Immune System Disorder
Conditions
Keywords
Anti-CD38 monoclonal antibody
Brief summary
Primary Objectives: * Phase 1: To characterize the safety and tolerability of isatuximab in kidney transplant candidates. * Phase 2: To evaluate the efficacy of isatuximab in desensitization of participants awaiting kidney transplantation. Secondary Objectives: * Phase 2: To characterize the safety profile of isatuximab in kidney transplant candidates. * To characterize the pharmacokinetic (PK) profile of isatuximab in kidney transplant candidates. * To evaluate the immunogenicity of isatuximab. * To assess the overall efficacy of isatuximab in desensitization of participants awaiting kidney transplantation.
Detailed description
The study had a screening period of up to 28 days, a treatment period of up to 12 weeks, a site visit FUP of up to 26 weeks, and an extended follow-up (FUP) until study cut-off. The study duration involved site visit per participant (i.e., screening, treatment, site visit FUP was approximately 42 weeks. The study duration included extended FUP per participant was approximately 97.7 weeks (depending on when the participant was enrolled).
Interventions
Pharmaceutical form: Solution for infusion Route of administration: Intravenous
DRUGAcetaminophen (paracetamol) or equivalent
Pharmaceutical form: Tablets Route of administration: Oral
DRUGRanitidine or equivalent
Pharmaceutical form: Solution Route of administration: Intravenous
Pharmaceutical form: Solution Route of administration: Intravenous
Pharmaceutical form: Solution Route of administration: Intravenous
Pharmaceutical form: Tablets Route of administration: Oral
Sponsors
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of chronic kidney disease (CKD) and active candidate on the kidney donor waitlist at the time of screening. * Body mass index (BMI) \</=40 kg/m\^2. * Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. * Capable of giving signed informed consent. For Participants in Cohort A: active candidates on the kidney waitlist with living donor. For Participants in Cohort B: active candidates on the kidney waitlist with no living donor cleared for donation.
Exclusion criteria
* Significant cardiac dysfunction. * Known active, recurrent, or chronic infection. * Active lupus or uncontrolled diabetes. * Prior treatment with rituximab within 6 months from SAR650984 administration. * Inadequate organ and bone marrow function at screening. * Pregnant or breastfeeding women or women who intend to become pregnant during participation in the study. * Known intolerance or hypersensitivity to any component of SAR650984 or pre-medications. * Participants who were not suitable for participation as judged by the Investigator. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | An AE was defined as any untoward medical occurrence in a participant 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 hospitalization or prolongation of existing hospitalization, 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). |
| Number of Participants With Hematological Abnormalities | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 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/L. |
| Number of Participants With Renal Function Abnormalities | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 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 equal to) \<= to less than (\<) 90 milliliter/minute/1.73 meter square (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). |
| Number of Participants With Abnormal Electrolytes Parameters | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | Abnormal electrolyte parameters assessed were hypernatremia, hyponatremia, hyperkalemia, hypokalemia, hypercalcemia, hypocalcemia, blood bicarbonate decreased, hypermagnesemia, hypomagnesemia and 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 per liter (mmol/L) and \>115 mmol/L. |
| Number of Participants With Abnormal Metabolism Parameters | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | Abnormal metabolism parameters assessed were hypoglycemia, hypoalbuminemia and glycated Hemoglobin (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 was estimated as per PCSA criteria: \>8%. |
| Number of Participants With Liver Function Abnormalities | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 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. |
| Percentage of Participants With Response | From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks) | Response was defined as the percentage of participants meeting at least one of the predefined desensitization 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 (\>=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 a SAB assay, for antibodies with Baseline MFI \>=3000. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Anti-drug Antibodies (ADA) Against Isatuximab | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | ADA responses were categorized 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 participants without pre-existing ADA. |
| Duration of Response (DOR) | From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks) | Duration of response (DOR) was defined as time (in weeks) from laboratory sample collection date used in determining a participant to be a responder (defined as participants meeting at least one of the predefined desensitization efficacy criteria: reduction in cPRA resulting in at least 100% increase of likelihood of finding a compatible donor; reduction in antibody titer \[\>=75% reduction from Baseline\] to achieve target cPRA; elimination of \>=1 anti-HLA antibody i.e. MFI reduced to \<2000 as measured by a SAB assay, for antibodies with Baseline MFI \>=3000) up to the laboratory sample collection date when participant was confirmed as no longer meeting any response criterion (i.e., non-responder) or the date of death due to any cause, whichever occurs first. DOR was analyzed using Kaplan-Meier method. |
| Number of Participants Achieving Target cPRA | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 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 participants who achieved target cPRA was assessed using the Organ Procurement and Transplantation Network (OPTN) calculator during the specified timepoint were reported in this outcome measure. Participants who retained their target cPRA values were censored at the date of the last available laboratory assessment achieving their target cPRA. |
| Duration for Achieving Target cPRA | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | Duration of achieving target cPRA was defined as the time (in weeks) from laboratory sample collection date of achieving target cPRA (defined as the reduction of cPRA required to achieve at least 100% increase of LCD) the first time up to the laboratory sample collection date when no longer achieving target cPRA calculated using OPTN calculator or the date of death due to any cause, whichever occurs first. The duration of achieving target cPRA was assessed using the Kaplan-Meier method. |
| Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks) | Number of participants with anti-HLA-antibody (Baseline MFI \>=3000) reduced to \<2000 as measured using a SAB assay per central laboratory assessment was reported in this outcome measure. Participants were categorized 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 summarized. |
| Pharmacokinetics (PK) Parameters: Concentration Observed at the End of First Intravenous Infusion (Ceoi) of Isatuximab | At End of infusion on Cycle 1 Day 1 | Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab. |
| Time to Transplant | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 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. |
| Number of Kidney Transplant Offers | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | Number of kidney transplants offers received for each participant was reported in the outcome measure. Data on transplant offers were collected and followed up until study cut-off date. |
| Time to First Antibody Mediated Rejection (AMR) Episode | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | Time to first AMR was defined as time 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 participants without any AMR were censored at the participant's last assessment or contact date collected in the study or at the analysis cut-off date, whichever was earlier. |
| Percentage of Participants Who Experienced Any Antibody Mediated Rejection (AMR) | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | Antibody mediated rejection was defined as the graft rejection due to generation of antibodies against the graft. The number of participants with AMR field checked as 'yes' based on the graft rejection biopsy in the electronic case report form was considered. |
| Number of Participants With Graft Survival at 6 Months Post-Transplant | At 6 Months post-transplant | Number of participants with graft survival status as functioning at 6-months post-transplant was reported in this outcome measure. |
| Time to First Transplant Offer | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 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. |
| PK Parameters: Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab | 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 | Cmax was defined as the maximum concentration observed after the first administration calculated using the noncompartmental analysis after the intravenous infusion of isatuximab. |
| PK Parameters: Time Taken to Reach Cmax (Tmax) After the First Infusion of Isatuximab | 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 | Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion of isatuximab. |
| PK Parameters: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab | 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 | 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. |
| PK Parameters: Time of Clast (Tlast) After First Infusion of Isatuximab | 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 | 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. |
| PK Parameters: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 2 Day 1 | Ctrough was the plasma concentration of isatuximab observed just before (pre-dose) treatment administration. |
| PK Parameters: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 Hours Over the Dosing Interval (AUC0-168 Hours) After First Infusion of Isatuximab | 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 | AUC0-168 hours was defined as the area under the plasma concentration versus time curve from time 0 to 168 hours post dose calculated using trapezoidal method after first infusion of isatuximab. |
Countries
Spain, United States
Participant flow
Recruitment details
Study was conducted at 6 active sites in 2 countries. A total of 23 participants were enrolled between 18 Jun 2020 and 02 Nov 2021 and received isatuximab monotherapy.
Pre-assignment details
Study was planned to be conducted in 2 parts: Phase 1 (safety run-in) and Phase 2 (efficacy). Sponsor decided to terminate the study for non-safety reasons on 02 May 2022. Based on available clinical data at time of interim analysis, it was determined that enrollment of remaining participants was unlikely to have any significant impact on study results and hence trial was stopped. Participant flow, baseline, outcome measures and safety data were presented for combined Phase 1 and 2 population.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Participants With cPRA >=99.90% Participants with cPRA \>=99.90%; (indicating 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 participant's decision to stop the treatment (maximum treatment duration: 13 weeks). | 12 |
| Cohort B: Participants With cPRA 80.00% to 99.89% Participants 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 participant's decision to stop the treatment (maximum treatment duration: 13 weeks). | 11 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort B: Participants With cPRA 80.00% to 99.89% | Total | Cohort A: Participants With cPRA >=99.90% |
|---|---|---|---|
| Age, Continuous | 48.2 years STANDARD_DEVIATION 12.3 | 49.0 years STANDARD_DEVIATION 11.8 | 49.7 years STANDARD_DEVIATION 11.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) White | 9 Participants | 13 Participants | 4 Participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 15 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 12 | 0 / 11 |
| other Total, other adverse events | 3 / 12 | 4 / 11 |
| serious Total, serious adverse events | 0 / 12 | 0 / 11 |
Outcome results
Primary
Number of Participants With Abnormal Electrolytes Parameters
Abnormal electrolyte parameters assessed were hypernatremia, hyponatremia, hyperkalemia, hypokalemia, hypercalcemia, hypocalcemia, blood bicarbonate decreased, hypermagnesemia, hypomagnesemia and 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 per liter (mmol/L) and \>115 mmol/L.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on all treated population. Here, 'number analyzed' = participants with available data for each specified category and 0 in the number analyzed field signifies that none of the participants were available for assessment of the specified parameter. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hyperkalemia: Grade 1 | 2 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypernatremia: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypernatremia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypernatremia: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hyponatremia: Grade 1 | 4 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hyponatremia: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hyponatremia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hyponatremia: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypernatremia: Grade 1 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hyperkalemia: Grade 2 | 3 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hyperkalemia: Grade 3 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hyperkalemia: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypokalemia: Grade 1 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypokalemia: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypokalemia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypokalemia: Grade 4 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypercalcemia: Grade 1 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypercalcemia: Grade 2 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypercalcemia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypercalcemia: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypocalcemia: Grade 1 | 6 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypocalcemia: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypocalcemia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypocalcemia: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypermagnesemia: Grade 1 | 2 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypermagnesemia: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypermagnesemia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypermagnesemia: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypomagnesemia: Grade 1 | 3 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypomagnesemia: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypomagnesemia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Hypomagnesemia: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Chloride (PCSA): <80 mmol/L | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Electrolytes Parameters | Chloride (PCSA): >115 mmol/L | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypermagnesemia: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypernatremia: Grade 1 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypercalcemia: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypernatremia: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Chloride (PCSA): >115 mmol/L | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypernatremia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypercalcemia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypernatremia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypermagnesemia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hyponatremia: Grade 1 | 1 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypercalcemia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hyponatremia: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypomagnesemia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hyponatremia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypocalcemia: Grade 1 | 5 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hyponatremia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypermagnesemia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hyperkalemia: Grade 1 | 6 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypocalcemia: Grade 2 | 2 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hyperkalemia: Grade 2 | 1 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Chloride (PCSA): <80 mmol/L | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hyperkalemia: Grade 3 | 2 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypocalcemia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hyperkalemia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypomagnesemia: Grade 1 | 3 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypokalemia: Grade 1 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypocalcemia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypokalemia: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypomagnesemia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypokalemia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypermagnesemia: Grade 1 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypokalemia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypomagnesemia: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Electrolytes Parameters | Hypercalcemia: Grade 1 | 1 Participants |
Primary
Number of Participants With Abnormal Metabolism Parameters
Abnormal metabolism parameters assessed were hypoglycemia, hypoalbuminemia and glycated Hemoglobin (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 was estimated as per PCSA criteria: \>8%.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on all treated population. Here, number analyzed = participants with available data for each specified category and 0 in the number analyzed field signifies that none of the participants were available for assessment of the specified parameter. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Metabolism Parameters | Hypoglycemia: Grade 1 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Metabolism Parameters | Hypoglycemia: Grade 2 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Metabolism Parameters | Hypoglycemia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Metabolism Parameters | Hypoglycemia: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Metabolism Parameters | Hypoalbuminemia: Grade 1 | 3 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Metabolism Parameters | Hypoalbuminemia: Grade 2 | 2 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Metabolism Parameters | Hypoalbuminemia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Abnormal Metabolism Parameters | Hypoalbuminemia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Metabolism Parameters | Hypoalbuminemia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Metabolism Parameters | Hypoglycemia: Grade 1 | 2 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Metabolism Parameters | Hypoalbuminemia: Grade 1 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Metabolism Parameters | Hypoglycemia: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Metabolism Parameters | Hypoalbuminemia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Metabolism Parameters | Hypoglycemia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Metabolism Parameters | Hypoalbuminemia: Grade 2 | 2 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Abnormal Metabolism Parameters | Hypoglycemia: Grade 4 | 0 Participants |
Primary
Number of Participants With Hematological Abnormalities
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/L.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on all treated population. Here, number analyzed = participants with available data for each specified category. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Platelet count decreased: Grade 1 | 2 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Neutrophil count decreased: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Anemia: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Neutrophil count decreased: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Platelet count decreased: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Neutrophil count decreased: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Anemia: Grade 2 | 3 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Lymphocyte count decreased: Grade 1 | 4 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Platelet count decreased: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Lymphocyte count decreased: Grade 2 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Anemia: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Lymphocyte count decreased: Grade 3 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Platelet count decreased: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Lymphocyte count decreased: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Anemia: Grade 1 | 6 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Monocytes (PCSA) > 0.7*10^9/L | 3 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Hematological Abnormalities | Neutrophil count decreased: Grade 1 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Monocytes (PCSA) > 0.7*10^9/L | 3 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Anemia: Grade 1 | 8 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Anemia: Grade 2 | 2 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Anemia: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Anemia: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Platelet count decreased: Grade 1 | 6 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Platelet count decreased: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Platelet count decreased: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Platelet count decreased: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Neutrophil count decreased: Grade 1 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Neutrophil count decreased: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Neutrophil count decreased: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Neutrophil count decreased: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Lymphocyte count decreased: Grade 1 | 2 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Lymphocyte count decreased: Grade 2 | 1 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Lymphocyte count decreased: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Hematological Abnormalities | Lymphocyte count decreased: Grade 4 | 0 Participants |
Primary
Number of Participants With Liver Function Abnormalities
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.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on all treated population. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | ALT increased: Grade 1 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | ALT increased: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | ALT increased: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | ALT increased: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | AST increased: Grade 1 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | AST increased: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | AST increased: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | AST increased: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | ALP increased: Grade 1 | 3 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | ALP increased: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | ALP increased: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | ALP increased: Grade 4 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | TB increased: Grade 1 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | TB increased: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | TB increased: Grade 3 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Liver Function Abnormalities | TB increased: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | TB increased: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | ALT increased: Grade 1 | 1 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | ALP increased: Grade 1 | 2 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | ALT increased: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | TB increased: Grade 1 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | ALT increased: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | ALP increased: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | ALT increased: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | TB increased: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | AST increased: Grade 1 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | ALP increased: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | AST increased: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | TB increased: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | AST increased: Grade 3 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | ALP increased: Grade 4 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Liver Function Abnormalities | AST increased: Grade 4 | 0 Participants |
Primary
Number of Participants With Renal Function Abnormalities
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 equal to) \<= to less than (\<) 90 milliliter/minute/1.73 meter square (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).
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on all treated population. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Renal Function Abnormalities | Creatinine increased: Grade 1 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Renal Function Abnormalities | Creatinine increased: Grade 2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Renal Function Abnormalities | Creatinine increased: Grade 3 | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Renal Function Abnormalities | Creatinine increased: Grade 4 | 11 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Renal Function Abnormalities | eGFR: 60<= - <90 mL/min/1.73m^2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Renal Function Abnormalities | eGFR: 30<= - <60 mL/min/1.73m^2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Renal Function Abnormalities | eGFR: 15<= - <30 mL/min/1.73m^2 | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Renal Function Abnormalities | eGFR: <15 mL/min/1.73m^2 | 12 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Renal Function Abnormalities | eGFR: <15 mL/min/1.73m^2 | 11 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Renal Function Abnormalities | Creatinine increased: Grade 1 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Renal Function Abnormalities | eGFR: 60<= - <90 mL/min/1.73m^2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Renal Function Abnormalities | Creatinine increased: Grade 2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Renal Function Abnormalities | eGFR: 15<= - <30 mL/min/1.73m^2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Renal Function Abnormalities | Creatinine increased: Grade 3 | 3 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Renal Function Abnormalities | eGFR: 30<= - <60 mL/min/1.73m^2 | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Renal Function Abnormalities | Creatinine increased: Grade 4 | 8 Participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)
An AE was defined as any untoward medical occurrence in a participant 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 hospitalization or prolongation of existing hospitalization, 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).
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on all treated population which included all participants who received at least one dose of isatuximab. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 3 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 4 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
Primary
Percentage of Participants With Response
Response was defined as the percentage of participants meeting at least one of the predefined desensitization 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 (\>=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 a SAB assay, for antibodies with Baseline MFI \>=3000.
Time frame: From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks)
Population: Analysis was performed on efficacy evaluable population which included all participants 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 analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Percentage of Participants With Response | 83.3 percentage of participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Percentage of Participants With Response | 81.8 percentage of participants |
Secondary
Duration for Achieving Target cPRA
Duration of achieving target cPRA was defined as the time (in weeks) from laboratory sample collection date of achieving target cPRA (defined as the reduction of cPRA required to achieve at least 100% increase of LCD) the first time up to the laboratory sample collection date when no longer achieving target cPRA calculated using OPTN calculator or the date of death due to any cause, whichever occurs first. The duration of achieving target cPRA was assessed using the Kaplan-Meier method.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on efficacy evaluable population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Duration for Achieving Target cPRA | NA weeks |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Duration for Achieving Target cPRA | 7.29 weeks |
Secondary
Duration of Response (DOR)
Duration of response (DOR) was defined as time (in weeks) from laboratory sample collection date used in determining a participant to be a responder (defined as participants meeting at least one of the predefined desensitization efficacy criteria: reduction in cPRA resulting in at least 100% increase of likelihood of finding a compatible donor; reduction in antibody titer \[\>=75% reduction from Baseline\] to achieve target cPRA; elimination of \>=1 anti-HLA antibody i.e. MFI reduced to \<2000 as measured by a SAB assay, for antibodies with Baseline MFI \>=3000) up to the laboratory sample collection date when participant was confirmed as no longer meeting any response criterion (i.e., non-responder) or the date of death due to any cause, whichever occurs first. DOR was analyzed using Kaplan-Meier method.
Time frame: From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks)
Population: Analysis was performed on responder population which included all participants 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. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Duration of Response (DOR) | NA weeks |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Duration of Response (DOR) | NA weeks |
Secondary
Number of Kidney Transplant Offers
Number of kidney transplants offers received for each participant was reported in the outcome measure. Data on transplant offers were collected and followed up until study cut-off date.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on efficacy-evaluable population. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Kidney Transplant Offers | 3 transplant offers |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Kidney Transplant Offers | 3 transplant offers |
Secondary
Number of Participants Achieving Target cPRA
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 participants who achieved target cPRA was assessed using the Organ Procurement and Transplantation Network (OPTN) calculator during the specified timepoint were reported in this outcome measure. Participants who retained their target cPRA values were censored at the date of the last available laboratory assessment achieving their target cPRA.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on efficacy evaluable population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants Achieving Target cPRA | 4 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants Achieving Target cPRA | 2 Participants |
Secondary
Number of Participants With Anti-drug Antibodies (ADA) Against Isatuximab
ADA responses were categorized 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 participants without pre-existing ADA.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on anti-drug antibodies (ADA) population which included all participants who receive at least 1 dose of isatuximab, with at least 1 available ADA result post-treatment. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Anti-drug Antibodies (ADA) Against Isatuximab | Treatment-induced ADA | 0 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Anti-drug Antibodies (ADA) Against Isatuximab | Treatment boosted ADA | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Anti-drug Antibodies (ADA) Against Isatuximab | Treatment-induced ADA | 0 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Anti-drug Antibodies (ADA) Against Isatuximab | Treatment boosted ADA | 0 Participants |
Secondary
Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction
Number of participants with anti-HLA-antibody (Baseline MFI \>=3000) reduced to \<2000 as measured using a SAB assay per central laboratory assessment was reported in this outcome measure. Participants were categorized 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 summarized.
Time frame: From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks)
Population: Analysis was performed on efficacy evaluable population. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | 1-5 antibodies | 4 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | >10-15 antibodies | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | >5-10 antibodies | 4 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | >15 antibodies | 1 Participants |
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | None | 2 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | >15 antibodies | 1 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | None | 2 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | 1-5 antibodies | 4 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | >5-10 antibodies | 4 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | >10-15 antibodies | 0 Participants |
Secondary
Number of Participants With Graft Survival at 6 Months Post-Transplant
Number of participants with graft survival status as functioning at 6-months post-transplant was reported in this outcome measure.
Time frame: At 6 Months post-transplant
Population: Analysis was performed on efficacy evaluable population. Here, overall number of participants analyzed signifies participants with evaluable data for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Number of Participants With Graft Survival at 6 Months Post-Transplant | 1 Participants |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Number of Participants With Graft Survival at 6 Months Post-Transplant | 0 Participants |
Secondary
Percentage of Participants Who Experienced Any Antibody Mediated Rejection (AMR)
Antibody mediated rejection was defined as the graft rejection due to generation of antibodies against the graft. The number of participants with AMR field checked as 'yes' based on the graft rejection biopsy in the electronic case report form was considered.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Data for this outcome measure was not collected and analyzed as no participants experienced a kidney transplant graft loss due to an AMR episode, as of study terminated date.
Secondary
Pharmacokinetics (PK) Parameters: Concentration Observed at the End of First Intravenous Infusion (Ceoi) of Isatuximab
Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.
Time frame: At End of infusion on Cycle 1 Day 1
Population: Analysis was performed on pharmacokinetic (PK) population which included all participants who receive at least 1 dose of isatuximab, with at least 1 available concentration result post treatment. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Pharmacokinetics (PK) Parameters: Concentration Observed at the End of First Intravenous Infusion (Ceoi) of Isatuximab | 290 micrograms per milliliter (mcg/mL) | Standard Deviation 128 |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Pharmacokinetics (PK) Parameters: Concentration Observed at the End of First Intravenous Infusion (Ceoi) of Isatuximab | 270 micrograms per milliliter (mcg/mL) | Standard Deviation 101 |
Secondary
PK Parameters: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 Hours Over the Dosing Interval (AUC0-168 Hours) After First Infusion of Isatuximab
AUC0-168 hours was defined as the area under the plasma concentration versus time curve from time 0 to 168 hours post dose calculated using trapezoidal method after first infusion of isatuximab.
Time frame: 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
Population: Analysis was performed on PK population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | PK Parameters: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 Hours Over the Dosing Interval (AUC0-168 Hours) After First Infusion of Isatuximab | 29400 micrograms*hours/milliliter (mcg*h/mL) | Standard Deviation 7400 |
| Cohort B: Participants With cPRA 80.00% to 99.89% | PK Parameters: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 Hours Over the Dosing Interval (AUC0-168 Hours) After First Infusion of Isatuximab | 20000 micrograms*hours/milliliter (mcg*h/mL) | Standard Deviation 5240 |
Secondary
PK Parameters: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab
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.
Time frame: 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
Population: Analysis was performed on PK population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | PK Parameters: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab | 104 mcg/mL | Standard Deviation 41.7 |
| Cohort B: Participants With cPRA 80.00% to 99.89% | PK Parameters: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab | 76.3 mcg/mL | Standard Deviation 21.3 |
Secondary
PK Parameters: Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab
Cmax was defined as the maximum concentration observed after the first administration calculated using the noncompartmental analysis after the intravenous infusion of isatuximab.
Time frame: 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
Population: Analysis was performed on PK population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | PK Parameters: Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab | 295 mcg/mL | Standard Deviation 128 |
| Cohort B: Participants With cPRA 80.00% to 99.89% | PK Parameters: Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab | 285 mcg/mL | Standard Deviation 94 |
Secondary
PK Parameters: Time of Clast (Tlast) After First Infusion of Isatuximab
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.
Time frame: 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
Population: Analysis was performed on PK population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | PK Parameters: Time of Clast (Tlast) After First Infusion of Isatuximab | 166.00 hours |
| Cohort B: Participants With cPRA 80.00% to 99.89% | PK Parameters: Time of Clast (Tlast) After First Infusion of Isatuximab | 167.00 hours |
Secondary
PK Parameters: Time Taken to Reach Cmax (Tmax) After the First Infusion of Isatuximab
Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion of isatuximab.
Time frame: 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
Population: Analysis was performed on PK population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | PK Parameters: Time Taken to Reach Cmax (Tmax) After the First Infusion of Isatuximab | 3.67 hours |
| Cohort B: Participants With cPRA 80.00% to 99.89% | PK Parameters: Time Taken to Reach Cmax (Tmax) After the First Infusion of Isatuximab | 3.40 hours |
Secondary
PK Parameters: Trough Plasma Concentrations (Ctrough) of Isatuximab
Ctrough was the plasma concentration of isatuximab observed just before (pre-dose) treatment administration.
Time frame: Cycle 2 Day 1
Population: Analysis was performed on PK population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | PK Parameters: Trough Plasma Concentrations (Ctrough) of Isatuximab | 308 mcg/mL | Standard Deviation 79.4 |
| Cohort B: Participants With cPRA 80.00% to 99.89% | PK Parameters: Trough Plasma Concentrations (Ctrough) of Isatuximab | 246 mcg/mL | Standard Deviation 60.6 |
Secondary
Time to First Antibody Mediated Rejection (AMR) Episode
Time to first AMR was defined as time 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 participants without any AMR were censored at the participant's last assessment or contact date collected in the study or at the analysis cut-off date, whichever was earlier.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Data for this outcome measure was not collected and analyzed as no participants experienced a kidney transplant graft loss due to an AMR episode as of study terminated date.
Secondary
Time to First Transplant Offer
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.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on efficacy-evaluable population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Time to First Transplant Offer | 373 days |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Time to First Transplant Offer | 156 days |
Secondary
Time to Transplant
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.
Time frame: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Population: Analysis was performed on efficacy evaluable population. Here, overall number of participants analyzed signifies participants with available data for this outcome measure and included only participants who accepted transplant offer. Data was planned to be collected and analyzed for the combined Phase 1 and 2 population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Participants With cPRA >=99.90% | Time to Transplant | 445 days |
| Cohort B: Participants With cPRA 80.00% to 99.89% | Time to Transplant | 259.5 days |