & Asthma Clinical Research
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Institute for Asthma and Allergy PC
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • Bernstein Clinical Research Center, LLC
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • PennState Health Milton S. Hershey Medical Center
  • 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:

• Males and females aged ≥ 12 years
• Diagnosed with clinically confirmed C1-INH HAE
• Experienced ≥ 3 HAE attacks during the 3 months before Screening
• Participated in the Run-in Period for at least 1 month (CSL312-naïve subjects only)
• Experienced at least an average of 1 HAE attack per month during the Run-in Period

Exclusion Criteria:

• Concomitant diagnosis of another form of angioedema, such as idiopathic or acquired angioedema or recurrent angioedema associated with urticaria
• Use of C1-INH products, androgens, antifibrinolytics or other small molecule medications for routine prophylaxis against HAE attacks at least 2 weeks before the first day of the Run-in Period
• Use of monoclonal antibodies such as lanadelumab (Takhzyro®) 3 months before the first day of the Run-in Period.
• Female subjects use estrogen-containing oral contraceptives or hormone replacement therapy within 4 weeks prior to screening
• Female or male subjects who are fertile and sexually active not using or not willing to use an acceptable method of contraception to avoid pregnancy during the study and for 30 days after receipt of the last dose of CSL312
• Pregnant, breastfeeding, or not willing to cease breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CSL312; Fully human immunoglobulin G subclass 4/lambda recombinant inhibitor monoclonal antibody administered subcutaneously	Biological: CSL312; Fully human immunoglobulin G subclass 4/lambda recombinant inhibitor monoclonal antibody; Other Names: garadacimab; Factor XIIa inhibitor monoclonal antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAE)		Approximately up to 54 months
Percentage of Participants With TEAE	The percentage of participants was rounded to one place of decimal.	Approximately up to 54 months
Number of TEAE		Approximately up to 54 months
TEAE Rates Per Injection	The TEAE rate per injection was calculated as the number of TEAE/ total number of injections. The number of injections was defined as the total injections received by participants during the respective safety evaluation period.	Approximately up to 54 months
TEAE Rates Per Participant Year	The TEAE rate per participant year was calculated as the total number of TEAE/ participant years. Participant years was defined as the sum of the time (in years) that participant were exposed to study treatment during the respective safety evaluation period.	Approximately up to 54 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Time-normalized Number (Per Month) of Hereditary Angioedema (HAE) Attacks During the Run-in Period and 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.	Run-in Period: Up to Day 60 and Treatment Period: Approximately up to 52 months
The Time-normalized Number (Per Year) of HAE Attacks During Treatment Period	Time-normalized number of HAE attacks per year during treatment was calculated per participant as: [number of HAE attacks / length of participant treatment in days]*365.25.	Approximately up to 52 months
Percentage Reduction in the Attack Rate During the Treatment Period Compared to the Run-in Period	The percentage reduction 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).	Run-in Period: Up to 60 days and Treatment Period: Approximately up to 52 months
Number of Participants With Percentage Reduction (of >=50%, >=70%, >=90%, and 100%) in HAE Attacks	The number of participants who achieved a percentage reduction in HAE attacks of >=50% (also considered as responders), >=70%, >=90%, and 100% (attack free) during the Treatment Period compared with the Run-in Period. The percentage reduction in the time-normalized number of HAE attacks per month was calculated as 100*[1 - (time-normalized number of HAE attacks per month under CSL312 treatment / time-normalized number of HAE attacks per month during Run-in Period)].	Run-in Period: Up to Day 60 and Treatment Period: Approximately up to 52 months
The Time-normalized Number (Per Month) of HAE Attacks 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 during treatment period / length of participant treatment in days]*30.4375.	Approximately up to 52 months
The Time-normalized Number (Per Year) of HAE Attacks Requiring On-demand Treatment	Time-normalized number of HAE attacks requiring on demand treatment per year was calculated per participant as: [number of HAE attacks requiring on demand treatment during treatment period / length of participant treatment in days]*365.25.	Approximately up to 52 months
The Time-normalized Number (Per Month) of Moderate and/or Severe HAE Attacks	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.	Approximately up to 52 months
The Time-normalized Number (Per Year) of Moderate and/or Severe HAE Attacks	Time-normalized number of moderate or severe HAE attacks per year during treatment period was calculated per participant as: [number of moderate or severe HAE attacks /length of participant treatment in days]*365.25.	Approximately up to 52 months
Number of Participants Rating Their Response to Therapy as Good or Excellent	Number of participants rating their response to therapy as good or excellent was evaluated as per Subject's Global Assessment of Response to Therapy (SGART) questionnaire. SGART is a patient-reported outcome that represents the participant's overall response to treatment 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. Cumulative responses as "Good or Excellent" are reported for this outcome measure.	At Months 12, 24, and 36
Percentage of Participants Rating Their Response to Therapy as Good or Excellent	Percentage of participants rating their response to therapy as good or excellent was evaluated as per SGART questionnaire. SGART is a patient-reported outcome that represents the participant's overall response to treatment 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. Cumulative responses as "Good or Excellent" are reported for this outcome measure. The percentage of participants was rounded to one place of decimal.	At Months 12, 24, and 36
Number of Participants Experiencing Serious Adverse Events (SAE), Experiencing Death, Related TEAE, TEAE Leading to Study Discontinuation		Approximately up to 54 months
Percentage of Participants Experiencing SAE, Experiencing Death, Related TEAE, TEAE Leading to Study Discontinuation	The percentage of participants was rounded to one decimal place.	Approximately up to 54 months
Number of Participants Experiencing TEAE by Severity	Severity of AE was assessed by the investigator and categorized as mild, moderate and severe. A mild AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living. A moderate AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant. A severe AE that interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention.	Approximately up to 54 months
Percentage of Participants Experiencing TEAE by Severity	Severity of AE was assessed by the investigator and categorized as mild, moderate and severe. A mild AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living. A moderate AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant. A severe AE that interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention. The percentage of participants was rounded to one decimal place.	Approximately up to 54 months
Number of Participants Experiencing Adverse Events of Special Interest (AESI)	The AESI defined for this study were thromboembolic events, abnormal bleeding events, and severe hypersensitivity including anaphylaxis. The AESI reported have been identified by investigators.	Approximately up to 54 months
Percentage of Participants Experiencing AESI	The AESI defined for this study were thromboembolic events, abnormal bleeding events, and severe hypersensitivity including anaphylaxis. The AESI reported have been identified by investigators.	Approximately up to 54 months
Number of Participants With Laboratory Findings Reported as TEAE		Approximately up to 54 months
Percentage of Participants With Laboratory Findings Reported as TEAE	The percentage of participant was rounded to one place of decimal.	Approximately up to 54 months
Number of Participants With Normal C1-esterase Inhibitor (nC1-INH) Experiencing TEAE		Approximately up to 54 months
Percentage of Participants With nC1-INH Experiencing TEAE		Approximately up to 54 months
Number of Participants With Anti-CSL312 Antibodies		At Day 1, Months 6, 12, 36 and 43 (end of treatment [EOT])
Percentage of Participants With Anti-CSL312 Antibodies	The percentage of participants was rounded to one decimal place.	At Day 1, Months 6, 12, 36 and 43 (EOT)

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Guilarte M, Lumry WR, Magerl M, Martinez Saguer I, Reshef A, Sobotkova M, Braverman J, Lawo JP, Wieman L, Nenci C, Katelaris CH. Garadacimab improves long-term health-related quality of life in patients with hereditary angioedema. Allergy Asthma Proc. 2025 May 1;46(3):192-199. doi: 10.2500/aap.2025.46.250027.
• Staubach P, Craig TJ, Fukuda T, Aygoren-Pursun E, Hakl R, Braverman J, Lawo JP, Pollen M, Nenci C, Li PH, Farkas H. Becoming attack-free further improves health-related quality of life in patients with hereditary angioedema receiving garadacimab. Allergy Asthma Proc. 2025 May 1;46(3):200-208. doi: 10.2500/aap.2025.46.250026.

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2021
• Primary Completion (Actual): November 21, 2025
• Study Completion (Actual): November 21, 2025

Study Registration Dates

• First Submitted: February 1, 2021
• First Submitted That Met QC Criteria: February 1, 2021
• First Posted (Actual): February 4, 2021

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immunologic Deficiency Syndromes; Skin Diseases; Urticaria; Skin Diseases, Vascular; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin and Connective Tissue Diseases; Angioedema; Angioedemas, Hereditary; Immunologic Factors; Physiological Effects of Drugs; Antibodies, Monoclonal
• Other Study ID Numbers: CSL312_3002; 2020-003918-12 (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