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

Tracking Information

• First Submitted Date: October 17, 2018
• First Posted Date: October 19, 2018
• Results First Submitted Date: October 13, 2022
• Results First Posted Date: November 8, 2022
• Last Update Posted Date: November 8, 2022
• Actual Study Start Date: October 29, 2018
• Actual Primary Completion Date: October 15, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 13, 2022)

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

• Original Primary Outcome Measures (submitted: October 17, 2018): Time normalized number of HAE attacks [ Time Frame: 13 weeks ]

Current Secondary Outcome Measures (submitted: October 13, 2022)

• 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
• 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.
• The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
• The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
• The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
• The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 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 [ 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
• 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 ]
• 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 ]
• Maximum Concentration (Cmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 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 [ Time Frame: 13 weeks ]
• Time of Maximum Concentration (Tmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
• Terminal Elimination Half-life (T1/2) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
• Clearance (CL/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 [ Time Frame: 13 weeks ]
• 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 ]
• 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.

Original Secondary Outcome Measures (submitted: October 17, 2018)

• The number of responder subjects and HAE attack-free 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
• The percentage of responder subjects and HAE attack-free 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.
• The person-time adjusted rate of HAE attack-free subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 13 weeks ]
• The number of mild, moderate or severe HAE attacks, as well as mild, moderate or severe HAE attacks treated with on-demand HAE medication, in subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 13 weeks ]
• The time-normalized number of mild, moderate or severe HAE attacks, as well as mild, moderate or severe HAE attacks treated with on-demand HAE medication, in subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 13 weeks ]
• The percentage of mild, moderate or severe HAE attacks, as well as mild, moderate or severe HAE attacks treated with on-demand HAE medication, in subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 13 weeks ]
• Maximum concentration (Cmax) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 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 [ Time Frame: 13 weeks ]
• Accumulation ratio (AR) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 13 weeks ]
• Time of maximum concentration (Tmax) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 13 weeks ]
• Terminal elimination half-life (T1/2) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 13 weeks ]
• Total systemic clearance (CLtot) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 13 weeks ]
• Volume of distribution during the elimination phase (Vz) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [ Time Frame: 13 weeks ]
• The number of subjects with C1-INH HAE with adverse events, serious adverse events, adverse events of special interest, injection site reactions, inhibitory antibodies to CSL312 during Treatment Period 1 [ Time Frame: 13 weeks ]
  Special interest is defined as anaphylaxis, thromboembolic events, and bleeding events.
• The percentage of subjects with C1-INH HAE with adverse events, serious adverse events, adverse events of special interest, injection site reactions, inhibitory antibodies to CSL312 during Treatment Period 1 [ Time Frame: 13 weeks ]
  Special interest is defined as anaphylaxis, thromboembolic events, and bleeding events.

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

Descriptive Information

• Brief Title: A Study to Investigate CSL312 in Subjects With Hereditary Angioedema (HAE)
• Official Title: A Multicenter, Randomized, Placebo-controlled, Parallel-arm Study to Investigate the Efficacy, Pharmacokinetics, and Safety of CSL312 in Subjects With Hereditary Angioedema
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

• Condition: Hereditary Angioedema

Intervention

• Biological: Factor XIIa antagonist monoclonal antibody
  Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use
  Other Name: CSL312
• Drug: Placebo
  Buffer without active ingredient

Study Arms

• Placebo Comparator: Placebo
  Subjects with C1-INH HAE receiving buffer only
  Intervention: Drug: Placebo
• Active Comparator: CSL312 (low)
  Subjects with C1-INH HAE receiving low dose CSL312
  Intervention: Biological: Factor XIIa antagonist monoclonal antibody
• Active Comparator: CSL312 (med)
  Subjects with C1-INH HAE receiving medium dose CSL312
  Intervention: Biological: Factor XIIa antagonist monoclonal antibody
• Active Comparator: CSL312 (high)
  Subjects with C1-INH HAE receiving high dose CSL312
  Intervention: Biological: Factor XIIa antagonist monoclonal antibody
• Active Comparator: CSL312 (med/high)
  Subjects with C1-INH HAE receiving medium/high dose CSL312
  Intervention: Biological: Factor XIIa antagonist monoclonal antibody

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 1, 2020): 44
• Original Estimated Enrollment (submitted: October 17, 2018): 50
• Actual Study Completion Date: October 15, 2021
• Actual Primary Completion Date: October 15, 2021 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Germany, Israel, United States

Administrative Information

• NCT Number: NCT03712228
• Other Study ID Numbers: CSL312_2001; 2018-000605-24 ( 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: No

• 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: October 2022