Clinical Trial Results:
A Randomized, Double-blind, Placebo-controlled, Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of Garadacimab in Participants with Idiopathic Pulmonary Fibrosis
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Summary
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EudraCT number |
2021-003162-12 |
Trial protocol |
DE DK AT PL IT BE ES |
Global end of trial date |
02 Jan 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Dec 2024
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First version publication date |
07 Dec 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CSL312_2002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05130970 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
CSL Behring LLC
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Sponsor organisation address |
1020 First Avenue, King of Prussia, Pennsylvania, United States, 19406
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Public contact |
Trial Registration Coordinator, CSL Behring LLC, +1 610-878-4000, clinicaltrials@cslbehring.com
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Scientific contact |
Trial Registration Coordinator, CSL Behring LLC, +1 610-878-4000, clinicaltrials@cslbehring.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
22 Mar 2024
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Jan 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to investigate the safety of Garadacimab in participants with Idiopathic pulmonary fibrosis (IPF).
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Protection of trial subjects |
This study was carried out in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the ethical principles that have their origin in the Declaration of Helsinki, all applicable national and local regulations, and Standard Operating Procedures for clinical research and development at CSL Behring. The study protocol and all amendments were approved by the Independent Ethics Committees (IEC)/ institutional review boards (IRBs) of the participating centers. Participant informed consent was obtained and documented according to the provisions of ICH GCP and applicable regulatory requirements. Written informed consent was provided by each participant before any protocol-specific procedures were carried out.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Feb 2022
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 9
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Country: Number of subjects enrolled |
Spain: 4
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Denmark: 5
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Country: Number of subjects enrolled |
Germany: 7
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Country: Number of subjects enrolled |
Canada: 1
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Country: Number of subjects enrolled |
United Kingdom: 8
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Country: Number of subjects enrolled |
United States: 40
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Country: Number of subjects enrolled |
Australia: 1
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Worldwide total number of subjects |
81
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EEA total number of subjects |
31
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
5
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From 65 to 84 years |
73
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85 years and over |
3
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Recruitment
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Recruitment details |
This study was conducted at 47 study sites in 11 countries (Australia, Austria, Belgium, Canada, Denmark, Germany, Italy, Poland, Spain, the United Kingdom [UK], and the United States of America [USA]). No participants from Italy were enrolled in the study. | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 131 potential participants were screened for eligibility. Out of these, 81 participants met all selection criteria and were enrolled in the study, and 50 individuals failed to meet the selection criteria and were not enrolled in the study. | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Garadacimab | |||||||||||||||||||||||||||
Arm description |
Participants received garadacimab intravenous (IV) loading dose followed by 3 subcutaneous (SC) doses. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Garadacimab
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Investigational medicinal product code |
CSL312
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Other name |
Factor XIIa antagonist monoclonal antibody
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
Participants received garadacimab IV loading dose followed by 3 SC doses.
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Arm title
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Placebo | |||||||||||||||||||||||||||
Arm description |
Participants received a matching placebo IV loading dose, followed by 3 SC doses. | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
Participants received a matching placebo IV loading dose, followed by 3 SC doses.
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Baseline characteristics reporting groups
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Reporting group title |
Garadacimab
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Reporting group description |
Participants received garadacimab intravenous (IV) loading dose followed by 3 subcutaneous (SC) doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received a matching placebo IV loading dose, followed by 3 SC doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Garadacimab
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Reporting group description |
Participants received garadacimab intravenous (IV) loading dose followed by 3 subcutaneous (SC) doses. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants received a matching placebo IV loading dose, followed by 3 SC doses. | ||
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End point title |
Number of Participants With Treatment-emergent (TE) Serious Adverse Events (SAEs) [1] | |||||||||
End point description |
A TE SAE is defined as an SAE reported at or after the start of the first administration of study treatment. A SAE is defined as any untoward medical occurrence that at any dose results in: death, life-threatening event, initial or prolongation of existing hospitalization, disability or incapacity, congenital anomaly or birth defect, or any other medically significant event. This analysis was performed on the safety analysis set (SAS). The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
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End point type |
Primary
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End point timeframe |
Up to 22 weeks
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: Primary end point data were summarized by frequency counts and percentages as per protocol; no primary hypothesis was planned. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Percentage of Participants With TE SAEs [2] | ||||||||||||
End point description |
A TE SAE is defined as an SAE reported at or after the start of the first administration of study treatment. A SAE is defined as any untoward medical occurrence that at any dose results in: death, life-threatening event, initial or prolongation of existing hospitalization, disability or incapacity, congenital anomaly or birth defect, or any other medically significant event. This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
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End point type |
Primary
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End point timeframe |
Up to 22 weeks
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: Primary end point data were summarized by frequency counts and percentages as per protocol; no primary hypothesis was planned. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants With TE Adverse Events of Special Interests (AESIs) [3] | |||||||||
End point description |
The following TEAEs were considered as AESIs: Bleeding events that were abnormal in the opinion of the investigator, thromboembolic events (non-systemic thrombosis [e.g., localized thrombosis associated with vascular access] was not considered an AESI), and severe hypersensitivity including anaphylaxis. This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
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End point type |
Primary
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End point timeframe |
Up to 22 weeks
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: Primary end point data were summarized by frequency counts and percentages as per protocol; no primary hypothesis was planned. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Percentage of Participants With TE-AESIs [4] | ||||||||||||
End point description |
The following TEAEs were considered as AESIs: Bleeding events that were abnormal in the opinion of the Investigator, Thromboembolic events (non-systemic thrombosis [e.g., localized thrombosis associated with vascular access] was not considered an AESI), and Severe hypersensitivity including anaphylaxis. This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
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End point type |
Primary
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End point timeframe |
Up to 22 weeks
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: Primary end point data were summarized by frequency counts and percentages as per protocol; no primary hypothesis was planned. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants With Garadacimab Induced Anti-drug Antibodies (ADAs) in Plasma [5] | |||||||||||||||
End point description |
This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo. Here, number of subjects analyzed (N) included all subjects who were evaluated for this endpoint. Number analyzed (n), included all subjects who were evaluated for this endpoint for the specified timepoint.
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End point type |
Primary
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End point timeframe |
At Day 36 and Day 92 after the first treatment
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: Primary end point data were summarized by frequency counts and percentages as per protocol; no primary hypothesis was planned. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Percentage of Participants With Garadacimab Induced ADAs in Plasma [6] | ||||||||||||||||||
End point description |
This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo. Here, number of subjects analyzed (N) included all subjects who were evaluated for this endpoint. Number analyzed (n), included all subjects who were evaluated for this endpoint for the specified timepoint.
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End point type |
Primary
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End point timeframe |
At Day 36 and Day 92 after the first treatment
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: Primary end point data were summarized by frequency counts and percentages as per protocol; no primary hypothesis was planned. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as Adverse Events (AEs) [7] | |||||||||
End point description |
This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
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End point type |
Primary
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End point timeframe |
Up to 14 weeks after treatment
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: Primary end point data were summarized by frequency counts and percentages as per protocol; no primary hypothesis was planned. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Percentage of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as AEs [8] | ||||||||||||
End point description |
This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
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End point type |
Primary
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End point timeframe |
Up to 14 weeks after treatment
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: Primary end point data were summarized by frequency counts and percentages as per protocol; no primary hypothesis was planned. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Trough Plasma Concentration (Ctrough) After Subcutaneous (SC) Administration of Garadacimab [9] | ||||||||||||
End point description |
This analysis was performed on pharmacokinetic analysis set (PKS). The PKS was defined as all participants in the SAS who received >= 1 dose of garadacimab with >= 1 measurable concentration of garadacimab after administration. Here, number of subjects analyzed (N) included all subjects who were evaluated for this endpoint. Number analyzed (n), included all subjects who were evaluated for this endpoint for the specified timepoint.
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End point type |
Secondary
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End point timeframe |
At Day 36 and Day 64
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| Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As planned, statistics are reported for all PK parameters for the garadacimab arms only. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Maximum Plasma Concentration (Cmax) (Last SC Dosing Interval Only) of Garadacimab [10] | ||||||||
End point description |
This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received >= 1 dose of garadacimab with >= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
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End point type |
Secondary
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End point timeframe |
After dosing on Day 64
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| Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As planned, statistics are reported for all PK parameters for the garadacimab arms only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Maximum Plasma Concentration (Tmax) (Last SC Dosing Interval Only) of Garadacimab [11] | ||||||||
End point description |
This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received >= 1 dose of garadacimab with >= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
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End point type |
Secondary
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End point timeframe |
After dosing on Day 64
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| Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As planned, statistics are reported for all PK parameters for the garadacimab arms only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Concentration-time Curve Over the Dose Interval (AUC0-tau) (Last SC Dosing Interval Only) of Garadacimab [12] | ||||||||
End point description |
This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received >= 1 dose of garadacimab with >= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
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End point type |
Secondary
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End point timeframe |
After dosing on Day 64
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| Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As planned, statistics are reported for all PK parameters for the garadacimab arms only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Ctrough After IV Administration of Garadacimab [13] | ||||||||
End point description |
This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received >= 1 dose of garadacimab with >= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
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End point type |
Secondary
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End point timeframe |
At Day 8
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| Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As planned, statistics are reported for all PK parameters for the garadacimab arms only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Cmax After IV Administration of Garadacimab [14] | ||||||||
End point description |
This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received >= 1 dose of garadacimab with >= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
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End point type |
Secondary
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End point timeframe |
After dosing on Day 1
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| Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As planned, statistics are reported for all PK parameters for the garadacimab arms only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Tmax After IV Administration of Garadacimab [15] | ||||||||
End point description |
This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received >= 1 dose of garadacimab with >= 1 measurable concentration of garadacimab after administration.
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End point type |
Secondary
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End point timeframe |
After dosing on Day 1
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| Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As planned, statistics are reported for all PK parameters for the garadacimab arms only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Mean Change From Baseline in FXIIa-mediated Kallikrein Activity | ||||||||||||
End point description |
This analysis was performed on pharmacodynamic analysis set (PDS). The PDS was defined as all participants in the SAS for whom analysis results were obtained for >= 1 of the exploratory biomarkers of interest. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
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End point type |
Secondary
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End point timeframe |
Baseline, and at Day 92
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean Percentage of Baseline in FXIIa-mediated Kallikrein Activity | ||||||||||||
End point description |
Percent baseline is calculated by using the formula visit value / baseline value multiplied by 100, percent baseline is reported as percentage in the outcome measure. This analysis was performed on PDS. The PDS was defined as all participants in the SAS for whom analysis results were obtained for >= 1 of the exploratory biomarkers of interest. Here, number of subjects analyzed (N) included all subjects who were evaluated for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, and at Day 92
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to 22 weeks
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Adverse event reporting additional description |
This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.1
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Reporting groups
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Reporting group title |
Garadacimab
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Reporting group description |
Participants received garadacimab IV loading dose followed by 3 SC doses. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received a matching placebo IV loading dose, followed by 3 SC doses. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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15 Nov 2021 |
• Clarified the process for breaking the blind in an emergency situation. |
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18 Jan 2022 |
• Modified study halting criteria. |
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18 Oct 2022 |
• Removed exclusion criterion 8 to allow administration of non-live influenza virus vaccines or SARS-CoV-2 vaccines before and during study participation.
• Updated the Schedule of Assessments to clarify the INR and prothrombin measurement procedures
• Revised wording in exclusion criterion 12 to clarify that standard of care medication was also prohibited during the Treatment and Observation Period.
• Revised wording for SC administration regarding anatomical site of injection and the number of injections per dose.
• Added an additional citation and reference for DLCO.
• Low-dose aspirin was specifically mentioned in the table of permitted therapies.
• For clarification, the wording for halting criteria due to ECG prolongation was revised.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
