Clinical Trial Results:
A Pivotal Phase 3 Trial to Evaluate the Safety and Efficacy of Clazakizumab for the Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Transplant Recipients
Summary
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EudraCT number |
2018-003682-34 |
Trial protocol |
CZ HU BE DE NL AT ES |
Global end of trial date |
08 Apr 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Apr 2025
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First version publication date |
19 Apr 2025
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Other versions |
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 |
CSL300_3001 (previously VKTX01)
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03744910 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Vitaeris: VKTX01 | ||
Sponsors
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Sponsor organisation name |
CSL Behring LLC
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Sponsor organisation address |
1020 First Avenue, King of Prussia, PA, United States, 19406
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Public contact |
Trial Registration Coordinator, CSL Behring LLC, +1 610-878-4697, clinicaltrials@cslbehring.com
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Scientific contact |
Trial Registration Coordinator, CSL Behring LLC, +1 610-878-4697, 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 |
24 Jun 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 |
08 Apr 2024
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
1. To evaluate the efficacy of clazakizumab in preventing all-cause allograft loss (including death) or irreversible loss of allograft function due to CABMR.
2. To evaluate the efficacy of clazakizumab in slowing/preventing the progressive loss of kidney function (as measured by eGFR using the Modification of Diet in Renal Disease 4 (MDRD4) equation [Interim analysis #2]).
3. To evaluate the safety of clazakizumab.
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Protection of trial subjects |
The study was conducted according to the principles of the World Medical Association’s Declaration of Helsinki and the International Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP), CSL Behring has ensured that the study complies with all local, federal or country-specific regulatory requirements. A written informed consent in compliance with Part 50 of Title 21 of the Code of Federal Regulations (CFR), with the Declaration of Helsinki, ICH guidelines, federal and / or local regulations, and advance approval by the Institutional Review Board / Independent Ethics Committee (IRB / IEC) was obtained from each participant prior to entering the study or performing any unusual or non-routine procedure that involves risk to the participant, including washout of any medications.
Any amendments to the protocol or informed consent form (ICF) were reviewed and approved by the IRB / IEC before the changes were implemented in the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Oct 2019
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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 |
Netherlands: 12
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Country: Number of subjects enrolled |
Spain: 23
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Country: Number of subjects enrolled |
Sweden: 1
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Country: Number of subjects enrolled |
Austria: 1
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Country: Number of subjects enrolled |
Czechia: 4
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Country: Number of subjects enrolled |
France: 21
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Country: Number of subjects enrolled |
Germany: 9
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Country: Number of subjects enrolled |
Hungary: 15
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Country: Number of subjects enrolled |
Australia: 9
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Country: Number of subjects enrolled |
Canada: 11
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Country: Number of subjects enrolled |
Korea, Democratic People's Republic of: 22
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Country: Number of subjects enrolled |
Switzerland: 5
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Country: Number of subjects enrolled |
United States: 61
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Worldwide total number of subjects |
194
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EEA total number of subjects |
86
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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) |
180
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From 65 to 84 years |
14
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 139 study sites in 13 countries: Canada, United States, Austria, Czechia, France, Germany, Hungary, Netherlands, Spain, Sweden, Switzerland, Democratic People's Republic of Korea, and Australia. | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 382 participants were screened, of which 188 were screen failures. Of the screened participants, 194 were randomized in a 1:1 ratio to receive study interventions (Clazakizumab or Placebo). Participants who reached the primary endpoint of allograft loss or death are combined and reported as Completed in the participant flow. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall study (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, Monitor, Carer, Assessor | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Clazakizumab | |||||||||||||||||||||||||||
Arm description |
Participants received clazakizumab via subcutaneous (SC) injection once every 4 weeks (Q4W) until the participant: permanently discontinued the investigational product (IP), withdrew from the study, experienced allograft loss, died, or reached the common treatment end date (CTED), whichever occurred first during this study. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Clazakizumab
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Investigational medicinal product code |
CSL300
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Other name |
Genetically engineered humanized anti-IL-6 mAb
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
12.5 milligram per millilliter (mg/mL) SC injection Q4W.
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Arm title
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Placebo | |||||||||||||||||||||||||||
Arm description |
Participants received Placebo by SC injection Q4W until the participant: permanently discontinued IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study. | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
Placebo
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
0.9% w/v NaCl, SC injection Q4W.
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Baseline characteristics reporting groups
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Reporting group title |
Clazakizumab
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Reporting group description |
Participants received clazakizumab via subcutaneous (SC) injection once every 4 weeks (Q4W) until the participant: permanently discontinued the investigational product (IP), withdrew from the study, experienced allograft loss, died, or reached the common treatment end date (CTED), whichever occurred first during this study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received Placebo by SC injection Q4W until the participant: permanently discontinued IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Clazakizumab
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Reporting group description |
Participants received clazakizumab via subcutaneous (SC) injection once every 4 weeks (Q4W) until the participant: permanently discontinued the investigational product (IP), withdrew from the study, experienced allograft loss, died, or reached the common treatment end date (CTED), whichever occurred first during this study. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants received Placebo by SC injection Q4W until the participant: permanently discontinued IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study. |
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End point title |
Change From Baseline to Week 52 in Estimated Glomerular Filtration Rate (eGFR) | ||||||||||||
End point description |
This primary outcome measure was the one from the first interim analysis. Analysis was performed on the intent-to-treat (ITT) analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of study drug and who had a baseline assessment and at least 1 post baseline assessment of eGFR.
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End point type |
Primary
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End point timeframe |
From Baseline to Week 52
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Statistical analysis title |
Clazakizumab versus (v) Placebo | ||||||||||||
Comparison groups |
Clazakizumab v Placebo
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Number of subjects included in analysis |
191
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
Method |
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Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-2.75
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-5.84 | ||||||||||||
upper limit |
0.35 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.563
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Notes [1] - Pre-specified for interim analysis. |
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End point title |
Number of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function [2] | |||||||||
End point description |
Composite all-cause allograft loss or irreversible loss of allograft function, defined as time to first occurrence of any of the following components:
• eGFR < 15 milliliters per minute per 1.73 square meters (mL/min/1.73 m^2)*
• return to dialysis*
• allograft nephrectomy
• retransplantation
• death from any cause, or
• a sustained (greater than or equal to [>=] 60 days) 40% decline in eGFR from Baseline.
*Total cumulative duration of sustained eGFR < 15 mL/min/1.73 m^2 AND / OR dialysis >= 60 days.
If the eGFR < 15 mL/min/1.73 m^2 was the only component reached, the value must be sustained over at least 60 days and must be confirmed by a repeat measurement after >= 60 days from the first measurement. The number of participants with composite all-cause allograft loss or irreversible loss of allograft function are reported here. Time-to-event data were not calculated due to the study’s termination. Analysis was performed on the ITT analysis set.
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End point type |
Primary
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End point timeframe |
From Baseline to 4 years
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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: Statistical analysis assessment was not performed as planned because of early study termination due to futility (at Interim Analysis). |
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No statistical analyses for this end point |
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End point title |
Percentage of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function [3] | ||||||||||||
End point description |
Composite all-cause allograft loss or irreversible loss of allograft function, defined as time to first occurrence of any of the following components:
• eGFR < 15 mL/min/1.73 m^2*
• return to dialysis*
• allograft nephrectomy
• retransplantation
• death from any cause, or
• a sustained (>= 60 days) 40% decline in eGFR from Baseline.
*Total cumulative duration of sustained eGFR < 15 mL/min/1.73 m^2 AND / OR dialysis >= 60 days.
If the eGFR < 15 mL/min/1.73 m^2 was the only component reached, the value must be sustained over at least 60 days and must be confirmed by a repeat measurement after >= 60 days from the first measurement. The percentage of participants with composite allograft loss or irreversible loss of allograft function are reported here. Time-to-event data were not calculated due to the study’s termination. Analysis was performed on the ITT analysis set.
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End point type |
Primary
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End point timeframe |
From Baseline to 4 years
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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: Statistical analysis assessment was not performed as planned because of early study termination due to futility (at Interim Analysis). |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and Adverse Events of Special Interest (AESIs) [4] | ||||||||||||||||||
End point description |
Analysis was performed on the safety analysis set (SAS). The SAS consisted of all randomized participants who had received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Up to 4 years
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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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints. |
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No statistical analyses for this end point |
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End point title |
Percentage of Participants With TEAEs, Serious TEAEs, and AESIs [5] | |||||||||||||||||||||
End point description |
Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Up to 4 years
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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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints. |
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No statistical analyses for this end point |
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End point title |
Number of Participants Who Tested Positive for Polyoma BK Virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) [6] | ||||||||||||||||||||||||||||||||||||
End point description |
Number of participants who tested positive for BKV, CMV or EBV according to the maximum measured viral amount (International Units/mL [IU/mL]) after baseline are reported here. Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘number analyzed’, 'n' = participants with available data for each specified category. Lower limit of quantification = LLOQ.
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End point type |
Primary
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End point timeframe |
From baseline up to 4 years
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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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Abnormal Laboratory Test Results [7] | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Laboratory tests included liver function test (LFTs), complete blood count (CBC), plasma lipids, high-sensitivity C-reactive protein (hsCRP). Only participants with abnormal laboratory test results are reported here. Here, ULN = upper limit of normal, LLN = lower limit of normal, ALT = Alanine aminotransferase and AST = Aspartate aminotransferase. Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants analyzed’, 'N' = participants with evaluable data for this outcome measure.
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End point type |
Primary
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End point timeframe |
Up to 4 years
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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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints. |
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No statistical analyses for this end point |
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End point title |
Percentage of Participants With Abnormal Laboratory Test Results [8] | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Laboratory tests included LFTs, CBC, plasma lipids, hsCRP. Only percentage of participants with abnormal laboratory test results are reported here. Here, ULN = upper limit of normal, LLN = lower limit of normal, ALT = Alanine aminotransferase and AST = Aspartate aminotransferase. Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants analyzed’ = participants with evaluable data for this outcome measure.
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End point type |
Primary
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End point timeframe |
Up to 4 years
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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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Abnormal Vital Signs, Electrocardiograms (ECGs), and Physical Examination [9] | |||||||||
End point description |
Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Up to 4 years
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Notes [9] - 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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Positive Anti-drug Antibodies [10] | |||||||||||||||||||||
End point description |
Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants’ = participants with available data for this outcome measure and 'number analyzed', 'n' = participants with available data for each specified timepoint.
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End point type |
Primary
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End point timeframe |
Baseline, Weeks 12, 24, and 48
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Notes [10] - 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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints. |
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No statistical analyses for this end point |
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End point title |
Percentage of Participants With Positive Anti-drug Antibodies [11] | ||||||||||||||||||||||||
End point description |
Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, 'overall number of participants' = participants with available data for this outcome measure and 'number analyzed', 'n' = participants with available data for each specified timepoint.
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End point type |
Primary
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End point timeframe |
Baseline, Weeks 12, 24, and 48
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Notes [11] - 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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Composite All-cause Allograft Loss | |||||||||
End point description |
Composite all-cause allograft loss, defined as, time to first occurrence of any of the following components:
• eGFR < 15 mL/min/1.73 m^2 (total cumulative duration of sustained eGFR < 15 mL/min/1.73 m^2 AND / OR dialysis >= 60 days)
• return to dialysis
• allograft nephrectomy
• retransplantation, or
• death from any cause.
The number of participants with composite all-cause allograft loss are reported here. Analysis was performed on the ITT analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of study drug and who had a baseline assessment and at least 1 post baseline assessment of eGFR.
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End point type |
Secondary
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End point timeframe |
Up to 4 years
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No statistical analyses for this end point |
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End point title |
Percentage of Participants With Composite All-cause Allograft Loss | ||||||||||||
End point description |
Composite all-cause allograft loss, defined as, time to first occurrence of any of the following components:
• eGFR < 15 mL/min/1.73 m^2 (total cumulative duration of sustained eGFR < 15 mL/min/1.73 m^2 AND / OR dialysis >= 60 days)
• return to dialysis
• allograft nephrectomy
• retransplantation, or
• death from any cause
The percentage of participants with composite all-cause allograft loss are reported here. Analysis was performed on the ITT analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of study drug and who had a baseline assessment and at least 1 post baseline assessment of eGFR.
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End point type |
Secondary
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End point timeframe |
Up to 4 years
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No statistical analyses for this end point |
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End point title |
Number of Participants With Irreversible Loss of Allograft Function | |||||||||
End point description |
Irreversible loss of allograft function as defined by a 40% decline in eGFR from Baseline sustained for at least 60 days. Analysis was performed on the ITT analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of the investigational product, had a Baseline assessment, and had at least 1 post-baseline assessment of eGFR.
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End point type |
Secondary
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End point timeframe |
From Baseline to 4 years
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No statistical analyses for this end point |
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End point title |
Percentage of Participants With Irreversible Loss of Allograft Function | ||||||||||||
End point description |
Irreversible loss of allograft function as defined by a 40% decline in eGFR from Baseline sustained for at least 60 days. Analysis was performed on the ITT analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of the investigational product, had a Baseline assessment, and had at least 1 post-baseline assessment of eGFR.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to 4 years
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Participants With Death-censored Allograft Loss | |||||||||
End point description |
This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
From Baseline to 4 years
|
|||||||||
|
||||||||||
Notes [12] - This secondary endpoint assessment was not performed as planned due to early study termination. [13] - This secondary endpoint assessment was not performed as planned due to early study termination. |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Percentage of Participants With Death-censored Allograft Loss | ||||||||||||
End point description |
This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to 4 years
|
||||||||||||
|
|||||||||||||
Notes [14] - This secondary endpoint assessment was not performed as planned due to early study termination. [15] - This secondary endpoint assessment was not performed as planned due to early study termination. |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Urine Albumin Creatinine Ratio (UACR) | ||||||||||||
End point description |
Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants analyzed’ = participants with available data for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Percent Change From Baseline in Mean Fluorescent Intensity for Donor-Specific Antibodies (DSA) | ||||||||||||||||||
End point description |
Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants analyzed’ = participants with available data for this outcome measure and ‘number analyzed’, 'n' = participants with available data for each specified category
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Banff Lesion Grading Score (2015 Criteria) of Pre-treatment to Post-treatment (Week 52) Kidney Biopsies | ||||||||||||
End point description |
This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Notes [16] - This secondary endpoint assessment was not performed as planned due to early study termination. [17] - This secondary endpoint assessment was not performed as planned due to early study termination. |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Acute Rejection Episodes of T Cell-mediated Rejection (TCMR) and Antibody-mediated Rejection (ABMR) | ||||||||||||
End point description |
This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline up to End of treatment (up to approximately 4 years)
|
||||||||||||
|
|||||||||||||
Notes [18] - This secondary endpoint assessment was not performed as planned due to early study termination. [19] - This secondary endpoint assessment was not performed as planned due to early study termination. |
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Overall Participant Survival | |||||||||
End point description |
This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 4 years
|
|||||||||
|
||||||||||
Notes [20] - This secondary endpoint assessment was not performed as planned due to early study termination. [21] - This secondary endpoint assessment was not performed as planned due to early study termination. |
||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Maximum Concentration at Steady State (Cmax ss) of CSL300 [22] | ||||||||
End point description |
A subset of participants (out of the enrolled participants in the main study) had the option to participate in a pharmacokinetic (PK)/ Pharmacodynamic (PD) sub-study. Analysis was performed on the PK/ PD analysis set. The PK/PD substudy analysis set consisted of all participants in the SAS who consented to be a part of the PK / PD substudy and had at least 1 quantifiable PK concentration of investigational product after administration. Here, “overall number of participants analyzed’ = participants with available data for this outcome measure.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to Week 24
|
||||||||
Notes [22] - 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, PK Data is reported for the applicable arm "Clazakizumab" only. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Trough Concentrations at Steady State (Ctrough ss) of CSL300 [23] | ||||||||
End point description |
A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study. Analysis was performed on the PK/PD analysis set. The PK/PD substudy analysis set consisted of all participants in the SAS who consented to be a part of the PK / PD substudy and had at least 1 quantifiable PK concentration of investigational product after administration. Here, “overall number of participants analyzed’ = participants with available data for this outcome measure.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to Week 24
|
||||||||
Notes [23] - 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, PK Data is reported for the applicable arm "Clazakizumab" only. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Area Under the Concentration-time Curve (AUC0-tau) at Steady State of CSL300 [24] | ||||||||
End point description |
A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study. Analysis was performed on the PK/PD analysis set. The PK/PD substudy analysis set consisted of all participants in the SAS who consented to be a part of the PK / PD substudy and had at least 1 quantifiable PK concentration of investigational product after administration. Here, “overall number of participants analyzed’ = participants with available data for this outcome measure.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to Week 24
|
||||||||
Notes [24] - 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, PK Data is reported for the applicable arm "Clazakizumab" only. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Time of Maximum Concentration at Steady State (Tmax ss) of CSL300 [25] | ||||||||
End point description |
A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study. Analysis was performed on the PK/PD analysis set. The PK/PD substudy analysis set consisted of all participants in the SAS who consented to be a part of the PK / PD substudy and had at least 1 quantifiable PK concentration of investigational product after administration. Here, “overall number of participants analyzed’ = participants with available data for this outcome measure.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to Week 24
|
||||||||
Notes [25] - 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, PK Data is reported for the applicable arm "Clazakizumab" only. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to 4 years
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The SAS consisted of all randomized participants who received at least 1 dose of study drug. The participants in the SAS were analyzed according to the actual treatment received.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
|
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Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Clazakizumab
|
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Reporting group description |
Participants received clazakizumab via SC injection Q4W until the participant: permanently discontinued the IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received Placebo via SC injection Q4W until the participant: permanently discontinued IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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07 Dec 2018 |
• Allowed therapies for required Pneumocystis jiroveci pneumonia (PJP) prophylaxis was broadened.
• Instructions regarding the determination of DSA eligibility criteria were further clarified and expanded.
• The section on biomarkers and pharmacogenomics research was expanded. |
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06 Feb 2019 |
• The target dose of IP was reduced from 25 mg SC Q4W to 12.5 mg SC Q4W.
• The exclusion of participants with prior exposure to clazakizumab was expanded.
• The risks and precautions section was updated to reflect updates from the most recent Investigator brochure.
• Treatment options for managing hypogammaglobulinemia were added.
• The concomitant medications section was updated to reflect changing clinical practice.
• The duration of protocol-specified PJP prophylaxis was reduced to the first year of the study. |
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29 Oct 2019 |
• Inclusion and exclusion criteria were updated.
• Due to the potential confounding long-term effects of proteasome inhibitors on the immune system, participants with any prior exposure to proteasome inhibitors were to be excluded from the study.
• The requirement for participants to use “highly effective methods of contraception” was amended.
• Throughout the protocol, the terminology for discontinuation of IP was clarified so that the term “discontinuation” now refers to permanent discontinuation and the term “withholding” refers to temporary discontinuation.
• The dose modification guidelines were clarified and expanded throughout the protocol.
• Recommendations regarding concomitant background immunosuppression were clarified.
• The first planned formal safety review by the Data Safety and Monitoring Board (DSMB) was changed to occur after 50 participants (instead of 100 participants) had been randomized and received at least 1 dose of IP.
• The guidelines for participants with severe hypogammaglobulinemia were amended to add a 4-week waiting period after reduction of background immunosuppression followed by a recheck of IgG levels before implementing treatment with IV immunoglobulin.
• Home health visits were added.
• Changes were made to clarify the process for reporting pre-existing medical conditions that met the definition of a SAE. • The appearance of Clazakizumab Drug Product in 12.5 mg/mL vials was corrected to state “clear, colorless solution. |
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11 Dec 2019 |
• Exclusion criteria was amended to allow for participants with fully excised ulcerative colitis to enter the study.
• The protocol was revised to include COVID-19 PCR testing at Screening and an additional exclusion criteria was added to exclude participants with an active COVID-19 infection. Serologic blood tests were not required during the study.
• The schedule of mandatory in-clinic visits was amended.
• The rescreening procedures were amended.
• The prohibited medications section was amended. |
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04 Feb 2021 |
• Inclusion and exclusion criteria were updated.
• The definition, End of treatment (EOT) was added to the schedule of events (SOE) and throughout the protocol, and the definition of end of study (EOS) was updated.
• A PK/PD sub-study was added to better capture clazakizumab exposures and relate these to IL-6 and hsCRP levels.
• Patient-reported outcome assessments were added to the protocol to assess Health-related quality of life (HRQoL). |
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30 Apr 2021 |
• Clarified the required timing of the biopsy required to determine study eligibility.
• Corrected table to reflect administration of subcutaneous clazakizumab.
• Removed an exploratory healthcare utilization objective and endpoint.
• Outlined that patient-reported outcome assessments would not have been performed for participants randomized prior to the deployment of an electronic clinical outcome assessment solution. |
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12 Jul 2022 |
• The overall study design and treatment duration was changed.
• The frequency of procedures in Years 2 to End of Study was decreased.
• The study procedures were updated based upon the changes to the Schedule of Events in Years 2 to End of Study.
• Added a new secondary objective.
• A corresponding new secondary endpoint was added to the study.
• A description of the common treatment end date (CTED) criteria was added throughout the protocol.
• Text that was currently described in the Investigator Brochure was removed from the protocol.
• Access to study product after the end of the study would now be available at the discretion of the treating physician and offered to participants as agreed upon in their respective country.
• Participants who received Intravenous immunoglobulin (IVIG) underwent PK assessments.
• The inclusion and exclusion criteria were modified to increase the number of participants.
• Text from the Clinical Trials Facilitation and Coordination Group was added to the adequate contraception language.
• Participants who permanently discontinue IP remained in the study until the common treatment end date.
• Text regarding unblinding procedures was amended to provide clear directions in the case of a suspected unexpected serious adverse reaction (SUSAR).
• Text describing dose, administration, storage, accountability, and destruction of IP was deleted.
• Text regarding allowed concomitant medication was updated.
• Recommendations for immunizations within 6 weeks prior to the start of Screening was added to the protocol.
•A detailed description of EOS procedures was provided for participants who completed the study, participants who permanently discontinued IP, participants who withdrew from the study, and participants who were on treatment when the primary endpoint of the study was reached.
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10 Jul 2023 |
• The primary objective and endpoint and associated footnote were revised.
• The “EOS visit terminology was revised to the “Safety Follow-up Visit (SFV)” or the “Common treatment end visit (CTEV)”, where applicable.
• Testing methodology for COVID-19 was expanded to include rapid antigen testing.
• Protocol text under the synopsis subsection was modified.
• “Secondary Safety Endpoints” was revised to “Safety Endpoints”.
• Protocol text was revised to outline the sequence of assessments and also for managing study participants who remain in the study after permanently discontinuing IP.
• Text describing calcineurin inhibitor (CNI) monitoring was revised.
• “Acceptable” methods of contraception were removed.
• Secondary objectives were revised to include the previous primary efficacy objective as the first secondary objective.
• Added statement regarding how to manage study participants who reach the endpoint of “a sustained (>= 60 days) 40% decline in eGFR from Baseline”.
• Sites increased to 155.
• Inclusion and exclusion criteria revised.
• Administration of live vaccines was revised to prohibited during the study.
• Revised dose range of mycophenolate mofetil (MMF) and mycophenolic acid (MPA) (allowed concomitant medications).
• Study schema, Schedule of events table, and footnotes updated.
• Revised protocol text: -regarding participants who discontinue IP due to pregnancy. -withholding or discontinuing IP due to AE, abnormal LFTs, neutropenia and / or thrombocytopenia, and BKV, CMV, or EBV viral infection. -emergency unblinding of IP.
• Drug product description was updated.
• Added statement to refer the reader to the CSL300 Investigator’s Brochure.
• Protocol text for procedures and visit schedule were updated.
• The timing of the DSA analysis and renal biopsy was revised.
• Allowed participant to rescreen for administrative reason. |
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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. | |||
The study was terminated due to futility after the planned interim analysis based on the change in eGFR from baseline to Week 52 and analysis was conducted where feasible using the data collected by the time of study termination. |