Clinical Trial Results:
A Phase 1b/2 Study to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of Isatuximab (SAR650984) in Patients Awaiting Kidney Transplantation
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Summary
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EudraCT number |
2019-004154-28 |
Trial protocol |
ES |
Global end of trial date |
02 May 2022
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Results information
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Results version number |
v2(current) |
This version publication date |
16 Jul 2023
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First version publication date |
17 May 2023
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Other versions |
v1 |
Version creation reason |
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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 |
TED16414
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04294459 | ||
WHO universal trial number (UTN) |
U1111-1238-9716 | ||
Other trial identifiers |
IND: 143523 | ||
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Sponsors
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Sponsor organisation name |
Sanofi-Aventis Recherche & Développement
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Sponsor organisation address |
1 Avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
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Public contact |
Trial Transparency Team, Sanofi Aventis Recherche & Développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi Aventis Recherche & Développement, Contact-US@sanofi.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 |
28 Nov 2022
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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 May 2022
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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 |
- Phase 1: To characterise the safety and tolerability of isatuximab in kidney transplant candidates.
- Phase 2: To evaluate the efficacy of isatuximab in desensitisation of subjects awaiting kidney transplantation.
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Jun 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Spain: 11
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Country: Number of subjects enrolled |
United States: 12
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Worldwide total number of subjects |
23
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EEA total number of subjects |
11
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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) |
21
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
Study was conducted at 6 active sites in 2 countries. A total of 23 subjects were enrolled between 18 Jun 2020 and 02 Nov 2021 and received isatuximab monotherapy. Study was planned to be conducted in 2 parts: Phase 1 (safety run-in) & Phase 2 (efficacy). | |||||||||||||||
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Pre-assignment
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Screening details |
Sponsor decided to terminate study for non-safety reasons on 02 May 2022 after interim analysis. It was determined that enrolment of remaining subjects was unlikely to have any significant impact on study results & hence trial was stopped. Subject disposition, baseline, endpoints & safety data were presented for combined Phase 1 and 2 population. | |||||||||||||||
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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 |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cohort A: Subjects With cPRA >=99.90% | |||||||||||||||
Arm description |
Subjects with calculated panel reactive antibodies (cPRA) greater than or equal to (>=) 99.90 percent (%) (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or subject’s decision to stop the treatment (maximum treatment duration:13 weeks). | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Isatuximab
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Investigational medicinal product code |
SAR650984
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Other name |
Sarclisa
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days).
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Arm title
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Cohort B: Subjects With cPRA 80.00% to 99.89% | |||||||||||||||
Arm description |
Subjects with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or subject’s decision to stop the treatment (maximum treatment duration: 13 weeks). | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Isatuximab
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Investigational medicinal product code |
SAR650984
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Other name |
Sarclisa
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days).
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Baseline characteristics reporting groups
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Reporting group title |
Cohort A: Subjects With cPRA >=99.90%
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Reporting group description |
Subjects with calculated panel reactive antibodies (cPRA) greater than or equal to (>=) 99.90 percent (%) (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or subject’s decision to stop the treatment (maximum treatment duration:13 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort B: Subjects With cPRA 80.00% to 99.89%
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Reporting group description |
Subjects with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or subject’s decision to stop the treatment (maximum treatment duration: 13 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort A: Subjects With cPRA >=99.90%
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Reporting group description |
Subjects with calculated panel reactive antibodies (cPRA) greater than or equal to (>=) 99.90 percent (%) (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or subject’s decision to stop the treatment (maximum treatment duration:13 weeks). | ||
Reporting group title |
Cohort B: Subjects With cPRA 80.00% to 99.89%
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Reporting group description |
Subjects with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or subject’s decision to stop the treatment (maximum treatment duration: 13 weeks). | ||
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End point title |
Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [1] | |||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a subject who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious adverse events (SAEs) were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (defined as the time from the first dose of study drug until study cut-off date). Analysis was performed on all treated population which included all subjects who received at least one dose of isatuximab. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Primary
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End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 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: As the endpoint was descriptive in nature, no statistical analysis was reported. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Number of Subjects With Hematological Abnormalities [2] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Abnormal hematological parameters assessed were anemia, platelet count decreased, neutrophil count decreased, lymphocyte count decreased and monocytes. The hematological abnormality grades were based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Monocytes were assessed as per potentially clinically significant abnormality (PCSA) criteria defined as: greater than (>) 0.7*10^9/Litre. Analysis was performed on all treated population. Here, "n" = subjects with available data for each specified category. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Primary
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End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 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: As the endpoint was descriptive in nature, no statistical analysis was reported. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Renal Function Abnormalities [3] | |||||||||||||||||||||||||||||||||
End point description |
Abnormal renal parameters assessed were creatinine increased and estimated Glomerular Filtration Rate (eGFR). The renal function abnormality grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. eGFR was assessed as per PCSA criteria: 60 less than or equal to (<=) to less than (<) 90 millilitres per minute per 1.73 square metre (mL/min/1.73m^2) (Mild), 30<= to <60 mL/min/1.73m^2 (Moderate), 15<=to <30 mL/ min/1.73m^2 (Severe), <15 mL/min/1.73m^2 (End Stage Renal Disease). Analysis was performed on all treated population. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Primary
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End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 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: As the endpoint was descriptive in nature, no statistical analysis was reported. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Abnormal Electrolytes Parameters [4] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Abnormal electrolyte parameters assessed were hypernatremia, hyponatremia, hyperkalemia, hypokalemia, hypercalcemia, hypocalcemia, blood bicarbonate decreased, hypermagnesemia, hypomagnesemia, chloride. The abnormal grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Chloride was estimated as per PCSA criteria: < 80 millimoles/litre [mmol/L] and > 115 mmol/L. Analysis was performed on all treated population. Here, "n" = subjects with available data for each specified category and "99999" is used as a space filler which signifies that none of the subjects were available for assessment. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Primary
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End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 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: As the endpoint was descriptive in nature, no statistical analysis was reported. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Abnormal Metabolism Parameters [5] | ||||||||||||||||||||||||||||||||||||
End point description |
Abnormal metabolism parameters assessed were hypoglycemia, hypoalbuminemia and glycated Hemoglobin A1c (HbA1c). The abnormal grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. HbA1c >8% was estimated as per PCSA criteria. Analysis was performed on all treated population. Here, "n" = subjects with available data for each specified category and “99999” is used as a space filler which signifies that none of the subjects were available for assessment. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Primary
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End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
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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: As the endpoint was descriptive in nature, no statistical analysis was reported. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Liver Function Abnormalities [6] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Abnormal liver function parameters assessed were Alanine aminotransferase (ALT) increased, Aspartate aminotransferase (AST) increased, Alkaline phosphatase (ALP) increased, and Total bilirubin (TB) increased. The abnormal grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Analysis was performed on all treated population. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Primary
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End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
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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: As the endpoint was descriptive in nature, no statistical analysis was reported. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Subjects With Response [7] | ||||||||||||
End point description |
Response was defined as the percentage of subjects meeting at least one of the predefined desensitisation efficacy criteria as measured by single antigen bead (SAB) assay as follows:
reduction in cPRA resulting in at least 100% increase of likelihood of finding a compatible donor; reduction in antibody titer (greater than or equal to [>=]75% reduction from Baseline) to achieve target cPRA; elimination of >=1 human leukocyte antigen (HLA) antibody (i.e., mean fluorescence intensity (MFI) reduced to <2000) as measured by SAB assay, for antibodies with Baseline MFI >=3000. Analysis performed on efficacy evaluable population which included all subjects who received at least 1 dose of isatuximab, with an evaluable Baseline and at least 1 evaluable post-baseline efficacy assessment and received >=75% of planned cumulative doses. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Primary
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End point timeframe |
From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks)
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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: As the endpoint was descriptive in nature, no statistical analysis was reported. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Pharmacokinetics (PK) Parameters: Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab | ||||||||||||
End point description |
Ceoi is the plasma concentration observed at the end of IV infusion of isatuximab. Analysis was performed on pharmacokinetic (PK) population which included all subjects who received at least 1 dose of isatuximab, with at least 1 available concentration result post treatment. Here, "number of subjects analysed" = subjects with available data for this endpoint. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Secondary
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End point timeframe |
At End of infusion on Cycle 1, Day 1
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PK Parameters: Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab | ||||||||||||
End point description |
Cmax was defined as the maximum concentration observed after the first administration, calculated using the non-compartmental analysis after the IV infusion of isatuximab. Analysis was performed on PK population. Here, "number of subjects analysed" = subjects with available data for this endpoint. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Secondary
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End point timeframe |
At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1]
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PK Parameters: Time Taken to Reach Cmax (Tmax) After the First infusion of of Isatuximab | ||||||||||||
End point description |
Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the IV infusion of isatuximab. Analysis was performed on PK population. Here, "number of subjects analysed" = subjects with available data for this endpoint. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Secondary
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End point timeframe |
At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1]
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PK Parameters: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab | ||||||||||||
End point description |
Clast was defined as the last concentration of isatuximab observed above the lower limit of quantification, calculated using non-compartmental analysis after the first infusion of isatuximab. Analysis was performed on PK population. Here, "number of subjects analysed" = subjects with available data for this endpoint. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
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End point type |
Secondary
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||||||||||||
End point timeframe |
At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1]
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
PK Parameters: Time of Clast (Tlast) After First Infusion of Isatuximab | ||||||||||||
End point description |
Tlast was defined as the time of last concentration observed above the lower limit of quantification, calculated using the non-compartmental analysis after the intravenous infusion of isatuximab. Analysis was performed on PK population. Here, "number of subjects analysed" = subjects with available data for this endpoint. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1]
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
PK Parameters: Trough Plasma Concentrations (Ctrough) of Isatuximab | ||||||||||||
End point description |
Ctrough was the plasma concentration of isatuximab observed just before (pre-dose) treatment administration. Analysis was performed on PK population. Here "number of subjects analysed" = subjects with available data for this endpoint. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Pre-dose on Cycle 2 Day 1
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
PK Parameters: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 hr Over the Dosing Interval (AUC0-168 hr) After First Infusion of Isatuximab | ||||||||||||
End point description |
AUC0-168 hr was defined as the area under the plasma concentration versus time curve from time 0 to 168 hours post dose calculated using trapezoidal after first infusion of isatuximab. Analysis was performed on PK population. Here, "number of subjects analysed" = subjects with available data for this endpoint. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1]
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||
End point title |
Number of Subjects With Anti-drug Antibodies (ADA) Against Isatuximab | |||||||||||||||
End point description |
ADA responses were categorised as treatment boosted ADA and treatment-induced ADA. Treatment boosted ADA was defined as pre-existing ADAs with a significant increase in the ADA titer during the study compared to the Baseline titer. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in subjects without pre-existing ADA. Analysis was performed on anti-drug antibodies (ADA) population which included all subjects who received at least 1 dose of isatuximab, with at least 1 available ADA result post-treatment. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||
End point title |
Duration of Response (DOR) | ||||||||||||
End point description |
Time from lab sample collection date used to determine responder subject (meeting at least 1 predefined desensitisation efficacy criteria: reduction (red) in cPRA resulting in at least 100% increase of likelihood of finding compatible donor; red in antibody titer [>=75% red from Baseline] to achieve target cPRA; elimination of >=1 anti-HLA antibody i.e. MFI reduced to <2000 [SAB assay], for antibodies with Baseline MFI >=3000) when subject confirmed as no longer meeting any response criterion (non-responder)/date of death, whichever 1st. Kaplan-Meier method. Analysed on responder population: subjects who received at least 1 dose of isatuximab, with evaluable Baseline & at least 1 evaluable post-baseline efficacy assessment & received >=75% of planned cumulative dose. "Number of subjects analysed" = subjects with available data, '99999' = space filler denotes median & upper limit of 95 % confidence interval not estimable due to less subjects with event. Combined Phase 1 & 2 population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||
End point title |
Number of Subjects Achieving Target cPRA | |||||||||
End point description |
Target calculated panel reactive antibodies (cPRA) was defined as the reduction of cPRA required to achieve at least 100% increase of likelihood of compatible donor (LCD). Number of subjects who achieved target cPRA assessed using the Organ Procurement and Transplantation Network (OPTN) calculator during the specified timepoint were reported in this endpoint. Subjects who retained their target cPRA values were censored at the date of the last available laboratory assessment achieving their target cPRA. Analysis was performed on efficacy evaluable population. Here, "number of subjects analysed" = subjects with available data for this endpoint. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
From first dose of study drug until end of follow-up period (maximum duration: up to 97.7 weeks)
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||
End point title |
Duration for Achieving Target cPRA | ||||||||||||
End point description |
Duration of achieving target cPRA was defined as time (in weeks) from laboratory sample collection date of achieving target cPRA (defined as reduction of cPRA required to achieve at least 100% increase of LCD) the first time up to laboratory sample collection date when no longer achieving target cPRA calculated using OPTN calculator or date of death due to any cause, whichever occurs first. Duration of achieving target cPRA was assessed using Kaplan-Meier method. Analysis was performed on efficacy evaluable population. Here, "number of subjects analysed" = subjects with available data for this endpoint and '99999' was used as space filler that denotes that median & upper limit of 95% confidence interval (CI) were not estimable due to insufficient number of subjects with events & '-9999' space filler denotes lower limit of 95% CI not estimable due to insufficient number of subjects with events. Data was planned to be collected and analysed for combined Phase 1 and 2 population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose of study drug until end of follow-up period (maximum duration: up to 97.7 weeks)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||
End point title |
Number of Subjects With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | ||||||||||||||||||||||||
End point description |
Number of subjects with anti-HLA-antibody (Baseline MFI >=3000) reduced to <2000 as measured using a SAB assay per central laboratory assessment was reported in this endpoint. Subjects were categorised in various categories of number of antibodies which were reduced as: none, 1-5, >5-10, >10-15, and >15. If multiple visits had the same number of total anti-HLA antibody reduction, the last visit data was summarised. Analysis was performed on efficacy evaluable population. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||
End point title |
Time to First Transplant Offer | ||||||||||||
End point description |
Time to first transplant offer was defined as time (in days) from date of first study treatment dose up to date of first kidney transplant offer. Data on transplant status were collected and followed up until study cut-off date. Analysis was performed on efficacy-evaluable population. Here, "number of subjects analysed" = subjects with available data for this endpoint. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Time to Transplant | ||||||||||||
End point description |
Time to transplant was defined as time (in days) from date of first study treatment dose up to date of kidney transplant. Data on transplant status were collected and followed up until study cut-off date. Analysis was performed on efficacy evaluable population. Here, "number of subjects analysed" = subjects with available data for this endpoint and included only subjects who accepted transplant offer. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Number of Kidney Transplant Offers | ||||||||||||
End point description |
Number of kidney transplants offers received for each subject was reported in the endpoint. Data on transplant offers were collected and followed up until study cut-off date. Analysis was performed on efficacy evaluable population. Data was planned to be collected and analysed for the combined Phase 1 and 2 population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Time to First Antibody Mediated Rejection (AMR) Episode | ||||||||||||
End point description |
Time to first AMR was defined as time (in days) from date of first study treatment dose up to date of biopsy with first AMR (defined as the graft rejection due to generation of antibodies against the graft). Transplanted subjects without any AMR were censored at the subject’s last assessment or contact date collected in the study or at the analysis cut-off date, whichever was earlier. Data for this endpoint was not collected and analysed as no subjects experienced a kidney transplant graft loss due to an AMR episode as of study terminated date.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
|
||||||||||||
|
|||||||||||||
| Notes [8] - No subjects experienced kidney transplant graft loss due to AMR episodes. [9] - No subjects experienced kidney transplant graft loss due to AMR episodes. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects Who Experienced Any Antibody Mediated Rejection (AMR) | ||||||||||||
End point description |
Antibody mediated rejection was defined as the graft rejection due to generation of antibodies against the graft. The number of subjects with AMR field checked as 'yes' based on the graft rejection biopsy in the electronic case report form was considered. Data for this endpoint was not collected and analysed as no subjects experienced a kidney transplant graft loss due to an AMR episode, as of study terminated date.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
|
||||||||||||
|
|||||||||||||
| Notes [10] - No subjects experienced kidney transplant graft loss due to AMR episodes. [11] - No subjects experienced kidney transplant graft loss due to AMR episodes. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||
End point title |
Number of Subjects With Graft Survival at 6 Months Post-Transplant | |||||||||
End point description |
Number of subjects with graft survival status as functioning at 6-months post-transplant was reported in this endpoint. Analysis was performed on efficacy evaluable population. Here, "number of subjects analysed" = subjects with evaluable data for this endpoint.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At 6 Months post-transplant
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
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Timeframe for reporting adverse events |
From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
|
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Adverse event reporting additional description |
Analysis was performed on all treated population.
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
|
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|
Reporting groups
|
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Reporting group title |
Cohort A: Subjects With cPRA >=99.90%
|
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Reporting group description |
Subjects with cPRA >=99.90% (indicates active candidates on kidney transplant waitlist) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or subject's decision to stop the treatment (maximum treatment duration: 13 weeks). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort B: Subjects With cPRA 80.00% to 99.89%
|
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Reporting group description |
Subjects with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or subject’s decision to stop the treatment (maximum treatment duration: 13 weeks). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
23 Jul 2020 |
Following changes were made: Provided option to adapt the premedication depending on individual situation; Clarified monitoring and risks related to viral reactivation; Added indirect Coombs tests after treatment period during Site Visit follow-up period (FUP) if Cycle (C)2Day (D)1 was positive; Ensured a post-treatment sample was collected in case C3D1 sample was not collected or if subject discontinued treatment prior to C3D1; Modified sample collection timepoint to reduce wait time/burden for study subjects; Provided flexibility and potentially reduced site visit for study subjects; Updated isatuximab approval status and number of treated subjects; Updated infusion rates based on fixed volume infusion method; Corrected typographical error; Added obinutuzumab to require 6 months washout period; Included flexibility and ease of continuation of study during regional or national emergency such as Covid-19; Updated management guideline on Grade 2 and 3 IR including permanent discontinuation of study treatment at third infusion reactions (IR); “AE or” was added to the sentence: “However, if either of the following conditions applies, then the event must be recorded and reported as an AE or SAE (instead of a disease related event [DRE]):”; Pregnancy test frequency was corrected to be consistent with Schedule of Activities; Minor editorial and format changes. |
||
01 Feb 2022 |
Following changes were made: Criteria for cPRA reduction was corrected from “at least 50% increase of likelihood” to “at least 100% increase of likelihood”; Editorial changes were made to clarify that history of active or latent tuberculosis was relevant if within 24 weeks prior to IMP initiation, and “(peritoneal, etc.)” were specific to the “deep tissue/space infection”; Clarified on need for individual serology and viral load tests; minor editorial and format changes were done. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Study was terminated for non-safety reasons on 02 May 2022. It was determined that enrolment of remaining subjects was unlikely to have any significant impact on results. All 23 subjects enrolled were followed-up per protocol until termination date. | |||
