Clinical trial NCT04294459
Conditions: Immune System Disorder
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2020-06-18; Completion date: 2022-05-02
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

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).

Arms: arm 1: Participants with calculated panel reactive antibodies (cPRA) \>=99.90% (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 participant's decision to stop the treatment (maximum treatment duration: 13 weeks). arm 2: 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).
Interventions: intervention 1: Isatuximab SAR650984 intervention 2: Acetaminophen (paracetamol) or equivalent intervention 3: Ranitidine or equivalent intervention 4: Diphenhydramine or equivalent intervention 5: Methylprednisolone or equivalent intervention 6: Montelukast or equivalent
Intervention descriptions: intervention 1: Pharmaceutical form: Solution for infusion

Route of administration: Intravenous intervention 2: Pharmaceutical form: Tablets

Route of administration: Oral intervention 3: Pharmaceutical form: Solution

Route of administration: Intravenous intervention 4: Pharmaceutical form: Solution

Route of administration: Intravenous intervention 5: Pharmaceutical form: Solution

Route of administration: Intravenous intervention 6: Pharmaceutical form: Tablets

Route of administration: Oral

Protocol documents:
Prot_000.pdf: 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 02 
All 
01 Feb 2022, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 
All 
23 July 2020, version 1 (electronic 1.0) 
Original Protocol 
 
07 Nov 2019, version 1 (electronic 2.0) 
Amended protocol 02 (01 FEB 2022) 
This amended protocol 02 (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
To clarify throughout the protocol that the target cPRA is defined as achieving a 100% increase in 
the likelihood of finding a compatible donor. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3.0 Objectives and 
Endpoints 
10.9 Desensitization 
response criteria 
Criteria for cPRA reduction is corrected from 
“at least 50% increase of likelihood” to “at 
least 100% increase of likelihood”. 
To correct inconsistencies and to align with Section 
10.9, Table 13, which defines target cPRA as the 
reduction of cPRA required to achieve at least 100% 
increase in the likelihood of a compatible donor 
(LCD) 
5.2 Exclusion criteria 
E06:  Editorial changes made to clarify that 
history of active or latent tuberculosis is 
relevant if within 24 weeks prior to IMP 
initiation, and “(peritoneal, etc)” are specific to 
the “deep tissue/space infection”. 
Changes made to improve clarity on E06. 
10.2 Clinical 
laboratory tests 
Table 11, footnote “a” added to clarify that 
serology and viral load tests listed serve as a 
guidance, and study sites should determine 
which serology and viral load tests are 
required to confirm participant’s eligibility and 
to enable appropriate viral reactivation 
monitoring for HBV, HCV, HIV, EBV, and CMV 
as per protocol 
Clarification on need for individual serology and viral 
load tests. 
All document 
Minor editorial and format changes. 
Accuracy. 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 02 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 3 
LIST OF TABLES ........................................................................................................................................... 7 
LIST OF FIGURES .......................................................................................................................................... 8 
1 
PROTOCOL SUMMARY ................................................................................................................. 9 
1.1 
SYNOPSIS ....................................................................................................................................... 9 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 17 
1.3.1 
Pharmacokinetic/anti-drug antibodies (ADAs) flowchart ................................................................ 22 
1.3.1.1 
Treatment period: Cycle 1 (rich sampling) ..................................................................................... 22 
1.3.1.2 
Treatment period: Cycle 2 and beyond (sparse sampling) ............................................................ 23 
2 
INTRODUCTION ............................................................................................................................ 24 
2.1 
STUDY RATIONALE...................................................................................................................... 24 
2.1.1 
HLA sensitized patients: Unmet medical need .............................................................................. 24 
2.1.2 
Current desensitization therapies .................................................................................................. 26 
2.1.3 
Targeting CD38 for plasma cell depletion as a desensitization strategy ....................................... 27 
2.2 
BACKGROUND ............................................................................................................................. 29 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 30 
2.3.1 
Benefits .......................................................................................................................................... 30 
2.3.2 
Potential and identified risks .......................................................................................................... 30 
2.3.2.1 
Isatuximab ...................................................................................................................................... 30 
2.3.2.2 
Potential risk of desensitization therapies in patients awaiting transplantation ............................. 31 
2.3.3 
Preventive measures to minimize the risk of isatuximab ............................................................... 32 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 34 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 35 
4 
STUDY DESIGN ............................................................................................................................ 37 
4.1 
OVERALL DESIGN ........................................................................................................................ 37 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 38 
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4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 39 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 40 
5 
STUDY POPULATION .................................................................................................................. 41 
5.1 
INCLUSION CRITERIA .................................................................................................................. 41 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 42 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 44 
5.4 
SCREEN FAILURES...................................................................................................................... 44 
6 
STUDY INTERVENTION ............................................................................................................... 46 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 46 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 48 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 49 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 49 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 49 
6.5.1 
Rescue Medicine ............................................................................................................................ 50 
6.6 
DOSE MODIFICATION .................................................................................................................. 51 
6.6.1 
General rules .................................................................................................................................. 51 
6.6.2 
Dose delay and dose omission ...................................................................................................... 51 
6.6.3 
General guidelines for the management of adverse events .......................................................... 52 
6.6.4 
General guidelines for the management of infusion reactions ...................................................... 53 
6.6.5 
Retreatment of participants ............................................................................................................ 55 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 55 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 56 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 56 
7.1.1 
Definitive discontinuation ............................................................................................................... 56 
7.1.2 
Temporary discontinuation ............................................................................................................. 57 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 57 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 58 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 59 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 59 
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8.1.1 
Efficacy assessment - Central laboratory assessments ................................................................ 59 
8.1.2 
Efficacy assessment - Local laboratory assessment ..................................................................... 60 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 60 
8.2.1 
Physical examinations ................................................................................................................... 60 
8.2.2 
Vital signs ....................................................................................................................................... 60 
8.2.3 
Electrocardiogram .......................................................................................................................... 60 
8.2.4 
Echocardiography .......................................................................................................................... 60 
8.2.5 
Clinical safety laboratory assessments .......................................................................................... 61 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 61 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 62 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 63 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 63 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 63 
8.3.5 
Pregnancy ...................................................................................................................................... 63 
8.3.6 
Cardiovascular and death events .................................................................................................. 64 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 64 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 64 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 64 
8.5 
PHARMACOKINETICS .................................................................................................................. 65 
8.5.1 
Non-compartmental analysis ......................................................................................................... 65 
8.5.2 
Population approach ...................................................................................................................... 65 
8.6 
PHARMACODYNAMICS ............................................................................................................... 66 
8.7 
GENETICS ..................................................................................................................................... 66 
8.8 
BIOMARKERS ............................................................................................................................... 66 
8.8.1 
Immune cell profiling ...................................................................................................................... 66 
8.8.2 
Functional B-cell assay .................................................................................................................. 66 
8.8.3 
Determination of serum total immunoglobulin levels ..................................................................... 66 
8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 67 
8.10 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 67 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 68 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 68 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 68 
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9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 69 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 69 
9.4.1 
Efficacy analyses ........................................................................................................................... 69 
9.4.2 
Safety analyses .............................................................................................................................. 70 
9.4.3 
Analyses of immunogenicity .......................................................................................................... 71 
9.4.4 
Pharmacokinetic analyses ............................................................................................................. 71 
9.4.5 
Other analyses ............................................................................................................................... 72 
9.5 
INTERIM ANALYSES  ................................................................................................................... 72 
9.5.1 
Data Monitoring Committee (DMC) ................................................................................................ 72 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 73 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 73 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 73 
10.1.2 
Financial disclosure........................................................................................................................ 73 
10.1.3 
Informed consent process .............................................................................................................. 74 
10.1.4 
Data protection ............................................................................................................................... 74 
10.1.5 
Committees structure ..................................................................................................................... 75 
10.1.6 
Dissemination of clinical study data ............................................................................................... 75 
10.1.7 
Data quality assurance .................................................................................................................. 76 
10.1.8 
Source documents ......................................................................................................................... 76 
10.1.9 
Study and site closure .................................................................................................................... 77 
10.1.10 Publication policy ........................................................................................................................... 77 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 78 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 79 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 83 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 86 
10.6 
APPENDIX 6: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 87 
10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 87 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 87 
10.9 
APPENDIX 9: DESENSITIZATION RESPONSE CRITERIA......................................................... 87 
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10.10 
APPENDIX 10: CLUSTER OF DIFFERENTIATION 38 BLOOD TEST INTERFERENCE 
GUIDELINE .................................................................................................................................... 89 
10.11 
APPENDIX 11: ABBREVIATIONS ................................................................................................. 93 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY ................................................................ 94 
10.12.1 Amended protocol 01 (23 July 2020) ............................................................................................. 94 
10.13 
APPENDIX 13: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 97 
11 
REFERENCES ............................................................................................................................... 98 
 
LIST OF TABLES  
Table 1 - Dose level and schedule in Phase 1 .............................................................................................. 12 
Table 2 - Objectives and endpoints ............................................................................................................... 34 
Table 3 - Overview of study interventions administered ............................................................................... 46 
Table 4 - Dose level and schedule in Phase 1 .............................................................................................. 47 
Table 5 - General management guidelines for adverse events .................................................................... 52 
Table 6 - Management guidelines for infusion reaction ................................................................................ 54 
Table 7 - List of pharmacokinetic parameters and definitions ....................................................................... 65 
Table 8 - Populations for analyses ................................................................................................................ 69 
Table 9 - Efficacy analyses ........................................................................................................................... 70 
Table 10 - Safety analyses ............................................................................................................................ 71 
Table 11 - Protocol-required safety laboratory assessments ........................................................................ 78 
Table 12 - Highly effective contraceptive methods ....................................................................................... 85 
Table 13 - Examples of target cPRA reduction ............................................................................................. 87 
Table 14 - Examples of antibody titer ............................................................................................................ 88 
Table 15 - 75% reduction in antibody titer from baseline .............................................................................. 88 
Table 16 - Example of ≥75% reduction in antibody titer from baseline to achieve target cPRA ................... 88 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 15 
Figure 2 - Duration of study period (per participant) ..................................................................................... 16 
Figure 3 - Relationship between cPRA and likelihood of finding a compatible donor ................................... 25 
Figure 4 - Desensitization of heart transplant candidate with daratumumab ................................................ 28 
Figure 5 - Schematic representation of the different mechanisms of action possibly triggered by isatuximab 
according to the levels of CD38 expression in normal and tumor cells ........................................................ 29 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: 
A Phase 1b/2 study to evaluate the safety, pharmacokinetics, and 
preliminary efficacy of isatuximab (SAR650984) in patients awaiting 
kidney transplantation 
Short title: 
 
Safety, pharmacokinetics, and preliminary efficacy of isatuximab in 
patients awaiting kidney transplantation 
Rationale: 
About 30% of the kidney transplant waitlist patients are sensitized to human leukocyte antigen 
(HLA). The HLA sensitized patients are at risk for early graft loss from antibody mediated 
rejection (AMR) due to the presence of alloantibodies or donor-specific antibodies (DSAs), 
leading to prolonged wait time because of the lower likelihood of finding a compatible donor 
compared to those who are not sensitized. Current desensitization therapies (not registered by 
competent health authorities) aim to overcome the humoral incompatibility by removing or 
reducing the strength of alloantibodies, but do not target the terminally differentiated 
antibody-secreting plasma cells which express high level of cluster of differentiation (CD) 38. 
Isatuximab, an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) directed against CD38, 
has shown clinical response in relapsed/refractory multiple myeloma patients as a single agent and 
in combination with immunomodulatory agents, and is being developed in other advanced 
malignancies. In general, isatuximab is well-tolerated clinically with a manageable safety profile. 
This study is designed to explore whether isatuximab may have activity in desensitization of 
patients awaiting kidney transplantation. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Phase 1: To characterize the safety and tolerability 
of isatuximab in kidney transplant candidates.  
• 
Adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities.  
• 
Phase 2: To evaluate the efficacy of isatuximab in 
desensitization of patients awaiting kidney 
transplantation.  
• 
Response rate (RR) defined as the proportion of 
participants meeting at least one of the predefined 
desensitization efficacy criteria, from baseline up to 
26 weeks after treatment period, measured by 
single antigen bead (SAB) assay per central 
laboratory assessment as follows:  
- 
Reduction in calculated panel reactive 
antibodies (cPRA) resulting in at least 100% 
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Objectives 
Endpoints 
increase of likelihood of finding a compatible 
donor (for target cPRA, see Section 10.9).  
- 
Reduction in antibody titer (≥75% reduction 
from baseline) to achieve target cPRA (see 
Section 10.9).  
- 
Elimination of ≥1 anti-HLA-antibody (ie, mean 
fluorescence intensity [MFI] reduced to <2000) 
as measured by a SAB assay, for antibodies 
with baseline MFI ≥3000.  
Secondary 
• 
Phase 2: To characterize the safety profile of 
isatuximab in kidney transplant candidates.  
• 
AEs/SAEs, and laboratory abnormalities.  
• 
To characterize the pharmacokinetic (PK) profile of 
isatuximab in kidney transplant candidates.  
• 
PK parameters of isatuximab (see Table 7)  
• 
To evaluate the immunogenicity of isatuximab.  
• 
Incidence of anti-drug antibodies (ADA) against 
isatuximab.  
• 
To assess the overall efficacy of isatuximab in 
desensitization of patients awaiting kidney 
transplantation.  
• 
Duration of response (DoR) per central laboratory 
assessment.  
• 
Proportions of participants and duration achieving 
target cPRA per local laboratory assessment.  
• 
Number of anti-HLA-antibody with baseline MFI 
≥3000 reduced to <2000 as measured in a SAB 
assay per central laboratory assessment.  
• 
Transplantability including time to first transplant 
offer, time to transplant, and number of transplant 
offers, if applicable.  
• 
Time to first AMR episode and rate of AMR, if 
applicable.  
• 
Graft survival at 6 months post-transplant, if 
applicable.  
Overall design: 
This is a Phase 1b/2 open-label, non-randomized, multi-center study to evaluate the safety, PK, 
and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. The study will 
be conducted in 2 phases (see Figure 1 for study design schema):  
Phase 1 (safety run-in) 
A minimum of 6 safety evaluable participants with cPRA ≥80% will be enrolled at the dose level 
to be tested without interruption in Phase 1. In order to be considered as safety evaluable, 
participants must have received at least 90% of the planned cumulative doses of the first cycle 
(unless they discontinue investigational medical product [IMP] due to pre-defined unacceptable 
toxicity). 
Pre-defined unacceptable toxicity is defined as any verified Grade 4 AEs or laboratory 
abnormalities (except infusion reactions [IR]) occurring during the first cycle of treatment, unless 
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solely due to the underlying disease or due to a cause obviously unrelated to the IMP, if confirmed 
by the Sponsor and recruiting Investigators. 
The totality of the safety findings, including all AEs occurring during treatment, unless solely due 
to the underlying disease or due to a cause obviously unrelated to IMP, will be taken into 
consideration for confirming the Phase 2 dose. Phase 2 of the study will be initiated after 6 safety 
evaluable participants have completed first cycle observation period where the dose level is 
determined to be sufficiently well-tolerated. 
If the starting dose (SD) is determined not to be sufficiently well-tolerated, 6 additional 
(minimum) safety evaluable participants will be enrolled at dose level minus 1 (DL-1) (see 
Table 1 for details on the dose levels and schedule for Phase 1). 
Overall safety monitoring will also be performed throughout the conduct of the study. 
Upon completion of the first cycle safety observation period for each participant enrolled in 
Phase 1, participants will continue study procedures until study completion (see “Duration of 
study period [per participant]” in Figure 2). 
Phase 2 
In Phase 2, two cohorts will be included: 
Cohort A: Participants with cPRA ≥99.90%; active candidates on the kidney waitlist. Up to 
6 participants with living donor can be enrolled into Cohort A. 
Cohort B: Participants with cPRA 80.00% to 99.89%; active candidates on the kidney waitlist 
with no living donor cleared for donation.  
Disclosure Statement: This is a Single Group, Treatment study with 1 arm (2 cohorts) that is not 
masked. All participants will receive isatuximab monotherapy. 
Number of participants: 
In Phase 1, approximately 6 to 12 safety evaluable participants are expected to be enrolled (see 
Section 9.3 for definition of Safety Evaluable Population). 
Approximately 24 to 36 participants (Phase 1 and Phase 2) are expected to be enrolled if the SD is 
retained as the Phase 2 dose or approximately 30 to 42 participants are expected to be enrolled if 
DL-1 is the Phase 2 dose. 
A maximum of 6 replacements per cohort is allowed for participants who: 
• enroll in Phase 1 and receive <90% of the planned cumulative doses within the first cycle 
(unless they discontinue IMP due to pre-defined unacceptable toxicity), or 
• receive <75% of planned cumulative doses within 3 cycles, or 
• have consecutive dose interruption of >28 days, or 
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• do not complete site visit follow-up period (FUP), after agreement with Medical Monitor. 
Intervention groups and duration: 
All participants will receive isatuximab monotherapy and the planned treatment duration is 
3 cycles (each cycle is 28 days). 
Starting dose and de-escalation design: 
Starting dose is 10 mg/kg once weekly (QW) for 4 weeks followed by once every 2 weeks 
(Q2W). If the SD is determined not to be sufficiently well-tolerated, 6 additional (minimum) 
safety evaluable participants will be enrolled at DL-1. Dose levels and schedule for Phase 1 are 
detailed in Table 1.  
Overall safety monitoring will also be performed throughout the conduct of the study. 
Table 1 - Dose level and schedule in Phase 1  
Dose Level 
Isatuximab 
1 cycle = 4 weeks (28 days) 
SD 
10 mg/kg 
QW × 4 for Cycle 1 → Q2W for cycles 2 and 3 
DL-1 
5 mg/kg 
QW × 4 for Cycle 1 → Q2W for Cycles 2 and 3 
Abbreviations: DL-1 = dose level minus 1, QW = once weekly, Q2W = once every 2 weeks, SD = starting dose 
Duration of study period (per participant): 
The study will have 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 FUP which include telephone contacts every 
90 days and information collection until study cut-off, death, or lost to follow-up. The study 
cut-off is planned at 26 weeks after the last participant completes the treatment period, or when 
the last ongoing participant is lost to follow-up, whichever is earlier. The Sponsor may choose to 
extend the study cut-off date depending on the enrollment rate observed to facilitate adequate 
follow-up data collection. Participants who wish to proceed to transplantation when a compatible 
donor becomes available while on study must discontinue IMP immediately, and complete an 
early discontinuation (E/D) visit prior to transplantation if clinically feasible, and proceed to 
extended FUP. The study duration that involves site visit per participant (ie, screening, treatment, 
site visit FUP) will be approximately 42 weeks. The study duration including extended FUP per 
participant will be approximately 78 weeks (depending when the participant is enrolled). 
Treatment period: The cycle duration is 28 days and a complete treatment period is comprised 
of 3 cycles of IMP treatment. Participants will continue treatment until receiving 3 cycles of IMP, 
unacceptable AE per Investigator’s judgment, or participants’ decision to stop the treatment.  
Site visit FUP: Participants completing the treatment period and who are able to remain on study 
will return to the study sites for study procedures. 
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Extended FUP: The following participants will be followed-up every 90 days by phone calls 
until study cut-off date, death, or lost to follow-up, whichever comes first: 
• Participants who completed or discontinued from site visit FUP 
• Participants who proceed to transplantation during treatment period or site visit FUP. 
During extended FUP, specified information per protocol will also be collected by the study site 
(see Schedule of Activities [SoA], Section 1.3). 
Study interventions 
Investigational medicinal product 
Isatuximab: 
• Formulation: Sterile 20 mg/mL concentrate for solution for infusion in single use vials 
containing 20 mg/mL (500 mg/25 mL) isatuximab in 20 mM histidine, 10% (w/v) sucrose, 
0.02% (w/v) polysorbate 80, pH 6.0. 
• Route of administration: Intravenous (IV) infusion. 
• Dose regimen: Refer to the section above (Table 1) for Phase 1 dose regimen. Dose for 
Phase 2 will be determined based on the safety data from Phase 1. The Sponsor may 
decide to test an isatuximab dose of 20 mg/kg in case of inadequate efficacy and/or PK 
results. 
Noninvestigational medicinal product 
Premedication: 
All participants will receive the following premedications to prevent or reduce the incidence or 
severity of IRs, approximately 15 to 30 minutes prior to isatuximab infusion (no longer than 
60 minutes). Premedication is mandatory for the first 4 isatuximab infusions (see criteria below 
for subsequent infusions). The use of ranitidine or equivalent as part of IR premedication is left to 
the medical judgement of the Investigator. The standard premedication regimen will include: 
• Acetaminophen 650 to 1000 mg oral route (PO) (or equivalent) 
• Diphenhydramine 25 to 50 mg IV (or equivalent) 
• Methylprednisolone 100 mg IV (or equivalent) 
• Montelukast 10 mg PO (or equivalent) 
Noninvestigational medicinal products (NIMP) will be locally sourced and the formulations may 
vary. 
Premedication for prevention of IR has to be given for the first four isatuximab infusions, and the 
first infusion using fixed volume infusion following approval of Amended Protocol 01 (applicable 
for participants enrolled under original Protocol). 
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For a participant who has no IR upon 4 consecutive infusions, premedication for the subsequent 
infusions is optional at the Investigator’s discretion. 
Statistical considerations: 
The participants treated at the Phase 2 dose during Phase 1 will be included in the efficacy 
analysis together with the participants in Phase 2.  
• Sample size calculations 
With a minimum sample size of 12 participants per cohort and 1-sided alpha of 0.025, the analysis 
will have at least 80% power to demonstrate that the RR is significantly better than 
 assuming 
the true RR is 
, based on exact test. A null hypothesis of 
 is selected representing placebo 
control as there is currently no approved or standard therapy for desensitization, and there is no 
expected decrease in anti-HLA antibody levels or cPRA in patients who do not undergo 
desensitization therapy. 
• Primary analysis: 
- 
AEs and laboratory abnormalities in Phase 1 will be listed. 
- 
Response rate by cohort will be summarized using descriptive statistics. A 95% 
2-sided confidence interval will be computed using the Clopper-Pearson method. 
• Analysis of secondary endpoints: 
- 
All secondary (if applicable/possible) endpoints will be summarized descriptively and 
presented by cohort. Categorical variables (eg, rates and proportions) will be tabulated 
via frequency distributions. Continuous variables (eg, change from baseline) will be 
summarized by providing the number of observations (n), mean, median, standard 
deviation, minimum, and maximum. Duration of response (DoR) and other time to 
event variables will be analyzed using Kaplan-Meier method. 
- 
No hypothesis/significance testing will be performed. 
Data Monitoring Committee: No
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1.2 
SCHEMA  
 
Figure 1 - Graphical study design  
 
Abbreviations: cPRA = calculated panel reactive antibodies, DL-1 = dose level minus 1 
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Figure 2 - Duration of study period (per participant)  
 
 
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Procedure 
Screening  
(up to 28 days 
before Day 1) 
Treatment Period (12 weeks) 
Site Visit FUP 
(26 weeks)a 
 
Extended 
FUPc 
Notes 
All on-treatment 
procedures should be 
performed prior to IMP 
administration unless 
indicated otherwise 
Cycle 1 
(28 Days) 
Cycle 2 
(28 days) 
Cycle 3 
(28 days) 
E/Db 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
D1 of every 4 
weeks 
Time Window (days) 
 
±1 
±1 
±1 
±1 
±2 
±2 
±2 
±2 
±7 
±7 
±7 
AE review 
X 
===============================→ 
X (beyond 30 days after last dose of IMP: 
only ongoing related AEs, new related 
AEs until resolution/ stabilization) 
Stabilization is defined 
as an AE ongoing 
without any change 
for at least 3 months 
SAE review 
X 
===============================→ 
X (beyond 30 days after last dose of IMP: 
only ongoing SAEs, new related SAEs 
until resolution/ stabilization) 
Prior/concomitant/post 
medicationm 
X 
===============================→ 
X 
X 
X 
See Section 6.5 
Participant/Transplant (if 
applicable) Status 
Xn 
Xn 
Xo 
Xo 
 
Abbreviations: ADA = anti-drug antibody, AE = adverse event, CMV = cytomegalovirus, cPRA = calculated panel reactive antibodies, D = Day, EBV = Epstein-Barr virus, ECG = electrocardiogram, E/D = early 
discontinuation, FUP = follow-up period, HBV = hepatitis B virus, hCG = human chorionic gonadotropin, HCV = hepatitis C virus, HIV = human immunodeficiency virus, HLA = human leukocyte antigen, ID = 
identification number, IMP = investigational medicinal product, MFI = mean fluorescence intensity, PK = pharmacokinetics, SAB = single antigen bead, SoA = Schedule of Activities, SAE = serious adverse event, 
WOCBP = women of childbearing potential. 
a Week 1 visit for site visit FUP will occur 15 days after Cycle 3 Day 15 (±7 days), or 15 (±7) days after the last dose of IMP if participant discontinued IMP. Depending on local arrangements and preference of the 
Investigator, site visit FUP procedures may be performed at the study site or at the participant’s home by a health care professional. Study procedures not performed at the study site must also be documented in 
the source documents and recorded in the appropriate pages of the eCRF by the study site. 
b For E/D, study procedures will be performed 30±7 days after last IMP administration if discontinued study during treatment period, or within 30 days if discontinued during site visit FUP. Participants who 
discontinued IMP but remain on the study and proceed to complete site visit FUP do not need to complete E/D. Participants who wish to proceed to transplantation when a compatible donor becomes available 
while on study must discontinue IMP immediately, and complete an E/D visit prior to transplantation if clinically feasible, and proceed to extended FUP. 
c In addition to the phone calls every 90 days, study site will collect information per the SoA throughout the extended FUP. 
d Vital sign assessment includes blood pressure, pulse rate, temperature, and respiratory rate. During the treatment period, vital signs should be obtained prior to start of each IMP infusion, 1 hour after start of 
infusion, at the end of infusion, and during the infusion if clinically indicated. 
e Pregnancy test can be performed at home for participants during the FUP or if date of test does not match with FUP visit and the site must record this in the source document. Test should be performed at the end 
of isatuximab treatment (ie, Week 1 of site visit FUP or E/D visit [±7 days]), and 5 months (±7 days) after the last dose of IMP. 
f 
Post-treatment tests are only applicable for HBV, CMV, and EBV, and only has to be performed at Site Visit FUP Week 9 if baseline result is positive or as clinically indicated. In case HBV vaccination will be 
started before first study treatment administration, anti-HBs should be monitored at approximately 1, 2, and 3 months after end of vaccination (±7 days, or at the next blood sampling). For participants with positive 
anti-HBc and negative HBsAg and undetectable HBV deoxyribonucleic acid (DNA) at study entry (past resolved infection, resolving acute infection, or receiving antiviral treatment with controlled infection), close 
monitoring of viral reactivation (greater than 1log10 IU/mL increase in HBV DNA or reappearance of HBsAg or detection of HBV DNA in patients with resolved infection) throughout and following the end of study 
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treatment should be proposed (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and HBV DNA at Site Visit FUP Week 9 and Week 25, or until initiation of further desensitization 
therapy/transplant surgery). In case of viral reactivation during study treatment (greater than 1log10 IU/mL increase in HBV DNA or reappearance of HBsAg or detection of HBV DNA in participants with resolved 
infection), close monitoring of ALT and AST approximately every month (may coincide with the next scheduled blood sampling ±7 days), up to study treatment discontinuation. HBV DNA to be done as per 
Investigator's and/or specialist advice. 
g Only if screening result is positive and not tested during site visit FUP. 
h Assessment not required to be repeated prior to Cycle 1 Day 1, if screening assessments were performed within 7 days prior to the first IMP infusion and met the entry criteria. Window for assessment is within 
1 working day prior to IMP infusion. 
i 
Blood type (if not already done) and phenotype (according to the site protocol). Recommended phenotype includes Rh system (C/c and E/e), Kell system (K/k); Duffyn system (Fya/Fyb); Kidd system (Jka/Jkb); 
MNS system (M/N, S/s), and indirect antiglobulin test (IAT; indirect Coombs test). Blood type card will be kept by the participant with the study card. Blood type and blood product transfusions are to be recorded in 
the electronic case report form. The blood bank needs to be informed that the participant is receiving a treatment with an anti-CD38 and a potential interference with the Coombs test is possible (see Section 10.10). 
IAT (indirect Coombs test) to be repeated at C2D1 (if not performed at this visit, it can be done at the next blood sampling); if post-treatment (ie, C2D1) IAT (indirect Coombs test) is positive, subsequent tests to be 
performed at site Visit FUP Weeks 1, 13, and 25, and E/D if discontinued during Site Visit FUP.  
j 
Blood sample must be collected prior to IMP administration. Window for assessment is within 1 working day prior to IMP infusion. 
k Blood draw time points that do not coincide with site visits may be collected at the local facility or at the participant’s home by a health care professional (depending upon local arrangements and preference of the 
Investigator), provided that samples are collected with designated tubes and per laboratory manual. Blood drawn should be performed prior to dialysis (if dialysis is performed on the same day). 
l 
Only if site visit FUP sample (ie, Week 17) not collected. 
m Include any desensitization therapy. For participants who proceed to transplantation after E/D, or completion of treatment and/or site visit FUP, also collect immunosuppression regimen. 
n Collect the following information: Start and end date(s) when listed as active candidate on the waitlist for kidney transplant, waitlist ID and transplant center code (if applicable, and if local regulation allows and in 
line with the most recent participant signed informed consent form), virtual or donor-specific cross matching results, and dates of all transplant offers (if any, indicate whether offers were accepted and reasons of 
rejecting offers). 
o Collect the following information: Start and end date(s) when listed as active candidate on the waitlist for kidney transplant (if status has changed), virtual or donor-specific cross matching results, dates of all 
transplant offers (if any, indicate whether offers were accepted and reasons of rejecting offers), solid organ transplant surgery, participant survival status, graft survival status, dates of biopsy proven acute rejection 
episodes (antibody mediated and/or T-cell mediated), and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation. 
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2 
INTRODUCTION  
In the United States (US), close to 800 000 patients have end stage renal disease (ESRD), and the 
number of cases continues to rise by about 20 000 cases per year (1). Approximately 100 000 
patients are currently on the waitlist for kidney transplantation (2), but only about 20% of these 
patients will proceed to transplantation due to donor organ shortage (3). Approximately 30% of 
the kidney transplant patients on the waitlist are sensitized to HLA with cPRA ≥20% (cPRA is 
reciprocally proportional to the likelihood of finding a matching donor) (4, 5). Human leukocyte 
antigen sensitization can occur as a result of previous pregnancies, blood transfusions, or previous 
transplants. The HLA sensitized patients are at risk for rapid graft loss from AMR by pre-existing 
donor-specific alloantibodies, decreasing chances of finding a matching donor and hence leading 
to prolonged wait times as compared to those who are not sensitized. 
Desensitization therapy aims to overcome the humoral incompatibility by removing or reducing 
the presence of reactive antibodies, thereby increasing the chance of finding compatible or 
acceptable donors for transplantation. However, the current most common desensitization 
protocols involve plasmapheresis, intravenous immunoglobulin (IVIG), and/or rituximab which 
do not target the terminally differentiated antibody-secreting plasma cells that are responsible for 
alloantibody production in the bone marrow and are hence often associated with a quick rebound 
effect (6, 7). 
Isatuximab is an IgG1 monoclonal antibody directed against CD38, a receptor antigen expressed 
on hematopoietic cells. In particular, CD38 is highly expressed in plasma cells - the primary 
source of antibody production (8, 9). Isatuximab is currently being developed for treatment of 
multiple myeloma, and other advanced malignancies including solid tumors and lymphomas, and 
may have clinical utility in desensitization for kidney transplantation. 
2.1 
STUDY RATIONALE  
2.1.1 HLA sensitized patients: Unmet medical need  
For patients with ESRD, transplantation is associated with decreased mortality, better quality of 
life, and lower expenditures, compared to chronic dialysis treatment (10, 11). Unfortunately, HLA 
sensitized patients have prolonged wait time for transplant and may never find a compatible donor 
depending on the extent of sensitization. This is attributed to the presence of anti-HLA antibodies 
that bear a high risk of causing rapid rejection of a new organ and therefore limit a candidate’s 
possibilities to accept organ offers (12, 13). Even for patients with living donors, transplantation 
may not be possible due to positive cross-match with their willing donors. For kidney transplant 
candidates waitlisted for deceased donor organs, the likelihood of finding a compatible donor is 
highly dependent on their cPRA score. The cPRA (in the US cPRA is established by the Organ 
Procurement and Transplantation Network) provides a standardized evaluation of the degree of 
sensitization of a transplant candidate to HLA antigens. Use of cPRA has increased the allocation 
efficiency and access for sensitized patients waiting for a kidney transplant, particularly for 
patients with a cPRA ≥80% (14, 15). Much of the literature focuses on “broadly” or “highly” 
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sensitized patients who have been variably defined using cPRA cut-off values of 50+, 80+, or 
higher. However, even patients with cPRA values as low as 30 theoretically require a greater 
number of match runs to have a 95% chance of finding an acceptable donor as compared to 
candidates with cPRA of 10 and 20 (16). Of note, a positive correlation between cPRA and DSA 
has been observed, and DSA may confer immunologic risk (17, 18, 19, 20). A meta-analysis of 
7 retrospective cohort studies revealed a nearly 2-fold risk of AMR (relative risk: 1.98, 95% 
confidence interval: 1.36 – 2.89) and 76% increased risk of graft failure associated with the 
presence of DSA as compared to the absence of DSA (21). Therefore, a higher cPRA implies a 
higher likelihood of positive cross-matches between the donor pool and the waitlisted patient, and 
therefore a lower likelihood of finding a compatible donor. It has been reported that cPRA with 
decimals (cPRAd) is inversely related to the likelihood of finding a compatible donor, as 
described by the following equation and Figure 3 (22).  
𝐿𝐶𝐷= 1 𝑖𝑛 
1
1 −𝑐𝑃𝑅𝐴 
Figure 3 - Relationship between cPRA and likelihood of finding a compatible donor  
 
Abbreviations: cPRA = calculated panel reactive antibodies, cPRAd = calculated panel reactive antibody with decimals, LCD = likelihood of 
compatible donor 
The median waiting time to transplantation in the US was reported to be 4 years, while sensitized 
patients often endure waiting times exceeding 5 years (3, 23). With the introduction of the Kidney 
Allocation System (KAS) in December 2014 giving highly sensitized patients additional points, 
the deceased donor transplantation rate became more balanced across different cPRA compared to 
pre-KAS (increased transplantation rate in patients with cPRA 90% to 99.9%) (24). However, 
access to transplant remains considerably lower post-KAS for candidates with cPRA >99.9% who 
are considered as “difficult-to match” patients (25). In addition, the transplant rate for cPRA 80% 
to 89% candidates decreased, and the waitlist mortality continued to increase for very highly 
sensitized patients with cPRA ≥98% compared to other patients (24). The long-term risk of death 
is significantly lower in patients who undergo transplantation compared to patients who remain on 
the waitlist and continue dialysis (relative risk 0.32; P <0.001) (26). In addition, prolonged 
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dialysis has resulted in shorter patient and graft survival after transplantation (27, 28). An 
unintended consequence of KAS is the disproportionate allocation of highest quality of kidneys 
(kidney donor profile index ≤20) in highly sensitized patients (cPRA ≥99%) which is correlated 
with survival, which created a disadvantage for the majority of other kidney transplant waitlist 
candidates (cPRA <99%) (29). National prioritization access programs similar to KAS have been 
implemented by ex-US countries (eg, ETKAS by Eurotransplant, PATHI in Spain). While it may 
be unattainable to achieve a system with absolutely no undesirable disparities in access to 
transplantation, a standardized desensitization therapy that can effectively convert HLA sensitized 
patients to lower cPRA levels (eg, non-sensitized or less sensitized) would help to further resolve 
the imbalance in kidneys allocation, and/or reduce the need to transport donor organs across long 
distance for those who requiring expanded access to match with a compatible donor organ. 
Pre-transplantation desensitization can reduce alloantibody titers to a level that is sufficiently low, 
resulting in an acceptable cross-match which allows for transplantation with low risk of AMR. A 
study on desensitization in HLA-incompatible kidney recipients and survival demonstrated 
significant survival benefits of pre-transplantation desensitization in patients who underwent 
HLA-incompatible live-donor kidney transplantation (30). The 8-year survival rate for 
desensitized patients was 80.6% compared to 30.5% for the dialysis group and 49.1% for the 
dialysis-or-transplantation group (P <0.0001). Therefore, desensitization is an important option 
for HLA sensitized patients to increase access to kidney transplantation, as this confers to better 
clinical outcome in addition to being more cost-effective than chronic dialysis treatment. 
2.1.2 Current desensitization therapies  
Currently, there is no approved or standard therapy for desensitization in patients awaiting kidney 
transplantation. The landscape of current desensitization therapies in use by physicians has been 
extensively reviewed (5, 31, 32, 33). 
Plasmapheresis is one of the oldest techniques used in removing circulating antibodies. 
Plasmapheresis must be performed on a daily basis as a standalone treatment as antibody rebound 
occurs after each session (31). In practice, plasmapheresis is usually used in conjunction with 
other desensitization agents, and most commonly with IVIG. 
The exact mechanism of IVIG is not thoroughly understood; however, possibilities include 
regulation of B-cell antibody production, neutralization of circulating anti-HLA antibodies, 
inhibition of complement mediated inflammation, and various pro-inflammatory cytokines (5). 
The clinical utility of IVIG in kidney transplant desensitization was demonstrated in the 
randomized, double-blinded, placebo-controlled NIH IG02 trial (34). Patients who received IVIG 
2 mg/kg have shown significant reduction in panel reactive antibody levels (p <0.033) and higher 
transplant rate compared to placebo (35% versus 17%). However, similar to plasmapheresis, IVIG 
alone does not durably suppress anti-HLA antibody levels and is associated with antibody 
rebound. Nevertheless, IVIG remains the backbone in current desensitization protocols. As 
mentioned above, a study on desensitization in HLA-incompatible kidney recipients and survival 
demonstrated significant survival benefits in patients treated with plasmapheresis and low dose 
IVIG prior to kidney transplantation (30). It was also reported that the use of IVIG and rituximab 
in highly sensitized patients successfully reduced mean panel reactive antibody (PRA) by 44% 
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from baseline (p <0.001) (35). Nevertheless, similar to plasmapheresis, efficacy of IVIG is limited 
with additional cycles, and antibody rebound remains a major problem for this approach (36, 37). 
Rituximab is a chimeric mAb targeting CD20. It is approved in the US and Europe for multiple 
indications including Non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid 
arthritis. The rationale for using rituximab in kidney transplant desensitization is to deplete CD20 
positive B-cells, including precursors for plasma cells (32). Rituximab has been widely accepted 
in desensitization protocols, in combination with plasmapheresis and/or IVIG. While eliminating 
B-cells may prevent recurrence of antibodies to some extent, rituximab was not able to eliminate 
DSA-producing long-lived plasma cells that reside in the bone marrow niche as such plasma cells 
typically do not express CD20 (23, 33). 
Bortezomib was recently explored as a desensitization agent with the aim to deplete plasma cells. 
Bortezomib was approved in the US and Europe for treatment of multiple myeloma and mantle 
cell lymphoma. Studies have reported the use of bortezomib in combination with other classical 
desensitization protocols resulting in significant decrease in HLA antibody MFI and reversal of 
acute rejection (7). This is likely attributed to its ability to trigger apoptosis of CD138+CD20- 
bone marrow derived plasma cells, thereby blocking anti-HLA antibody production. However, 
bortezomib was not well-tolerated, making it difficult to incorporate into desensitization protocols 
(5). Nevertheless, the clinical experience with bortezomib supported targeting long-lived plasma 
cells could be a viable strategy in effective removal of alloantibodies and potentially sustain 
reduction in DSA levels (7). 
2.1.3 Targeting CD38 for plasma cell depletion as a desensitization strategy  
Short-lived plasma cells rise rapidly in the spleen following antigen exposure, allowing for 
immediate production of antibody in response to acute infections. For sustained humoral immune 
response, selection of antigen-exposed B-cells occurs within the germinal center which eventually 
mature into long-lived plasma cells within the bone marrow, producing over 80% of antibodies 
detectable in the serum (38, 39). The CD38 is expressed on germinal center B-cells and 
differentiated plasma cells. In particular, plasma cell differentiation is associated with high 
positivity of CD38, where CD38 expression of normal plasma cells is much higher compared to 
other CD38 positive hematopoietic cells in the peripheral blood and bone marrow including 
monocytes, natural killer cells (NK-cells), activated T-cells, and B-cell progenitors (8, 39, 40). 
Therefore, CD38 is a rational target for depleting plasma cells that produce alloantibodies or 
DSAs, which is potentially a more effective strategy in desensitization for kidney transplantation. 
Anti-CD38 monoclonal antibodies currently in clinical development include daratumumab 
(approved in the US and Europe for use in multiple myeloma), isatuximab (Phase 3 development), 
and MOR202 (development terminated in China). To date, there is no clinical study to 
systematically evaluate the use of anti-CD38 monoclonal antibodies in desensitization for solid 
organ transplant. A recent study reported the use of daratumumab in desensitization in a heart 
transplant candidate (41). Multiple courses of plasmapheresis, high-dose IVIG, and rituximab 
result in no significant changes in cPRA (cPRA=98%) with deterioration of clinical condition. 
Following 8 weekly injections of daratumumab (16 mg/kg), the patient’s cPRA significantly 
decreased to 62% and subsequently enabled heart transplantation (Figure 4). The decrease in 
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anti-HLA antibody was associated with high depletion of peripheral CD38+ plasma cells. 
Anti-CD38 monoclonal antibody was also shown to effectively treat AMR in a clinical case of 
refractory AMR in a combined heart and kidney transplant recipient, where histologic analysis 
revealed T-cell mediated rejection (TCMR) and AMR with plasma cell predominant infiltration. 
Conventional therapy such as high dose steroid pulses, plasmapheresis, anti-thymocyte globulin, 
rituximab, and high dose IVIG was ineffective in treating the AMR. Following treatment with 
daratumumab combined with eculizumab, de novo DSA was dramatically declined and allograft 
functions were significantly improved. While 2 of the 9 DSAs reascended 20 weeks after 
daratumumab treatment, retreatment with daratumumab decreased the DSAs significantly. 
Another study of daratumumab for treatment of AMR in a kidney transplant recipient also 
reported similar effect of daratumumab in treating resistant AMR in a highly sensitized HLA-
incompatible kidney transplant recipient (42). The effectiveness of daratumumab in removing 
harmful antibodies was also demonstrated in a patient who developed pure red-cell aplasia that is 
refractory to standard treatments following allogenic stem cell transplantation (43). After first 
dose of daratumumab at 16 mg/kg (total 6 weeks of treatment), transfusion dependence was fully 
resolved with subsequent complete removal of anti-A antibodies and sustained normal differential 
blood count. Importantly, at 10-month follow-up, no graft-versus-host-disease (GVHD) or 
opportunistic infection was observed. 
Figure 4 - Desensitization of heart transplant candidate with daratumumab  
 
Abbreviations: Ab = antibody, HLA = human leukocyte antigen 
Similar to daratumumab, isatuximab targets CD38 positive cells. To date, clinical studies have 
demonstrated activity in multiple myeloma patients (see Investigator’s Brochure for details), and 
has recently met primary endpoint of prolonging progression-free survival in patients with 
relapsed/refractory multiple myeloma in its first randomized Phase 3 trial (44). It was reported 
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that isatuximab induces the above mechanisms of action depending on the CD38 expression on 
the target cells (Figure 5) (8). Direct apoptosis, antibody-dependent cellular cytotoxicity (ADCC), 
antibody-dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity 
(CDC) could be triggered depending on the CD38 expression on target cells. Although isatuximab 
activity was not directly tested in normal plasma cells, it is expected that isatuximab can 
effectively deplete normal plasma cells based on the extremely high expression of CD38 on these 
cells. The authors also demonstrated that isatuximab depletes CD38 high B-cell precursors and 
NK-cells ex vivo, which have lower CD38 expression than normal plasma cells. 
Figure 5 - Schematic representation of the different mechanisms of action possibly triggered by 
isatuximab according to the levels of CD38 expression in normal and tumor cells  
 
Abbreviations: ADCC = antibody-dependent cellular cytotoxicity, ADCP = antibody-dependent cellular phagocytosis, CD = cluster of 
differentiation, CDC = complement dependent cytotoxicity 
Based on the above, it is hypothesized that isatuximab (anti-CD38 monoclonal antibody) can 
target long-lived plasma cells and result in sustained removal of alloantibodies and DSA by 
depleting their production source. Consequently, desensitization with isatuximab in patients 
awaiting transplantation may increase access to transplantation for this immunologically 
disadvantaged group of HLA sensitized patients, decrease wait and dialysis time, and potentially 
achieve better clinical outcome. 
The primary objectives of this study are to assess safety and PK of isatuximab in patients awaiting 
kidney transplantation, and to assess its ability to decrease anti-HLA antibodies and cPRA. 
2.2 
BACKGROUND  
Isatuximab (SAR650984) is an IgG1 class naked mAb binding selectively the human CD38 
membrane protein. Isatuximab has been approved, in some countries, in combination with 
pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who 
have received at least two prior therapies including lenalidomide and a proteasome inhibitor 
(bortezomib or carfilzomib or ixazomib). Isatuximab is also being developed for the treatment of 
a number of hematological malignancies and solid tumors. 
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Depending on the CD38 expression level, isatuximab has the capacity to kill CD38 positive tumor 
cells by a combination of 4 distinct biological mechanisms: 
• ADCC 
• ADCP 
• CDC 
• Pro-apoptotic activity 
As of cut-off date of 05 January 2020, an estimated 1652 patients were treated with isatuximab in 
multiple myeloma and other malignancies, including 147 patients with various solid tumors 
known to bear minimal tumor CD38. In general, isatuximab is well-tolerated clinically with a 
manageable safety profile. The most common adverse reactions are IRs which are clinically 
manageable. Infusion reactions are not dose-dependent and tend to occur most frequently during 
the first infusion. Overall, the most current findings from the clinical experience acquired from 
multiple clinical studies with isatuximab in multiple indications have not identified any potential 
safety risks or concerns in addition to those described in the Investigator’s Brochure of 
isatuximab. When given in combination with other anticancer agents, the overall safety profile of 
the combinations appears consistent with the safety profile of each drug individually. 
Together with the efficacy and PK/pharmacodynamic (PD) analyses, 20 mg/kg given QW for the 
first 28-day cycle, and Q2W after Cycle 1 is the selected dose for the single agent study in the 
multiple myeloma indication. In other clinical studies, isatuximab 10 mg/kg is the selected dose 
when combining with other anticancer therapies. 
Refer to isatuximab Investigator’s Brochure for the most updated nonclinical and clinical studies 
of isatuximab. 
2.3 
BENEFIT/RISK ASSESSMENT  
2.3.1 Benefits  
Refer to Section 2.1. 
2.3.2 Potential and identified risks  
2.3.2.1 Isatuximab  
Isatuximab has been investigated either as monotherapy or in combination in participants with 
hematological malignancies and other advanced malignancies. The safety profile of isatuximab 
monotherapy has been assessed by a pooled analysis of completed monotherapy studies 
TED10893 (Phase 1 and Phase 2 Stage 1, including 181 participants with multiple myeloma), and 
TED14154 (relapsed/refractory multiple myeloma) where the most common treatment emergent 
adverse events (TEAE), excluding the AEs corresponding to laboratory abnormalities, include 
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IRs, fatigue, nausea, anemia, cough, upper respiratory infection, diarrhea, headache and dyspnea. 
Infusion reactions occurred in 53.8% of the 212 participants assessed. 
The IRs associated with isatuximab in participants who are administered appropriate primary 
prophylaxis (see also Section 2.3.3) are most common with the first administration of the drug, are 
not dose-dependent, are Grade 1 to 2 severity, are manageable with standardized precautions 
detailed in each study protocol, are resolved either spontaneously or with standard medication by 
the next day following the infusion, and the participants do not appear to sustain sequelae. The 
IRs generally do not cause treatment discontinuation, and do not tend to recur at subsequent 
administrations of isatuximab. 
Another identified risk is that isatuximab binds to endogenous CD38 found at low levels on red 
blood cells and may interfere with routine blood bank compatibility testing and cross-matching, 
with false-positive indirect Coombs test. This interference is limited to the minor blood groups 
(not affect the ABO and Rh typing). See Section 10.10 for details.  
The CD38 antigen is expressed on normal immune cells. Isatuximab could modulate cell survival 
and differentiation of both lymphoid and myeloid cells in patients. This modulation could have 
decreased all CD38+ cells and their lineage cells as an identified risk of opportunistic infections in 
patients with chronic kidney disease (CKD). In addition, suppression of immune system (with its 
ability to detect and destroy cancer cells) may increase the risk of second primary malignancies.  
Please refer to the current version of the isatuximab Investigator’s Brochure for more detailed 
information about the known risks of isatuximab. 
2.3.2.2 Potential risk of desensitization therapies in patients awaiting transplantation  
Desensitization therapies are immunosuppressive in nature, infection (especially cytomegalovirus 
[CMV] and polyoma virus) and malignancy maybe a potential risk (33). Conflicting results have 
been published on whether desensitization therapies such as rituximab would result in higher rate 
and severity of infections (5, 33, 45). A single-center retrospective study dedicated to 
understanding infectious complications from desensitization treatment was conducted (46). In this 
study, a total of 361 patients were included in the analysis. After an average of 18-month follow-
up, patients who received rituximab plus IVIG for desensitization were found to have similar 
infection rates compared to patients who did not receive desensitization treatment. According to 
the authors, the infection rates observed were also similar to that reported in the literature. In a 
systematic review of the use of rituximab for desensitization in renal transplantation, no 
statistically significant higher incidence of infectious complications in patients treated with 
rituximab was observed (47). Lower rates of CMV viremia and viral infections were identified, 
and may be attributed to fewer episodes of rejection and associated steroid therapy. 
A couple of publications have reported potential immunomodulatory effects of anti-CD38 mAb 
such as T-regulatory cell suppression and T-cell activation in multiple myeloma patients (48, 49). It 
is unknown whether these immunomodulatory effects observed in multiple myeloma patients would 
translate into potential concern for TCMR in patients post transplantation. While individual reports 
have suggested use of anti-CD38 may lead to TCMR (41, 42), further investigation is warranted to 
assess the benefit/risk ratio. Nevertheless, the main cause of kidney transplant failure is usually 
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attributed to AMR, which is strongly associated with graft loss, whereas TCMR was not (50, 51). It 
should be noted that no GVHD was observed in the clinical case that reported the use of 
daratumumab to desensitize a patient who received ABO-mismatched stem cell transplantation (43). 
2.3.3 Preventive measures to minimize the risk of isatuximab  
To minimize the risk of IRs, all participants treated with isatuximab should routinely receive 
primary prophylactic treatment with diphenhydramine 25 to 50 mg IV (or equivalent), 
methylprednisolone 100 mg IV (or equivalent), acetaminophen (paracetamol) 650 to 1000 mg 
orally (or equivalent), and montelukast 10 mg orally (or equivalent), approximately 15 to 30 
minutes (and never longer than 60 minutes) prior to the isatuximab infusion to minimize the 
incidence and severity of IR commonly observed with certain mAbs. It is recommended that 
prescribing information of each of these medications to be considered in the context of each 
patient’s clinical situation. 
In an attempt to further mitigate the incidence and severity of IRs, infusion of isatuximab is 
administered in a titrated manner (see Section 6.1). In the event of a mild or moderate 
hypersensitivity reaction, the isatuximab infusion should be interrupted and may subsequently 
resume after recovery, at a slower infusion rate, under close monitoring and with supportive care 
as needed. Prior to restarting the infusion, participants may receive additional medication per the 
judgment of the Investigator; recommended medications consist of diphenhydramine 25 mg IV 
and methylprednisolone 100 mg IV (or equivalent). In the event of a severe hypersensitivity 
reaction, treatment with isatuximab is to be immediately and permanently discontinued. Detailed 
management guidelines for IRs are also provided in Section 6.6.4.  
Isatuximab infusion administered in units of mL per hour has been evaluated in Study TCD14079 
Part B. A total of 47 patients were included in this study. The primary endpoint of the study was 
achieved as no Grade ≥3 IRs were reported, therefore confirming the feasibility of the fixed 
volume infusion method of isatuximab administration. The overall incidence of IRs was 40.4%. 
For the risk of neutropenia and infections, Investigators are recommended to monitor complete 
blood cell counts periodically during the treatment. Antibiotics, antifungal, and antiviral 
prophylaxis can be considered during the treatment. Patients with neutropenia should be 
monitored for signs of infection. No dose reductions of isatuximab are recommended. Dose delays 
and the use of colony stimulating factors (eg, granulocyte-colony stimulating factor [G-CSF]) 
may be required to allow improvement of neutrophil count. 
To mitigate potential risk of infections in patients receiving isatuximab, participants with active, 
recurrent, or chronic infections requiring treatment are excluded from the study. Furthermore, 
participants with positive hepatitis core antigen but hepatitis B surface antigen (HBsAg) negative 
must receive prophylactic antiviral therapy prior to IMP initiation, and should continue therapy 
until end of site visit FUP or early discontinuation. Potential viral reactivation (including hepatitis 
B virus [HBV], CMV, and Epstein-Barr virus [EBV]) in participants will be monitored pre- and 
post-treatment with isatuximab. 
To avoid potential problems with blood transfusion, the American Association of Blood Banks 
recommends that patients being treated with anti-CD38 antibodies have blood type and screen 
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tests performed prior to treatment (ie, at screening see Section 1.3). After the treatment and each 
time before blood transfusion, the antibody screen test (indirect Coombs test) should be 
performed. After a patient begins taking anti-CD38 antibodies, ABO/RhD typing can be 
performed normally; for antibody detection and identification, dithiothreitol (DTT)-treated cells 
can be used to eliminate the interference (see Section 10.10 for details). 
In regard to the aforementioned potential risk of TCMR, participants who received isatuximab and 
subsequently proceed to solid organ transplantation are recommended to receive anti-thymocyte 
globulin (as indicated for prophylaxis of acute rejection) and steroids maintenance as part of the 
post-transplant immunosuppression regimen. During extended FUP, post-transplant status 
including rejection episodes and graft survival will be collected. 
Additionally, careful monitoring of AEs and laboratory abnormalities, continuous direct 
communication between the Investigators and the monitoring team, and the adherence to the dose 
modification rules specified in the study protocol, are the continuous measures that will minimize 
the risks in study participants. 
Overall, the anticipated benefit/risk ratio of isatuximab supports the conduct of study TED16414 
in participants diagnosed with CKD awaiting kidney transplantation. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of isatuximab may be found in the Investigator’s Brochure. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
Phase 1: To characterize the safety and tolerability 
of isatuximab in kidney transplant candidates.  
• 
Adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities.  
• 
Phase 2: To evaluate the efficacy of isatuximab in 
desensitization of patients awaiting kidney 
transplantation.  
• 
Response rate (RR) defined as the proportion of 
participants meeting at least one of the predefined 
desensitization efficacy criteria, from baseline up to 
26 weeks after treatment period, measured by 
single antigen bead (SAB) assay per central 
laboratory assessment as follows:  
- 
Reduction in calculated panel reactive 
antibodies (cPRA) resulting in at least 100% 
increase of likelihood of finding a compatible 
donor (for target cPRA, see Section 10.9).  
- 
Reduction in antibody titer (≥75% reduction 
from baseline) to achieve target cPRA (see 
Section 10.9).  
- 
Elimination of ≥1 anti-HLA-antibody (ie, mean 
fluorescence intensity [MFI] reduced to <2000) 
as measured by a SAB assay, for antibodies 
with baseline MFI ≥3000.  
Secondary 
• 
Phase 2: To characterize the safety profile of 
isatuximab in kidney transplant candidates.  
• 
AEs/SAEs, and laboratory abnormalities.  
• 
To characterize the pharmacokinetic (PK) profile of 
isatuximab in kidney transplant candidates.  
• 
PK parameters of isatuximab (see Table 7)  
• 
To evaluate the immunogenicity of isatuximab.  
• 
Incidence of anti-drug antibodies (ADA) against 
isatuximab.  
• 
To assess the overall efficacy of isatuximab in 
desensitization of patients awaiting kidney 
transplantation.  
• 
Duration of response (DoR) per central laboratory 
assessment.  
• 
Proportions of participants and duration achieving 
target cPRA per local laboratory assessment.  
• 
Number of anti-HLA-antibody with baseline MFI 
≥3000 reduced to <2000 as measured in a SAB 
assay per central laboratory assessment.  
• 
Transplantability including time to first transplant 
offer, time to transplant, and number of transplant 
offers, if applicable.  
• 
Time to first AMR episode and rate of AMR, if 
applicable.  
• 
Graft survival at 6 months post-transplant, if 
applicable.  
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Objectives 
Endpoints 
Tertiary/exploratory 
• 
To assess other preliminary efficacy of isatuximab 
in desensitization of patients awaiting kidney 
transplantation. 
 
 
  
 
 
  
 
 
 
 
 
• 
To assess the biological effects of isatuximab on 
immune cell populations and identify potential 
predictive and/or PD biomarkers 
 
 
 
 
 
• 
To perform PK/PD analysis. 
 
 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy and safety assessments chosen for use in this study is considered well 
established and relevant in the renal transplant setting. In addition, suitable steps have been built 
into each of these assessments to ensure their reliability and accuracy and to minimize any risks to 
patient safety. 
Safety and tolerability are the primary objectives of the Phase 1 with endpoints including 
AEs/SAEs and laboratory abnormalities. The safety objective is extended as a secondary objective 
for Phase 2. Monitoring of safety data is described in detail in Section 8.3 and Section 10.3. 
Efficacy of isatuximab in desensitization is the primary objective for Phase 2. Participants are 
considered as responders if meeting at least one of the predefined desensitization efficacy criteria 
as outlined in Section 3. The predefined desensitization efficacy criteria are designed to capture 
the ability of isatuximab in removing/reducing circulating anti-HLA antibody. Calculated panel 
reactive antibody is a standardized parameter to estimate the unacceptable risk against the national 
donor population, based upon unacceptable HLA antigens which the transplant candidates have 
antibodies against. The SAB assay is the most widely accepted method for precisely identifying 
the anti-HLA antibodies due to its much-improved sensitivity and specificity compared to older 
methods such as cytotoxicity or flow cytometry. The assay is considered to be acceptable as a 
semi-quantitative assay (negative or positive), with MFI of <2000 may be considered negative at 
multiple kidney transplant centers. The MFI variability has been reported as up to 62%; while 
standardized operating procedure could reduce variability to <25% even across centers and with 
different reagents (52, 53). The TED16414 study utilizes a central laboratory for primary efficacy 
assessment and the MFI variability is expected to be <25%. As a conservative approach to 
mitigate false positive RR, the third predefined efficacy criterion (ie, elimination of ≥1 anti-HLA 
antibody) is only applicable to antibodies with baseline MFI ≥3000 to account for possible assay 
variability. Moreover, reduction in anti-HLA antibody strengths are being evaluated by antibody 
dilution (ie, second criterion) instead of quantifying MFI values (54, 55). 
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Duration of response (assessed both locally and centrally) is included as a secondary endpoint to 
address potential antibody rebound concern, which is commonly observed with current 
desensitization protocols. If applicable, transplantability and post-transplant outcomes will also be 
captured as secondary endpoints. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 1b/2 open-label, non-randomized, multi-center study to evaluate the safety, PK, 
and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. The study will 
be conducted in 2 phases (see Figure 1 for study design schema):  
Phase 1 (safety run-in)  
A minimum of 6 safety evaluable participants with cPRA ≥80% will be enrolled at the dose level 
to be tested without interruption in Phase 1. In order to be considered as safety evaluable, 
participants must have received at least 90% of the planned cumulative doses of the first cycle 
(unless they discontinue IMP due to pre-defined unacceptable toxicity). 
Pre-defined unacceptable toxicity is defined as any verified Grade 4 AEs or laboratory 
abnormalities (except IRs) occurring during the first cycle of treatment, unless solely due to the 
underlying disease or due to a cause obviously unrelated to IMP, if confirmed by the Sponsor and 
recruiting Investigators. 
The totality of the safety findings, including all AEs occurring during treatment, unless solely due 
to the underlying disease or due to a cause obviously unrelated to IMP, will be taken into 
consideration for confirming the Phase 2 dose. Phase 2 of the study will be initiated after 6 safety 
evaluable participants have completed first cycle observation period where the dose level is 
determined to be sufficiently well-tolerated. 
If the SD is determined not to be sufficiently well-tolerated, 6 additional (minimum) safety 
evaluable participants will be enrolled at DL-1 (see Table 4 for details on the dose levels and 
schedule for Phase 1). 
Overall safety monitoring will also be performed throughout the conduct of the study. 
Upon completion of the first cycle safety observation period for each participant enrolled in 
Phase 1, participants will continue study procedures until study completion (see “Duration of 
study period [per participant]” in Figure 2). 
Phase 2 
In Phase 2, two cohorts will be included: 
Cohort A: Participants with cPRA ≥99.90%; active candidates on the kidney waitlist. Up to 
6 participants with living donor can be enrolled into Cohort A. 
Cohort B: Participants with cPRA 80.00% to 99.89%; active candidates on the kidney waitlist 
with no living donor cleared for donation.  
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The study will have 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 FUP which include telephone contacts every 
90 days and information collection until study cut-off, death, or lost to follow-up. The study 
cut-off is planned at 26 weeks after the last participant completes the treatment period, or when 
the last ongoing participant is lost to follow-up, whichever is earlier. The Sponsor may choose to 
extend the study cut-off date depending on the enrollment rate observed to facilitate adequate 
follow-up data collection. Participants who wish to proceed to transplantation when a compatible 
donor becomes available while on study must discontinue IMP immediately, and complete an E/D 
visit prior to transplantation if clinically feasible, and proceed to extended FUP. The study 
duration that involves site visit per participant (ie, screening, treatment, site visit FUP) will be 
approximately 42 weeks. The study duration including extended FUP per participant will be 
approximately 78 weeks (depending when the participant is enrolled). 
Treatment period: The cycle duration is 28 days and a complete treatment period is comprised 
of 3 cycles of IMP treatment. Participants will continue treatment until receiving 3 cycles of IMP, 
unacceptable AE per Investigator’s judgment, or participants’ decision to stop the treatment. 
Site visit FUP: Participants completing the treatment period and who are able to remain on study 
will return to the study sites for study procedures. 
Extended FUP: The following participants will be followed-up every 90 days by phone calls, 
until study cut-off date, death, or lost to follow-up, whichever comes first: 
• Participants who completed or discontinued from site visit FUP 
• Participants who proceed to transplantation during treatment period or site visit FUP. 
During extended FUP, specified information per protocol will also be collected by study site (see 
Section 1.3). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This is a Phase 1b/2 open-label, non-randomized, multi-center study to evaluate the safety, 
preliminary efficacy, and PK of isatuximab (SAR650984) in patients awaiting kidney 
transplantation. 
The HLA sensitized patients with high cPRA have low likelihood of finding a compatible donor. 
Currently no approved or standard therapy is available for desensitization. An effective 
desensitization therapy with a durable response has the potential to increase the likelihood for 
transplant candidates to find a compatible donor, reduce time on dialysis, and a better clinical 
outcome. 
As the safety profile of isatuximab is well-established, Phase 1 (safety run-in) is designed to 
characterize the safety and tolerability of isatuximab in patients with CKD, and to confirm the 
Phase 2 dose in this patient population. 
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Phase 2 is designed to assess preliminary efficacy of isatuximab in desensitizing HLA sensitized 
patients awaiting kidney transplantation, which includes assessing change in cPRA and anti-HLA 
antibody levels. 
The patient population enrolled in the Phase 1 and Phase 2 is identical, which allows for inclusion 
of patients enrolled in the Phase 1 treated with Phase 2 dose in efficacy analysis. 
4.3 
JUSTIFICATION FOR DOSE  
In the case where oncology drugs are used in desensitization protocols or clinical studies 
exploring efficacy in desensitization for solid organ transplant, the full therapeutic doses (ie, doses 
approved in oncology or other indications) were commonly utilized (5, 33). Rituximab 
(375 mg/m2 or 1 g; approved for use in Non-Hodgkin’s lymphoma and rheumatoid arthritis) is 
widely accepted for the use in desensitization protocols including combination with IVIG and/or 
plasmapheresis for kidney transplantation (56). For instance, in a study where highly sensitized 
patients were allocated to intervention group versus control group (57), the intervention group 
received 2 doses of high dose IVIG, a single dose of rituximab (375 mg/m2 on Day 1), and a 
single cycle of bortezomib (1.3 mg/m2, on Days 15, 18, 21, and 24), for which the short courses of 
rituximab and bortezomib are of the same dose levels used in their corresponding approved 
oncology indications (375 mg/m2 rituximab for Non-Hodgkin’s lymphoma, or 375 mg/m2 
rituximab on Day 1 in combination with 1.3 mg/m2 bortezomib on Days 1, 4, 8, and 11 for mantle 
cell lymphoma). The regimen was well-tolerated and the AEs were consistent with that expected 
for the monotherapy drugs. 
Based on safety, efficacy, PK, and PK/PD data analyses, the dose/schedule of isatuximab when 
used as monotherapy for the treatment of multiple myeloma is 20 mg/kg QW × 4 followed by 
Q2W. In multiple myeloma patients, isatuximab displays nonlinear PK with target-mediated drug 
disposition. Isatuximab undergoes elimination by parallel linear and nonlinear pathways. In the 
range of plasma concentrations achieved with a 10 mg/kg QW/Q2W dose and schedule, linear 
clearance is the predominant elimination pathway as it represents approximately 90% of total 
clearance at steady state, indicative of the saturation of the target. As a large protein, isatuximab is 
expected to be eliminated by non-saturable proteolytic catabolism processes. Renal excretion and 
hepatic enzyme-mediated metabolism of intact isatuximab are unlikely to play a major role in the 
elimination of isatuximab. Thus, variations/modifications in renal and hepatic function are 
unlikely to affect the elimination of isatuximab (58). From population PK analysis (n=476 
multiple myeloma patients), mild (n=192), moderate (n=163), and severe (n=12) renal 
impairment, and mild hepatic impairment (n=65) had no impact on isatuximab PK. 
In CKD patients without multiple myeloma disease, less target-mediated drug disposition is 
anticipated compared to multiple myeloma patients. Isatuximab monotherapy demonstrated 
activity at doses ≥10 mg/kg with no clear dose response between 10 mg/kg and 20 mg/kg, clinical 
safety data also supported that 10 mg/kg is sufficiently well-tolerated in patients with advanced 
cancer who received more than 1 year of treatment. Therefore, 10 mg/kg QW × 4 followed by 
Q2W over a 12-week period is proposed to be tested in this study. 
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4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit (including extended FUP), or at study cut-off, death, or lost to 
follow-up. 
The study cut-off is defined as 26 weeks after the last participant completes the treatment period, 
or when the last ongoing participant is lost to follow-up, whichever is earlier. The Sponsor may 
choose to extend the end of the study depending on the enrollment rate observed to facilitate 
adequate follow-up data collection. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be 18 to 70 years of age inclusive, at the time of signing the informed 
consent.  
Type of participant and disease characteristics 
I 02. Diagnosis of CKD and active candidate on the kidney waitlist at the time of screening. 
For Participants in Cohort A: 
I 03. cPRA ≥99.90% within 4 weeks of IMP initiation as per local laboratory assessment 
(unacceptable antigens defined as MFI ≥2000), and stable within 6 months prior to IMP 
initiation based on medical history or samples, if available. 
For participants in Cohort B: 
I 04. cPRA 80.00% to 99.89% within 4 weeks of IMP initiation as per local laboratory 
assessment (unacceptable antigens defined as MFI ≥2000), and stable within 6 months 
prior to IMP initiation based on medical history or samples, if available. 
I 05. Participant with no living donor cleared for donation at the time of screening. 
Weight 
I 06. Body mass index (BMI) ≤40 kg/m2. 
Sex 
I 07. Male or Female 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
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a) Male participants 
Male participants with female partners of childbearing potential are required to use 
effective contraceptive methods as detailed in Appendix 4 (Section 10.4) of this 
protocol starting 2 weeks before IMP administration, during treatment period, and until 
5 months after last dose of isatuximab. 
b) Female participants 
Female participants of childbearing potential are required to use effective 
contraceptive methods as detailed in Appendix 4 (Section 10.4) of this protocol 
starting 2 weeks before IMP administration, during treatment period, and until 
5 months after last dose of isatuximab. Female participants of childbearing potential 
must be willing or able to be tested for pregnancy (see Section 10.4 for details). 
Informed Consent 
I 08. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.  
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Known malignancy requiring active treatment within 3 years prior to IMP initiation, with 
the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of 
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. 
E 02. History of significant cardiac dysfunction such as New York Heart Association 
classification for chronic heart failure III-IV, symptomatic cardiovascular disease, major 
clinically significant electrocardiogram (ECG) abnormality, left ventricular ejection 
fraction <40%, clinically significant ventricular arrhythmias, myocardial infarction within 
6 months prior to IMP initiation, or unstable or poorly controlled angina pectoris despite 
treatment. 
E 03. In the opinion of Investigator, participant with severe autonomic dysfunction leading to 
chronic hypotension. 
E 04. Evidence of active mucosal or internal bleeding. 
E 05. History of 2 or more events of pulmonary embolism or deep-vein thrombosis. 
E 06. Known active, recurrent or chronic infection requiring parenteral or oral anti-infective 
treatment; including primary or secondary immunodeficiency, a history of active or latent 
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tuberculosis or history of deep tissue/space infection (peritoneal, etc) within 24 weeks prior 
to IMP initiation, or any serious infection within 8 weeks prior to IMP initiation. 
E 07. Participants on peritoneal dialysis with a history of peritoneal infection at any time during 
the 12 weeks prior to IMP initiation. 
E 08. Participants on peritoneal dialysis with a positive culture or high cell count numbers on 
peritoneal fluid indicative of confirmed or suspected infection at the time of screening. 
E 09. Known active hepatitis B or C viral infection, or human immunodeficiency virus (HIV).  
- 
Participants with positive hepatitis B core antigen (anti-HBc or HBcAb) but HBsAg 
negative who received prophylactic antiviral therapy prior to IMP initiation are eligible 
and should continue therapy until end of treatment period or E/D visit. Participants 
with negative HBsAg and positive HBV deoxyribonucleic acid (DNA) observed 
during screening period will be evaluated by a specialist or Investigator for start of 
antiviral treatment: study treatment could be proposed if HBV DNA becomes negative 
and all the other study criteria are still met. 
- 
Participants with antiviral therapy for HCV started before initiation of IMP and 
positive HCV antibodies are eligible. The antiviral therapy for HCV should continue 
throughout the treatment period until seroconversion. Participants with positive anti-
HCV and undetectable HCV ribonucleic acid (RNA) without antiviral therapy for 
HCV are eligible. 
E 10. Participants with active lupus or uncontrolled diabetes, per Investigator’s judgment. 
Prior/concomitant therapy 
E 11. Prior treatment with an agent (approved or investigational) that blocks CD38 (patients who 
had previously participated in a study with an anti-CD38 but have written confirmation 
they were on control arm are allowed). 
E 12. Prior treatment with biological therapy, major surgery, desensitization therapy, or 
immunosuppressive therapy (up to 10 mg prednisone/day or equivalent is allowed) within 
28 days from initiation of IMP. 
E 13. Recipients of any live attenuated vaccine(s) within 4 weeks of IMP initiation. 
E 14. Received treatment with rituximab or obinutuzumab within 6 months from initiation of 
IMP. 
E 15. Received prior liver, heart, or lung transplantation. 
E 16. Received cell transplantation or cell therapy within 5 years prior to IMP initiation. 
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Prior/concurrent clinical study experience 
E 17. Prior treatment with any investigational drugs within 28 days from initiation of IMP or 
concomitant enrollment in any other clinical study involving an investigational study 
treatment. 
Diagnostic assessments 
E 18. Inadequate organ and bone marrow function at the Screening Visit: 
- 
Absolute neutrophil count (ANC) <1500/mm3 (1.5 × 109/L), 
- 
Platelets <90 × 109/L (platelet transfusion is not allowed within 7 days before the 
screening hematological test), 
- 
Hemoglobin <9 g/dL or <5.6 mmol/L (without transfusion 7 days before the screening 
hematological test), 
- 
Total bilirubin >1.5 upper limit of normal (ULN), 
- 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 × ULN, 
- 
Alkaline phosphatase (ALP) >2.5 × ULN. 
Other exclusions 
E 19. Pregnant or breastfeeding women or women who intend to become pregnant during 
participation in the study. 
E 20. Known intolerance or hypersensitivity to any component of isatuximab or premedications. 
E 21. Participant not suitable for participation, whatever the reason (including medical, ethical, 
or clinical conditions), as judged by the Investigator, or participants potentially at risk of 
noncompliance to study procedures. 
E 22. Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 
of the International Council for Harmonisation [ICH] Good Clinical Practice [GCP] 
Ordinance E6). 
5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently treated. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
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authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. 
• A participant who is rescreened ≤56 days (ie, 2 × the 28-day screening period) from the 
most recent consent form signature date, and for whom several procedures are still valid, 
the participant does not need to sign another consent form and this is considered as 
temporary screen failure. Investigator should ensure the willingness of the participant to 
continue and repeat any out of protocol window screening procedures. This verbal 
agreement should be documented in the participant’s chart and all the tests out of protocol 
window should be repeated and entered in the additional eCRF pages. 
• If screening window will be prolonged for >56 days, and the individual becomes eligible 
for the study, then rescreening is allowed, but in this situation patient must sign a new 
consent form and all screening procedures must be repeated. A different participant 
identification will be issued, while the other identification for this participant should be 
recorded as Screen Failure. There is no requirement for a waiting period between a screen 
failure date and the rescreening date. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 3 - Overview of study interventions administered  
Intervention name 
Isatuximab 
Premedications (see description after 
this table for NIMP) 
Type 
Drug 
See description after this table for 
NIMP 
Dose formulation 
Concentrated solution for infusion 
See description after this table for 
NIMP 
Unit dose strength(s) 
20 mg/mL (500 mg/25 mL) isatuximab in 
20 mM histidine, 10% (w/v) sucrose, 
0.02% (w/v) polysorbate 80, pH 6.0 
See description after this table for 
NIMP 
Dosage level(s) 
See Table 4 for details on the dose levels 
and schedule  
See description after this table for 
NIMP 
Route of administration 
IV infusion 
See below for rate and duration of infusion 
See description after this table for 
NIMP 
IMP and NIMP 
IMP 
NIMP 
Packaging and labeling 
Isatuximab will be provided in 1 glass vial 
per box. Each vial and box will be labeled 
as required per country requirement 
Each treatment container will 
dependent on country sourcing. Each 
container will be labeled as required 
per country requirement 
Abbreviations: IMP = investigational medicinal product, IV = intravenous, NIMP = noninvestigational medicinal product. 
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, isatuximab may be supplied from the site to the participant via a 
Sponsor-approved courier company where allowed by local regulations and approved by the 
participant. 
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Starting dose of investigational medicinal product (isatuximab) and de-escalation design 
The SD of IMP is 10 mg/kg QW for 4 weeks followed by Q2W. If the SD is determined not to be 
sufficiently well-tolerated, 6 additional (minimum) safety evaluable participants will be enrolled 
at DL-1 (ie, 5 mg/kg QW for 4 weeks followed by Q2W) (see Table 4 for details on the dose 
levels and schedule for Phase 1). 
Overall safety monitoring will also be performed throughout the conduct of the study. 
Table 4 - Dose level and schedule in Phase 1  
Dose Level 
Isatuximab 
1 cycle = 4 weeks (28 days) 
SD 
10 mg/kg 
QW × 4 for Cycle 1 → Q2W for cycles 2 and 3 
DL-1 
5 mg/kg 
QW × 4 for Cycle 1 → Q2W for Cycles 2 and 3 
Abbreviations: DL-1 = dose level minus 1, QW = once weekly, Q2W = once every 2 weeks, SD = starting dose 
The totality of the safety findings, including all AEs occurring during treatment, unless solely due 
to the underlying disease or due to a cause obviously unrelated to IMP, will be taken into 
consideration for confirming the Phase 2 dose. Phase 2 of the study will be initiated after 6 safety 
evaluable participants have completed first cycle observation period where the dose level is 
determined to be sufficiently well-tolerated. 
Rate and duration of infusion 
The rates of isatuximab infusion are as follows: 
• First infusion: Initiate infusion at 25 mL/hour. In the absence of IRs after 1 hour of 
infusion, increase infusion rate by 25 mL/hour increments every 30 minutes, to a 
maximum of 150 mL/hour. 
• Second infusion: Initiate infusion at 50 mL/hour. In the absence of IRs after 30 minutes of 
infusion, increase rate to 100 mL/hour for 30 minutes, and then to 200 mL/hour until the 
total volume is infused. 
• Third and subsequent infusions: Initiate infusion at a fixed infusion rate of 200 mL/hour, 
until the total volume is infused. 
• In the presence of IR: See Section 6.6.4. 
For details of IMP preparation and administration, refer to pharmacy manual. 
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Noninvestigational medicinal products (Premedications) 
All participants will receive the following premedications to prevent or reduce the incidence or 
severity of IRs, approximately 15 to 30 minutes prior to isatuximab infusion (no longer than 
60 minutes). Premedication is mandatory for the first 4 isatuximab infusions (see criteria below 
for subsequent infusions). The use of ranitidine or equivalent as part of IR premedication is left to 
the medical judgement of the Investigator. The standard premedication regimen will include: 
• Acetaminophen 650 to 1000 mg PO (or equivalent) 
• Diphenhydramine 25 to 50 mg IV (or equivalent) 
• Methylprednisolone 100 mg IV (or equivalent) 
• Montelukast 10 mg PO (or equivalent) 
Noninvestigational medicinal products will be locally sourced and the formulations may vary. 
Premedication for prevention of IR has to be given for the first four isatuximab infusions, and the 
first infusion using fixed volume infusion following approval of Amended Protocol 01 (applicable 
for participants enrolled under Original Protocol).  
For a participant who has no IR upon 4 consecutive infusions, premedication for the subsequent 
infusions is optional at the Investigator’s discretion.  
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Any quality issue noticed with the receipt or use of an IMP/NIMP (appearance, pertaining 
documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. Some 
deficiencies may be recorded through a complaint procedure (see Section 8.3.8). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
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Under no circumstances will the Investigator supply IMP to a third party (except for 
direct-to-patient shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Administration of the study intervention will be supervised by the Investigator or 
Sub-Investigator. 
The person responsible for drug dispensing is required to maintain adequate records of the IMP. 
These records (eg, drug movement form) include the date the IMP is received from the Sponsor, 
dispensed to the participant and destroyed or returned to the Sponsor. The packaging batch 
number (IMP number) must be recorded on the drug accountability form. The person responsible 
for drug administration to the participant will record precisely the date and the time of drug 
administration to the participant. 
Deviation(s) from the prescribed dosage regimen should be recorded in the electronic case report 
form (eCRF). 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Prohibited concomitant medications: 
Prohibited concomitant medications (until end of Site Visit FUP, or E/D, or participant undergoes 
transplantation) are described below: 
• Concurrent treatment with any desensitization procedure or anti-neoplasm therapy not 
specified in the protocol, including chemotherapy, immunotherapy, hormonal therapy, 
targeted therapy, biological therapy, other investigational drug, or curative radiotherapy. 
• Concomitant treatment with immunosuppression medications are prohibited, except for: 
- 
use in premedication defined in the study protocol, 
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- 
treatment of any life-threatening emergency, 
- 
low dose corticosteroids (eg, up to 10 mg prednisone/day or equivalent) as needed for 
Investigator’s judgment, and  
- 
a brief course (≤7 days) of systemic corticosteroid for prophylaxis (eg, contrast dye 
allergy) or for the treatment of non-autoimmune conditions (eg, delayed-type 
hypersensitivity reactions cause by contact allergen). 
• Investigational therapy (other than protocol-mandated study intervention) is prohibited 
within 28 days prior to initiation of IMP, during treatment period, and during site visit 
FUP. 
• Live vaccines should be avoided. However, given the increased risk of infection, routine 
vaccinations are recommended for the participants and their contacts. Prophylactic 
vaccination is recommended for influenza A and B virus, pneumococci, and haemophilus 
influenza. 
• Phase 1 only: Prophylactic use of hematopoietic growth factors (eg, G-CSF, granulocyte 
macrophage-colony stimulating factor [GM-CSF]) during the first cycle observation 
period. Curative treatment and prophylactic use of erythropoietin is allowed. 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor if required. 
HBV vaccination could be considered, following investigator’s discretion, for patients with 
negative HBsAg, total anti-HBc, anti-HBs and HBV-DNA. At least 3 doses of vaccine will be 
administered at monthly intervals, the first one 1-2 weeks before start of study treatment. Anti-
HBs should be monitored at approximately 1, 2 and 3 months after end of vaccination (±7 days, or 
at the next blood sampling). Anti-HBs above 100 mU/mL will indicate a good seroconversion, 
between 10 and 100 mU/mL moderate seroconversion that can be limited in time, less than 
10 mU/mL will indicate no response to vaccination. 
If antiviral therapy for HBV or HCV was started before initiation of IMP and patient was eligible 
for the trial, the antiviral therapy for HBV or HCV should continue throughout the treatment 
period as recommended by specialist or Investigator. 
See Section 6.6.3 in case of hepatitis B viral reactivation (sub section “Guidance in case of 
hepatitis B reactivation occurring under study treatment”). 
6.5.1 Rescue Medicine  
The Sponsor will not supply any rescue medication. The site will use standard and locally 
acceptable rescue medications in line with current box labeling, as appropriate. However, the 
risk-benefit of use of such medications must be assessed case-by-case by the Investigator or his 
team. The date and time of rescue medication administration as well as the name and dosage 
regimen of the rescue medication must be recorded.  
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6.6 
DOSE MODIFICATION  
6.6.1 General rules  
Cycle delay (ie, delay of IMP for Cycle 2 and 3), dose delay, or dose omission (ie, omission 
within a cycle) are permitted in case of toxicity. 
Administration of the IMP will be discontinued in the event of a TEAE that persists despite 
appropriate dose modifications or any other AE that, in the opinion of the Investigator, warrants 
discontinuation. 
There will be no dose reduction for isatuximab. 
Any changes to IMP administration must be recorded in the eCRF. 
6.6.2 Dose delay and dose omission  
Within a cycle, the treatment window is ±1 day for each of the weekly administrations and 
±2 days for each of the Q2W administrations. Within a cycle, a dose is deemed to have been 
delayed if the treatment is ≥2 days beyond the theoretical day of treatment for weekly dose, or 
≥3 days beyond the theoretical day of treatment for Q2W dose. The reason for dose delay must be 
captured. The participant will receive the next infusion/cycle after recovery from the AE. 
If infusion has been delayed within a cycle, the next dose of IMP should be administered at the 
planned time interval between the 2 administrations (eg, if Cycle 1 Day 15 administration was 
administered on Day 17, the planned Day 22 should be administered on Day 24 ±1 day). 
Participants may have dose delay, cycle delay, or dose omission if an AE occurs and does not 
recover according to the following rules: 
• In Cycle 1 (for weekly administration) if an AE occurs and the participant does not 
recover on the day of planned infusion or within the following 3 days, infusion of 
isatuximab (Day 8, Day 15, or Day 22) may be omitted. 
• In Cycles 2 and 3: 
- 
For Day 1 infusions: If an AE occurs and the participant does not recover on the day of 
planned infusion, the cycle may be delayed up to a maximum of 2 weeks. 
- 
For Day 15 infusions: If an AE occurs and the participant does not recover on the day 
of planned infusion or within the following 7 days, infusion of isatuximab may be 
omitted. 
• If the AE is not recovered within 14 days: 
- 
IMP may be delayed up to 56 days. 
- 
After a cycle delay of >14 days and ≤56 days, it is per Investigator’s decision to restart 
the treatment or the IMP that is omitted, if a clear benefit from therapy is observed and 
after consultation with the Medical Monitor. 
- 
The IMP must be definitively permanently discontinued if the dose/cycle delay is 
longer than 56 days. 
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Guidance in case of hepatitis B reactivation occurring under study treatment 
In case of viral reactivation during study treatment (greater than 1log10 IU/mL increase in HBV 
DNA or reappearance of HBsAg or detection of HBV DNA in patients with resolved infection*), 
study treatment will be hold and specialist should be consulted for initiation of anti-viral treatment 
and monitoring of the patient. Re-start of study treatment should be agreed between sponsor, 
investigator and specialist (hepatologist) if controlled infection. Close monitoring of ALT and 
AST approximately every month (may coincide with the next scheduled blood sampling ±7 days) 
up to study treatment discontinuation. HBV DNA to be done as per Investigator’s or specialist 
advice. 
* Previous known history of acute or chronic hepatitis B or the presence of total anti-HBc 
with/without anti-HBs; HBsAg negative; undetectable serum HBV DNA; normal ALT levels. 
6.6.4 General guidelines for the management of infusion reactions  
Participants should routinely receive premedications prior to isatuximab infusion as detailed in 
Section 6.1 to reduce the risk and severity of IRs commonly observed with mAbs. 
Infusion reactions typically occur within 24 hours from the start of the infusion. 
If an IR is observed, participants must also be informed of the potential risk of recurrent similar 
reactions at subsequent infusions. The guidelines for management of IRs are summarized in 
Table 6. 
Participants may receive additional medication per the judgment of the Investigator. Additional 
recommended medications are: diphenhydramine 25 mg IV (or equivalent) and 
methylprednisolone 100 mg IV (or equivalent). 
Participant who experience Grade 2 IRs, or first/second Grade 3 IR, may resume isatuximab 
infusion after temporary interruption, under close monitoring and with therapy as needed. 
Once the Grade 2 IR or first/second Grade 3 IR has improved or resolved according to Table 6, 
the infusion may be restarted as follows at the Investigator’s discretion: 
• First infusion:  Infusion could be restarted at one-half (12.5 mL/hour) of the initial 
infusion rate when the IR improves to Grade ≤1. If symptoms do not recur after 
30 minutes, the infusion rate may be increased by 25 mL/hour increments every 
30 minutes, until the total volume is infused or reaching 150 mL/hour, whichever is 
earlier. 
• Second infusion:  Infusion could be restarted at one-half (25 mL/hour) of the initial 
infusion rate when the IR improves to Grade ≤1. If symptoms do not recur after 
30 minutes, the infusion rate may be increased by 50 mL/hour increments every 30 
minutes, until the total volume is infused or reaching 200 mL/hour, whichever is earlier. 
• Third and subsequent infusions:  Infusion could be restarted at one-half (100 mL/hour) 
of the initial infusion rate when the IR improves to Grade ≤1. If symptoms do not recur 
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after 30 minutes, the infusion rate may be increased by 50 mL/hour increments every 
30 minutes, until the total volume is infused or reaching 200 mL/hour, whichever is 
earlier. 
Participants with Grade 3 IR (third Grade 3, or do not fulfil criteria to restart infusion as per 
Table 6) or Grade 4 IR must permanently discontinue the treatment with isatuximab. 
Grade 3 or higher IRs for isatuximab must be reported as adverse event of special interests 
(AESIs) (see Section 8.3). Study personnel should consult the Medical Monitor for further 
guidance regarding retreatment of participants with IRs and regarding issues of premedication 
management (eg, alternative medications for participants allergic or intolerant to premedication 
agents), or to determine if locally used equivalent medications are acceptable. 
Table 6 - Management guidelines for infusion reaction  
Infusion related reaction grading (NCI-CTCAE 
version 5.0 criteria) 
Recommendation 
Grade 1 
Mild transient reaction; infusion interruption not indicated; 
intervention not indicated. 
Continuation of isatuximab infusion is per the judgment 
of the Investigator following close direct monitoring of the 
participant’s clinical status. 
Grade 2 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDS, narcotics, IV fluids); prophylactic medications 
indicated for ≤24 hours). 
Stop isatuximab infusion. Give additional medication(s) with 
IV diphenhydramine 25 mg (or equivalent) and/ or 
IV methylprednisolone 100 mg (or equivalent), and/or other 
supportive care as needed. 
Isatuximaba may be resumed only after participant 
recovery, with reduced infusion rate and with close 
monitoring. 
Grade 3 
Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); recurrence of 
symptoms following initial improvement; hospitalization 
indicated for clinical sequelae. 
Stop isatuximab infusion. Give additional medication(s) with 
diphenhydramine 25 mg IV (or equivalent) and/or IV 
methylprednisolone 100 mg (or equivalent) and/or 
epinephrine as needed until resolution of the AE or until the 
AE improves to Grade 1.  Only then, the infusion may be 
restarted at the Investigator’s discretion: if so, the infusion rate 
should be half of the initial infusion rate, and it may be 
increased subsequently, at the Investigator’s discretion. 
If the severity of an infusion-related AE returns to Grade 3 
after the restart of the infusion, the same procedure described 
above may be repeated at the Investigator’s discretion.  If a 
Grade 3 infusion-related AE occurs for a 3rd time, treatment 
with isatuximab will be definitively discontinued for that 
participant. 
If symptoms do not resolve rapidly, do not improve after 
interruption of the isatuximab infusion, they recur after initial 
improvement with appropriate medications, or they require 
hospitalization, treatment with isatuximab should be 
definitively discontinued. 
Report as AESI. 
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Infusion related reaction grading (NCI-CTCAE 
version 5.0 criteria) 
Recommendation 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Definitive discontinuation of isatuximab. Give additional 
premedication with diphenhydramine 25 mg IV (or equivalent) 
and/or IV methylprednisolone 100 mg (or equivalent) and/or 
epinephrine as needed. 
Report as AESI. 
Abbreviations: AESI = adverse event of special interest, CTCAE = common terminology criteria for adverse events, IR = infusion reaction, 
IV = intravenous, NCI = National Cancer Institute, NSAIDS = nonsteroidal anti-inflammatory drugs. 
a Isatuximab: the infusion should be completed within 16 hours from the end of infusion preparation or a new infusion should be prepared 
with the remaining dose to be administered the same day. 
6.6.5 Retreatment of participants  
The participants must have recovered to National Cancer Institute (NCI) common terminology 
criteria for adverse events (CTCAE) Grade ≤1 or to the baseline status before initiation of the next 
cycle at the same dose level. 
In the event of an AE causing a delay, in order for participants to be retreated, see Section 6.6.1 to 
Section 6.6.4 for recommendations. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
The IMP will not be provided after the end of the treatment period. The participant’s treatment 
after study discontinuation will be at the discretion of the treating physician. 
For participants who received isatuximab treatment and subsequently proceed to solid organ 
transplantation, it is recommended to include the following as part of the post-transplant 
immunosuppression regimen: 
• Anti-thymocyte globulin (rabbit) as indicated for prophylaxis of acute rejection. 
• Steroids during maintenance phase, with tapering if applicable. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Refer to Section 7.1 and Section 7.2 for details regarding discontinuation of study intervention 
and participant discontinuation. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Definitive discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued (except in the case of 
discontinuation due to transplantation), the participant will remain in the study to be evaluated as 
per the assessments planned for site visit FUP. See the SoA (Section 1.3) for data to be collected 
at the time of discontinuation of study intervention.  
The IMPs should be continued until end of treatment period whenever possible.  
In case the IMP is stopped, it should be determined whether the stop can be made temporarily. 
Any IMP discontinuation must be fully documented in the eCRF. 
Pregnancy will lead to definitive treatment discontinuation in all cases. 
Treatment with the IMP should be discontinued in any of the following cases: 
• At the participant’s request, at any time and irrespective of the reason (participant’s 
decision), or at the request of their legally authorized representative without any effect on 
their care. “Legally authorized representative” is considered to be an individual or judicial 
or other body authorized under applicable law to consent on behalf of a prospective patient 
to the patient’s participation in the procedure(s) involved in the research.  
• If, in the Investigator’s opinion, continuation of the IMP would be detrimental to the 
participant’s well-being, such as: 
- 
unacceptable AE, 
- 
poor compliance to the study protocol, 
- 
any other reason such as intercurrent illness that prevents further administration of 
IMP (will be specified). 
• Participant is lost to follow-up. 
• Completion of the 3 cycles of treatment period. 
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed. 
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Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation (per Investigators discretion) before making a laboratory/ECG abnormality-driven 
decision of definitive discontinuation of the IMP for the concerned participant. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
In the case of participants discontinuing IMP during treatment period due to transplantation, the 
participants should complete an E/D visit (30±7 days after last IMP) if clinically feasible, and 
proceed to extended FUP.  
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Treating Investigator because 
of suspected AEs or disruption of the clinical trial due to a regional or national emergency 
declared by a governmental agency (Appendix 13 [Section 10.13]). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
eCRF. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
• The participant will be permanently discontinued from the study intervention if 
discontinued from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study (ie, 
continue participation in site visit FUP and extended FUP). 
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The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, eg, medical 
record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be reallocated (treated) in the study. Their 
inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• The total volume of blood required for all assessments as per protocol is expected to be 
within the recommended safe limit for human in clinical trials by the local Institutional 
Review Boards and Ethics Committees. 
• For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Appendix 13 (see Section 10.13). 
• In exceptional cases, under regional or national emergencies (eg, natural disaster, 
epidemic/pandemic, terrorist attack), onsite visits may be replaced with telephone/remote 
visits. For example, patient interview for medical history/prior medications could be 
performed by phone, local safety labs and some efficacy assessments could be performed 
off-site/at the participant’s home (eg, home nursing) if agreed by patient and permissible 
per local regulations. In such circumstances, visit window may be expanded, if needed 
(eg, ±14 days for visits).  
8.1 
EFFICACY ASSESSMENTS   
8.1.1 Efficacy assessment - Central laboratory assessments  
The primary efficacy endpoint, selective secondary, and exploratory efficacy endpoints will be 
assessed by the central laboratory using the SAB assay (see Section 10.9). For the purpose of 
cPRA and anti-HLA antibody determination, unacceptable antigens are defined as those with MFI 
≥2000. The cPRA will be computed based on cPRA calculator developed by the Organ 
Procurement and Transplantation Network, with values to be provided with 2 decimal places. 
Refer to the laboratory manual for details regarding sample collection, processing, storage, and 
shipment. 
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8.1.2 Efficacy assessment - Local laboratory assessment  
The cPRA levels assessed by the local laboratory will be captured for the analysis of one of the 
secondary efficacy endpoints. Frequency of assessment will be performed as per the local 
standard of practice. If possible, cPRA levels should be reported to 2 decimal points (eg, 99.99%) 
based on cPRA calculator developed by the Organ Procurement and Transplantation Network, in 
addition to locally reported cPRA, with unacceptable antigens defined as those with MFI ≥2000. 
8.2 
SAFETY ASSESSMENTS   
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the major 
body systems. Height (only at screening) and weight will also be measured and recorded. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Vital signs  
• During the treatment period, vital signs are to be monitored just before starting infusion of 
the IMP, 1 hour after the start of the infusion, at the end of infusion, and during the 
infusion if clinically indicated. 
• Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
8.2.3 Electrocardiogram  
A single 12-lead ECG will be obtained at screening using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
8.2.4 Echocardiography  
Two-dimensional echocardiography coupled with Doppler flow studies will be performed at 
screening to evaluate the left ventricular ejection fraction and other relevant cardiac function 
assessments, as needed. Echocardiography should be performed at dry weight, and/or on a 
non-dialysis day. 
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8.2.5 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or after the last dose of study intervention should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the Investigator or Medical Monitor. 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA. 
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event of special interest (AESI) 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP/NIMP; 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]) 
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• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with isatuximab is defined as increase of at 
least 30% of the intended administered dose at each infusion (expressed in unit per 
body weight) to be administered in the specified duration or if the dose is administered 
in less than half the recommended duration of administration. 
- 
An overdose (accidental or intentional) with NIMP is defined as increase of at least 
30% of the intended administered dose at each administration, 
- 
In case of accidental or intentional overdose with IMP/NIMP, even not fulfilling a 
seriousness criterion, is to be reported to the Sponsor immediately (within 24 hours) 
using the AE form together with the SAE complementary form to be entered in the 
eCRF. 
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 
• Other project specific AESI 
- 
Grade ≥3 IRs. An IR occurs typically within 24 hours from the start of the infusion.  
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs and SAEs will be collected from the signing of the ICF until the time points specified in 
the SoA (Section 1.3). 
Beyond 30 days after the last dose of IMP, only ongoing related AEs, ongoing SAEs, and new 
related AEs/SAEs will be followed up until resolution/stabilization. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
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8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. Beyond 30 days after the last dose of IMP, only ongoing 
related AEs, ongoing SAEs, and new related AEs/SAEs will be followed up until 
resolution/stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in Appendix 3 
(Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• Adverse events that are considered expected will be specified in the reference safety 
information. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.3.5 Pregnancy  
• Details of all pregnancies in any female participant and any female partner of male 
participant who becomes pregnant 2 weeks before the first dose of isatuximab treatment, 
while the male participant is in the study, and within 5 months after the last dose of 
isatuximab treatment will be collected. 
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• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Cardiovascular and death events  
Cardiovascular and death events should be reported as per the protocol. See Section 8.3 for 
details.  
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Disease-related events (DREs) are typically associated with disease progression under the study 
according to the Investigator’s opinion, and that the Investigator deem to be obviously unrelated 
to the IMP. 
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an AE or SAE (instead of a DRE): 
• The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual participant. 
OR 
• The Investigator considers that there is a reasonable possibility that the event was related 
to study intervention. 
In addition, death occurred beyond 30 days after the last IMP administration that is not due to an 
AE related to IMP, or is unrelated to ongoing AE/SAE, will not be reported as an SAE even 
though the event may meet the definition of a SAE. 
8.3.8 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
There is no information on specific recommendations regarding overdose with isatuximab. In case 
of overdose, participants should be closely monitored for signs and symptoms of adverse 
reactions, and appropriate symptomatic treatment should be instituted. 
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In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or delays will be made by the Investigator in consultation 
with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
Blood samples will be collected for the measurement of isatuximab concentrations in plasma as 
described in the PK flowcharts (see Section 1.3.1). Instructions for the collection and handling of 
biological samples will be provided by the Sponsor in a separate laboratory manual. The actual 
date and time of each sample will be recorded. These samples will be tested by the Sponsor’s 
designee. 
8.5.1 Non-compartmental analysis  
Pharmacokinetic parameters will be calculated using the non-compartmental methods from 
isatuximab plasma concentrations. The parameters will include, but may not be limited to the 
following (Table 7): 
Table 7 - List of pharmacokinetic parameters and definitions  
Parameters 
Definition 
Ceoi 
Concentration observed at the end of intravenous 
infusion 
Cmax 
Maximum concentration observed after the first infusion 
tmax 
Time to reach Cmax 
Clast 
Last concentration observed above the lower limit of 
quantification after the first infusion 
tlast 
Time of Clast 
Ctrough 
Concentration observed just before treatment 
administration during repeated dosing 
AUC0 T 
Area under the plasma concentration versus time curve 
calculated using the trapezoidal method over the dosing 
interval T (168 hours) 
8.5.2 Population approach  
Population PK approaches may be used. If done, the data generated will be reported in a separate 
report(s). 
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8.6 
PHARMACODYNAMICS  
Refer to Section 8.8 for PD biomarkers. 
8.7 
GENETICS  
Genetics are not evaluated in this study. 
8.8 
BIOMARKERS  
• Collection of samples for other biomarker research is also part of this study. Blood 
samples for biomarker research are required and will be collected from all participants in 
this study as specified in the SoA. 
• Samples will be tested for the presence and/or function of specific immune cells especially 
CD38 expression cells as well as total immunoglobulin to evaluate their association with 
the observed clinical responses in reduced anti-HLA antibodies to anti-CD38 treatment. 
Detailed instructions for sample preparation and shipping for the biomarkers will be provided to 
the study sites in a separate laboratory manual. 
8.8.1 Immune cell profiling  
Blood samples will be collected from all participants for the flow cytometric analysis of immune 
cells before and after the treatment with isatuximab. The blood sampling time points are depicted 
in the SoA (Section 1.3). Sample preparation and analysis will be conducted by the Sponsor’s 
designee. Blood immune cells will be incubated with mAbs which detect specific cell surface and 
intracellular proteins. Based on the combination of bound antibodies to the immune cells distinct 
cell populations and specific cell types can be identified. One major aim is to determine the 
alteration of percentage and cell count of CD38 expressing cells in blood upon isatuximab 
treatment. Other immune cell populations may also be examined. 
8.8.2 Functional B-cell assay  
Blood samples will be collected to enable possible functional assessment of memory B-cells 
depletion. Blood sampling time points before and after treatment with isatuximab are depicted in 
the SoA (Section 1.3). Sample preparation and analysis will be conducted by the Sponsor’s 
designee(s). Peripheral B-cells will be processed for subsequent analysis of anti-HLA 
alloreactivity upon isatuximab treatment. 
8.8.3 Determination of serum total immunoglobulin levels  
Blood samples will be collected from all participants for the measurement of total 
immunoglobulin levels before and after the treatment with isatuximab. The blood sampling time 
points are depicted in the SoA (Section 1.3). Sample preparation and analysis will be conducted 
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by the Sponsor’s designee. In particular the levels of ImmunoglobulinG are of interest in order to 
estimate the efficacy of isatuximab treatment. 
Additional analysis, not specified in the protocol but related to the drug action and/or effect of 
IMP, may be conducted on the remaining samples pending evolving literature. 
8.9 
IMMUNOGENICITY ASSESSMENTS  
Blood samples will be collected for assessing the presence of ADA against isatuximab in plasma 
from all participants as described in the PK/ADA flowcharts (see Section 1.3.1). These samples 
will be tested by the Sponsor’s designee. 
Refer to the laboratory manual for details regarding sample collection, processing, storage, and 
shipment. 
Plasma samples will be screened for antibodies binding to isatuximab and the titer of confirmed 
positive samples will be reported. 
8.10 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Not applicable. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
Phase 1: There is no formal statistical hypothesis. 
Phase 2:  
• Null hypothesis: True RR 
 
• Alternative hypothesis: True RR
 
9.2 
SAMPLE SIZE DETERMINATION  
In Phase 1, approximately 6 to 12 safety evaluable participants are expected to be enrolled (see 
Section 9.3 for definition of Safety Evaluable Population). 
Approximately 24 to 36 participants (Phase 1 and Phase 2) are expected to be enrolled if the SD is 
retained as the Phase 2 dose or approximately 30 to 42 participants are expected to be enrolled if 
DL-1 is the Phase 2 dose. 
A maximum of 6 replacements per cohort is allowed for participants who: 
• enroll in Phase 1 and receive <90% of the planned cumulative doses within the first cycle 
(unless they discontinue IMP due to pre-defined unacceptable toxicity), or 
• receive <75% of planned cumulative doses within 3 cycles, or 
• have consecutive dose interruption of >28 days, or 
• do not complete site visit follow-up period (FUP), after agreement with Medical Monitor. 
Phase 2: 
• With a minimum sample size of 12 participants per cohort and 1-sided alpha of 0.025, the 
analysis will have at least 80% power to demonstrate that RR is significantly better than 
assuming the true RR is 
, based on exact test.  
• A null hypothesis of 
is selected representing placebo control as there is currently no 
approved or standard therapy for desensitization, and there is no expected decrease in 
anti-HLA antibody levels or cPRA in patients who do not undergo desensitization therapy. 
The participants treated at the Phase 2 dose during Phase 1 will be included in the analysis 
together with the participants in Phase 2. 
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9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 8): 
Table 8 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF. 
All Treated 
Includes all participants who receive at least 1 dose of isatuximab. This population 
is the primary population for the analyses of safety parameters, unless otherwise 
noted. All analyses using this population will be based on the dose level actually 
received. 
Safety Evaluable (Phase 1) 
Includes all participants enrolled in Phase 1 who receive ≥90% planned cumulative 
doses of isatuximab within Cycle 1 (unless IMP is discontinued due to pre-defined 
unacceptable toxicity). 
Efficacy Evaluable 
Includes All Treated Population who fulfill the study eligibility criteria, with an 
evaluable baseline and at least 1 evaluable postbaseline efficacy assessment, and 
receive ≥75% of planned cumulative doses. This is the primary population for 
efficacy analyses. 
PK 
Includes All Treated Population with at least 1 available concentration result 
post-treatment (whichever the cycle and even if dosing is incomplete) with adequate 
documentation of date and time of dosing and date and time of sampling.  
ADA 
Includes All Treated Population with at least 1 available ADA result (negative, 
positive, or inconclusive) post-treatment (whichever the cycle and even if dosing is 
incomplete). 
Abbreviations: ADA = anti-drug antibody, ICF = informed consent form, IMP = investigational medicinal product, PK = pharmacokinetic. 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will be developed and finalized before the database lock and 
will describe the participant populations to be included in the analyses and procedures for 
accounting for missing, unused, and spurious data. For a regional or national emergency declared 
by a governmental agency, contingency measures are included in Appendix 13 (Section 10.13). 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. 
9.4.1 Efficacy analyses  
Analysis of primary efficacy endpoint: 
• In Phase 2, the RR by cohort will be summarized using descriptive statistics. A 95% 
2-sided confidence interval will be computed using the Clopper-Pearson method (Table 9). 
Analyses of secondary endpoints: 
• All secondary endpoints (if applicable) during Phase 2 will be summarized descriptively 
and presented by cohort. Categorical variables (eg, rates and proportions) will be tabulated 
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via frequency distributions. Continuous variables (eg, change from baseline) will be 
summarized by providing the number of observations (n), mean, median, standard 
deviation, minimum, and maximum. Duration of response and other time to event 
variables will be analyzed using the Kaplan-Meier method (Table 9). Participants not 
reaching an event will be censored at their last follow-up visit. 
• No hypothesis/significance testing will be performed. 
Table 9 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary: Response rate (per central laboratory) 
Descriptive statistics and Clopper-Pearson method 
Secondary: 
• 
Rate/Proportion of participants: 
Descriptive statistics 
- 
achieving target cPRA (per local laboratory) 
- 
with AMR (if applicable) 
- 
with graft survival at 6 months post-transplant 
(if applicable) 
• 
Number of: 
Descriptive statistics 
- 
anti-HLA-antibody eliminated (per central 
laboratory) 
- 
transplant offers (if applicable) 
• 
Duration of: 
Kaplan-Meier method 
- 
response (DoR) (based on central laboratory) 
- 
achieving target cPRA (based on local 
laboratory) 
• 
Time to event: 
Kaplan-Meier method 
- 
first transplant offer 
- 
transplant (if applicable) 
- 
first AMR episode (if applicable) 
Tertiary/Exploratory 
Will be described in the SAP and finalized before the 
database lock. 
Abbreviations: AMR = antibody mediated rejection, cPRA = calculated panel reactive antibodies, DoR = duration of response, HLA = human 
leukocyte antigen, SAP = statistical analysis plan. 
9.4.2 Safety analyses  
All safety analyses will be performed on the Safety Evaluable Population for Phase 1 and All 
Treated Population for Phase 2. 
For safety analyses, the observation period will be divided into 3 segments: 
• The pretreatment period is defined as the time from when the participants give informed 
consent to the first administration of the IMP. 
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• The on-treatment period is defined as the time from the first dose of IMP up to 30 days 
after the last dose of IMP. 
• The post-treatment period is defined as the time starting 31 days after the last dose of IMP 
to study cut-off. 
Analyses of adverse events 
Adverse events will be coded according to Medical Dictionary for Regulatory Activities 
(MedDRA) and graded according to NCI-CTCAE (version 5.0 criteria). 
An overall summary of TEAEs will be provided. The number (%) of participants experiencing 
TEAEs by primary system organ class (SOC) and preferred term (PT) will be summarized by 
CTCAE grade (all grades and Grade ≥3). Similar summary tables will be generated for treatment 
related TEAEs, AESIs, TEAEs leading to treatment discontinuation, serious TEAEs, and TEAEs 
with fatal outcome. Post-treatment AEs will be analyzed separately. 
Clinical laboratory evaluations 
All laboratory abnormalities will be graded according to NCI-CTCAE, when applicable. The 
number (%) of participants with laboratory abnormalities (ie, all grades and grade ≥3) will be 
tabulated using the worst grade during on-treatment period. 
Table 10 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
Primary: AEs/SAEs, and laboratory abnormalities in Phase 1 
Will be listed  
Secondary: AEs/SAEs, and laboratory abnormalities in 
Phase 2 
Will be summarized using descriptive statistics 
Exploratory 
Not applicable 
Abbreviations: AE = adverse event, SAE = serious adverse event 
9.4.3 Analyses of immunogenicity  
Immunogenicity analyses and the potential impact on PK will be described in the SAP, and will 
be performed on the ADA population. 
9.4.4 Pharmacokinetic analyses  
The non-compartmental PK analysis will be described in the SAP, and will be performed on the 
PK population.  
If applicable, the population PK analyses will be described in the Population PK analysis plan 
(PAP) provided by PKDM Modeling and Simulation group and the results will be described in a 
separate report.  
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9.4.5 Other analyses  
The biomarker exploratory analyses will be described in the SAP and finalized before the 
database lock.  
9.5 
INTERIM ANALYSES   
No interim analyses are planned. 
9.5.1 Data Monitoring Committee (DMC)  
Not applicable. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH GCP Guidelines 
- 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
Participants who are rescreened (except for temporary screen failure) are required to sign a new 
ICF (see Section 5.4 for details). 
The ICF will contain a separate section that addresses the use of remaining mandatory samples for 
optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a participant’s agreement to 
allow any remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will not provide this separate signature. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 13 (see Section 10.13). 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation). 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on afro American population for the Food and Drug Administration 
[FDA] or on Japanese population for the Pharmaceuticals and Medical Devices Agency in Japan). 
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• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.5 Committees structure  
Study Committee 
Composition of the Study Committee will vary based on the matter discussed, but it will generally 
include Sponsor representatives and at least 2 key Investigators. The Study Committee will 
convene ad hoc when required, to review data (including Phase 1) and provide strategic 
recommendations on study medical decisions. 
10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
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10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically signing 
the case report form (CRF). 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
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10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
10.1.10 
Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
The tests detailed in Table 11 will be performed by the local laboratory. 
• The results must be entered into the eCRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by the local regulations. 
• For women of childbearing potential (WOCBP), a serum pregnancy test will be performed 
at screening. For all other planned time points (see Section 1.3), a serum or urine human 
chorionic gonadotropin (hCG) pregnancy test will be performed. Pregnancy test can be 
performed at home for participants during the FUP or if date of test does not match with 
FUP visit and the site must record this in the source document. Test should be performed 
at Screening (ie, ≤7 days prior to first IMP), C2D1, C3D1, at the end of isatuximab 
treatment (ie, Week 1 of site visit FUP or E/D visit [±7 days]), and 5 months (±7 days) 
after the last dose of IMP. 
Table 11 - Protocol-required safety laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
Platelet count 
 
RBC count 
 
Hemoglobin 
 
Hematocrit 
 
WBC count with differential: 
 
Neutrophils (absolute neutrophil count)) 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistry 
 
Urea or BUN 
 
Uric acid 
 
Creatinine 
 
eGFR (MDRD) 
 
Glucose fasting 
 
Hemoglobin A1c (screening, site visit FUP Week 9, E/D visit; and as clinically indicated) 
 
Potassium 
 
Chloride 
 
Sodium 
 
Magnesium 
 
Phosphate 
 
Calcium 
 
Bicarbonate (screening, site visit FUP Week 9, E/D visit; and as clinically indicated) 
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Laboratory assessments 
Parameters 
 
AST/SGOT 
 
ALT/SGPT 
 
Alkaline phosphatase 
 
Total and direct bilirubin 
 
LDH 
 
Total protein 
 
Albumin 
 
PTH assessment (screening, site visit FUP Week 9, E/D visit; and as clinically indicated) 
Other tests 
• 
Coagulation: prothrombin time or INR, and activated PTT 
• 
Blood typing interference test (see Section 1.3, footnote i) 
• 
Serologya: HBV (HBsAg, anti-HBc [total and IgM], anti-HBs), HCV (anti-HCV), HIV (HIV 
antibody), CMV (IgG and IgM), EBV (early antigen, VCA-IgG, VCA-IgM, nuclear antigen 
antibody) 
• 
Viral loada: HBV DNA, HCV RNA, EBV DNA, CMV DNA 
The results of each test must be entered into the eCRF 
Abbreviations: anti-HBc = antibody to hepatitis B core antigen; anti-HBs = antibody to hepatitis B surface antigen; ALT = alanine 
aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, CMV = cytomegalovirus, EBV = Epstein-Barr virus, eCRF = 
electronic case report form, E/D = early discontinuation, eGFR = estimated glomerular filtration rate, DNA =deoxyribonucleic acid, 
FUP = follow-up period, HBV = hepatitis B virus, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV = human 
immunodeficiency virus, IgG= immunoglobulin G, IgM = immunoglobulin M, INR = international normalized ratio, LDH = lactic acid 
dehydrogenase, MDRD = Modification of Diet in Renal Disease, PTH = parathyroid hormone, PTT = partial thromboplastin time, RBC = red 
blood cell, RNA = ribonucleic acid, SGOT = serum glutamic-oxaloacetic transaminase, SGPT = serum glutamic-pyruvic transaminase, VCA = 
viral capside antigen, WBC = white blood cell. 
NOTES: Blood chemistry, hematology: assessments are not required to be repeated prior to Cycle 1 Day 1 if the screening laboratory 
assessments were performed within 7 days prior to first the IMP administration and met entry criteria. The window for blood chemistry and 
hematology is within 1 working day prior to IMP administration. 
a Study sites should determine which serology and viral load tests are required to confirm participant’s eligibility and to enable appropriate viral 
reactivation monitoring for HBV, HCV, HIV, EBV, and CMV as per protocol. The tests listed serve as a guidance and may not require all tests 
to be performed if selective results are conclusive on participant’s viral infection status and sufficiently support safety monitoring. 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
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• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg: 
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
c) Is life-threatening 
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The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
d) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
e) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
f) Is a congenital anomaly/birth defect 
g) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the eCRF. 
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• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Sponsor in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The NCI-CTCAE version 5.0 will be used to assess the severity of AEs/SAEs  
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure and/or Product Information, 
for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that 
the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to Sponsor 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
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include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
REPORTING OF SAES 
SAE reporting to Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor by telephone. 
• Contacts for SAE reporting can be found in the Investigator Study File. 
SAE reporting to Sponsor via paper CRF  
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor if the electronic system is unavailable. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator Study File. 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
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A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
CONTRACEPTION GUIDANCE: 
Females of childbearing potential or male participants with female partners of childbearing 
potential are required to use effective contraceptive methods starting 2 weeks before IMP 
administration, during treatment period, and until 5 months after last dose of isatuximab. 
Male participants 
• Male participants with heterosexual partners of reproductive potential (WOCBP) are 
eligible to participate if they agree to use the following during the protocol defined 
timeline: 
- 
Refrain from donating sperm 
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and 
- 
At least 1 of the following conditions applies: 
Are and agree to remain abstinent from penile-vaginal intercourse on a long-term and 
persistent basis, when this is their preferred and usual lifestyle, 
or 
Agree to use a male condom plus an additional contraceptive method with a failure 
rate of <1% per year (see table for female participants). 
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom for the time defined in the protocol. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 12. 
Table 12 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly effective methods that are user independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the woman of childbearing potential (WOCBP) and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study intervention, which may reduce the efficacy of the contraceptive 
method. In this case, 2 highly effective methods of contraception should be utilized during the intervention period and for at least 3 months 
after the last dose of study intervention 
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COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant 2 weeks before the first dose of isatuximab 
treatment, while the male participant is in the study, and within 5 months after the last 
dose of isatuximab treatment. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. If 
applicable, the follow-up will be approximately at least 1 year after the birth. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant 2 weeks before the first dose of isatuximab treatment, while 
participating in the study, and within 5 months after the last dose of isatuximab treatment. 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant’s pregnancy. The participant will be followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the participant and the neonate and the information will be forwarded to 
the Sponsor. If applicable, the follow-up will be approximately at least 1 year after the 
birth. Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
10.5 
APPENDIX 5: GENETICS  
Not applicable. 
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10.6 
APPENDIX 6: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS  
Not applicable. 
10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
Not applicable. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.9 
APPENDIX 9: DESENSITIZATION RESPONSE CRITERIA  
The target cPRA (ie, reduction of cPRA required to achieve at least 100% increase of likelihood 
of compatible donor [LCD]) is calculated according to the following equation (22). Examples of 
target cPRA reduction are presented in Table 13. 
𝐿𝐶𝐷= 1 𝑖𝑛 
1
1 −𝑐𝑃𝑅𝐴 
Table 13 - Examples of target cPRA reduction  
Baseline 
Target 
cPRA 
LCD 
cPRA 
LCD 
99.99% 
1:10000 
99.98% 
1:5000 
99.90% 
1:1000 
99.80% 
1:500 
99.80% 
1:500 
99.60% 
1:250 
99.60% 
1:250 
99.20% 
1:125 
99.50% 
1:200 
99.00% 
1:100 
99.00% 
1:100 
98.00% 
1:50 
97.50% 
1:40 
95.00% 
1:20 
95.00% 
1:20 
90.00% 
1:10 
90.00% 
1:10 
80.00% 
1:5 
80.00% 
1:5 
60.00% 
1:2.5 
Abbreviations: cPRA = calculated panel reactive antibodies, LCD = likelihood of compatible donor 
Participants with baseline cPRA 100.00% will be assigned with cPRA 99.99% for computational 
purpose. 
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Antibody titer is defined as the last dilution of serum at which positive results is obtained 
(eg, MFI ≥2000) (54). Examples of antibody titer based on MFI are illustrated in Table 14. 
Table 14 - Examples of antibody titer  
 
Neat Serum 
1:2 
1:4 
1:8 
1:16 
1:32 
Titer 
Antigen 1 MFI 
13430 
12492 
6250 
3123 
1550 
790 
8 
Antigen 2 MFI 
18320 
20820 
10501 
5206 
2604 
1302 
16 
Antigen 3 MFI 
11020 
5493 
2750 
1384 
688 
360 
4 
Abbreviations: MFI = mean fluorescence intensity 
Using similar concept, Table 16 illustrates an example in which the second predefined 
desensitization criterion (ie, ≥75% reduction in antibody titer from baseline to achieve target 
cPRA, see Table 15) may be met. In this example, participant’s baseline cPRA is measured by 
SAB as 97.50%, the target cPRA is therefore 95.00% as defined in Table 13. Through serial 
dilution of the serum collected at baseline, titer required to achieve target cPRA is 16 (ie, achieved 
at 1:16 dilution). Subsequent post-treatment serum is therefore diluted at 1:4 (ie, 75% reduction 
from 1:16) to determine whether target cPRA is achieved. At Cycle 3 Day 1, target cPRA is 
reached at 1:4 dilution therefore meeting the aforementioned predefined desensitization criterion. 
Table 15 - 75% reduction in antibody titer from baseline  
Baseline 
75% Reduction 
Titer 
Dilution 
Titer 
Dilution 
2 
1:2 
1 
Neat 
4 
1:4 
1 
Neat 
8 
1:8 
2 
1:2 
16 
1:16 
4 
1:4 
32 
1:32 
8 
1:8 
64 
1:64 
16 
1:16 
128 
1:128 
32 
1:32 
256 
1:256 
64 
1:64 
512 
1:512 
128 
1:128 
Table 16 - Example of ≥75% reduction in antibody titer from baseline to achieve target cPRA  
 
Neat 
Serum 
1:2 
Titer = 2 
1:4 
Titer = 4 
1:8 
Titer = 8 
1:16 
Titer = 16 
Response 
Criterion Met 
Baseline 
cPRA 
97.50% 
97.50% 
97.50% 
96.00% 
95.00% 
(target cPRA) 
 
C2D1 cPRA 
96.00% 
 
96.00% 
 
 
No 
C3D1 cPRA 
96.00% 
 
95.00% 
(target cPRA) 
 
 
Yes 
Abbreviations:  C2D1 = Cycle 2 Day 1, C3D1 = Cycle 3 Day 1, cPRA = calculated panel reactive antibodies 
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10.10 APPENDIX 10: CLUSTER OF DIFFERENTIATION 38 BLOOD TEST INTERFERENCE 
GUIDELINE  
 
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10.11 APPENDIX 11: ABBREVIATIONS  
 
ADA: 
anti-drug antibody 
ADCC: 
antibody-dependent cellular cytotoxicity 
ADCP: 
antibody-dependent cellular phagocytosis 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
AMR: 
antibody mediated rejection 
ANC: 
absolute neutrophil count 
AST: 
aspartate aminotransferase  
CD: 
cluster of differentiation 
CDC: 
complement dependent cytotoxicity 
CKD: 
chronic kidney disease 
CMV: 
cytomegalovirus 
CONSORT: 
Consolidated Standards of Reporting Trials 
cPRA: 
calculated panel reactive antibodies 
CRF: 
case report form 
CTCAE: 
common terminology criteria for adverse events 
DL-1: 
dose level minus 1 
DNA: 
deoxyribonucleic acid 
DoR: 
duration of response 
DRE: 
Disease-related event 
DSA: 
donor-specific antibody 
E/D: 
early discontinuation 
EBV: 
Epstein-Barr virus 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
ESRD: 
end stage renal disease 
FSH: 
follicle stimulating hormone 
FUP: 
follow-up period 
GCP: 
Good Clinical Practice 
G-CSF: 
granulocyte-colony stimulating factor 
GVHD: 
graft-versus-host-disease 
HBsAg: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HIV: 
human immunodeficiency virus 
HLA: 
human leukocyte antigen 
HRT: 
hormonal replacement therapy 
IAT: 
indirect antiglobulin test 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IEC: 
Independent Ethics Committee 
IgG1: 
immunoglobulinG1 
IMP: 
investigational medical product 
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IR: 
infusion reactions 
IRB: 
Institutional Review Board 
IV: 
intravenous 
IVIG: 
intravenous immunoglobulin 
KAS: 
Kidney Allocation System 
LCD: 
likelihood of compatible donor 
mAb: 
monoclonal antibody 
MFI: 
mean fluorescence intensity 
NCI: 
National Cancer Institute 
NIMP: 
noninvestigational medicinal product 
NK-cell: 
natural killer cell 
PD: 
pharmacodynamic 
PK: 
pharmacokinetic 
PO: 
oral route 
Q2W: 
once every 2 weeks 
QW: 
once weekly 
RNA: 
ribonucleic acid 
RR: 
response rate 
SAB: 
single antigen bead 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
starting dose  
SoA: 
Schedule of Activities 
TCMR: 
T-cell mediated rejection  
TEAE: 
treatment emergent adverse events 
ULN: 
upper limit of normal 
US: 
United States 
WOCBP: 
women of childbearing potential 
 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.12.1 
Amended protocol 01 (23 July 2020)  
This amended protocol 01 (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
 
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OVERALL RATIONALE FOR THE AMENDMENT  
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; 2.3.3 
Preventive measures 
to minimize the risk 
of isatuximab; 6.1 
Study intervention(s) 
administered 
Ranitidine is removed from standard 
premedication regimen and will be considered 
as per medical judgement of the Investigator. 
Criteria for optional premedication is simplified 
to base on no IR upon 4 consecutive 
infusions. 
To provide option to adapt the premedication 
depending on individual situation. 
1.3 SoA (footnote f); 
5.2 Exclusion criteria; 
6.5 Concomitant 
therapy; 6.6.3 
General guidelines 
for the management 
of adverse events; 
10.2 Appendix 2 
Clinical laboratory 
tests 
Included detailed guidance relating to viral 
reactivation monitoring and risks. As a new 
footnote “f” was implemented, numbering of 
following footnotes were shifted accordingly. 
 
 
 
To clarify monitoring and risks related to viral 
reactivation. 
 
 
 
 
1.3 SoA (footnote i) 
Added indirect Coombs tests after treatment 
period during Site Visit follow-up period (FUP) 
if C2D1 is positive. 
To investigate duration of blood typing interference 
following termination of isatuximab treatment. 
1.3 SoA (Blood draw 
for functional immune 
cell assay) 
Add sample collection during Site Visit FUP 
Week 1 or E/D if C3D1 sample not collected. 
To ensure a post-treatment sample is collected in 
case C3D1 sample is not collected or if patient 
discontinued treatment prior to C3D1. 
1.3.1.1 Treatment 
period: Cycle 1 (rich 
sampling)   
C1D1 EOI+4h (± 30 min) timepoint is modified 
to EOI+1h (+30 min) timepoint. 
Modification of sample collection timepoint to reduce 
wait time/burden for study participants. 
1.3.1.1 Treatment 
period: Cycle 1 (rich 
sampling)  
1.3.1.2 Treatment 
period: Cycle 2 and 
beyond (sparse 
sampling) 
Addition of allowing PK/ADA sample to be 
collected at participant’s home by a health 
care professional (depending on local 
arrangements). 
To provide flexibility and potentially reduce site visit 
for study participants. 
2.2 Background 
Updates of isatuximab approval status and 
number of treated patients. 
To provide updates aligned with updates of 
isatuximab IB ed11. 
2.3.3 Preventive 
measures to 
minimize the risk of 
isatuximab; 6.1 Study 
intervention(s) 
administered; 6.6.4 
General guidelines 
for the management 
of infusion reactions 
Updated infusion rates based on fixed volume 
infusion method. 
Switching to faster infusion schedule with a fixed 
distribution volume will reduce hospital chair time 
(particularly in some specific challenging situations 
like pandemic restrictions) and increase convenience 
for patients and sites. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion criteria 
For participants in Cohort B (I04): cPRA upper 
limit corrected from 99.80% to 99.89%. 
Correction of typographical error. 
5.2 Exclusion criteria 
E14:  Added obinutuzumab to require 6 
months washout period. 
Inclusion of obinutuzumab in E14 as it has similar 
mechanism of action as rituximab which is 
mentioned in the original E14. 
7.1.2 Temporary 
discontinuation 
8.0 Study 
assessments and 
procedures 
9.4 Statistical 
analyses  
10.1.3 Informed 
consent process 
10.13 Appendix 13. 
Contingency 
measures for a 
regional or national 
emergency that is 
declared by a 
governmental 
agency.   
The following text was added: “Temporary 
intervention discontinuation may be 
considered by the Treating Investigator 
because of suspected AEs or disruption of the 
clinical trial due to a regional or national 
emergency declared by a governmental 
agency (Section 10.13). For all temporary 
intervention discontinuations, duration should 
be recorded by the Investigator in the 
appropriate pages of the eCRF”. 
“Onsite visits” changed to “telephone/remote 
visits” for flexibility to continue the trial during 
regional or national emergency such as covid-
19 pandemic.  
Contingency Measures for a regional or 
national emergency are added. 
Include flexibility and ease of continuation of study 
during regional or national emergency such as 
Covid-19. 
6.6.4 General 
guidelines for the 
management of 
infusion reactions 
Updated management guideline on Grade 2 
and 3 IR including permanent discontinuation 
of study treatment at third IR. 
Clinical management of Grade 3 infusion reaction 
was updated to align with isatuximab IB ed11. 
Re-infusion rates following grades 2 and 3 infusion 
reactions were updated to align with the faster 
infusion protocol. 
8.3.7 Disease-related 
events and/or 
disease-related 
outcomes not 
qualifying as AEs or 
SAEs 
“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 DRE):” 
Clarification. 
10.2 Appendix 2 
Clinical laboratory 
tests 
Pregnancy test frequency is corrected to be 
consistent with SoA. 
Pregnancy test frequency was not consistent with 
Section 1.3 SoA (Screening, C2D1, C3D1 were 
missing). 
All document 
Minor editorial and format changes. List of 
abbreviations updated. 
Accuracy. 
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10.13 APPENDIX 13: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency declared by a 
governmental agency: 
 A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, epidemic/pandemic, terrorist attack) may prevent access to the 
clinical trial site. 
Contingency procedures are suggested below and in Section 8 for an emergency that prevents 
access to the study site, to ensure the safety of the participants, to consider continuity of the 
clinical study conduct, protect trial integrity, and assist in maintaining compliance with Good 
Clinical Practice in Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained 
prior to the implementation of these procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and screening and 
administration of study intervention may be temporarily delayed.  
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc.) may be planned for the collection of possible safety and/or efficacy data. For 
example, patient interview for medical history/prior medications could be performed by 
phone, local safety labs and some efficacy assessments could be performed off-site/at the 
participant’s home (eg, home nursing) if agreed by patient and permissible per local 
regulations. 
• If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely, if needed (eg, ±14 days for visits). 
• Use of local clinic or laboratory locations may be allowed. 
Contingencies implemented due to emergency will be documented.  
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg. study visit delays/treatment extension, use of 
local labs).  
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in multiple myeloma. Cytometry B Clin Cytom. 2016;90(1):61-72. 
41. Kwun J, Matignon M, Manook M, Guendouz S, Audard V, Kheav D, et al. Daratumumab in 
Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical 
Use. J Am Soc Nephrol. 2019;30(7):1206-19. 
42. Jordan SC, Vescio R, Toyada M, Ammerman N, Huang E, Peng A, et al. Daratumumab for 
treatment of antibody-mediated rejection in a kidney transplant recipient. [2019 American 
Transplant Congress abstract]. Am J Transplant. 2019;19 (suppl 3). 
43. Chapuy CI, Kaufman RM, Alyea EP, Connors JM. Daratumumab for Delayed Red-Cell 
Engraftment after Allogeneic Transplantation. N Engl J Med. 2018;379(19):1846-50. 
44. Sanofi Press Release. Isatuximab Phase 3 trial meets primary endpoint of prolonging 
progression free survival in patients with relapsed/refractory multiple myeloma. [internet]. 
2019 Feb 5. Available from: https://mediaroom.sanofi.com/en/press-releases/ 
45. Turza KC, Shafique M, Lobo PI, Sawyer RG, Keith DS, Brayman KL, et al. Infectious 
complications in living-donor kidney transplant recipients undergoing multi-modal 
desensitization. Surg Infect (Larchmt). 2014;15(3):182-6. 
46. Kahwaji J, Sinha A, Toyoda M, Ge S, Reinsmoen N, Cao K, et al. Infectious complications in 
kidney-transplant recipients desensitized with rituximab and intravenous immunoglobulin. 
Clin J Am Soc Nephrol. 2011;6(12):2894-900. 
47. Macklin PS, Morris PJ, Knight SR. A systematic review of the use of rituximab for 
desensitization in renal transplantation. Transplantation. 2014;98(8):794-805. 
48. Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes 
CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in 
multiple myeloma. Blood. 2016;128(3):384-94. 
49. Feng X, Zhang L, Acharya C, An G, Wen K, Qiu L, et al. Targeting CD38 Suppresses 
Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple 
Myeloma. Clin Cancer Res. 2017;23(15):4290-300. 
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50. Halloran PF, Reeve JP, Pereira AB, Hidalgo LG, Famulski KS. Antibody-mediated rejection, 
T cell-mediated rejection, and the injury-repair response: new insights from the Genome 
Canada studies of kidney transplant biopsies. Kidney Int. 2014;85(2):258-64. 
51. Sellarés J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, et al. Understanding the 
causes of kidney transplant failure: the dominant role of antibody-mediated rejection and 
nonadherence. Am J Transplant. 2012;12(2):388-99. 
52. Schinstock CA, Gandhi MJ, Stegall MD. Interpreting Anti-HLA Antibody Testing Data: A 
Practical Guide for Physicians. 2016 Aug;100(8):1619-28. 
53. Reed EF, Rao P, Zhang Z, Gebel H, Bray RA, Guleria I, et al. Comprehensive assessment and 
standardization of solid phase multiplex-bead arrays for the detection of antibodies to HLA. 
Am J Transplant. 2013 Jul;13(7):1859-70. 
54. Tambur AR, Glotz D, Herrera ND, Chatroop EN, Roitberg T, Friedewald JJ, et al. Can solid 
phase assays be better utilized to measure efficacy of antibody removal therapies? Hum 
Immunol. 2016 Aug;77(8):624-30. 
55. Tambur AR, Wiebe C. HLA Diagnostics: Evaluating DSA Strength by Titration. 
Transplantation. 2018 Jan;102(1S Suppl 1):S23-S30. 
56. Wongsaroj P, Kahwaji J, Vo A, Jordan SC. Modern approaches to incompatible kidney 
transplantation. World J Nephrol. 2015;4(3):354-62. 
57. Jeong JC, Jambaldorj E, Kwon HY, Kim MG, Im HJ, Jeon HJ, et al. Desensitization Using 
Bortezomib and High-dose Immunoglobulin Increases Rate of Deceased Donor Kidney 
Transplantation. Medicine (Baltimore). 2016;95(5):e2635. 
58. Meibohm B, Zhou H. Characterizing the impact of renal impairment on the clinical 
pharmacology of biologics. J Clin Pharmacol. 2012;52(1 Suppl):54S-62S. 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
LIST OF FIGURES .......................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 8 
1.2.1 
Estimands ...................................................................................................................................... 10 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 10 
3 
ANALYSIS POPULATIONS .......................................................................................................... 11 
4 
STATISTICAL ANALYSES ........................................................................................................... 12 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 12 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 12 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 13 
4.3.1 
Definition of endpoint(s) ................................................................................................................. 13 
4.3.2 
Main analytical approach ............................................................................................................... 14 
4.3.3 
Sensitivity analysis ......................................................................................................................... 15 
4.3.4 
Supplementary analyses ................................................................................................................ 15 
4.3.5 
Subgroup analyses ........................................................................................................................ 15 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 15 
4.4.1 
Key/Confirmatory secondary endpoint(s) ...................................................................................... 15 
4.4.2 
Supportive secondary endpoints .................................................................................................... 15 
4.4.2.1 
Definition of endpoints ................................................................................................................... 15 
4.4.2.2 
Main analytical approach ............................................................................................................... 17 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 18 
4.5.1 
Definition of endpoints ................................................................................................................... 18 
4.5.2 
Main analytical approach ............................................................................................................... 18 
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4.6 
MULTIPLICITY ISSUES ................................................................................................................ 19 
4.7 
SAFETY ANALYSES ..................................................................................................................... 19 
4.7.1 
Extent of exposure ......................................................................................................................... 19 
4.7.1.1 
Overall exposure ............................................................................................................................ 19 
4.7.1.2 
IMP exposure ................................................................................................................................. 20 
4.7.2 
Adverse events .............................................................................................................................. 22 
4.7.3 
Additional safety assessments ....................................................................................................... 25 
4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 25 
4.8 
OTHER ANALYSES....................................................................................................................... 27 
4.8.1 
PK analyses ................................................................................................................................... 27 
4.8.1.1 
Non-compartmental analysis: following the 1st administration ....................................................... 27 
4.8.1.2 
Over treatment concentrations: Ctrough and Ceoi ............................................................................. 28 
4.8.1.3 
Population PK analysis .................................................................................................................. 28 
4.8.2 
Immunogenicity analyses ............................................................................................................... 28 
4.8.2.1 
Analysis of Immunogenicity variables ............................................................................................ 29 
4.8.3 
Biomarker analyses........................................................................................................................ 29 
4.9 
INTERIM ANALYSES .................................................................................................................... 29 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 30 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 30 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 31 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 31 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 33 
5.4.1 
General conventions ...................................................................................................................... 33 
5.4.2 
DESENSITIZATION response criteria ........................................................................................... 36 
5.4.3 
Health Resources and Services Administration (HRSA): Research Plan ..................................... 37 
5.4.4 
Propensity score analysis .............................................................................................................. 42 
5.4.5 
Generic ranges for hematological and biochemistry parameters .................................................. 44 
6 
REFERENCES ............................................................................................................................... 45 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ................................................................................................................. 8 
Table 2 - Summary of primary estimand for main efficacy endpoint ............................................................. 10 
Table 3 - Populations for analyses ................................................................................................................ 11 
Table 4 - IMP dose reduction criteria ............................................................................................................ 21 
Table 5 - Sorting of AE tables ....................................................................................................................... 23 
Table 6 - Analyses of adverse events ........................................................................................................... 24 
Table 7 - Selections for other AESIs ............................................................................................................. 25 
Table 8 - Examples of target cPRA reduction ............................................................................................... 36 
Table 9 - Examples of antibody titer .............................................................................................................. 36 
Table 10 - 75% reduction in antibody titer from baseline .............................................................................. 37 
Table 11 - Example of ≥75% reduction in antibody titer from baseline to achieve target cPRA ................... 37 
Table 12 - Generic ranges for hematological parameters ............................................................................. 44 
Table 13 - Generic ranges for biochemistry parameters ............................................................................... 44 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................... 8 
Figure 2 - Duration of study period (per participant) ....................................................................................... 8 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for study TED16414 is based on the protocol amendment #2 
dated 01-Feb-2022. This section summarizes the major changes to the statistical analysis features 
in the SAP. 
The first participant was enrolled on 22-Jun-2020. The first interim analysis was performed on 
26-Aug-2021. 
Major changes in statistical analysis plan 
SAP 
Version 
Approval 
Date 
Changes 
Rationale 
1 
22-Apr-2021 
Not Applicable  
Original version 
2 
Current version 
Criteria for cPRA reduction is corrected from “at least 
50% increase of likelihood” to “at least 100% 
increase of likelihood”. 
To clarify that the target cPRA is defined 
as achieving at least 100% increase in the 
likelihood of finding a compatible donor, 
but this will not affect any mathematical 
derivations/calculations already in place. 
 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a Phase 1b/2 open-label, non-randomized, multi-center study to evaluate the safety, 
pharmacokinetics (PK), and preliminary efficacy of isatuximab in patients awaiting kidney 
transplantation. 
Patients sensitized to the human leukocyte antigen (HLA) with a high calculated panel reactive 
antibodies (cPRA) have low likelihood of finding a compatible donor. Currently no approved or 
standard therapy is available for desensitization. An effective desensitization therapy with a 
durable response has the potential to increase the likelihood for transplant candidates to find a 
compatible donor, reduce time on dialysis, and a better clinical outcome.  
The study will be conducted in 2 phases (see Figure 1 for study design schema). 
Phase 1 (safety run-in)  
As the safety profile of isatuximab is well-established, Phase 1 (safety run-in) is designed to 
characterize the safety and tolerability of isatuximab in patients with chronic kidney disease 
(CKD), and to confirm the Phase 2 dose in this patient population. A minimum of 6 safety 
evaluable participants with cPRA ≥80% will be enrolled at the dose level to be tested without 
interruption in Phase 1. In order to be considered as safety evaluable, participants must have 
received at least 90% of the planned cumulative doses of the first cycle (unless they discontinue 
investigational medicinal product (IMP) due to pre-defined unacceptable toxicity). 
Pre-defined unacceptable toxicity is defined as any verified Grade 4 adverse events (AEs) or 
laboratory abnormalities (except infusion reactions (IRs)) occurring during the first cycle of 
treatment, unless solely due to the underlying disease or due to a cause obviously unrelated to 
IMP, if confirmed by the Sponsor and recruiting Investigators. 
The starting dose of IMP is 10 mg/kg QW for 4 weeks followed by Q2W. If the starting dose is 
determined not to be sufficiently well-tolerated, 6 additional (minimum) safety evaluable 
participants will be enrolled at dose level (DL) -1 (ie, 5 mg/kg QW for 4 weeks followed by 
Q2W) (see protocol Table 4 for details on the DLs and schedule for Phase 1). 
Overall safety monitoring will also be performed throughout the conduct of the study. The totality 
of the safety findings, including all AEs occurring during treatment, unless solely due to the 
underlying disease or due to a cause obviously unrelated to IMP, will be taken into consideration 
for confirming the Phase 2 dose. Phase 2 of the study will be initiated after 6 safety evaluable 
participants have completed first cycle observation period where the dose level is determined to 
be sufficiently well-tolerated. 
Upon completion of the first cycle safety observation period for each participant enrolled in 
Phase 1, participants will continue study procedures until study completion. 
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Phase 2 
Phase 2 is designed to assess preliminary efficacy of isatuximab in desensitizing HLA sensitized 
patients awaiting kidney transplantation, which includes assessing change in cPRA and anti-HLA 
antibody levels. Approximately 24 to 36 participants (Phase 1 and Phase 2) are expected to be 
enrolled if the starting dose (10 mg/kg) is retained as the Phase 2 dose, or approximately 30 to 
42 participants are expected to be enrolled if DL-1 (5 mg/kg) is the Phase 2 dose. 
In Phase 2, two cohorts will be included: 
Cohort A: Participants with cPRA ≥99.90%; active candidates on the kidney waitlist. Up to 
6 participants with living donor can be enrolled into Cohort A. 
Cohort B: Participants with cPRA 80.00% to 99.89%; active candidates on the kidney waitlist 
with no living donor cleared for donation.  
The study will have a screening period of up to 28 days, a treatment period of up to 12 weeks, a 
site visit follow-up period (FUP) of up to 26 weeks, and an extended FUP which include 
telephone contacts every 90 days and information collection until study cut-off, death, or lost to 
follow-up. The study cut-off is planned at 26 weeks after the last participant completes the 
treatment period, or when the last ongoing participant is lost to follow-up, whichever is earlier. 
The Sponsor (Sanofi) may choose to extend the study cut-off date depending on the enrollment 
rate observed to facilitate adequate follow-up data collection. Participants who wish to proceed to 
transplantation when a compatible donor becomes available while on study must discontinue IMP 
immediately, complete an early discontinuation (E/D) visit prior to transplantation if clinically 
feasible, and proceed to extended FUP. The study duration that involves site visit per participant 
(ie, screening, treatment, site visit FUP) will be approximately 42 weeks. The study duration 
including extended FUP per participant will be approximately 78 weeks (depending when the 
participant is enrolled). 
Treatment period: The cycle duration is 28 days and a complete treatment period is comprised 
of 3 cycles of IMP treatment. Participants will continue treatment until receiving 3 cycles of IMP, 
unacceptable AE per Investigator’s judgment, or participants’ decision to stop the treatment. 
Site visit FUP: Participants completing the treatment period and who are able to remain on study 
will return to the study sites for study procedures. 
Extended FUP: The following participants will be followed-up every 90 days by phone calls, 
until study cut-off date, death, or lost to follow-up, whichever comes first: 
• Participants who completed or discontinued from site visit FUP 
• Participants who proceed to transplantation during treatment period or site visit FUP. 
During extended FUP, specified information per protocol will also be collected by study site (see 
protocol section 1.3). 
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Below figures show the study schema and duration of study period: 
Figure 1 - Graphical study design  
 
Figure 2 - Duration of study period (per participant)  
 
Details on schedule of activities (SoA) are provided in protocol section 1.3. 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
Phase 1: To characterize the safety and tolerability 
of isatuximab in kidney transplant candidates.  
• 
AEs/serious AEs (SAEs) and laboratory 
abnormalities.  
• 
Phase 2: To evaluate the efficacy of isatuximab in 
desensitization of patients awaiting kidney 
transplantation.  
• 
Response rate (RR defined as the proportion of 
participants meeting at least one of the predefined 
desensitization efficacy criteria, from baseline up to 
26 weeks after treatment period, measured by single 
antigen bead (SAB) assay per central laboratory 
assessment as follows:  
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Objectives 
Endpoints 
1. 
Reduction in cPRA resulting in at least 100% 
increase of likelihood of finding a compatible 
donor (for target cPRA, see protocol section 
10.9). 
2. 
Reduction in antibody titer (≥75% reduction 
from baseline) to achieve target cPRA (see 
protocol section 10.9).  
3. 
Elimination of ≥1 anti-HLA-antibody (ie, mean 
fluorescence intensity [MFI] reduced to <2000) 
as measured by a SAB assay, for antibodies 
with baseline MFI ≥3000.  
Secondary 
• 
Phase 2: To characterize the safety profile of 
isatuximab in kidney transplant candidates.  
• 
AEs/SAEs, and laboratory abnormalities.  
• 
To characterize the PK profile of isatuximab in 
kidney transplant candidates.  
• 
PK parameters of isatuximab (see protocol Table 7)  
• 
To evaluate the immunogenicity of isatuximab.  
• 
Incidence of anti-drug antibodies (ADA) against 
isatuximab.  
• 
To assess the overall efficacy of isatuximab in 
desensitization of patients awaiting kidney 
transplantation.  
• 
Duration of response (DoR) per central laboratory 
assessment.  
• 
Proportions of participants and duration achieving 
target cPRA per local laboratory assessment.  
• 
Number of anti-HLA-antibody with baseline MFI 
≥3000 reduced to <2000 as measured in a SAB 
assay per central laboratory assessment.  
• 
Transplantability including time to first transplant 
offer, time to transplant, and number of transplant 
offers, if applicable.  
• 
Time to first antibody mediated rejection (AMR) 
episode and rate of AMR, if applicable.  
• 
Graft survival at 6 months post-transplant, if 
applicable.  
Tertiary/exploratory 
• 
To assess other preliminary efficacy of isatuximab 
in desensitization of patients awaiting kidney 
transplantation. 
 
 
  
 
 
  
 
 
 
 
 
• 
To assess the biological effects of isatuximab on 
immune cell populations and identify potential 
predictive and/or PD biomarkers 
 
 
 
 
 
• 
To perform PK/PD analysis. 
 
 
 
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1.2.1 Estimands  
Primary estimand defined for the main efficacy endpoint is summarized in below Table 2. 
Table 2 - Summary of primary estimand for main efficacy endpoint  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level summary  
(Analysis and missing data 
handling) 
Primary efficacy objective: Phase 2: To evaluate the efficacy of isatuximab in desensitization of patients awaiting 
kidney transplantation 
Primary 
efficacy 
endpoint 
(Estimand 1)  
Response 
rate  
Efficacy-
evaluable 
Interruption/discontinuation 
of study intervention: 
Response rate will be 
analyzed regardless of 
intervention discontinuation 
(treatment policy) 
Response rate, defined as proportion of 
participants meeting at least one of the 
predefined desensitization efficacy criteria, 
from baseline up to 26 weeks after treatment 
period and two-sided 95% confidence 
intervals using the Clopper-Pearson method 
(1) 
2 
SAMPLE SIZE DETERMINATION  
Statistical hypotheses and sample size determination: 
Phase 1: There is no formal statistical hypothesis. Approximately 6 to 12 safety evaluable 
participants are expected to be enrolled. 
Phase 2: 
• Null hypothesis: True RR
 
• Alternative hypothesis: True RR 
 
With a minimum sample size of 12 participants per cohort and 1-sided alpha of 0.025, the analysis 
will have at least 80% power to demonstrate that RR is significantly better than 
assuming the 
true RR is 
, based on exact test. A null hypothesis of 
is selected representing placebo 
control as there is currently no approved or standard therapy for desensitization, and there is no 
expected decrease in anti-HLA antibody levels or cPRA in patients who do not undergo 
desensitization therapy. 
A maximum of 6 replacements per cohort is allowed for participants who: 
• enroll in Phase 1 and receive <90% of the planned cumulative doses within the first cycle 
(unless they discontinue IMP due to pre-defined unacceptable toxicity), or 
• receive <75% of planned cumulative doses within 3 cycles, or 
• have consecutive dose interruption of >28 days, or 
• do not complete site visit FUP, after agreement with Medical Monitor. 
Participants treated at the Phase 2 dose during Phase 1 will be included in the analysis together 
with the participants in Phase 2. 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 3 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the informed consent form (ICF). 
Enrolled 
Includes all participants from screened population who plan to continue in the 
treatment phase upon completion of screening, regardless of whether the study 
intervention (isatuximab) was received or not. 
All treated 
Includes all participants who receive at least 1 dose of isatuximab-. This population 
is the primary population for the analyses of safety parameters, unless otherwise 
noted. All analyses using this population will be based on the dose level actually 
received. 
Safety-evaluable (Phase 1) 
Includes all participants enrolled in Phase 1 who receive ≥90% planned cumulative 
doses of isatuximab within Cycle 1 (unless IMP is discontinued due to pre-defined 
unacceptable toxicity). 
Efficacy-evaluable 
Includes All Treated population who fulfill the study eligibility criteria, with an 
evaluable baseline and at least 1 evaluable postbaseline efficacy assessment and 
receive ≥75% of planned cumulative doses. This is the primary population for 
efficacy analyses. 
PK 
Includes All Treated population with at least 1 available concentration result post-
treatment (whichever the cycle and even if dosing is incomplete) with adequate 
documentation of date and time of dosing and date and time of sampling. 
ADA 
Includes All Treated population with at least 1 available ADA result (negative, 
positive, or inconclusive) post-treatment (whichever the cycle and even if dosing is 
incomplete). 
Participants exposed to isatuximab before or without being enrolled will not be considered 
enrolled and will not be included in any analysis population. The safety experience of these 
participants will be reported separately. 
Enrolled participants for whom it is unclear whether they took isatuximab will be considered as 
treated and will be included in the safety population. 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS   
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, minimum, and maximum. Categorical and ordinal data will be 
summarized using the count and percentage of participants. Time to event variables will be 
analyzed using the Kaplan-Meier method. 
The baseline value is defined as the last available value before the first dose of IMP. For 
participants enrolled but not treated, the baseline value is defined as the last available value before 
enrollment. 
Analyses will be performed by cohort (and overall) within Phase 2, for demographics and baseline 
characteristics. If Phase 1 dose level is reduced due to unacceptable toxicities, summaries may 
also be performed on Phase 1 participants, by dose level group.  
Observation period  
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the time from when the participants give 
informed consent to first IMP administration.  
• The on-treatment period (ie, treatment-emergent [TE] period) is defined as the period 
from the first IMP administration to the last IMP administration + 30 days. 
• The post-treatment period is defined as the time starting 31 days after the last dose of 
IMP to study cut-off. 
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 3 will 
be summarized. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently enrolled. If applicable, the number (%) of screen failures will be provided in the 
screened population. 
Enrolled participants will include screened participants who plan to continue in the treatment 
phase, ie, those for whom the investigator ticked “Yes” to the question “Will the subject continue 
in the Treatment phase?” in the Completion of Screening eCRF page. 
The number (%) of participants in the following categories will be provided:  
• Screened participants, and screen failures (if applicable) 
• Enrolled participants 
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• Enrolled but not treated participants  
• Enrolled and treated participants 
• Participants who completed the study treatment period as per protocol 
• Participants who did not complete the study treatment period as per protocol and main 
reason for definitive treatment discontinuation 
• Participants who completed the site visit follow-up period. 
• Participants who did not complete the site visit follow-up period and main reason for site 
visit follow-up discontinuation 
• Participants who completed the study/extended follow-up period. 
• Participants who did not complete the study/extended follow-up period and main reason 
for study/extended follow-up discontinuation 
• Participant status at last study contact 
If applicable, the number (%) of treated but not enrolled participants will also be presented.  
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the enrolled 
and/or treated population. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
4.3.1 Definition of endpoint(s)  
The primary endpoint in the Phase 1 portion of the study will focus on safety, ie, AEs/SAEs and 
laboratory abnormalities. Analysis details of these safety parameters are presented in Section 4.7.2 
and Section 4.7.3.1. 
In the Phase 2 portion of the study, the primary efficacy endpoint will be RR, to be defined as the 
proportion of participants meeting at least one of the predefined desensitization efficacy criteria, 
from baseline up to 26 weeks after treatment period, measured by SAB assay per central 
laboratory assessment as follows:  
• Reduction in cPRA resulting in at least 100% increase of likelihood of finding a 
compatible donor for target cPRA 
• Reduction in antibody titer (≥75% reduction from baseline) to achieve target cPRA  
• Elimination of ≥1 anti-HLA-antibody (ie, MFI reduced to <2000) as measured by a SAB 
assay, for antibodies with baseline MFI ≥3000 
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RR criterion 1: target cPRA 
The target cPRA, defined as the reduction of cPRA required to achieve at least 100% increase of 
likelihood of compatible donor (LCD), is calculated according to the following equation: 
𝐿𝐶𝐷= 1 𝑖𝑛 
1
1 −𝑐𝑃𝑅𝐴 
Participants with baseline cPRA 100.00% will be assigned with cPRA 99.99% for computational 
purpose. In addition, cPRA values will be rounded to 2 decimal places prior to LCD calculation 
(≥xx.xx5=round up, <xx.xx5=round down). 
RR criterion 2: antibody titer 
Antibody titer is defined as the last dilution of serum at which positive results is obtained 
(eg, MFI ≥2000). To potentially meet the second RR criterion, serial dilution of the serum 
collected at baseline is performed until the target cPRA is achieved. If subsequent post-treatment 
serum is diluted at ≥75% reduction from the baseline dilution that achieved target cPRA, and 
again meet target cPRA anytime within the 26-week post-treatment period, participant will have 
met RR criterion 2. 
RR criterion 3: anti-HLA-antibody 
An anti-HLA-antibody is considered to be eliminated if its MFI is reduced to <2000 at post-
treatment. Only antibodies with baseline MFI ≥3000 will be included for assessment under this 
criterion. 
4.3.2 Main analytical approach  
The primary efficacy analysis is based on a treatment policy estimand introduced in Section 1.2.1.  
This primary estimand is defined according to the following attributes: 
• The endpoint is RR, as defined in Section 4.3.1. 
• The treatment condition of interest is isatuximab 
• The analysis population is the efficacy-evaluable population (defined in Section 3) 
• The study intervention interruption/discontinuation intercurrent event will be handled with 
the treatment policy strategy. RR will be assessed based on the 3 criteria irrespective of 
study intervention interruption/discontinuation. 
• Population-level summary will be RR, defined as the proportion of participants meeting at 
least one of the predefined desensitization efficacy criteria (refer to Section 4.3.1), along 
with and two-sided 95% confidence intervals using the Clopper-Pearson method. 
Proportion of participants meeting each criterion will also be tabulated. 
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Calculation details and examples on RR criteria 1 and 2 are provided in Appendix 4, Section 5.4.2 
(DESENSITIZATION response criteria). 
For RR criterion 3, elimination of anti-HLA-antibody will be determined for each applicable 
molecular specificity. 
4.3.3 Sensitivity analysis  
In addition to planned protocol analysis of the primary endpoint, if cohort assignment based on 
local laboratory’s cPRA value collected at screening visit varies from the corresponding central 
laboratory’s baseline cPRA value in greater than 10% of the efficacy-evaluable participants per 
cohort, a sensitivity analysis of the primary efficacy endpoint will be conducted assigning 
participants to the respective cohort based on the central laboratory’s cPRA value. 
4.3.4 Supplementary analyses  
Not applicable. 
4.3.5 Subgroup analyses  
Not applicable.  
4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
4.4.1 Key/Confirmatory secondary endpoint(s)  
No key/confirmatory secondary endpoint. 
4.4.2 Supportive secondary endpoints  
4.4.2.1 Definition of endpoints  
The following secondary endpoints in the Phase 2 portion of the study are defined below, with the 
exception of PK parameters and immunogenicity/ADA against isatuximab which are described in 
Section 4.8.1 and Section 4.8.2, respectively: 
DoR per central laboratory assessment 
DoR (based on central laboratory assessment): defined as time from laboratory sample 
collection date used in determining a participant to be a responder up to the laboratory 
sample collection date when participant is no longer meeting any response criterion 
(ie, non-responder) or the date of death due to any cause, whichever occurs first. 
For participants with ongoing response at the time of the analysis, DoR will be 
censored at the date of the last available laboratory assessment showing response. Non-
responders will be excluded in the DoR summaries. 
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For responders meeting more than 1 criterion, DoR will be calculated from: [(earliest 
of start dates) up to (latest of end dates) + 1] across any response criteria durations. 
For responders having multiple DoRs within the same criterion but with gaps, only the 
1st DoR (or 1st set of DoRs for those meeting more than 1 criterion) will be 
summarized. A sensitivity analysis may be performed using the longest DoR (in lieu of 
1st DoR), if applicable. 
Proportion of participants and duration achieving target cPRA per local laboratory 
assessment (using OPTN-calculated and using locally reported cPRA values) 
Proportion of participants achieving target cPRA: will be summarized separately 
for cPRA values, based on OPTN calculator and based on locally reported values 
Duration of achieving target cPRA: defined as time from laboratory sample 
collection date of achieving target cPRA the first time up to the laboratory sample 
collection date when no longer achieving target cPRA or the date of death due to any 
cause, whichever occurs first. 
Participants who retain their target cPRA values will be censored at the date of the last 
available laboratory assessment achieving their target cPRA. Participants who do not 
achieve target cPRA will be excluded from the analysis. 
For participants with multiple durations (with gaps), only the 1st duration will be 
summarized. A sensitivity analysis may be performed using the longest duration (in 
lieu of the 1st duration), if applicable. 
Refer to Section 5.4.2, Table 8 for a table of target cPRA. 
Number of anti-HLA-antibody with baseline MFI ≥3000 reduced to <2000 as measured 
in a SAB assay per central laboratory assessment 
Reduction of anti-HLA-antibody is defined similarly as in RR criterion 3 
(Section 4.3.1), and will be summarized by the proportion of participants with pre-
specified ranges of anti-HLA-antibody reduction (eg, none, 1-5, >5-10, >10-15, … >x). 
Transplantability including time to first transplant offer, time to transplant, and number 
of transplant offers, if applicable 
Time to first transplant offer: defined as time from date of first IMP dose up to date 
of first transplant offer.  Study eCRF folder/page for transplant offer: 
TRANSPLANT/TRANSPLANT STATUS 
Time to transplant: defined as time from date of first IMP dose up to date of kidney 
transplant on/after first IMP start date.  Study eCRF FOLDER/page for date of kidney 
transplant surgery during study: TRANSPLANT/TRANSPLANT STATUS; KIDNEY 
TRANSPLANT SURGERIES [Transplant and Patient status subcategory=During 
study, and corresponding Date of kidney transplant] 
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Participants who do not receive any transplant offer or any transplant, and: 
• who died will be censored at the longest follow-up date across all participants 
in the study prior to the analysis cut-off date. 
• who are still alive will be censored at the participant’s last laboratory 
assessment date collected in the study or at the analysis cut-off date, 
whichever is earlier. 
Time to first AMR episode and rate of AMR (if applicable) 
Time to first AMR: defined as time from date of first IMP dose up to date of biopsy 
with first AMR.  Study eCRF FOLDER/page for date of biopsy with AMR: 
TRANSPLANT/GRAFT REJECTION BIOPSY 
Transplanted participants without any AMR will be censored at the participant’s last 
assessment/contact date collected in the study or at the analysis cut-off date, whichever 
is earlier. Participants who do not receive a transplant in the study will be excluded 
from this analysis. 
Rate of AMR: defined as proportion of participants with AMR field ticked as “yes” 
based on graft rejection biopsy eCRF page.  Study eCRF FOLDER/page for AMR: 
TRANSPLANT/GRAFT REJECTION BIOPSY 
Graft survival rate at 6 months post-transplant (if applicable) 
Graft survival rate at 6 months post-transplant: defined as proportion of 
participants with graft survival status at ≤6 months post-transplant=”Functioning”. 
Study eCRF FOLDER/page for date of biopsy with AMR: TRANSPLANT/GRAFT 
SURVIVAL AT LESS THAN OR EQUAL TO 6 MONTHS 
In addition, the proportion of participants with a functioning graft beyond 6 months 
post-transplant may be tabulated, if data are available. An adhoc analysis of graft 
survival may also be performed using the Kaplan-Meier method. 
4.4.2.2 Main analytical approach  
All secondary efficacy endpoints (if applicable) during Phase 2 will be summarized descriptively 
and presented by cohort. Categorical variables (eg, rates and proportions) will be tabulated via 
frequency distributions (ie, number and percents). Continuous variables (eg, change from 
baseline) will be summarized by providing the number of observations (n), mean, median, SD, 
minimum, and maximum. 
DoR and other time to event variables will be analyzed using the Kaplan-Meier method 
(ie, median and associated 95% confidence interval). No hypothesis/significance testing will be 
performed. 
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4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
4.5.1 Definition of endpoints  
The following tertiary/exploratory efficacy endpoints will be explored in the Phase 2 portion of 
the study: 
 
 
 
 
 
 
 
 
 
  
  
 
 
4.5.2 Main analytical approach  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.6 
MULTIPLICITY ISSUES  
No multiplicity issues are anticipated in this study. 
4.7 
SAFETY ANALYSES  
For the Phase 1 portion of the study, pre-defined unacceptable toxicities) will be listed by 
participant using the Safety-evaluable Phase 1 population defined in Section 3. 
All safety analyses detailed below will be performed on the All Treated population as defined in 
Section 3, unless otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned.  
• Safety data in participants who do not belong in the All treated (eg, treated but not 
enrolled) will be provided. 
4.7.1 Extent of exposure  
4.7.1.1 Overall exposure  
The dose information will be assessed by the following variables: 
• Overall number of cycles started, defined by the number of cycles in which at least one 
dose of any study interventions is administered. 
• Duration of IMP exposure (in weeks) is defined as [(last date of IMP administration) – 
(first date of IMP administration)] / 7.  
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• The first day of IMP administration is defined as the first administration date with non-
zero dose for the IMP. The last date of IMP administration is defined as follows: 
- 
date of the last IMP dose + 7 if the last cycle is a QW cycle or date of death + 1, 
whichever is earlier 
- 
date of the last IMP dose + 14 if the last cycle is a Q2W cycle or date of death + 1, 
whichever is earlier 
The total number of cycles started, number of cycles started by participants will be summarized as 
a quantitative variable and by category (number (%) of participants receiving 1 cycle, 2 cycles, 
3 cycles). The duration of overall exposure will be summarized quantitatively.  
The following variables will be computed to describe overall dose modification (cycle delay): 
• Cycle delay: A cycle is deemed as delayed if the (start date of the current cycle – start date 
of the previous cycle) – duration of a cycle (ie, 28) is >2 days. Cycle delay is not defined 
for the first cycle. 
Cycle delay will be analyzed at the participant (with number of participants used as denominator) 
and cycle (with number of cycles used as denominator) levels, as follows: 
• Number (%) of participants with a least 1 cycle delayed 
- 
Number (%) of participants with a cycle delayed between 3 and 7 days (using 
maximum delay across all cycles)  
- 
Number (%) of participants with a cycle delayed between 8 and 14 days (using 
maximum delay across all cycles) 
- 
Number (%) of participants with a cycle delayed >14 days (using maximum delay 
across all cycles) 
• Number (%) of cycles delayed 
- 
Number (%) of cycles delayed between 3 and 7 days 
- 
Number (%) of cycles delayed between 8 and 14 days 
- 
Number (%) of cycles delayed >14 days 
• Dose delay: within a cycle, the treatment window is ±1 day for each of the weekly 
administrations and ±2 days for each of the Q2W administrations. Within a cycle, a dose is 
deemed to have been delayed if the treatment is ≥2 days beyond the theoretical day of 
treatment for weekly dose, or ≥3 days beyond the theoretical day of treatment for Q2W 
dose. 
4.7.1.2 IMP exposure  
The dose information will be assessed by the following: 
• Total number of cycles started 
• Number of cycles started per participant  
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• Duration of IMP exposure (in weeks) is defined as [(last date of IMP administration) – 
(first date of IMP administration)] / 7.  
• The first day of IMP administration is defined as the first administration date with non-
zero dose for the IMP. The last date of IMP administration is defined as follows: 
- 
date of the last IMP dose + 7 if the last cycle is a QW cycle or date of death + 1, 
whichever is earlier 
- 
date of the last IMP dose + 14 if the last cycle is a Q2W cycle or date of death + 1, 
whichever is earlier 
• Actual dose (mg/kg): is defined as the actual dose (mg) administered divided by the body 
weight at the time 
• Cumulative dose (mg/kg): the cumulative dose is the sum of all actual doses (mg/kg) of 
IMP, given from first to last administration 
• Actual dose intensity (ADI [mg/kg/week]): defined as the cumulative dose (mg/kg) 
divided by the duration of IMP exposure (weeks) 
• Planned dose intensity (PDI [mg/kg/week]): corresponds to the planned dose (mg/kg) 
multiplied by the theoretical total number of doses started and divided by the theoretical 
cycle duration expressed in weeks (ie, 4 weeks per cycle started) 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/kg/week) 
PDI (mg/kg/week) 
The total number of doses, total number of cycles started, number of cycles started by participant 
will be summarized as a quantitative variable and by category (number [%] of participants 
receiving 1 cycle, 2 cycles, 3 cycles). Duration of IMP exposure, cumulative dose, ADI and RDI 
will be summarized quantitatively. 
The following variables will be derived to describe dose modifications:  
• Dose reduction: The first IMP administration will not be counted as a dose reduction. For 
the second and subsequent IMP administrations, dose reduction will be determined using 
the dose level intervals provided in Table 4, by comparing the current dose level to the 
previous dose level. If the current dose level is below the dose level interval of the 
previous dose administration, then the current dose level is considered reduced. 
Table 4 - IMP dose reduction criteria  
Actual dose level 
Dose level interval 
Starting dose (10 mg/kg) 
>7.5 mg/kg 
Dose level -1 (5 mg/kg) 
>0 mg/kg and ≤7.5 mg/kg 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards.  
• Dose interruption: A dose will be considered as interrupted if the IMP administration is 
stopped during an infusion regardless of whether it is restarted or not. 
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Dose modifications will be analyzed by participant and cycle as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose reduction  
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with a least 1 dose interruption 
• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose delayed 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of cycles with at least 1 dose reduction  
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
4.7.2 Adverse events  
General common rules for adverse events 
All AEs will be graded according to National cancer institute common terminology for adverse 
events [(NCI-CTCAE) version 5.0] and coded to a lower-level term (LLT), preferred term (PT), 
high-level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock. 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened or became 
serious during the on-treatment period 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period  
Similarly, deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
The primary focus of AE reporting will be on TEAEs.  Pre-treatment and post-treatment AEs will 
be described separately.  
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An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a 
pre-treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If the toxicity grade is missing for 1 of the treatment-emergent occurrences of an 
AE, the toxicity grade will be imputed with the maximal severity of the other occurrences. If the 
severity is missing for all the occurrences, the toxicity grade will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase, using the maximum (worst) grade by treatment phase. Summaries 
will be provided for all grades combined and for grade ≥3 (including Grade 5). Missing grades, if 
any, will be included in the “all grades” category.  
The AE tables will be sorted as indicated in Table 5. 
Table 5 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa, b 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the overall incidence. 
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by SOC and PT, unless otherwise specified.   
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE (any grade) 
• Any grade ≥3 TEAE 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment-emergent period) 
• Any TE SAE (any grade) 
• Any serious, treatment-related, TE SAE (any grade) 
• Any TEAE leading to definitive study treatment discontinuation 
• Any TE AESI 
• Any TE AESI grade ≥3 
• Any treatment-related TEAE (any grade) 
• Any grade ≥3 treatment-related TEAE 
The AE summaries of Table 6 will be generated with number (%) of participants experiencing at 
least one event. The analyses will be performed for all grades combined and for grades ≥3.  
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Table 6 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC and PT 
 
Primary SOC 
 
PT 
TEAE related to IMP treatment as per Investigator’s judgment 
Primary SOC and PT 
Treatment-emergent SAE 
Primary SOC and PT 
Treatment-emergent SAE related to IMP treatment as per 
Investigator’s judgment 
Primary SOC and PT 
TEAE leading to definitive study treatment discontinuation 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) 
Primary SOC and PT 
 
Primary SOC and PT 
Pretreatment AEs & SAEs 
Overviewa 
 
Primary SOC and PT 
Post-treatment AEs & SAEs  
Overviewa 
 
Primary SOC and PT 
TEAE leading to dose reduction 
Primary SOC and PT 
TEAE leading to dose interruption 
Primary SOC and PT 
a Will include the following AE categories: any AEs, any SAEs, any AEs leading to death, any AEs leading to permanent intervention 
discontinuation 
Analysis of deaths 
In addition to the analyses of deaths included in Table 6 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods by reason for death 
• An overview of Grade 5 AEs will be provided with the following categories: 
- 
Grade 5 AE (TEAE and post-treatment). 
- 
Fatal TEAE (regardless of date of death/period). 
- 
Grade 5 TEAE with a fatal outcome during the treatment period,  
- 
Any Grade TEAE with a fatal outcome during the post-treatment period.  
- 
Post-treatment Grade 5 AE (excluding a TEAE that worsened to Grade 5 during the 
post-treatment period). 
• Deaths in enrolled but not treated participants 
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Analysis of infusion reactions (IRs) classified as an AESI 
IR analysis will include all adverse events regardless of relationship to isatuximab. The IRs will 
be summarized as follow: 
• Number (%) of participants experiencing IRs according to investigator reported AEs 
presented by primary SOC and PT will be summarized by grade. 
• Description of the IR diagnoses (using the diagnosis reported and excluding symptoms). 
- 
Number (%) of participants’ action taken, 
- 
Number (%) of participants with only 1, ≥1, ≥2, ≥3, ≥4 and ≥5 episodes, 
- 
Number (%) of participants with first occurrence of IR at the first infusion and 
subsequent infusions, 
- 
Number (%) of participants with IR at the first and subsequent infusions, 
- 
Number (%) of participants with at least two episodes of IRs at the same infusion, 
- 
Day of onset from infusion, 
- 
Duration (in days). 
• Number of participants with symptoms of IRs (as reported by investigator) by SOC and 
PT. 
Analysis of other adverse events of special interest (AESIs) 
Other adverse events of special interest (AESIs) will be selected for analyses as indicated in 
Table 7. Number (%) of participants experiencing at least one event will be provided for each 
event of interest. Tables will be sorted as indicated in Table 5.  
Table 7 - Selections for other AESIs  
AESIs 
Selection 
Symptomatic overdose 
e-CRF specific tick box on the AE page 
Pregnancy 
e-CRF specific tick box on the AE page 
4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following routine laboratory variables (performed by local laboratories) and vital signs 
variables will be analyzed. Electrocardiogram (ECG), performed only at screening visit, will not 
be summarized. Left ventricular ejection fraction (LVEF) collected in the screening 
echocardiography will be summarized in the baseline characteristics table. 
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• Hematology:  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, red blood cell 
count (erythrocytes), platelet count, prothrombin time (expressed as international 
normalized ratio)  
- 
White blood cells: neutrophils, lymphocytes, monocytes, basophils, eosinophils 
• Clinical chemistry: 
- 
Metabolism: glucose (fasting), HbA1c*, total protein, albumin 
- 
Electrolytes: sodium, potassium, chloride, calcium, phosphorus, bicarbonate, 
magnesium  
- 
Renal function: creatinine*, urea, blood urea nitrogen (BUN), uric acid*, eGFR 
(MDRD equation)* 
- 
Liver function*: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total and direct bilirubin 
- 
Hepatitis screen: hepatitis B surface antigen, anti-hepatitis-C antibody 
- 
Parathyroid hormone (intact) 
*  Local laboratory normal ranges will be used for these laboratory variables. 
• Vital signs: heart rate, systolic and diastolic blood pressure, as well as, weight, respiratory 
rate, and body temperature (and route) 
Data below the lower limit of quantification limit (LLOQ) will be replaced by half of the LLOQ, 
data above the upper limit of quantification (ULOQ) will be replaced by ULOQ value. 
For hematological parameters and some selected biochemistry parameters, Sanofi sponsor generic 
ranges [lower limit of normal (LLN), upper limit of normal (ULN)] are defined and will be used 
for grading (see list of parameters in Section 5.4.5). For other biochemistry parameters (noted 
with * in laboratory variable list above), grading will be derived using local laboratory normal 
ranges. 
For serology and viral load parameters, results may be summarized via shift tables at baseline and 
at participant’s worst post-baseline visit. 
Analyses according to PCSA and NCI grading 
For laboratory variables, analyses according to NCI grading will be made based on NCI-CTCAE 
version specified in the protocol. For laboratory variables for which NCI-CTCAE scale is not 
applicable, potentially clinically significant abnormality (PCSA) summaries may be performed 
using sponsor or local laboratory normal ranges. 
In addition, for vital signs (ie, heart rate, systolic and diastolic blood pressure), PCSA analyses 
will be performed based on the PCSA criteria listed below. 
 
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Vital signs parameter 
PCSA criteria 
Systolic Blood Pressure (mmHg) 
≤ 95 mmHg and decrease from baseline ≥ 20 mmHg 
 
≥ 160 mmHg and increase from baseline ≥ 20 mmHg 
 
 
Diastolic Blood Pressure (mmHg) 
≤ 45 mmHg and decrease from baseline ≥ 10 mmHg 
 
≥ 110 mmHg and increase from baseline ≥ 10 mmHg 
 
 
Heart Rate (beats/min) 
≤ 50 beats/min and decrease from baseline ≥ 20 beats/min 
 
≥ 120 beats/min and increase from baseline ≥ 20 beats/min 
Analyses according to PCSA and NCI grading will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables and vital signs above, the incidence of participants with at least one 
PCSA during the treatment-emergent period will be summarized regardless of the baseline level 
and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
For laboratory variables graded by NCI-CTCAE, 
• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade.   
• The number (%) of participants with abnormal laboratory tests during the treatment-
emergent period will be summarized by grade.  When appropriate, the number (%) of 
participants with abnormality of any grade and with Grade 3-4 abnormalities will be 
provided. 
4.8 
OTHER ANALYSES  
4.8.1 PK analyses  
4.8.1.1 Non-compartmental analysis: following the 1st administration  
Individual concentrations and PK parameters of drug at Cycle 1 will be listed and summarized by 
descriptive statistics (such as the number of observations, arithmetic and geometric mean, median, 
SD, standard error (SE), coefficient of variation (CV)%, minimum, and maximum) by cohort and 
possibly overall. 
Mean concentration profiles over time will be plotted by cohort and possibly overall under the 
responsibility of Sanofi, Pharmacokinetic, Dynamic and Metabolism (PKDM), Translational 
Medicine and Early Development (TMED) department.  
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4.8.1.2 Over treatment concentrations: Ctrough and Ceoi  
Ctrough defined as a sample collected before dosing, in a time window of 6 to 8 days after the 
previous infusion for the QW administration, in a time window of 12 to 16 days after the previous 
infusion for the Q2W administration, will be included in the descriptive analysis irrespectively of 
interruption of infusion. However, Ctrough drawn outside time collection window described in the 
protocol PK flowcharts or collected after a dose deviation higher than ±50% from intended dose 
will be excluded from the analyses.  
Ceoi collected after significant infusion interruption, drawn outside collection of time window 
described in the PK flowcharts of the protocol or collected after a dose deviation higher than 
±50% from intended dose will be excluded from the analyses. 
Individual Ctrough and Ceoi will be listed and summarized with descriptive statistics (such as the 
number of observations, arithmetic and geometric mean, median, SD, SE, CV%, minimum, and 
maximum) by cohort and possibly overall. 
Mean (±SE) of Ctrough will be plotted over treatment phase by cohort and possibly overall. 
Individual Ctrough ratio (C2D1 vs C1D8 and C3D1 vs C1D8) and Ceoi ratio (C2D1 vs C1D1 and 
C3D1 vs C1D1) will be listed and summarized by descriptive statistics as described above by 
cohort and possibly overall.  
All concentration values below the LLOQ will be treated as zero in individual listing and 
respective descriptive statistics and will be replaced by LLOQ value for individual ratio and 
respective descriptive statistics. 
4.8.1.3 Population PK analysis  
Details of the population PK analysis plan will be provided in a separate document. 
4.8.2 Immunogenicity analyses  
Immunogenicity impact on PK analysis may be explored, depending on the ADA prevalence.  
Descriptive statistics of Ctrough as described above will be provided at each cycle in the subset of 
negative participants by cohort and possibly overall where positive or inconclusive participants 
will be observed. 
The impact of immunogenicity on PK will be assessed graphically by plotting individual Ctrough 
profiles of ADA positive participants (and the concentration of the administered drug at the same 
time as ADA positive result will be notified) along with mean (+/-SD) Ctrough profile of ADA 
negative participants by cohort and possibly overall. Descriptive statistics of Ctrough of ADA 
negative participants will be provided by cycle at the bottom of the plot. 
The impact on safety and efficacy endpoints may be further explored by graphical methods or 
descriptively, depending on the ADA prevalence. 
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4.8.2.1 Analysis of Immunogenicity variables  
A summary table by cohort and possibly overall with the number (%) of pre-existing ADA and 
negative participants at baseline, number (%) of boosted and induced participants (either transient, 
persistent or indeterminate) will be reported, along with descriptive statistics of titer. Prevalence 
and incidence will also be presented. 
In addition, for positive ADA participants, time to onset, duration of ADA response, and the 
characterization of the immune response (transient, persistent, indeterminate) will be provided 
using a summary table by cohort and possibly overall.  
An individual data listing with ADA samples status (positive, negative or inconclusive), the titer if 
applicable, date of first/last dose, duration of exposure, study period (cycle), time point and 
date/time of sampling along with Ctrough value of the drug will be provided for positive and 
inconclusive ADA participants. 
Note that treatment-boosted ADA are excluded from the analyses of ADA kinetics because this 
type of immune response differs mechanistically. 
4.8.3 Biomarker analyses  
Blood samples before and after treatment with IMP (isatuximab) will be collected from all 
participants for the: 
• flow cytometric analysis of immune cells: the percentage and the cell count of each 
immune cell population and sub-population will be summarized using descriptive statistics 
at each timepoint. Change from baseline will be also described to assess the biological 
effects of IMP on immune cell populations. A specific focus will be done on CD38 
expressing cells in blood to evaluate its alteration upon IMP treatment. Baseline 
expression of immune cells, especially CD38 expression cells, may be also associated with 
the observed clinical responses in reduced anti-HLA antibodies to anti-CD38 treatment. 
• possible functional assessment of memory B-cells depletion: peripheral B-cells will be 
processed for subsequent analysis of anti-HLA alloreactivity upon IMP treatment 
• measurement of total immunoglobulin levels: descriptive statistics will be used to 
summarize the total immunoglobulin levels and the levels of ImmunoglobulinG (IgG) at 
each timepoint and the change over time in order to estimate the impact of IMP treatment 
on the total IgG pool. Baseline levels of immunoglobulin may be also associated with the 
observed clinical responses in reduced anti-HLA antibodies to anti-CD38 treatment. 
4.9 
INTERIM ANALYSES  
Not applicable. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADA: 
anti-drug antibodies 
ADI: 
actual dose intensity 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
AMR: 
antibody mediated rejection 
CKD: 
chronic kidney disease 
cPRA: 
calculated panel reactive antibodies 
CV: 
coefficient of variation 
DL: 
dose level 
DoR: 
duration of response 
E/D: 
early discontinuation 
ECG: 
electrocardiogram 
eHR: 
electronic health record 
FUP: 
follow-up period 
HLA: 
human leukocyte antigen 
HLGT: 
high level group term 
HLT: 
high level term 
ICF: 
informed consent form 
IgG: 
ImmunoglobulinG 
IMP: 
investigational medicinal product 
IRs: 
infusion reactions 
LCD: 
likelihood of compatible donor 
LLN: 
lower limit of normal 
LLOQ: 
lower limit of quantification 
LLT: 
lower level term 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MFI: 
mean fluorescence intensity 
NCI-CTCAE: 
National cancer institute common terminology for adverse events 
OPO: 
Organ Procurement Organizations 
OPTN: 
Organ Procurement and Transplant Network 
PCSA: 
potentially clinically significant abnormality 
PDI: 
planned dose intensity 
PK: 
pharmacokinetics 
PKDM: 
Pharmacokinetic, Dynamic and Metabolism 
PT: 
preferred term 
RDI: 
relative dose intensity 
RR: 
response rate 
SAB: 
single antigen bead 
SAEs: 
serious adverse events 
SAP: 
statistical analysis plan 
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SD: 
standard deviation 
SE: 
standard error 
SoA: 
schedule of activities 
SOC: 
system organ class 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
TMED: 
Translational Medicine and Early Development 
ULN: 
upper limit of normal 
ULOQ: 
upper limit of quantification 
UNOS: 
United Network for Organ Sharing 
US: 
United States 
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
Not applicable. 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical/surgical history 
The following demographics and baseline characteristics, medical/surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the enrolled 
population. 
Demographic and baseline characteristics  
• age (in years) as continuous variable and age group categorical variable 
• sex (Male, Female) 
• race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White) 
• ethnicity (Hispanic or Latino, not Hispanic or Latino) 
• Other baseline characteristics (renal disease status, CPRA value [from local lab: OPTN-
calculated, locally reported; from central lab], blood type, height, weight, body mass index 
[BMI], LVEF, number of prior kidney transplants, sensitizing events) 
Renal disease status at study entry includes renal disease stage and duration, origin of renal 
insufficiency, dialysis time, and kidney waitlist information. 
Other baseline safety and efficacy parameters (apart from those listed above) will be presented 
along with the safety and efficacy summaries.  
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Medical/surgical history includes any past and/or concomitant diseases or past surgeries (except 
previous transplantation). Medical and surgical history will be coded to a LLT, PT, HLT, HLGT, 
and associated primary SOC using the MedDRA version in effect at Sanofi at the time of database 
lock. 
Other procedures 
Other procedures include those not planned in the protocol that are related to or performed as a 
result of any AE or following a pre-existing condition. Other procedures will be coded to a LLT, 
PT, HLT, HLGT, and associated primary SOC using the MedDRA version in effect at Sanofi at 
the time of database lock. 
Prior or concomitant medications, and other medications 
All medications (including IR medications, prior/post-transplant immunosuppression treatments, 
desensitization/AMR medications) will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD) using the version in effect at Sanofi at the time of database lock. 
• Prior medications are those the participant used prior to first IMP intake.  Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment period. 
• Concomitant medications are any interventions received by the participant concomitantly 
to the IMP during the on-treatment period. 
• Post-treatment medications are those the participant took during the post-treatment period 
(Section 4.1) up to the end of the study.  
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as post-treatment medication. If it cannot be determined whether a 
given medication was taken prior or concomitantly or post, it will be considered as prior, 
concomitant, and post-treatment medication. 
The prior and concomitant medications and other specific medications/treatments (ie, administered 
for IRs, prior/post-transplant immunosuppression treatments, desensitization/AMR medications) 
will be summarized separately, for the enrolled and treated population, by anatomic and 
therapeutic level. The summaries will be sorted by decreasing frequency of anatomic category 
(ATC) based on incidence. In case of equal frequency, alphabetical order will be used. 
Participants will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. 
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5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
5.4.1 General conventions  
Time since CKD stage diagnosis at study entry: (date of first IMP dose - date of diagnosis for 
most recent CKD stage at study entry) + 1, and convert to years 
Dialysis time: (date of first IMP dose – start date of most recent start/restart chronic dialysis) + 1, 
and convert to years 
Waitlist time: (date of first IMP dose – waitlist registration date (from transplant status at study 
entry)) + 1, and convert to years 
Creatinine clearance (eGFR) using the equation of MDRD formula: 
 
American)
African 
 
if
 
(1.212
 x 
Female)
 
if
 
(0.742
 x 
(Age)
 x 
 
(Scr)
 x 
175
 
GFR
-0 203
-1 154
=
 
with serum creatinine in mg/dL and age in year. 
Missing data 
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as denominator the number of participants with 
non-missing observation in the considered population. When relevant, the number of participants 
with missing data is presented. 
When incomplete or missing dates are found in the eCRF, attempts will be made to retrieve the 
complete date, especially for dates within the month prior to first IMP dose. However, if some 
dates remain incomplete, the following rules will be applied: 
Handling of disease characteristics missing/partial dates (including medical/surgical history, 
renal disease status at study entry) 
• If the day is missing, impute day with 1. 
• If the month is missing, impute month with 1. 
• If the year is missing, no imputation will be performed. 
Handling of medication missing/partial dates  
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
For prior transplant immunosuppression treatments, following rules will be applied: 
Missing/partial start date will be imputed as follows: 
• If year and month exist, day is missing, impute day with 1. 
• If only year exists, month and day are missing, impute both month and day with 1. 
• If year, month, and day are all missing, no imputation will be applied. 
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Missing/partial end date will be imputed in a two-step approach as follows: 
• Step 1: Use the following rule to impute end date: 
- 
If year and month exist, day is missing, impute day with 1. 
- 
If only year exists, month and day are missing, impute both month and day with 1. 
- 
If year, month, and day are all missing, no imputation will be applied. 
• Step 2: If imputed end date is earlier than start date, set the imputed end date the same as 
start date. 
Imputation of incomplete start date for post-transplant immunosuppression treatments and 
desensitization/AMR treatments/procedures  
For post-transplant immunosuppression treatments and desensitization/AMR 
treatments/procedures, if the start date is missing, it will be imputed as follows: 
• If start day and month are missing and start year is the same as treatment end year, start 
date will be set equal to treatment end date + 1. 
• If start day and month are missing and start year is after the treatment end year, start day 
and month will each be set to 01. 
• If start day is missing and start year and month is the same as the treatment end year and 
month, start day will be set equal to the treatment end day + 1. 
• If start day is missing and start month is before the treatment end month and start year is 
the same as treatment end year, start day will be set to 01. 
• If start day is missing and start month is after the treatment end month and start year is the 
same as treatment end year, the medication start day will be set to 01. 
• If start day is missing and start month is not missing and start year is after the treatment 
end year, start day will be set to 01. 
• If start day, start month and start year are all missing, start date will be set equal to the 
treatment end date + 1. 
No imputation will be done for missing/partial end dates. 
Handling of AEs with missing or partial date of onset 
Missing or partial AE onset dates (occurrence or becoming serious) will be imputed so that if the 
partial AE onset date information does not indicate that the adverse event started prior to 
treatment or after the TEAE period, the AE will be classified as treatment-emergent. In case of 
AEs worsening during the study, the emergence will also be based on the cycle of worsening. No 
imputation of AE end dates will be performed. These data imputations are for categorization 
purpose only and will not be used in listings. No imputation is planned for date of AE resolution.   
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Handling of death with missing or partial date of death 
The imputation for missing or partial death date will proceed as follows: 
• If the death day is missing and the death month and year are the same as the last month 
and year the participant was last known to be alive, the death day will be set equal to the 
last day the participant was known to be alive + 1. 
• If the death day is missing and the death month is after the month the participant was last 
known to be alive and the death year is the same as the year the participant was last known 
to be alive, the death day will be set to 01. 
• If the death day and month are missing and the death year is the same as the year the 
participant was last known to be alive, the death date will be set equal to the date the 
participant was last known to be alive + 1. 
• If the death day and month are missing and the death year is after the year the participant 
was last known to be alive, the death day and month will both be set to 01. 
If the date the participant was last known to be alive is partial or missing, no imputation for 
missing or partial death date will be performed. The last date the participant was known to be 
alive is the latest of the following: date of last IMP dose, date of last visit performed (when the 
participant is known to be alive according to subject status), date of last laboratory assessment, 
and date of last vital signs recorded. 
Handling of AEs with missing grade 
If the grade is missing for one of the TE occurrences of an AE, the maximal severity on the 
remaining occurrences will be considered. If the severity is missing for all the occurrences, no 
imputation will be done and missing grades will be summarized in the “all grades” category. 
Handling of missing assessment of relationship of AEs to IMP  
If the assessment of the relationship to the regimen is missing, then the relationship to the IMP 
regimen has to be assumed and the AE considered as such in the frequency tables of possibly 
related adverse events, but no imputation will be done at the data level. 
Handling of parameters expressed as inequality or approximation 
For some parameters (such as laboratory parameters), if the value is expressed as “<xx”, “≤xx, 
half of the numeric portion of the entry or limit of quantification will be used in calculations. 
Analysis windows for time points 
No analysis windows will be applied in the by-scheduled visit summaries. 
Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs and ADA will be used for 
computation of baseline, the last on-treatment value, analysis according to PCSAs/NCI grade, and 
the shift summaries for safety. 
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5.4.2 DESENSITIZATION response criteria  
The target cPRA (ie, reduction of cPRA required to achieve at least 100% increase of LCD is 
calculated according to the following equation (2). Examples of target cPRA reduction are 
presented in Table 8. 
𝐿𝐶𝐷= 1 𝑖𝑛 
1
1 −𝑐𝑃𝑅𝐴 
Table 8 - Examples of target cPRA reduction  
Baseline 
Target 
cPRA 
LCD 
cPRA 
LCD 
99.99% 
1:10000 
99.98% 
1:5000 
99.90% 
1:1000 
99.80% 
1:500 
99.80% 
1:500 
99.60% 
1:250 
99.60% 
1:250 
99.20% 
1:125 
99.50% 
1:200 
99.00% 
1:100 
99.00% 
1:100 
98.00% 
1:50 
97.50% 
1:40 
95.00% 
1:20 
95.00% 
1:20 
90.00% 
1:10 
90.00% 
1:10 
80.00% 
1:5 
80.00% 
1:5 
60.00% 
1:2.5 
Abbreviations: cPRA = calculated panel reactive antibodies, LCD = likelihood of compatible donor 
Participants with baseline cPRA 100.00% will be assigned with cPRA 99.99% for computational 
purpose. 
Antibody titer is defined as the last dilution of serum at which positive results is obtained 
(eg, MFI ≥2000) (3). Examples of antibody titer based on MFI are illustrated in Table 9. 
Table 9 - Examples of antibody titer  
 
Neat Serum 
1:2 
1:4 
1:8 
1:16 
1:32 
Titer 
Antigen 1 MFI 
13430 
12492 
6250 
3123 
1550 
790 
8 
Antigen 2 MFI 
18320 
20820 
10501 
5206 
2604 
1302 
16 
Antigen 3 MFI 
11020 
5493 
2750 
1384 
688 
360 
4 
Abbreviations: MFI = mean fluorescence intensity 
Using similar concept, Table 11 illustrates an example in which the second predefined 
desensitization criterion (ie, ≥75% reduction in antibody titer from baseline to achieve target 
cPRA, see Table 10) may be met. In this example, participant’s baseline cPRA is measured by 
SAB as 97.50%, the target cPRA is therefore 95.00% as defined in Table 8. Through serial 
dilution of the serum collected at baseline, titer required to achieve target cPRA is 16 (ie, achieved 
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at 1:16 dilution). Subsequent post-treatment serum is therefore diluted at 1:4 (ie, 75% reduction 
from 1:16) to determine whether target cPRA is achieved. At Cycle 3 Day 1, target cPRA is 
reached at 1:4 dilution therefore meeting the aforementioned predefined desensitization criterion. 
Table 10 - 75% reduction in antibody titer from baseline  
Baseline 
75% Reduction 
Titer 
Dilution 
Titer 
Dilution 
2 
1:2 
1 
Neat 
4 
1:4 
1 
Neat 
8 
1:8 
2 
1:2 
16 
1:16 
4 
1:4 
32 
1:32 
8 
1:8 
64 
1:64 
16 
1:16 
128 
1:128 
32 
1:32 
256 
1:256 
64 
1:64 
512 
1:512 
128 
1:128 
Table 11 - Example of ≥75% reduction in antibody titer from baseline to achieve target cPRA  
 
Neat 
Serum 
1:2 
Titer = 2 
1:4 
Titer = 4 
1:8 
Titer = 8 
1:16 
Titer = 16 
Response 
Criterion Met 
Baseline 
cPRA 
97.50% 
97.50% 
97.50% 
96.00% 
95.00% 
(target cPRA) 
 
C2D1 cPRA 
96.00% 
 
96.00% 
 
 
No 
C3D1 cPRA 
96.00% 
 
95.00% 
(target cPRA) 
 
 
Yes 
Abbreviations:  C2D1 = Cycle 2 Day 1, C3D1 = Cycle 3 Day 1, cPRA = calculated panel reactive antibodies 
5.4.3 Health Resources and Services Administration (HRSA): Research Plan  
This research plan provides details on the match run simulation process supporting the 
exploratory analysis on transplant offers (Section 4.5.2). 
1. Name of primary investigator(s), co-investigators, and contact person: 
Primary Investigators: 
 
, PhD - UNOS  
 
 
, PhD - Sanofi US 
Co-investigators:  
 
 - UNOS  
 
 - UNOS 
 
 - UNOS 
 
 - UNOS 
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 - Sanofi 
 
 - Sanofi 
 
 - Sanofi 
Contact person: 
, PhD 
 
2. Project title: 
Match Run Simulations of Kidney Transplant Candidates who Underwent Desensitization 
Treatment  
3. Project background: 
Sanofi has initiated a clinical study (TED16414) to investigate activity of an anti-CD38 antibody 
(isatuximab) in desensitization of kidney transplant candidates. The purpose of the TED16414 
clinical study is to evaluate the efficacy of isatuximab in lowering the amount of antibodies 
(ie, the efficacy of desensitization). Eligible patients on the TED16414 clinical study are active 
transplant waitlist candidates with calculated PRA (cPRA) values of 80%-100%, so patients 
enrolled on the TED16414 clinical study will be captured in OPTN Waiting List. The OPTN 
system creates a system generated ID called Waiting List ID that is unique to a patient registered 
on the Waiting List. Sanofi will collect and share the following information of the TED16414 
clinical study patients with UNOS: OPTN Waiting List ID, anti-HLA antibody profiles, and 
cPRA levels at baseline and monthly thereafter for approximately 9 months after treatments starts. 
UNOS will collaborate with Sanofi to explore the feasibility of using OPTN data to perform the 
following analytical activities: 
1. Generate a reliable external control arm for the TED16414 using OPTN data merged with 
the Optum® EHR dataset.  
• The Optum® de-identified Electronic Health Record dataset containing information 
on approximately ~105 million US patients starting from 2007 across various 
inpatient, outpatient, and specialty settings likely contains additional health 
information on a subset of patients who are on the OPTN kidney waitlist. Matched 
control subjects will be selected from the merged dataset. 
2. Perform kidney match run simulations (ie, rerun the kidney matches) of the TED16414 
patients using their anti-HLA antibody profiles and cPRA values at baseline and after 
treatment.  
• Performing match run simulations using the algorithm based on OPTN allocation 
policies and TED16414 participants’ data would allow a realistic assessment of 
potential clinical benefits as a result of the desensitization treatment effect from 
isatuximab.  
• Therefore, the match run simulations will be conducted to explore novel metrics or 
surrogate endpoints that measure transplantability of patients who received 
isatuximab, such as higher ranks on match run simulations or appearing on a higher 
number of matches.  Matched control subjects selected above may also be included in 
the match run simulations. 
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4. Target population: 
Adult patients on OPTN kidney waiting list and deceased donors with kidney match runs between 
December 2014 and December 2023.  
5. Question(s) your study will address: 
1. What is the overlap between OPTN waitlist and Optum EHR (ie, what is the number of 
OPTN waitlist patients found in Optum® EHR)?   
2. Do isatuximab treated patients have higher transplantability (eg, higher ranks or more 
matches) compared to pre-treatment, as well as compared to matched control patients? 
3. Is there a correlation between transplantability (eg, higher number of matches or higher 
ranks on match run simulations) and time to transplant or higher transplant rate? 
4. Can comparison of TED16414 clinical study outcome against retrospective control arm 
selected from OPTN data merged with Optum® EHR data inform possible clinical 
benefits in the context of real world data, where clinical outcome may include number of 
transplant offers, kidney graft survival, rejection rates?    
6. Hypotheses your study will test: 
The overall, primary hypotheses include: 
A) Isatuximab-treated patients have higher transplantability (eg, higher ranks or more 
matches on match run simulations) after treatment as compared to prior to treatment and 
matched control patients. 
B) Higher ranks or increased number of matches correlate with shorter time to transplant or 
higher transplant rate. 
7. Type of data you need for your study (check all that apply): 
__X_ Waiting list candidate file (ie, all registrations on waiting list, transplanted or not – also 
contains donor, transplant, and follow-up data for recipients) 
__X_ Transplant recipient file (ie, only patients who received transplants – also contains waiting 
list, follow-up, and donor data for recipients) 
__X_ Deceased donor file (ie, all deceased donors) 
____ Living donor file (ie, all living donors) 
__X_ Other (1) PTR dataset without the “other, specify” refusal reason; 2) for each historical 
kidney match run, candidate and donor data elements at the time match was run) 
8. Explain why you need patient identifiers for your study.  Include details on how you plan 
to link to any non-OPTN patient-level datasets: 
1. UNOS will receive patient identified datasets with identifiers described below from 
OPTN. 
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2. UNOS will create an indicator to flag these patients in the OPTN waiting list data as the 
TED16414 study participants.  
• UNOS will remove TED16414 patients and the multiply listed waitlist ID from the 
dataset to ensure the TED16414 patients will not be selected as matched control 
subjects in retrospective control arm. 
• UNOS will use the encrypted OPTN Waiting List ID and remove other OPTN ID’s for 
the data linkage described below. 
3. UNOS will need the following PHI (patient last name, first name, Social Security Number, 
date of birth, zip code of residence, state of residence, and gender) to link OPTN data with 
Optum® EHR. 
• UNOS will run the tokenization software from Datavant (subcontractor of Optum - 
https://datavant.com/wp-content/uploads/2018/05/Datavant_De-Identifying-and-
Linking-Structured-Data-Whitepaper.pdf) against the OPTN data. 
- 
All of the PHI will be removed by Datavant software and replaced by patient-
specific tokens.   
- 
UNOS will verify that PHI has been removed in the tokenized dataset.  
- 
UNOS will send the dataset to Optum via secure File Transfer Protocol (FTP) site.   
• Optum will run the Datavant tokenization software to tokenize Optum® EHR and then 
merge with OPTN data that only contains encrypted Waiting List ID (Note: Optum 
will not have access to any OPTN PHI or PII) 
- 
All PHI will be removed by the software and replaced by new patient-specific 
tokens in the merged dataset. 
- 
Optum will verify that the merged dataset does not contain any PHI or PII. 
- 
Optum will send the merged OPTN-Optum dataset to Sanofi via secure FTP site. 
- 
Optum will destroy OPTN data.   
4. Sanofi will select matched control patients from the merged OPTN-Optum dataset based 
on certain patient characteristics. When this is completed, Sanofi will send the Waiting 
List ID’s of the TED16414 study patients and the encrypted Waiting List ID’s of the 
matched control patients to UNOS via secure FTP site. 
5. UNOS will use the unencrypted OPTN Waiting List ID to perform the match run 
simulations. Only UNOS will have access to the crosswalk between OPTN encrypted 
and unencrypted Waiting List ID’s. 
• UNOS will provide Sanofi with individual level summary of the match simulations 
that includes the encrypted Waiting List ID and ranks for each candidate on the 
matches. 
9. Type of patient identifiers you need for your study (check all that apply): 
 
__X__ Patient name 
 
 __X__ Patient Social Security Number 
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__X__ Patient date of birth 
__X__ Patient zip code 
 
__X__ Unencrypted waiting list ID (encrypted ID is standard in STAR files) 
 
_____  Unencrypted transplant ID (encrypted ID is standard in STAR files) 
_____  Other patient identifier (                         ) 
 
_____  Donor name 
 
_____  Donor Social Security Number 
 
_____  Donor date of birth 
 
_ X__  Unencrypted donor ID (encrypted ID is standard in STAR files) 
 
_____  Other donor identifier (specify: ______________________) 
10. List other key variables you need for your study.  You may attach a separate list. 
• All variables included in STAR files and PTR dataset  
• Donor and candidate data elements that are used in match runs for each historical kidney 
match run (Note: these elements will only be accessed by UNOS for performing the match 
run simulations) 
11. Describe, in general, how the data are to be analyzed: 
• The number of patients on the OPTN kidney waitlist that overlap with Optum® EHR will 
be determined after the linkage. 
• Matched control subjects will be selected by Sanofi using exact or propensity score 
matching methods from the merged OPTN-Optum® EHR datasets (as specified in Section 
8, the merged datasets will not have any PHI or PII). Parameters for matching may include 
key patient characteristics used in the OPTN kidney allocation policy, such as waiting 
time, cPRA value, blood type, age, prior transplant, and location of transplant center. 
• Match run simulations will be performed by UNOS using the kidney allocation algorithm 
that is in place at the time of the simulations.   
- 
Match run simulations will be performed for the TED16414 study participants using 
pre- and post-treatment anti-HLA antibody profiles and cPRA values.   
- 
The results of the match-reruns will be summarized and this will include the ranks for 
each candidate on the matches.   
• The summary data from the match run simulations will be analyzed by Sanofi: 
- 
Number of matches will be compared among: (a) TED16414 participants pre-
treatment, (b) TED16414 participants post-treatment, (c) matched control subjects. 
- 
Rank scores of matches will be compared among: (a) TED16414 participants pre-
treatment, (b) TED16414 participants post-treatment, (c) matched control subjects. 
• Additionally, Sanofi will analyze whether higher matches or rank scores are correlated 
with shorter time to transplant/higher transplant rate and transplant outcomes such as 
patient survival, graft survival, or rejection rates. 
 
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12. Describe how you plan to use the data, including any plans to present or publish the 
data. 
Data summary will be included in the TED16414 clinical study reports and/or research study 
reports, which will be retained for regulatory and quality purposes. Aggregated results may also 
be published as an abstract and/or manuscript. The data summary and aggregated results will not 
contain any patient identifiers.  
13. Will you need updates of these data in the future?   
Yes - Every quarter for three years. 
5.4.4 Propensity score analysis  
Propensity score matching is commonly used to analyze observational data to reduce bias due to 
confounding variables that are unbalanced between groups of interest (eg, participants that 
received the treatment and those that did not). Propensity score matching will be utilized to 
attempt to select the appropriate participants from the real-world data pool (UNOS database, with 
the option of enriching the database by linking with participants’ data in the OPTUM eHR) for 
inclusion in the synthetic control arm (SCA) so that the distribution of baseline characteristics 
would be well balanced between the SCA and the treatment arm from the study. Two SCAs will 
be constructed separately to match the corresponding two cohorts of Phase 2 of this study. This 
section provides detailed procedures to carry out the propensity score matching: 
Step 1: Within the real-world data pool: (a) exclude TED16414 trial participants, (b) exclude real-
world data pool participants not satisfying TED16414 study entry criteria, based on available data 
collected in the UNOS/OPTUM databases; and (c) keep unique patient ID that map to multiple 
waitlist IDs. 
Step 2: Estimate propensity scores. The propensity score is the probability of assignment of the 
treatment conditional on the observed baseline covariates: 
𝑝(𝑥) = Pr(𝑇= 1|𝑋= 𝑥) 
Where 𝑇 is an indicator variable denoting the treatment received (𝑇=1 for study treatment vs. 𝑇=
0 for historical control) and 𝑋 is a vector representing the covariates to be included in the 
propensity score model. The propensity score will be estimated using a logistic regression model 
in which treatment status is regressed on observed baseline covariates. The baseline covariates 
included in the propensity score model may consist of the following disease characteristics:  
1. Blood type 
2. Gender 
3. Days on waiting list 
4. Days on dialysis  
5. Age 
6. cPRA 
7. Distance from the transplant center 
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Statistical Analysis Plan  
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The estimated propensity score is the predicted probability of treatment derived from the fitted 
logistic regression model. 
Step 3: Create SCA by selecting participants from the real-world data pool to match the 
participants enrolled in this study using the estimated propensity scores. The greedy nearest-
neighbor matching without replacement and a fixed 1-to-1 matching ratio will be used. Other 
matching ratios may also be explored. Participants enrolled in this study will be randomly ordered 
within each cohort. Then each participant will be matched to a historical participant whose 
propensity score is the closest to that of the enrolled participant and within a prespecified caliber. 
A caliper width equal to 0.25 of the pooled standard deviation of logit of the propensity score 
from the 2 groups will be used. Matching without replacement will be conducted, that is, the 
matched historical participants will be removed from consideration for further matching. This 
process will be repeated sequentially for all the enrolled participants in each cohort separately.  
Step 4: Post-matching evaluation of covariate balance. Whether the distribution of measured 
baseline covariates is similar between the study enrolled participants and historical SCA 
participants will be examined. Baseline covariates will be summarized with descriptive statistics 
for the study enrolled participants and SCA both before and after matching. Standardized 
difference in covariate means before and after matching will be computed and compared.  
For a continuous covariate, the standardized difference is: 
𝑑=
𝑥𝑡̅ −𝑥ℎ
̅̅̅
√(𝑠𝑡
2 + 𝑠ℎ
2)/2
 
Where 𝑥𝑡̅  and 𝑥ℎ
̅̅̅ denote the sample mean of the covariate for the study treatment arm and 
historical SCA arm, respectively; 𝑠𝑡
2 and 𝑠ℎ
2 denote the sample variance of the covariate for the 
study treatment arm and historical SCA arm, respectively. 
For categorical variables the standardized difference is defined as: 
𝑑=
𝑝𝑡̂ −𝑝ℎ
̂
√{𝑝𝑡̂ (1 −𝑝𝑡̂ ) + 𝑝ℎ
̂(1 −𝑝ℎ
̂)}/2
 
Where 𝑝𝑡̂  and 𝑝ℎ
̂ denote the category of covariate for the study treatment arm and historical SCA 
arm, respectively. For covariate with more than 2 categories, the standardized difference for each 
level of the categorical variable will be calculated. The absolute standardized differences should 
generally be less than 0.25. 
In order to minimize the selection bias, the propensity score matching process to construct the 
SCA arms will be conducted by Sanofi independent B&P group who will only have access to 
baseline covariates of participants from both study treatment and historical pool (ie, blinded by 
the results of the study and historical data).  
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5.4.5 Generic ranges for hematological and biochemistry parameters  
Table 12 - Generic ranges for hematological parameters  
Test 
Gender 
Unit 
Lower/Upper limit of normal 
Hemoglobin 
F 
g/L 
120 - 160 
Hemoglobin 
M 
g/L 
135 - 175 
Lymphocytes 
109/L 
1 - 2 
Neutrophils 
109/L 
1.8 - 3.15 
Platelets 
109/L 
150 - 350 
Leukocytes 
 
109/L 
4.5 - 11 
Eosinophils 
109/L 
0 - 0.4 
Basophils 
109/L 
0 - 0.15 
Monocytes 
109/L 
0.18 - 0.5 
Hematocrit 
M 
Ratio 
0.41 - 0.53 
Hematocrit 
F 
Ratio 
0.36 - 0.46 
Erythrocytes 
F 
1012/L 
4 - 5.2 
Erythrocytes 
M 
1012/L 
4.5 - 5.9 
INR 
 
ratio 
0.8 - 1.2 
Based on Kratz et al. (4) 
Table 13 - Generic ranges for biochemistry parameters  
Test 
Unit 
Lower – Upper limit of normal 
Albumin 
g/L 
35 - 55 
BUN 
mmol/L 
3.6 - 7.1 
Calcium 
mmol/L 
2.2 - 2.6 
Chloride 
mmol/L 
80 - 115 
Corrected calcium 
mmol/L 
2.2 - 2.6 
Glucose 
mmol/L 
3.9 - 7 
Bicarbonate (HCO3) 
mmol/L 
22 - 29 
Carbon dioxide 
mmol/L 
21 - 30 
Potassium 
mmol/L 
3.5 - 5 
Magnesium 
mmol/L 
0.8 - 1.2 
Sodium 
mmol/L 
136 - 145 
Phosphate 
mmol/L 
1 - 1.4 
Protein 
g/L 
55 - 80 
Urea 
mmol/L 
3.6 - 7.1 
 
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6 
REFERENCES  
 1. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika. 1934;26:404-13. 
2. Kransdorf EP, Pando MJ. Calculated panel reactive antibody with decimals: A refined metric 
of access to transplantation for highly sensitized candidates. Hum Immunol. 2017;78(3):252-6. 
3. Tambur AR, Glotz D, Herrera ND, Chatroop EN, Roitberg T, Friedewald JJ, et al. Can solid 
phase assays be better utilized to measure efficacy of antibody removal therapies? Hum 
Immunol. 2016;77(8):624-30. 
4. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory reference values. N Engl J 
Med. 2004;351(15):1548-63. 
 
 
 
 
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