CSL312 (Garadacimab) in the Prevention of Hereditary Angioedema Attacks

• ClinicalTrials.gov Identifier: NCT04656418
• Recruitment Status: Completed
• First Posted: December 7, 2020
• Results First Posted: June 29, 2023
• Last Update Posted: June 29, 2023
• Sponsor: CSL Behring
• Information provided by (Responsible Party): CSL Behring

Tracking Information

• First Submitted Date: December 1, 2020
• First Posted Date: December 7, 2020
• Results First Submitted Date: June 7, 2023
• Results First Posted Date: June 29, 2023
• Last Update Posted Date: June 29, 2023
• Actual Study Start Date: January 27, 2021
• Actual Primary Completion Date: June 7, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 7, 2023)

Time-Normalized Number of Hereditary Angioedema (HAE) Attacks Per Month During Treatment Period [ Time Frame: First injection up to 6 months ]

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.

• Original Primary Outcome Measures (submitted: December 1, 2020): Time-normalized number of hereditary angioedema (HAE) attacks during treatment period [ Time Frame: up to 6 months ]

Current Secondary Outcome Measures (submitted: June 7, 2023)

• Percentage Change in the Time-normalized Number of HAE Attacks Per Month During the Treatment Period Compared to the Run-in Period [ Time Frame: 6 months, first 3-months and second 3-months of treatment 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.
• Time-Normalized Number of HAE Attacks Per Month Requiring On-Demand Treatment [ Time Frame: 6 months, first 3-months and second 3-months of treatment period ]
  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.
• Time-Normalized Number of Moderate or Severe HAE Attacks Per Month [ Time Frame: 6 months, first 3-months and second 3-months of treatment period ]
  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.
• Time-normalized Number of HAE Attacks Per Month in the First 3-months and Second 3-months of Treatment Period [ Time Frame: 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.
• Relative Difference in Means in the Time-Normalized Number of HAE Attacks Per Month Between CSL312 to Placebo [ Time Frame: 6 months, first 3-months and second 3-months of treatment period ]
  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.
• Percentage of Participants With a Response to Subject's Global Assessment of Response to Therapy (SGART) [ Time Frame: Up to 6 months ]
  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).
• Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE), and AEs of Special Interest (AESI) [ Time Frame: From first dose of study drug up to 3 months after the last injection (approximately 8 months) ]
  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.
• Number of Participants With CSL312-induced Anti-CSL312 Antibodies [ Time Frame: Up to 8 months ]
• Number of Participants With Clinically Significant Abnormalities in Laboratory Assessments Reported as Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From first dose of study drug up to 3 months after the last injection (approximately 8 months) ]
  Laboratory assessments included: Hematology, biochemistry, urinalysis, and coagulation parameters.
• Percentage of Participants With at Least One AE, SAE, and AESI [ Time Frame: From first dose of study drug up to 3 months after the last injection (approximately 8 months) ]
  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.
• Percentage of Participants With CSL312-induced Anti-CSL312 Antibodies [ Time Frame: Up to 6 months ]
• Percentage of Participants With Clinically Significant Abnormalities in Laboratory Assessments Reported as TEAEs [ Time Frame: From first dose of study drug up to 3 months after the last injection (approximately 8 months) ]
  Laboratory assessments included: Hematology, biochemistry, urinalysis, and coagulation parameters.

Original Secondary Outcome Measures (submitted: December 1, 2020)

• Reduction in the HAE attack rate during the treatment period compared to the run-in period [ Time Frame: up to 6 months ]
• Time-normalized number of attacks requiring on-demand treatment [ Time Frame: 6 months, and first 3 months and second 3 months ]
• Time-normalized number of moderate and/or severe HAE attacks [ Time Frame: 6 months, and first 3 months and second 3 months ]
• Time-normalized number of HAE attacks at various timepoints during the treatment period [ Time Frame: First 3 months and second 3 months and 6 months ]
• Percent reduction in the time-normalized number of HAE attacks between CSL312 and Placebo [ Time Frame: 6 months, and first 3 months and second 3 months ]
• Subject's Global Assessment of Response to Therapy (SGART) [ Time Frame: Up to 6 months ]
  Comparison of the distribution of responses to therapy between CSL312 and placebo based on proportions of subjects with"excellent," "good," "fair," "poor or none" response to therapy
• Number of subjects with adverse events, adverse events of special interest, serious adverse events, CSL312-induced anti-CSL312 antibodies, clinically significant abnormalities in laboratory assessments [ Time Frame: Up to 8 months ]
• Percent of subjects with Adverse events, adverse events of special interest, serious adverse events, CSL312-induced anti-CSL312 antibodies, clinically significant abnormalities in laboratory assessments [ Time Frame: Up to 8 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: CSL312 (Garadacimab) in the Prevention of Hereditary Angioedema Attacks
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Hereditary Angioedema

Intervention

• Biological: CSL312
  Fully human immunoglobulin G subclass 4/lambda recombinant monoclonal antibody
  Other Names:

  • Factor XIIa inhibitor monoclonal antibody
  • garadacimab
• Drug: Placebo
  Buffer without active ingredient

Study Arms

• 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.
  Intervention: Biological: CSL312
• 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.
  Intervention: Drug: Placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 22, 2022): 64
• Original Estimated Enrollment (submitted: December 1, 2020): 60
• Actual Study Completion Date: June 7, 2022
• Actual Primary Completion Date: June 7, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Germany, Hungary, Israel, Japan, Netherlands, United States

Administrative Information

• NCT Number: NCT04656418
• Other Study ID Numbers: CSL312_3001; 2020-000570-25 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes

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.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• 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.

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.

• Current Responsible Party: CSL Behring
• Original Responsible Party: Same as current
• Current Study Sponsor: CSL Behring
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; CSL Behring LLC

• PRS Account: CSL Behring
• Verification Date: June 2023