Clinical trial NCT04661033
Conditions: Warm Autoimmune Hemolytic Anemia (wAIHA)
Keywords: (wAIHA)
Sponsor: Sanofi
Start date: 2021-09-09; Completion date: 2023-06-26
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objectives:

* Part A: To evaluate the safety and tolerability of subcutaneous injections of isatuximab in adults with wAIHA
* Part B: To evaluate the efficacy of the selected dose in adults with wAIHA

Secondary Objectives:

* Part A (Cohorts 2 and 3 only)
* To evaluate the efficacy of isatuximab in adults with wAIHA
* To evaluate the durability of response to isatuximab and time to response
* To evaluate the impact of isatuximab treatment on fatigue

Part B

* To evaluate the safety and tolerability of isatuximab in adults with wAIHA
* To evaluate the durability of response to isatuximab and time to response
* To evaluate the impact of isatuximab treatment on fatigue

Parts A (all Cohorts) and B

* To evaluate the effect of isatuximab on markers of hemolysis
* To characterize the pharmacokinetic profile of isatuximab in adults with wAIHA
* To evaluate the immunogenicity of isatuximab

Detailed description:
28 weeks (including screening)

Arms: arm 1: Participants received 2 doses of Isatuximab 140 milligrams (mg) (1 milliliter \[mL\]) via subcutaneous (SC) injection every 2 weeks (Q2W) on Day 1 and Day 15. arm 2: Participants received 6 doses of Isatuximab 280 mg (2 mL) via SC injection Q2W through Day 71. arm 3: Participants received 6 doses of Isatuximab 560 mg (4 mL) via SC injection Q2W through Day 71. arm 4: Participants were planned to receive 6 doses of Isatuximab up to 560 mg (4 mL) via SC injection Q2W through Day 71
Interventions: intervention 1: Isatuximab SAR650984
Intervention descriptions: intervention 1: Pharmaceutical form:Solution for injection Route of administration: Subcutaneous

Protocol documents:
Prot_000.pdf: 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE CHANGES
DOCUMENT HISTORY
Document
Country/Countries 
impacted by
amendement
Date, version
Amended Clinical Trial Protocol 06 
All 
28 March 2022, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 05 
All 
02 December 2021, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 04 
All 
31 August 2021, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
05 May 2021, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
01 March 2021, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
19 October 2020, version 1 (electronic 1.0) 
Original Protocol 
 
18 September 2020, version 1 (electronic 2.0)
AMENDED PROTOCOL 06 (28 Mar 2022)
This amended protocol (amendment 06) 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
Changes to inclusion/exclusion criteria for clarification and to address unnecessary eligibility 
requirements that may contribute to low enrollment rate.
Protocol amendment summary of changes table
Section # and Name
Description of Change
Brief Rationale
5.1 Inclusion criteria, criterion I02b 
Total bilirubin changed to total or 
indirect/unconjugated bilirubin above upper 
limit of normal  
Unconjugated bilirubin more 
specific for hemolysis 
5.2 Exclusion criteria, criterion E17 
Stable daily dose of steroids required for 
days prior to study enrollment. 
Decrease in required length of 
time to allow investigators more 
flexibility in changing steroid 
doses to treat ongoing disease 
prior to enrollment. 
5.2 Exclusion criteria  
E22 and E23 added 
Clarification for 
immunomodulatory non-cytotoxic 
concurrent medications 


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TABLE OF CONTENTS
AMENDED CLINICAL TRIAL PROTOCOL 06 ..............................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE CHANGES...............................................2 
TABLE OF CONTENTS..................................................................................................................................3 
LIST OF TABLES ...........................................................................................................................................7 
LIST OF FIGURES..........................................................................................................................................7 
1 
PROTOCOL SUMMARY .................................................................................................................8 
1.1 
SYNOPSIS.......................................................................................................................................8 
1.2 
SCHEMA........................................................................................................................................13 
1.3 
SCHEDULE OF ACTIVITIES (SOA)..............................................................................................16 
2 
INTRODUCTION............................................................................................................................20 
2.1 
STUDY RATIONALE......................................................................................................................20 
2.2 
BACKGROUND .............................................................................................................................20 
2.3 
BENEFIT/RISK ASSESSMENT.....................................................................................................21 
2.3.1 
Infusion reactions...........................................................................................................................22 
2.3.2 
Infections, COVID-19, and other risks ...........................................................................................23 
2.3.3 
Risk assessment............................................................................................................................24 
2.3.4 
Benefit assessment........................................................................................................................25 
2.3.5 
Overall benefit: risk conclusion ......................................................................................................26 
3 
OBJECTIVES AND ENDPOINTS .................................................................................................27 
3.1 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................29 
4 
STUDY DESIGN ............................................................................................................................30 
4.1 
OVERALL DESIGN........................................................................................................................30 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN.........................................................................31 
4.2.1 
Participant input into design...........................................................................................................31 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................32 
4.4 
END OF STUDY DEFINITION.......................................................................................................33 
5 
STUDY POPULATION ..................................................................................................................34 


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5.1 
INCLUSION CRITERIA..................................................................................................................34 
5.2 
EXCLUSION CRITERIA ................................................................................................................35 
5.3 
LIFESTYLE CONSIDERATIONS...................................................................................................37 
5.4 
SCREEN FAILURES......................................................................................................................38 
6 
STUDY INTERVENTION ...............................................................................................................39 
6.1 
STUDY INTERVENTION(S) ADMINISTERED..............................................................................39 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY.......................................................40 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .......................................40 
6.4 
STUDY INTERVENTION COMPLIANCE ......................................................................................41 
6.4.1 
Treatment accountability and compliance......................................................................................41 
6.4.2 
Return and/or destruction of treatments ........................................................................................41 
6.5 
CONCOMITANT THERAPY ..........................................................................................................41 
6.5.1 
Rescue therapy..............................................................................................................................42 
6.6 
DOSE MODIFICATION..................................................................................................................42 
6.6.1 
Retreatment criteria........................................................................................................................42 
6.7 
INTERVENTION AFTER THE END OF THE STUDY...................................................................43 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...........................................................................................44 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ......................................................................44 
7.1.1 
Definitive discontinuation ...............................................................................................................44 
7.1.2 
Temporary discontinuation.............................................................................................................45 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY..................................45 
7.3 
LOST TO FOLLOW UP .................................................................................................................46 
8 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................................47 
8.1 
EFFICACY ASSESSMENTS .........................................................................................................48 
8.2 
SAFETY ASSESSMENTS .............................................................................................................48 
8.2.1 
Physical examinations ...................................................................................................................48 
8.2.2 
Vital signs.......................................................................................................................................48 
8.2.3 
Electrocardiograms ........................................................................................................................49 
8.2.4 
Clinical safety laboratory assessments..........................................................................................49 


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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...........................................................49 
8.3.1 
Time period and frequency for collecting AE and SAE information...............................................50 
8.3.2 
Method of detecting AEs and SAEs...............................................................................................50 
8.3.3 
Follow-up of AEs and SAEs...........................................................................................................50 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................................50 
8.3.5 
Pregnancy......................................................................................................................................51 
8.3.6 
Adverse event of special interest ...................................................................................................51 
8.3.7 
Guidelines for reporting product complaints ..................................................................................52 
8.4 
TREATMENT OF OVERDOSE......................................................................................................52 
8.5 
PHARMACOKINETICS..................................................................................................................52 
8.5.1 
Pharmacokinetic and immunogenicity sampling times and handling procedures .........................52 
8.5.2 
Pharmacokinetic and immunogenicity bioanalytical method .........................................................53 
8.5.3 
Pharmacokinetic parameters .........................................................................................................53 
8.6 
PHARMACODYNAMICS ...............................................................................................................54 
8.6.1 
Immunophenotyping.......................................................................................................................54 
8.7 
GENETICS.....................................................................................................................................54 
8.8 
BIOMARKERS ...............................................................................................................................54 
8.9 
IMMUNOGENICITY ASSESSMENTS...........................................................................................54 
8.10 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ...........................................55 
8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH................................55 
9 
STATISTICAL CONSIDERATIONS..............................................................................................56 
9.1 
STATISTICAL HYPOTHESES.......................................................................................................56 
9.2 
SAMPLE SIZE DETERMINATION.................................................................................................56 
9.2.1 
Part A .............................................................................................................................................56 
9.2.2 
Part B .............................................................................................................................................56 
9.3 
POPULATIONS FOR ANALYSES.................................................................................................57 
9.4 
STATISTICAL ANALYSES ............................................................................................................57 
9.4.1 
General considerations ..................................................................................................................57 
9.4.2 
Primary endpoint(s)........................................................................................................................58 
9.4.2.1 
Part A .............................................................................................................................................58 
9.4.2.2 
Part B .............................................................................................................................................60 
9.4.3 
Secondary endpoint(s)...................................................................................................................61 
9.4.3.1 
Part A (Cohorts 2 and 3 only) ........................................................................................................61 


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9.4.3.2 
Part B .............................................................................................................................................62 
9.4.3.3 
Parts A and B.................................................................................................................................63 
9.4.4 
Tertiary/exploratory endpoint(s).....................................................................................................63 
9.4.4.1 
Pharmacodynamic analysis ...........................................................................................................63 
9.4.4.2 
Pharmacokinetic/pharmacodynamic analysis................................................................................63 
9.4.5 
Other safety analyse(s)..................................................................................................................63 
9.4.6 
Other analyse(s).............................................................................................................................64 
9.5 
INTERIM ANALYSES ....................................................................................................................64 
9.6 
COMMITTEES OR OTHER REVIEW BOARDS ...........................................................................64 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................65 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS.......65 
10.1.1 
Regulatory and ethical considerations ...........................................................................................65 
10.1.2 
Financial disclosure........................................................................................................................66 
10.1.3 
Informed consent process..............................................................................................................66 
10.1.4 
Data protection...............................................................................................................................67 
10.1.5 
Committee structure.......................................................................................................................69 
10.1.6 
Dissemination of clinical study data ...............................................................................................69 
10.1.7 
Data quality assurance ..................................................................................................................70 
10.1.8 
Source documents .........................................................................................................................71 
10.1.9 
Study and site start and closure.....................................................................................................71 
10.1.10 Publication policy ...........................................................................................................................72 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS .........................................................................72 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................74 
10.3.1 
Definition of AE ..............................................................................................................................74 
10.3.2 
Definition of SAE............................................................................................................................75 
10.3.3 
Recording and follow-up of AE and/or SAE...................................................................................76 
10.3.4 
Reporting of SAEs..........................................................................................................................78 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................78 
10.5 
APPENDIX 5: GENETICS .............................................................................................................81 
10.6 
APPENDIX 6: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................82 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS..............................................................83 
10.8 
APPENDIX 8: ABBREVIATIONS...................................................................................................83 


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10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY ..................................................................84 
10.10 
APPENDIX 10: QUESTIONNAIRES..............................................................................................88 
11 
REFERENCES...............................................................................................................................91 
LIST OF TABLES
Table 1 - Risk assessment ............................................................................................................................24 
Table 2 - Objectives and endpoints...............................................................................................................27 
Table 3 - Overview of IMP administered .......................................................................................................39 
Table 4 - Summary of bioanalytical method for PK and immunogenicity assessment .................................53 
Table 5 - List of pharmacokinetic parameters and definitions.......................................................................53 
Table 6 - Accuracy of the 95% confidence interval .......................................................................................56 
Table 7 - Populations for analyses ................................................................................................................57 
Table 8 - Primary endpoint analysis for Part A..............................................................................................58 
Table 9 - Primary endpoint analysis for Part B..............................................................................................60 
Table 10 - Protocol-required laboratory assessments ..................................................................................73 
Table 11 - Highly effective contraceptive methods .......................................................................................79 
LIST OF FIGURES
Figure 1 - Graphical study design .................................................................................................................13 
Figure 2 - Study periods for Part A Cohort 1.................................................................................................14 
Figure 3 - Study periods for Part A Cohorts 2 and 3 and Part B...................................................................15 


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1
PROTOCOL SUMMARY
1.1
SYNOPSIS
Protocol title: A multicenter, open-label, non-randomized, Phase 1b/2 study to evaluate the 
safety, pharmacokinetics, and efficacy of subcutaneous isatuximab in adults with
warm autoimmune hemolytic anemia
Short title:
Safety, pharmacokinetics, and efficacy of subcutaneous isatuximab in adults with
warm autoimmune hemolytic anemia
Rationale:
Warm autoimmune hemolytic anemia (wAIHA) is a disease defined by the aberrant production of 
autoantibodies directed against red blood cells. The primary antibody-producing cell of the body 
is the plasma cell, which has a life span of months to years and is hypothesized to be responsible 
for the persistence of autoantibody production in individuals with refractory wAIHA. Plasma cells 
express a high density of CD38, and the anti-CD38 monoclonal antibody isatuximab is expected 
to deplete these antibody-producing cells, which are not targeted by glucocorticoids, 
antiproliferatives, or B-cell depletion by anti-CD20 therapy. This study will assess isatuximab in 
participants with wAIHA who have failed to respond to prior therapy. The first part of this study 
will assess safety and determine the isatuximab dose for patients with wAIHA, and the second 
part of the study will assess efficacy.
Objectives and endpoints
Objectives
Endpoints
Primary
Part A: To evaluate the safety and 
tolerability of subcutaneous injections of 
isatuximab in adults with wAIHA.  
Standard clinical and laboratory parameters and adverse 
events. 
Part B: To evaluate the efficacy of the 
selected dose in adults with wAIHA. 
Overall response rate (response (R) or complete response 
(CR)) at Day 85. 
R is defined as an increase in 
baseline and an absence of transfusion in the last 7 days and 
absence of rescue medications in the past 4 weeks. 
Biochemical evidence of hemolysis may still be present.  
 
(men), no evidence of hemolysis (normal bilirubin, LDH, 
haptoglobin, and reticulocytes), absence of transfusion in the 
last 7 days and absence of rescue medication in the past 4 
weeks. 


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Objectives
Endpoints
Secondary
Part A (Cohorts 2 and 3 only) 
To evaluate the efficacy of isatuximab 
in adults with wAIHA.  
 
Overall response rate (response (R) or complete response 
(CR)) at Day 85. 
baseline and an absence of transfusion in the last 7 days and 
absence of rescue medications in the past 4 weeks. 
Biochemical evidence of hemolysis may still be present.  
 
(men), no evidence of hemolysis (normal bilirubin, LDH, 
haptoglobin, and reticulocytes), and absence of transfusion in 
the last 7 days and absence of rescue medication in the past 
4 weeks. 
To evaluate the durability of response 
to isatuximab and time to response.  
Proportion of participants with durable hemoglobin response by 
Day 169. Durable 
evaluable visits during the study period; with absence of 
transfusion and no rescue medication during the period of 
3 consecutive visits and for at least 7 days (transfusions) and 
4 weeks (rescue medication) prior to the first consecutive visit. 
Overall response rate at Day 169, median time to R or CR, 
median time to loss of R or CR (loss of R defined as hemoglobin 
<10 g/dL at two consecutive visits at least 7 days apart and 
initiation of new treatment for anemia or increase in steroid 
dose; loss of CR is defined as hemoglobin <11 g/dL (women) or 
<12 g/dL (men) at two consecutive visits at least 7 days apart), 
proportion of participants requiring rescue therapy (any wAIHA-
directed therapy other than prednisone or transfusion) or 
splenectomy. 
To evaluate the impact of isatuximab 
treatment on fatigue. 
FACIT-fatigue scale score at Day 85 and Day 169. 
Part B 
To evaluate the safety and tolerability of 
isatuximab in adults with wAIHA.  
 
Standard clinical and laboratory parameters and adverse 
events. 
To evaluate the durability of response 
to isatuximab and time to response. 
Proportion of participants with durable hemoglobin response by 
Day 169. D
evaluable visits during the study period; with absence of 
transfusion and no rescue medication during the period of 
3 consecutive visits and for at least 7 days (transfusions) and 
4 weeks (rescue medication) prior to the first consecutive visit. 
Overall response rate at Day 169, median time to R or CR, 
median time to loss of R or CR (loss of R defined as hemoglobin 
<10 g/dL at two consecutive visits at least 7 days apart and 
initiation of new treatment for anemia or increase in steroid 
dose; loss of CR is defined as hemoglobin <11 g/dL (women) or 
<12 g/dL (men) at two consecutive visits at least 7 days apart), 
proportion of participants requiring rescue therapy (any wAIHA-
directed therapy other than prednisone or transfusion) or 
splenectomy. 


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Objectives
Endpoints
To evaluate the impact of isatuximab 
treatment on fatigue. 
FACIT-fatigue scale score at Day 85 and Day 169. 
Parts A (all Cohorts) and B 
To evaluate the effect of isatuximab on 
markers of hemolysis. 
 
Change from baseline in LDH, haptoglobin, reticulocytes, and 
total bilirubin at 1, 2, 4, 8, 12, and 24 weeks. 
To characterize the pharmacokinetic 
profile of isatuximab in adults with 
wAIHA.  
PK parameters after subcutaneous administrations (including 
Cmax and AUC0-2 week). 
To evaluate the immunogenicity of 
isatuximab. 
Incidence and titer (if relevant) of anti-isatuximab antibodies. 
Overall design:
This is a Phase 1b/2 open-label, non-randomized, multicenter study to evaluate the safety, 
pharmacokinetics, and efficacy of subcutaneous isatuximab in adults with wAIHA. The study will 
be conducted in 2 parts: Part A for safety and dose-finding, and Part B for assessment of the efficacy 
of the selected dose regimen. Approximately 17 to 23 participants are expected to be enrolled, 
depending on the number of participants in Part A who receive the regimen chosen for Part B.
Part A will have 2 to 3 cohorts. Cohort 1 consists of 3 participants who will receive 2 doses of 
isatuximab 140 mg (1 mL) SC administered 2 weeks apart. Cohort 2 can open following a review 
of available safety, pharmacokinetic (PK), and pharmacodynamic (PD) data after the 
3 participants in Cohort 1 complete the Day 43 visit. Cohort 2 will consist of 3 participants who 
will receive isatuximab SC given every 2 weeks through Day 71 (total of 6 doses). The dose for 
Cohort 2 may be 70 mg (0.5 mL), 140 mg (1 mL), or 280 mg (2 mL), determined based on the 
safety profile, PK, and PD observed in Cohort 1.
Once the 3 participants in Cohort 2 have completed the Day 85 visit, an analysis of the available 
safety, PK, and PD data will be performed, and a decision will be made to either enroll 3 participants 
as an additional optional dose-finding cohort (Cohort 3) in which a dose up to 560 mg (4 mL) can be 
investigated, or to open Part B. If Cohort 3 is enrolled, Part B will open once available safety, PK, and 
PD data through the Day 85 visit from those participants have been reviewed. 
Participants in Cohort 1 who experience no response by the end of the treatment period, or a
response that subsequently wanes while still in follow up, can be retreated with 6 administrations 
of the dose selected for Cohort 2, Cohort 3, or Part B. Such participants will continue to be 
followed for at least 24 weeks from the first retreatment dose, but their response to the additional 
doses will not be included for efficacy analyses.
For the review of data between each cohort, the safety data will consist of clinical and laboratory 
parameters and adverse events. Unacceptable toxicity is defined as any verified Grade 4 AE or
laboratory abnormality (except infusion reactions [IRs]) occurring during the treatment period, 
unless due to the underlying disease or due to a cause unrelated to the Investigational Medicinal 
Product (IMP), if confirmed by the Sponsor and Investigators. PK data will include standard PK 
parameters, with a focus on isatuximab exposure (Cmax and AUC0-2 week). PD data will include 
hemoglobin levels, markers of hemolysis, and immune cell profiling. 


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A decision to de-escalate the dose between cohorts will primarily be based on safety signals, 
while a decision to dose escalate will primarily be based on an insufficient hemoglobin response. 
Additional PD and PK data will be used to help guide these decisions. While it is anticipated that
dose selection for each cohort will occur after all participants in the previous cohort have 
completed the Day 43 (Part A, Cohort 1) or Day 85 (Part A, Cohorts 2 and 3) visits, in certain 
circumstances such decisions may be made earlier if clear safety or efficacy signals emerge. All 
decisions regarding dose levels and the opening of new cohorts will be made by Sponsor 
representatives and the Principal Investigator at dose selection meetings.
Part B will consist of 8 to 14 participants who will receive isatuximab SC every 2 weeks for a 
total of 6 doses, at a dose to be determined by the totality of safety, PK, an PD data available from 
all participants in Part A. The maximum allowable dose in Part B is 560 mg. Approximately 
14 participants in the study will receive the isatuximab regimen selected for Part B. Thus, the 
number of participants in Part B may range from 8 to 14, depending on the number of participants 
in Part A who received that same regimen in the second or third cohort. 
Disclosure Statement: This is a single group treatment study that is not blinded.
Number of participants:
Approximately 17 to 23 participants are expected to be enrolled, depending on the number of 
participants in Part A who receive the regimen chosen for Part B.
Note
participate in a clinical study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled. 
Intervention groups and duration:
All participants will receive isatuximab subcutaneously. The screening period is up to 28 days, 
followed by a treatment period of 42 days (6 weeks) for Cohort 1 or 84 days (12 weeks) for the 
other participants in the trial. All participants will be followed for at least 24 weeks from the 
first isatuximab dose. The total length of the study, including screening, is 28 weeks. 
Study interventions
Investigational medicinal products
Isatuximab
Formulation: Solution at a concentration of 140 mg/mL.
Route of administration: subcutaneous injection.
Dose regimen: Subcutaneous every 2 weeks. The 3 participants in the first cohort of Part A 
will receive 2 doses; all other participants will receive 6 doses. The following dose levels 
are planned: 140 mg in the first cohort of Part A; 70 mg, 140 mg, or 280 mg in the 
second cohort of Part A, depending on the results of the first cohort. The dose level in the 


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optional third cohort in Part A and the Part B cohort will determined based on analyses of 
safety, PK, and PD from prior cohorts. 
An isatuximab dose up to a maximum of 560 mg SC may be administered in this study.
Non-investigational medicinal products
Pre-medication for infusion reactions: To be administered approximately 15 to 30 minutes
(and never >60 minutes) prior to the first two isatuximab administrations
-
Montelukast 10 mg orally 
-
Acetaminophen/paracetamol 650 to 1000 mg orally 
-
Famotidine 40 mg orally (or equivalent)
-
Diphenhydramine 25-50 mg orally (or equivalent)
Statistical considerations:
Main analysis populations:
-
Efficacy population and Safety population: All participants exposed to the IMP 
(regardless of the amount of treatment administered).
Analysis of primary endpoint: 
-
For Part A, the safety analysis will focus primarily on the treatment emergent period, 
defined as the time from the first IMP administration up to 30 days after the last IMP 
administration. Descriptive summaries of Treatment-Emergent Adverse Events and 
potentially clinically significant abnormalities for standard clinical and laboratory 
parameters will be provided in the safety population by dose level group.
-
For Part B, the proportion of overall response will be computed at Day 85 together 
with its exact 95% confidence interval using Clopper-Pearson method in the efficacy 
population. Participants whose response at Day 85 is not evaluable, whatever the 
reason (eg, early discontinuation), will be considered as non-responders.
Analysis of main secondary endpoints:
-
For Part A, secondary endpoints will be described by dose level group.
-
For Part B, safety analysis will be conducted using a similar approach as detailed for 
Part A above. The proportion of overall response at Day 169 and its exact 95% 
confidence interval using Clopper-Pearson method will be computed. In addition, a 
mixed-effect model for repeated measures will be implemented on the FACIT-fatigue 
scale score providing estimates and 95% confidence intervals at Day 85 and Day 169.
Other secondary endpoints will be described.
Data Monitoring Committee: There will not be a data monitoring committee for this study. 
Decisions regarding the dose for Cohorts 2 and 3 in Part A and for Part B will be made at dose 
selection meetings comprised of Sponsor representatives and the Principal Investigator.
















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2
INTRODUCTION
Isatuximab is an IgG1 monoclonal antibody directed against CD38, a signal-transducing receptor 
and multifunctional ectoenzyme expressed on hematopoietic cells. Plasma cells, the primary 
antibody-producing cells of the body, express the highest density of CD38. Isatuximab is 
currently approved for the treatment of relapsed refractory multiple myeloma (RRMM; multiple 
myeloma is a cancer of plasma cells) in combination with pomalidomide and dexamethasone, and 
is also being developed for the treatment of other advanced malignancies, including solid tumors 
and lymphomas. Plasma cells, which produce approximately 1000 antibodies per second per cell 
(1), are believed to play a central role in autoimmune diseases in which autoantibodies directly 
contribute to pathogenesis (2). By targeting the plasma cell, isatuximab may have a role in the 
treatment of autoimmune diseases.
Warm autoimmune hemolytic anemia (wAIHA) is the most common type of autoimmune 
hemolytic anemia. It is mediated by autoantibodies that target antigens on red blood cells (RBC). 
Approximately half of wAIHA cases are primary, without an apparent underlying disorder, and 
approximately half are secondary, typically associated with systemic lupus erythematosus or 
lymphomas. wAIHA can be quite severe, requiring frequent blood transfusion, and has a reported 
mortality rate of 11% (3). There are currently no approved therapies for wAIHA. First-line 
therapy typically consists of glucocorticoids, followed by rituximab then splenectomy and other 
immunosuppressive agents (such as azathioprine, mycophenolate mofetil, cyclosporine, and 
cyclophosphamide). Limited options exist for those who do not have an adequate response to 
these interventions. 
2.1
STUDY RATIONALE
The anti-CD38 antibody isatuximab targets antibody-producing plasma cells, which express a 
high density of CD38. Isatuximab treatment may decrease anti-RBC autoantibody levels in 
individuals with wAIHA, thereby decreasing RBC destruction and increasing hemoglobin levels. 
The first part of this study will assess safety and determine the isatuximab dose for this patient 
population. The second part of the study will assess efficacy.
2.2
BACKGROUND
Among antibody-producing cells, plasma cells are unique in that they are long-lived (lifespan of 
months to years), reside primarily in the spleen, bone marrow, and inflamed tissue, and do not 
express CD20, the target of rituximab (2). Neither conventional immunosuppressive therapies nor 
rituximab deplete plasma cells. As a result, there has been significant interest in the use of anti-
CD38 therapies in diseases in which antibodies play a significant role in pathogenesis. Currently 
there are 5 ongoing trials investigating anti-CD38 monoclonal antibodies for the treatment of 
autoimmune or antibody-mediated diseases. These diseases include: antibody-mediated rejection 
in the setting of kidney (NCT04294459) and heart (NCT04088903) transplantation, myasthenia 
gravis (NCT04159805), systemic lupus erythematosus (NCT03724916), and persistent primary 
immune thrombocytopenia (NCT04278924). 


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wAIHA is characterized by anti-RBC autoantibodies, which directly result in RBC destruction 
through Fc-related mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC)
or complement fixation. The diagnostic test for wAIHA is the direct Coombs test (also called the 
direct antiglobulin test (DAT)), which detects antibodies on the surface of RBCs. This test is
positive in over 99% of wAIHA patients, as compared to less than 1% of the general population 
(4). The depletion of autoantibodies in wAIHA should therefore directly impact disease 
pathogenesis and result in improvement of anemia. In a Phase 3 clinical trial comparing the 
combination of rituximab and steroids to steroids alone, all participants who no longer harbored 
anti-RBC antibodies at Week 52 (as demonstrated by a negative DAT) also achieved a complete 
response (5).
First-line treatment for wAIHA is corticosteroids, which results in long-term remission in 
approximately 30% of patients (6). Rituximab is often introduced as second-line therapy. While 
approximately 85% of individuals with wAIHA respond to rituximab, with over 50% maintaining 
disease-free survival at 2 years (7), options are limited for those who do not. These patients 
typically undergo splenectomy or are treated with other immunosuppressive or cytotoxic agents 
such as cyclophosphamide, many of which have significant adverse effects. There has been 
accumulating evidence that patients with autoimmune hemolytic anemia who do not respond to 
rituximab have continued autoantibody production mediated by plasma cells. In wAIHA patients 
who failed to respond to rituximab and subsequently underwent splenectomy, plasma cells 
secreting anti-RBC autoantibodies were present in the spleen (8). The hypothesis that plasma cells 
are responsible for continued RBC destruction in patients who fail rituximab has been tested 
through the use of bortezomib, a proteasome inhibitor that causes apoptosis of plasma cells. In 
two case series, a total of 12 wAIHA patients who failed numerous therapies including rituximab 
were treated with bortezomib (9, 10). Overall, 9 of the 12 patients had a response to bortezomib 
(5 partial responses and 4 complete responses). Additionally, case reports describe the use of 
daratumumab, another anti-CD38 monoclonal antibody, in 4 patients with rituximab-refractory 
hemolytic anemia following hematopoietic stem cell transplantation (HSCT) (11, 12). These 
patients were treated with multiple therapies, including rituximab and bortezomib, but a sustained 
response was observed in 3 of the 4 patients only following daratumumab therapy. A case report 
also describes a wAIHA patient who responded to daratumumab after being refractory to 
azathioprine and rituximab (13). Thus, isatuximab represents a promising approach for the 
treatment of wAIHA, particularly for those patients who have previously failed prior therapies. 
A detailed description of the chemistry and pharmacology of isatuximab, and its efficacy in the 
setting of RRMM and other hematological malignancies, is provided in the Investig
Brochure and package insert. 
2.3
BENEFIT/RISK ASSESSMENT
As of the cut-off date of 05 January 2020, it was estimated that approximately 1652 individuals
have been treated with intravenous isatuximab in the setting of multiple myeloma and other 
malignancies, including various solid tumors. In general, isatuximab is well-tolerated. The most 
common adverse reactions for isatuximab are infusion reactions (IRs), which are clinically
manageable. 


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Isatuximab has been investigated either as monotherapy or in combination with other anticancer 
agents in patients with hematological malignancies and other advanced malignancies. When 
isatuximab is given in combination with other anticancer agents, the overall safety profile of the 
combination appears consistent with the safety profile of each drug individually. The safety 
profile of isatuximab monotherapy has been assessed by a pooled analysis of monotherapy studies 
in 212 participants with multiple myeloma (TED10893 and TED14154). In these studies, the most 
common treatment emergent adverse events (TEAE), excluding the AEs corresponding to 
laboratory abnormalities, included IRs, fatigue, nausea, anemia, cough, upper respiratory 
infection, diarrhea, headache, and dyspnea. No safety data is available from healthy volunteers or 
non-oncology patient populations.
2.3.1
Infusion reactions
Infusion reactions occurred in 53.8% of the 212 participants assessed in studies TED10893 and 
TED14154. Almost all participants received pre-medication for infusion reactions. Approximately 
98% of infusion reactions were Grade 1 or 2, with 2 Grade 3 and 6 Grade 4 reactions. There were 
no deaths. There was not a clear dose-response relationship for the incidence of IRs, but the 
6.8% of participants experienced an IR) than at doses 
<10 mg/kg (35.4% of participants experienced an IR). The majority of IRs occurred with the 
first infusion and all IRs were reported on the day of infusion. Among participants who received 
doses <10 mg/kg, no infusion reactions occurred after the second infusion.
The underlying mechanism of infusion reactions due to immune-cell directed monoclonal 
antibodies remains unclear, but these reactions appear to be reduced with subcutaneous 
administration (14). Approximately 50% of RRMM patients who receive intravenous 
daratumumab experience an IR, even in the setting of pre- and post-medication. In a study of 
daratumumab SC (also administered with pre- and post-medication), patients who received 
1200 mg or 1800 mg of daratumumab SC had an IR incidence of 12.5% and 24.4%, respectively, 
significantly lower than the incidence seen with IV administration (15). In a healthy volunteer 
study of the anti-CD38 monoclonal antibody TAK-079, in which participants received maximum 
doses of 0.06 mg/kg IV and 0.6 mg/kg SC, no infusion reactions were reported (16). Two of 
6 participants who received 0.6 mg/kg SC did have mild cytokine release syndrome, as 
demonstrated by minimal cytokine increases and the presence of mild clinical symptoms 
(headache, dizziness, and chills). Of note, no pre-medication or post-medication to prevent or 
reduce the incidence of infusion reactions was administered in that study. 
Preliminary data for the incidence of infusion reactions for isatuximab SC is available from 
protocol TCD15484. As of March 2020, 11 participants with RRMM have completed the first
cycle of isatuximab 1000 mg SC in combination with pomalidomide (1 cycle consists of 4 weekly 
isatuximab injections). Among these patients, there was only a single recorded infusion reaction 
(graded as mild), which occurred with the first infusion.
Overall, the available data for anti-CD38 antibodies suggest that infusion reactions occur less 
frequently when the antibody is administered subcutaneously and at low doses. In this study, 
participants will receive pre-medication before the first two administrations of isatuximab.
Participants may also receive these medications prior to subsequent doses if deemed necessary by 
the Investigator, in consultation with the Sponsor.


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2.3.2
Infections, COVID-19, and other risks
While plasma cells can produce pathogenic autoantibodies, they also produce protective 
antibodies, such as those that emerge following infection or vaccination. By depleting plasma
cells, isatuximab has the potential to increase the risk of infection, although conclusions in this 
regard from RRMM studies are difficult as RRMM patients have an inherently increased risk of 
infection. Data collected from the use of the anti-CD38 monoclonal antibody daratumumab in the 
setting of RRMM has been conflicting. In one study with 30 RRMM patients, 4 weeks of 
daratumumab therapy did not significantly alter the levels of polyclonal IgG, although levels of 
IgA, IgM, and IgE did significantly decline (17). Additionally, 17 RRMM patients were 
vaccinated against S. pneumoniae and H. influenzae Type B during daratumumab therapy and had 
response rates similar to that of RRMM patients not treated with daratumumb (17). In another 
study, significant rates of hypogammaglobulinemia, a known risk factor for infection, were seen, 
and occurred as early as 4 weeks after the start of daratumumab in some patients (18 and 
communication with author). Internal data with isatuximab in RRMM patients has shown that
patients with non-IgG myelomas treated with isatuximab for 6 months did not have significant 
declines in overall IgG levels, although IgA levels declined in patients with IgG myelomas. The 
effect of isatuximab on the production of anti-infective antibodies therefore remains uncertain.
If isatuximab does in fact decrease levels of antiviral antibodies, participants infected with SARS-
CoV-2 during isatuximab treatment may experience a longer or more severe infection, or may not 
generate protective antibodies as a result of infection. Testing for SARS-CoV-2 infection during 
screening will be determined by the Investigators and Sponsor based on local guidelines and 
COVID-19 prevalence at each site. Participants known to have had COVID-19 prior to study 
entry must be fully recovered in order to be eligible for participation. Participants enrolled in the 
study will be counseled to avoid situations that may place them at increased risk for COVID-19. If 
a patient is diagnosed with COVID-19 during the study, isatuximab will be discontinued. If the 
participant is asymptomatic but has a positive SARS-CoV-2 test, the decision regarding 
discontinuation will be made by the Investigator in consultation with the Sponsor. Once the 
patient is fully recovered, the decision to restart treatment will be made by the Investigator and 
Sponsor.
The effect of isatuximab on vaccination responses is unknown. By targeting plasma cells, 
isatuximab may interfere with vaccine-elicited immune responses. However, a series of RRMM 
patients who received vaccinations against S. pneumoniae, H. influenzae type B, and seasonal 
influenza during daratumumab treatment produced protective IgG antibody titers (17). Thus,
vaccination during isatuximab treatment may indeed elicit protective titers. Antibody titers for 
common vaccines will be measured before, during, and after isatuximab therapy. While SARS-
CoV-2 vaccination may be administered at any time during the study, it is recommended that the 
final vaccine dose be administered at least 2 weeks prior to the first dose of isatuximab, or that the
vaccine be administered 30 days or more after the final dose of isatuximab.
CD38 is expressed on other lymphoid and myeloid cells, but at densities lower than plasma cells. 
Isatuximab could affect these cell populations as well. Modulation of such cells could increase the 
risk of infection and the risk of malignancies. A higher rate of secondary primary malignancies 
was observed in multiple myeloma patients who received isatuximab, pomalidomide, and 
dexamethasone as compared to those who received pomalidomide and dexamethasone alone.


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However, the rate of secondary malignancies among patients who received isatuximab was not 
higher than the background rate in multiple myeloma patients.
Based on its mechanism of action, isatuximab can cause fetal harm when administered to a 
pregnant woman by causing fetal immune cell depletion and decreased bone density.
Isatuximab may cause neutropenia. Higher rates of neutropenia and febrile neutropenia were
observed in multiple myeloma patients treated with isatuximab, pomalidomide, and 
dexamethasone as compared to those who received pomalidomide and dexamethasone alone.
RBCs express CD38, but at significantly lower density than plasma cells. Worsening of anemia is 
not expected, and anemia was not reported in healthy volunteers who received the anti-CD38 
monoclonal antibody TAK-079 (16). Because isatuximab binds to CD38 found on red blood cells,
it may interfere with routine blood bank compatibility testing and cross-matching, resulting in a 
false-positive indirect Coombs test. This interference is limited to the minor blood groups.
Isatuximab may also interfere with serum protein electrophoresis and immunofixation tests.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of isatuximab may be found in the 
insert. 
2.3.3
Risk assessment
Table 1 - Risk assessment
Potential risk of clinical 
significance
Summary of data/rationale for 
risk
Mitigation strategy
Infusion reactions 
Infusion reactions are a common side 
effect of anti-CD38 monoclonal antibodies. 
However, these reactions appear to occur 
less frequently with subcutaneous 
administration and at lower doses.  
Pre-medication for infusion reactions with 
diphenhydramine, famotidine, 
acetaminophen/paracetamol, and 
montelukast will be given prior to the first two 
administrations of isatuximab. Steroids (in 
addition to what the participant is already 
taking for wAIHA) will not be administered as 
such administration could confound the 
efficacy analysis. If an investigator wishes to 
continue pre-medication after the second 
isatuximab dose, this may be performed in 
consultation with the Sponsor.  
Infection 
Isatuximab may increase the risk of 
infection by depleting immune cells, 
particularly plasma cells, which produce 
antibodies. Data for the risk of infection 
with isatuximab derives primarily from 
multiple myeloma patients, who are at 
increased risk of infection as a result of 
their disease.  
Serum immunoglobulin levels will be checked 
at screening and monitored throughout the 
study to detect instances of 
hypogammaglobulinemia. Participants with 
hypogammaglobulinemia may be treated with 
 


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Potential risk of clinical 
significance
Summary of data/rationale for 
risk
Mitigation strategy
COVID-19 
Isatuximab may decrease levels of 
antiviral antibodies and result in more 
severe infection, or prevent the 
development of immunity following 
infection. 
The need for SARS-CoV-2 testing during 
screening will be determined by the Sponsor 
and the Investigators at each site. 
Participants will be counseled to avoid 
situations that may place them at increased 
risk for COVID-19. If a patient is diagnosed 
with SARS-CoV-2 during the study, 
isatuximab will be at least temporarily 
discontinued. If the participant is 
asymptomatic but has a positive SARS-CoV-
2 test, the decision regarding discontinuation 
will be made by the Investigator in 
consultation with the Sponsor. 
Embryo-fetal toxicity 
Isatuximab can cause fetal harm when 
administered to a pregnant woman by 
causing fetal immune cell depletion and 
decreased bone density. 
WOCBP are required to use contraception 
during the study and for 5 months after the 
last isatuximab dose. Pregnancy testing will 
be performed every 4 weeks during the 
study. 
Neutropenia 
Isatuximab may cause neutropenia 
Complete blood counts will be monitored 
throughout the study. 
Malignancy 
Secondary malignancies were observed 
following isatuximab treatment in multiple 
myeloma patients 
Patients will undergo clinical assessments for 
14 weeks after the last isatuximab dose. Of 
note, patients with multiple myeloma have an 
increased rate of secondary malignancies, 
and isatuximab does not appear to increase 
this rate above background levels. 
Additionally, there is no evidence of an 
elevated risk of malignancies among wAIHA 
patients. 
Interference with laboratory tests
Isatuximab may cause a false-positive 
indirect Coombs test and may interfere 
with serum protein electrophoresis and 
immunofixation tests 
Blood typing will be performed prior to 
isatuximab dosing if not previously obtained 
within the past 1 month. 
2.3.4
Benefit assessment
Individuals with wAIHA who are refractory to current therapies have substantial morbidity 
associated with their disease, including fatigue, exertional dyspnea, thromboembolism, and the 
need for frequent blood transfusions. Severe cases can be life-threatening. Treatment with
isatuximab may improve hemoglobin levels and possibly resolve anemia in these individuals,
resulting in sustained improvements in quality of life and potential long-term treatment-free 
remission.


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2.3.5
Overall benefit: risk conclusion
Considering the measures taken to minimize risk to participants participating in this study, the 
potential risks identified in association with isatuximab are justified by the anticipated benefits 
that may be afforded to participants with wAIHA.


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3
OBJECTIVES AND ENDPOINTS
Table 2 - Objectives and endpoints
Objectives
Endpoints
Primary
Part A: To evaluate the safety and 
tolerability of subcutaneous injections of 
isatuximab in adults with wAIHA.  
Standard clinical and laboratory parameters and adverse 
events. 
Part B: To evaluate the efficacy of the 
selected dose in adults with wAIHA. 
Overall response rate (response (R) or complete response 
(CR)) at Day 85. 
baseline and an absence of transfusion in the last 7 days and 
absence of rescue medications in the past 4 weeks. 
Biochemical evidence of hemolysis may still be present. 
 
(men), no evidence of hemolysis (normal bilirubin, LDH, 
haptoglobin, and reticulocytes), and absence of transfusion in 
the last 7 days and absence of rescue medication in the past 
4 weeks. 
Secondary
Part A (Cohorts 2 and 3 only) 
To evaluate the efficacy of isatuximab in 
adults with wAIHA.  
 
Overall response rate (response (R) or complete response 
(CR)) at Day 85. 
baseline and an absence of transfusion in the last 7 days and 
absence of rescue medications in the past 4 weeks. 
Biochemical evidence of hemolysis may still be present.  
 
(men), no evidence of hemolysis (normal bilirubin, LDH, 
haptoglobin, and reticulocytes), and absence of transfusion in 
the last 7 days and absence of rescue medication in the past 
4 weeks. 
To evaluate the durability of response to 
isatuximab and time to response.  
Proportion of participants with durable hemoglobin response 
by Day 169. 
consecutive evaluable visits during the study period; with 
absence of transfusion and no rescue medication during the 
period of 3 consecutive visits and for at least 7 days 
(transfusions) and 4 weeks (rescue medication) prior to the 
first consecutive visit. 
Overall response rate at Day 169, median time to R or CR, 
median time to loss of R or CR (loss of R defined as 
hemoglobin <10 g/dL at two consecutive visits at least 7 days 
apart and initiation of new treatment for anemia or increase in 
steroid dose; loss of CR is defined as hemoglobin <11 g/dL 
(women) or <12 g/dL (men) at two consecutive visits at least 7 
days apart), proportion of participants requiring rescue therapy 
(any wAIHA-directed therapy other than prednisone or 
transfusion) or splenectomy. 


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Objectives
Endpoints
To evaluate the impact of isatuximab 
treatment on fatigue. 
FACIT-fatigue scale score at Day 85 and Day 169. 
Part B 
To evaluate the safety and tolerability of 
isatuximab in adults with wAIHA.  
 
Standard clinical and laboratory parameters and adverse 
events. 
To evaluate the durability of response to 
isatuximab and time to response. 
Proportion of participants with durable hemoglobin response 
by Day 169. D
consecutive evaluable visits during the study period; with 
absence of transfusion and no rescue medication during the 
period of 3 consecutive visits and for at least 7 days 
(transfusions) and 4 weeks (rescue medication) prior to the 
first consecutive visit. 
Overall response rate at Day 169, median time to R or CR, 
median time to loss of R or CR (loss of R defined as 
hemoglobin <10 g/dL at two consecutive visits at least 7 days 
apart and initiation of new treatment for anemia or increase in 
steroid dose; loss of CR is defined as hemoglobin <11 g/dL 
(women) or <12 g/dL (men) at two consecutive visits at least 7 
days apart), proportion of participants requiring rescue therapy 
(any wAIHA-directed therapy other than prednisone or 
transfusion) or splenectomy. 
To evaluate the impact of isatuximab 
treatment on fatigue. 
FACIT-fatigue scale score at Day 85 and Day 169. 
Parts A (all Cohorts) and B 
To evaluate the effect of isatuximab on 
markers of hemolysis. 
 
Change from baseline in LDH, haptoglobin, reticulocytes, and 
total bilirubin at 1, 2, 4, 8, 12, and 24 weeks. 
To characterize the pharmacokinetic 
profile of isatuximab in adults with wAIHA.  
PK parameters after subcutaneous administrations (including 
Cmax and AUC0-2 week). 
To evaluate the immunogenicity of 
isatuximab. 
Incidence and titer (if relevant) of anti-isatuximab antibodies. 
Tertiary/Exploratory
Parts A (all Cohorts) and B 
To describe the effect of isatuximab on 
levels of circulating immune cells with 
high CD38 expression. 
 
Levels of plasmablasts and NK cells.  
To describe the effect of isatuximab on 
levels of circulating immune cells with 
moderate to low CD38 expression. 
Levels of B cells and T cell subsets and other cells types. 
To evaluate the PK/PD relationship. 
Relationship of PK parameters to hemoglobin levels and 
levels of plasmablasts and NK cells. 
To evaluate the effect of isatuximab on 
immunoglobulin levels. 
Total IgG, IgM, and IgA levels. 
To evaluate the effect of isatuximab on 
vaccine antibody titers. 
Measles, mumps, tetanus, and diphtheria titers. 
To evaluate genetic determinants of 
isatuximab response. 
Relationship between FcgrIII polymorphisms and other genes 
and isatuximab response. 
Immune cell gene expression using RNAseq and/or 
scRNAseq. 


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Objectives
Endpoints
To describe the effect of isatuximab on 
bone marrow plasma cells, particularly 
those producing anti-RBC antibodies. 
 
Part B only 
To investigate the effect of isatuximab on 
quality of life 
Levels of plasma cells from bone marrow biopsy in 
participants who have a biopsy/aspirate performed. 
 
 
 
Change in the following assessments: Patient Global 
Impression of Change (PGIC), Patient Global Impression of 
Severity (PGIS), Clinical Global Impression of Efficacy (CGI-
E), Clinical Global Impression of Improvement (CGI-I), Clinical 
Global Impression of Severity (CGI-S) 
3.1
APPROPRIATENESS OF MEASUREMENTS
The efficacy endpoints for this study are based on international consensus guidelines for the 
diagnosis and treatment of autoimmune hemolytic anemia (19). Similar endpoints have been used 
in randomized Phase 3 trials of rituximab in individuals with wAIHA (5, 6). Considering that the
current study is a Phase 1b/2 study, the primary endpoint will be evaluated at 12 weeks (Day 85), 
as opposed to 1 year, as was done in the Phase 3 studies above. The durability of the response will 
be evaluated as a secondary endpoint at 24 weeks (Day 169).


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4
STUDY DESIGN
4.1
OVERALL DESIGN
This is a Phase 1b/2 open-label, non-randomized, multicenter study to evaluate the safety, 
pharmacokinetics, and efficacy of subcutaneous isatuximab in adults with wAIHA. The study will 
be conducted in 2 parts: Part A for safety and dose-finding, and Part B for assessment of the 
efficacy of the selected dose regimen. Approximately 17 to 23 participants are expected to be 
enrolled, depending on the number of participants in Part A who receive the regimen chosen for 
Part B.
Part A will have 2 to 3 cohorts. Cohort 1 consists of 3 participants who will receive 2 doses of 
isatuximab 140 mg (1 mL) SC administered 2 weeks apart. Cohort 2 can open following a review 
of available safety, pharmacokinetic (PK), and pharmacodynamic (PD) data after the 
3 participants in Cohort 1 complete the Day 43 visit. Cohort 2 will consist of 3 participants who 
will receive isatuximab SC given every 2 weeks through Day 71 (total of 6 doses). The dose for 
Cohort 2 may be 70 mg (0.5 mL), 140 mg (1 mL), or 280 mg (2 mL), determined based on the 
safety profile, PK, and PD observed in Cohort 1. 
Once the 3 participants in Cohort 2 have completed the Day 85 visit, an analysis of the available 
safety, PK, and PD data will be performed, and a decision will be made to either enroll 
3 participants as an additional optional dose-finding cohort (Cohort 3) in which a dose up to 
560 mg (4 mL) can be investigated, or to open Part B. If Cohort 3 is enrolled, Part B will open 
once available safety, PK, and PD data through the Day 85 visit from those participants have been 
reviewed. 
Participants in Cohort 1 who experience no response by the end of the treatment period, or a
response that subsequently wanes while still in follow up, can be retreated, after completing the
Day 43 visit, with 6 administrations of the dose selected for the Cohort 2, Cohort 3, or Part B.
Such participants will continue to be followed for at least 24 weeks from the first retreatment 
dose, but their response to the additional doses will not be included for efficacy analyses.
For the review of data between each cohort, the safety data will consist of clinical and laboratory 
parameters and adverse events. Unacceptable toxicity is defined as any verified Grade 4 AE or 
laboratory abnormality (except infusion reactions [IRs]) occurring during the treatment period, 
unless due to the underlying disease or due to a cause unrelated to the IMP, if confirmed by the 
Sponsor and Investigators. PK data will include standard PK parameters, with a focus on
isatuximab exposure (Cmax and AUC0-2 week). PD data will include hemoglobin levels, markers of 
hemolysis, and immune cell profiling. 
A decision to de-escalate the dose between cohorts will primarily be based on safety signals, 
while a decision to dose escalate will primarily be based on an insufficient hemoglobin response. 
Additional PD and PK data will be used to help guide these decisions. While it is anticipated that 
dose selection for each cohort will occur after all participants in the previous cohort have 
completed the Day 43 (Part A, Cohort 1) or Day 85 (Part A, Cohorts 2 and 3) visits, in certain 
circumstances such decisions may be made earlier if clear safety or efficacy signals emerge. All 


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decisions regarding dose levels and the opening of new cohorts will be made by Sponsor 
representatives and the Principal Investigator at dose selection meetings. See Section 10.1.5 for
the composition of the dose selection committee.
Part B will consist of 8 to 14 participants who will receive isatuximab SC every 2 weeks for a 
total of 6 doses, at a dose to be determined by the totality of safety, PK, an PD data available from 
all participants in Part A. The maximum allowable dose in Part B is 560 mg. Approximately 
14 participants in the study will receive the isatuximab regimen selected for Part B. Thus, the 
number of participants in Part B may range from 8 to 14, depending on the number of participants 
in Part A who received that same regimen in the second or third cohort. 
All participants will receive isatuximab subcutaneously. The screening period is 28 days, followed 
by a treatment period of 42 days (6 weeks) for Cohort 1 or 84 days (12 weeks) for the other 
participants in the trial. All participants will be followed for at least 24 weeks from the 
first isatuximab dose. The total length of the study, including screening, is 28 weeks. 
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
This study was designed to select and evaluate a dose of isatuximab that may offer substantial 
benefit for individuals with wAIHA who have failed prior therapies. Considering that the study 
population is rare and often without alternative treatment options, the starting dose for the study 
was selected with the goal that it would deplete at least 70%-80% of plasma cells 
(see Section 4.3).
While isatuximab is generally well-tolerated in RRMM patients, the first 3 participants in this 
study (Cohort 1) will receive only 2 doses as an initial evaluation of safety. The maximum 
allowable dose in this study, 560 mg, represents approximately 50% of the dose utilized in 
RRMM, as individuals with wAIHA have considerably less CD38 target abundancy than RRMM 
patients.
Participants in Part A who received the regimen selected for Part B will be included in the 
efficacy analysis. Thus, the number of participants in Part B may range from 8 to 14 to obtain 
approximately 14 participants overall who receive the regimen selected for Part B. The study was 
designed in this manner to maximize the contribution of each participant for this rare population. 
Hemoglobin levels, which constitute the primary endpoint of the study, are a direct measure of 
disease activity.
4.2.1
Participant input into design
Participants were not directly involved in the design of the trial, but input was received from 
physicians who care for patients with wAIHA who are refractory to available therapies.


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4.3
JUSTIFICATION FOR DOSE
The starting dose for this study (140 mg) was determined by simulations that incorporated in vitro 
data and data derived from RRMM patients treated with isatuximab, and through a comparison of 
doses utilized in different populations with the anti-CD38 antibody TAK-079. 
In in vitro depletion experiments, different doses of isatuximab were added to plasmablasts 
isolated from healthy volunteers and individuals with autoimmune disease. Based on these 
experiments, the target plasma isatuximab concentration required to result in a 70%-80% 
Simulations were then performed utilizing this target isatuximab concentration. These simulations 
were based on a population PK model developed in RRMM patients treated with isatuximab 
monotherapy at doses ranging from 1 to 20 mg/kg IV. Additional parameters included rates of 
subcutaneous absorption for monoclonal antibodies in general and preliminary data from 
isatuximab administered subcutaneously, and the interindividual variability of isatuximab 
observed in RRMM patients. The assumption was made that wAIHA patients will have 
significantly less target abundancy than RRMM patients, and therefore significantly less target-
mediated drug disposition (TMDD). The simulation considered scenarios of no TMDD as well as 
10%, 25%, and 50% of the maximum elimination rate (Vmax, which corresponds to the degree of 
TMDD) seen in RRMM patients. 
These simulations demonstrated that a dose of 140 mg (2 mg/kg) administered every 2 weeks 
would achieve levels consistently above the target threshold in most patients even in the setting of 
moderate TMDD (25% Vmax of RRMM). 
The isatuximab dose selected for this trial is also consistent with available data from studies 
conducted with the anti-CD38 monoclonal antibody TAK-079, which has been tested in healthy 
volunteers and RRMM patients. The doses of TAK-079 tested in healthy volunteers ranged from 
0.0003-0.06 mg/kg IV and from 0.03-0.6 mg/kg SC. The dose of 0.6 mg/kg SC demonstrated the 
greatest PD effect, with a >90% reduction in plasmablasts (16). In a Phase 1b study in RRMM 
patients, fixed doses of 45-600 mg SC (0.6-8.6 mg/kg) were tested. The maximum PD effect was 
observed at 300 mg SC (4.3 mg/kg) (20). A comparison of these studies reveals that the dose that 
resulted in the maximum PD effect in healthy volunteers was approximately 14% of the dose at 
which a maximum PD effect was observed in RRMM patients. The amount of CD38+ cells in 
wAIHA patients treated with steroids is similar to that of healthy volunteers (8). Thus, a dose of 
an anti-CD38 antibody shown to have a significant PD effect in healthy volunteers would also be 
expected have a significant PD effect in wAIHA patients. The isatuximab monotherapy dose 
shown to have the maximum PD effect is 20 mg/kg (21). The starting dose for the current trial, 
140 mg (2 mg/kg) is 10% of that dose, similar to the ratio of the TAK-079 healthy volunteer and 
RRMM doses.
In an ongoing study evaluating isatuximab SC in combination with pomalidomide and 
dexamethasone in RRMM patients (TCD15484), doses of 1000 mg and 1400 mg SC are being 
tested. Thus, the starting dose in this study (140 mg SC) represents 10%-14% of the dose 
currently being tested in RRMM patients receiving isatuximab subcutaneously. 


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The number of doses of an anti-CD38 antibody required for a sustained response in autoimmune 
diseases in general and wAIHA in particular is unknown. In the case reports cited above in which 
daratumumab was administered for hemolytic anemia as a result of HSCT, it was administered 
weekly at the oncology dose (16 mg/kg) for a total of 4-11 doses (11, 12). In current studies of 
TAK-079 for myasthenia gravis and primary immune thrombocytopenia, TAK-079 is being 
administered weekly for a total of 8 weeks.
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 Day 169 visit.
The end of the study is defined as the date of the last visit of the last participant in the study.


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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 years of age, inclusive, at the time of signing the informed 
consent.
Type of participant and disease characteristics
I 02.
Males and females with a confirmed diagnosis of primary wAIHA or systemic lupus 
erythematosus (SLE)-associated wAIHA (without other SLE-related manifestations apart 
from cutaneous and musculoskeletal manifestations) who meet the following criteria:
a) Hemoglobin level <10 g/dL at Screening.
b)
0 mg/dL and total or indirect/unconjugated bilirubin above 
the upper limit of normal).
c) Positive direct antiglobulin test (DAT) (IgG or IgG + complement C3d pattern or IgM 
warm autoantibodies [positive dual DAT]).
I 03.
Participants who have previously failed to maintain a sustained response after treatment 
with corticosteroids (corticosteroid-refractory or corticosteroid-dependent primary 
wAIHA).
I 04.
Part A only: Participants who have previously failed to maintain a sustained response after 
treatment with rituximab (or other anti-CD20 monoclonal antibodies). The last dose of the
anti-CD20 antibody must have been administered at least 12 weeks before enrollment.
Part B: Participants who have had an insufficient response to at least 1 prior therapy in 
addition to corticosteroids (splenectomy is regarded as a prior therapy).
Note: For criteria specific to participants enrolled in France, see Appendix 7 (Section 10.7)
I 05.
Eastern Cooperative Oncology Group (ECOG) performance status Grade 2 or lower.
I 06.
Up-to-date vaccination status as per local guidelines.


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Contraception
I 07.
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. Additionally:
a) Male participants must be surgically sterile for at least 90 days or agree when sexually 
active with female partners of childbearing potential to use a male condom for 
5 months after the last dose of isatuximab.
b) Female participants must be post-menopausal, surgically sterile, or be established on 
screening) and agree to continue to use the same highly effective 
method of birth control for 5 months after the last dose of isatuximab. Highly effective 
methods of contraception include intrauterine device (IUD; Mirena®), established use 
of oral, implanted, or transdermal hormonal method of contraception associated with 
inhibition of ovulation, bilateral tubal ligation, or permanent birth control via the 
Essure procedure. Participants who practice true abstinence, because of the 
the purpose of study participation) are exempt from contraceptive requirements. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) 
and withdrawal are NOT acceptable methods of contraception. 
Informed Consent
I 08.
Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of
the protocol 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. Clinically significant medical history or ongoing chronic illness that would jeopardize the 
safety of the participant or compromise the quality of the data derived from his or her 
participation in the study as determined by the Investigator.
E 02. Serious infection that required hospitalization within 3 months prior to enrollment.
E 03. Secondary wAIHA from any cause including drugs, lymphoproliferative disorders, 
infectious or autoimmune disease (SLE without other SLE-related manifestations apart 
from cutaneous and musculoskeletal manifestations is allowed), or active hematologic 
malignancies. Participants with positive antinuclear antibodies but without a definitive 
diagnosis of an autoimmune disease are allowed.
E 04. History of coagulation or bleeding disorders (Evans Syndrome is allowed).


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E 05. Uncontrolled or active HBV infection: Participants with positive HBsAg and/or HBV 
DNA. Of note:
Patient can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) and
HBsAg and HBV DNA are negative. 
-
If anti-HBV therapy in relation with prior infection was started before initiation of 
IMP, the anti-HBV therapy and monitoring should continue throughout the study 
treatment period.
Participants with negative HBsAg and positive HBV DNA observed during screening 
period will be evaluated by a specialist for start of anti-viral treatment; study treatment 
could be proposed if HBV DNA becomes negative and all the other study criteria are still 
met.
Active HCV infection: positive HCV RNA and positive anti-HCV. Of note:
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 RNA without antiviral therapy 
for HCV are eligible.
E 06. HIV infection.
E 07. Positive SARS-CoV-2 molecular test (if COVID-19 testing required).
E 08. Serum gammaglobulin levels <3 g/L.
E 09. Ferritin levels below the lower limit of normal.
E 10. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >3 x ULN.
E 11. Prothrombin time (PT/INR) or activated partial thromboplastin time (aPTT) above the 
ULN and deemed to be clinically significant by the Investigator.
E 12. WBC count < 3.0 x 109/L or neutrophil count < 1.5 x 109/L
E 13. Females who are pregnant, lactating, or considered unreliable with respect to contraceptive 
practice.
E 14. Recent history of substance abuse or mental illness. 
E 15. Treatment for malignant disease within 3 years prior to enrollment.
Prior/concomitant therapy 
E 16. Receipt of live vaccine(s) within 3 months prior to enrollment.


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E 17. Concurrent treatment with corticosteroids, unless the participant has been on a stable daily 
dose for 15 days prior to enrollment.
E 18. Concurrent treatment with erythropoietin, unless the patient has been on a stable dose for 
3 months prior to enrollment.
E 19. Concurrent use of iron supplementation, unless the patient has been on a stable dose for
30 days prior to enrollment.
E 20. Treatment with cyclophosphamide within 4 weeks prior to enrollment.
E 21. Treatment with cytotoxic drugs (other than cyclophosphamide) within 12 weeks prior to
enrollment.
E 22. Treatment with non-cytotoxic, immunomodulatory drugs (including but not limited to 
Cyclosporine, Sirolimus, Tacrolimus, Idelalisib, Ibrutinib), excluding biologic agents, 
within 4 weeks prior to enrollment.
E 23. Treatment with any biologic agent within 12 weeks prior to enrollment.
E 24. Use of prescribed or over-the-counter medications, supplements, vitamins, and/or herbal 
remedies within 2 weeks before enrollment which, in the judgment of the Investigator, 
.
Prior/concurrent clinical study experience 
E 25. Concurrent treatment with other experimental drugs or participation in another clinical trial 
with any investigational drug within 30 days or 5 half-lives, whichever is greater, prior to 
treatment start.
E 26. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent.
Other exclusions
E 27. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures.
E 28. Participants who are employees of the clinical study site or other individuals directly 
involved in the conduct of the study, or immediate family members of such individuals
(in conjunction with Section 1.61 of the ICH-GCP Ordinance E6).
5.3
LIFESTYLE CONSIDERATIONS
No lifestyle restrictions are required for this study in addition to any restrictions that may be in 
place as a result of the par


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5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. 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 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.


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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
All details of preparation and administration of isatuximab are provided in the Pharmacy Manual. 
Details of the IMP and diluted solution storage conditions are provided in the Pharmacy Manual.
Table 3 - Overview of IMP administered
Type 
Drug 
Dose formulation
Solution for subcutaneous administration 
Unit dose strength(s)
140 mg/mL isatuximab, 9 mM histidine, 110 mM L-Arginine 
monohydrochloride, 0.4% (w/v) Poloxamer 188 and 2% (w/v) sucrose, pH 6.2. 
Each vial contains a nominal content of 1960 mg of isatuximab C1P3F3.  
Dosage level(s)
Part A, Cohort 1: 140 mg every 2 weeks x 2 
Part A, Cohort 2: 70 mg, 140 mg, or 280 mg every 2 weeks x 6, based on 
results from Cohort 1 
Part A, Cohort 3, and Part B: Dose administered every 2 weeks x 6; dose 
level to be determined based on results from prior Cohorts; the dose will not 
exceed 560 mg 
Route of administration
Subcutaneous route  
Use
Experimental 
IMP and NIMP
IMP  
Packaging and labeling
Study Intervention will be provided in one glass vial per box. Each vial and 
box will be labeled according regulatory country requirement. 
Current/Former name(s) or 
alias(es)
Isatuximab SAR650984
Non-investigational medicinal products
Pre-medication for prevention of infusion reactions will be administered prior to the 
first two (2) administrations of isatuximab for all participants. Premedication will consist of the 
following regimen: 
Diphenhydramine, famotidine, acetaminophen/paracetamol, montelukast 
Route of administration: Oral 
Dose regimen: To be administered approximately 15 to 30 minutes (and never 
>60 minutes) prior to isatuximab 
-
Montelukast 10 mg orally 


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-
Acetaminophen/paracetamol 650 to 1000 mg orally 
-
Famotidine 40 mg orally (or equivalent)
-
Diphenhydramine 25-50 mg orally (or equivalent)
The above medications may be used post-treatment for any infusion reactions that occur. If an 
investigator wishes to continue pre-medication after the second isatuximab dose, this may be 
performed in consultation with the Sponsor. 
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 (deficiency in condition, 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 8.3.7).
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.
Under no circumstances will the Investigator supply IMP to a third party (except for DTP 
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
This is an open-label and non-randomized study; participants who meet all the inclusion criteria 
and none of the exclusion criteria will be eligible for inclusion in the study. Each participant will 
be registered and receive an incremental identification number per site corresponding to his/her 
order of enrollment in the study.


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6.4
STUDY INTERVENTION COMPLIANCE
6.4.1
Treatment accountability and compliance
Administration of the study treatment 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 for patient and destroyed or returned to the Sponsor. The packaging batch number 
(IP00xxxxx) must be recorded on the drug accountability form. 
The person responsible for drug administration to the patient will record precisely the date and the 
time of the drug administration to the patient. 
6.4.2
Return and/or destruction of treatments
Partially used and used IMP will be destroyed at the study site according to the standard practices 
of the site after an accurate accountability has been performed and signed by the Investigator 
(or the Pharmacist). A detailed treatment log form of the destroyed IMP will be established with 
the Investigator (or the Pharmacist) and countersigned by the Investigator and the Monitoring 
Team. 
The Investigator must not destroy the unused IMP unless Sanofi provides written authorization.
Further guidance and information for the accountability purpose of use and unused study 
interventions are provided in the pharmacy manual.
6.5
CONCOMITANT THERAPY
Any medication 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
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Participants who experience an infusion reaction may be treated post-injection with the 
medications listed in Section 6.1, as well as additional medications, if deemed necessary by the 
investigator.
The SARS-CoV-2 vaccine is permitted during the study, as per local standard of care, investigator 
discretion, and local labels. If feasible, it is preferable that the last dose of the SARS-CoV-2
vaccine be administered at least 2 weeks prior to the first dose of isatuximab, or for the vaccine to
be administered 30 days or more after the final dose of isatuximab.


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HBV vaccination could be considered,
for participants 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 1, 2, and 3 months after the end of vaccination. Anti-HBs above 
100 mU/mL indicates good seroconversion, between 10 and 100 mU/mL moderate 
seroconversion that can be limited in time, and less than 10 mU/mL indicates no response to 
vaccination.
If antiviral therapy for HBV or HCV was started before initiation of IMP and the patient was
eligible for the trial, the antiviral therapy for HBV or HCV should continue throughout the 
treatment period as recommended by a specialist.
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*), study treatment will be held and a specialist consulted for initiation of anti-viral 
treatment and monitoring of the patient. Restart of study treatment should be agreed between 
sponsor, investigator and specialist (hepatologist) if infection is controlled. Close monitoring of 
ALT and AST should continue up to study treatment discontinuation. HBV DNA to be monitored
as per 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.
6.5.1
Rescue therapy
The use of rescue medications is allowable during the study. The date and time of rescue medicine 
as well as the name and dosage regimen of the rescue medication/intervention must be recorded.
6.6
DOSE MODIFICATION
Dose modification is not allowed within a cohort, with the exception of participants in Cohort 1,
who may be re-dosed with the dose selected for Cohort 2, Cohort 3, or Part B if they experience 
no response or a response that subsequently wanes.
6.6.1
Retreatment criteria
Participants in Cohort 1 may receive additional study interventions if they meet retreatment
criteria and agree to be retreated. The retreatment criteria are as follows:
No response in hemoglobin (R) by end of the treatment period (Day 43).
A hemoglobin response (R) that subsequently wanes prior to the end of study, with 
hemoglobin falling below 10 g/dL on 2 occasions at least 7 days apart
These participants will be followed for a total of 24 weeks from the first retreatment dose, but the 
retreatment period will not be included in PK, PD, or efficacy analyses.


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6.7
INTERVENTION AFTER THE END OF THE STUDY
There will be no further interventions following the end of the study.


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7
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
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 (definitive discontinuation). If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for safety.
Pregnancy will lead to definitive treatment discontinuation in all cases.
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in Section 10.6 or if the 
Investigator believes that it is in best interest of the participant.
Treatment with the IMP should be discontinued in any of the following cases:
decision), or at the request of their legally authorized representative without any effect on
their care. 
nsidered to be an individual or judicial
or other body authorized under applicable law to consent on behalf of a prospective patient
on of the IMP would be detrimental to the
-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.
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.
Any abnormal laboratory value that could result in treatment discontinuation will be immediately 
rechecked for confirmation (within 24 hours) before making a decision regarding 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.


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If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP.
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the electronic-case report form (e-CRF) when considered as confirmed.
7.1.2
Temporary discontinuation
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (described in Section 8). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
case report form (CRF) or eCRF.
Temporary discontinuation will occur for participants diagnosed with COVID-19. Once the 
patient is fully recovered, the decision to restart treatment will be determined by the Investigator 
and Sponsor.
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. 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 both from the study intervention and 
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.
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.


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All study withdrawals should be recorded by the Investigator in the appropriate screens of the e-
CRF and in the 
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 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 
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. 
utine 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 maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will be within a safe limit for 
human clinical trials as recommended by the local Institutional Review Boards and Ethics 
Committees. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples.
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, pandemic, terrorist attack) may prevent access to the clinical 
trial site.
Contingency procedures are suggested below and in Section 7.1.2, Section 9.4, and 
Section 10.1.3 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/enrollment/randomization/administration of study intervention may be delayed.
Attempts should be made to perform all assessments in accordance with the approved 
protocol to the extent possible. In case this is not possible due to a temporary disruption 
caused by an emergency, focus should be given to assessments necessary to ensure the 
safety of participants and those important to preserving the main scientific value of the 
study.


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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.
If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely.
Use of local clinic or laboratory locations may be allowed.
Contingencies implemented due to emergency will be documented.
8.1
EFFICACY ASSESSMENTS
The primary efficacy endpoint, overall response rate, is determined by hemoglobin levels and 
markers of hemolysis, which will be assessed by the central lab.
The FACIT-fatigue scale will be administered by investigators at each site as per the SoA.
8.2
SAFETY ASSESSMENTS
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical examinations
A physical examination will include, at a minimum, assessment of the skin, lungs, 
cardiovascular system, and abdomen. Height (at screening only) 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 adverse 
event.
8.2.2
Vital signs
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
On Day 1, vital signs will be assessed prior to isatuximab administration and 1, 2, and 
4 hours after administration. On Day 15, vital signs will be assessed prior to isatuximab 
administration and 1 and 2 hours after administration. On other days of isatuximab 
administration, vital signs will assessed prior to isatuximab administration and 1 hour after 
administration.
If a participant has an IR, at the subsequent isatuximab administration vital signs will be 
assessed prior to administration and at 1, 2, and 4 hours after administration; for the 
following administration, vital signs will be assessed prior to administration and at 1 and 
2 hours after administration; for the remaining administrations vital signs will be assessed 
prior to administration and at 1 hour after administration. 


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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 performed with the participant sitting
and preceded by at least 5 minutes of rest for the participant in a quiet setting without 
distractions (eg, television, cell phones).
8.2.3
Electrocardiograms
A 12-lead ECG will be obtained as part of the screening procedures (see Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. 
8.2.4
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 CRF. 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 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 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
Adverse events 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, particularly those that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention or study 
(see Section 7).


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8.3.1
Time period and frequency for collecting AE and SAE information
All SAEs will be collected from the signing of the informed consent form (ICF) and throughout 
the study.
All AEs will be collected from the time of first IMP administration and throughout the study, as 
specified in the SoA (Section 1.3).
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 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.
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. All SAEs and AEs of special interest (as defined in
Section 8.3.6), will be followed 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 provided 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 
(IRB)/Independent Ethics Committees (IEC), and Investigators.
Adverse events that are considered expected will be specified in the 
Brochure.


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Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows:
-
For SUSARs that are life-threatening or result in death, reporting is immediately to 
regulatory authorities, from the moment the Sponsor has the minimum criteria for 
reporting a suspected SAE/SUSAR and at the latest within 7 days in Eudravigilance.
-
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor.
An Investigator who receives an Investigator safety report describing a SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it and will notify the IRB/IEC, if appropriate according to local 
requirements. It is the responsibility of the Sponsor to assess whether an event meets the 
criteria for a SUSAR, and therefore, is expedited to regulatory authorities.
8.3.5
Pregnancy
Details of all pregnancies in female participants and female partners of male participants
will be collected after the start of study intervention and until the end of the study. 
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
Adverse event of special interest
Adverse event of special interest
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
g 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 
-
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 
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Symptomatic overdose (serious or nonserious) with IMP
-
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least 
twice the intended dose within the intended therapeutic interval.
Increase in alanine transaminase (ALT) >3 x ULN
8.3.7
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
The Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the Investigator/treating physician should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities.
3. Document appropriately in the CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5
PHARMACOKINETICS
8.5.1
Pharmacokinetic and immunogenicity sampling times and handling procedures
The blood PK collection time points are defined to measure plasma isatuximab concentrations and 
to conduct the PK analysis:
The sampling times for blood collection can be found in the SoA (Section 1.3).
It is of utmost importance to collect all blood samples at the specified times and according 
to the specifications.
Samples missed or lost for any reason should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF. Actual dates and times of drug administration 
should also be precisely recorded.


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The sampling times for isatuximab PK and ADA may be reduced during the course of the 
study based on updated knowledge of isatuximab behavior, upon notification from the 
Sponsor. 
Refer to the separate Laboratory Manual for details concerning handling procedures.
8.5.2
Pharmacokinetic and immunogenicity bioanalytical method
A brief outline of the bioanalytical assay is provided in Table 4.
Table 4 - Summary of bioanalytical method for PK and immunogenicity assessment
Sample type
PK + anti-isatuximab antibody
Analyte 
Isatuximab and anti-isatuximab antibody 
Matrix 
Plasma 
Analytical technique 
Immunoassay 
Blood sample volume 
3 mL per sample (1 sample for PK and 1 sample for ADA)  
Site of bioanalysis 
Labcorp Early Development Laboratories 
Abbreviations: ADA = Anti-drug antibody; PK = Pharmacokinetic; UK = United Kingdom. 
8.5.3
Pharmacokinetic parameters
The following PK parameters will be calculated with PKDMS software (Pharsight), using non-
compartmental methods from plasma concentrations of isatuximab. The parameters will include, 
but may not be limited to the following:
Table 5 - List of pharmacokinetic parameters and definitions
Parameters
Isatuximab
Definition
Cmax 
X 
Maximum concentration observed after the first infusion 
tmax 
X 
Time to reach Cmax 
Clast 
X 
Last concentration observed above the lower limit of quantification after the first 
infusion 
tlast 
X 
Time of Clast 
Ctrough 
X 
Concentration observed just before treatment administration during repeated dosing 
AUClast 
X 
Area under the plasma concentration versus time curve calculated using the 
trapezoidal method from time zero to time of the last concentration observed above 
the lower limit of quantification (ie, Clast) 
AUC0-T 
X 
Area under the plasma concentration versus time curve calculated using the 
trapezoidal method over the dosing interval T (336 h) 


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8.6
PHARMACODYNAMICS
8.6.1
Immunophenotyping
Levels of immune cells with high CD38 expression (ie, plasmablasts and NK cells) and low CD38 
expression (B and T cells, including TREG cells) will be assessed by flow cytometry at the time 
points listed in the SoA (Section 1.3). Additionally, optional bone marrow biopsies/aspirates may 
allow for the assessment of plasma cells within the bone marrow. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual.
8.7
GENETICS
Peripheral blood will be collected for DNA isolation on Day 1 for an analysis of immune genetic 
determinants to isatuximab response, such as 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent.
See Appendix 5 (Section 10.5) for information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in the laboratory 
manual.
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 using RNAseq and/or single-cell RNAseq to evaluate 
the association of gene expression with the observed clinical response to isatuximab.
8.9
IMMUNOGENICITY ASSESSMENTS
Antibodies to isatuximab will be evaluated in plasma samples collected from all participants 
according to the SoA. Additionally, plasma samples should also be collected at the final visit from 
participants who discontinued study intervention or were withdrawn from the study. These 
samples will be tested by the Sponsor or Sponsor s designee.
Plasma samples will be screened for antibodies binding to isatuximab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to isatuximab and/or further characterize the immunogenicity of isatuximab.
The detection and characterization of antibodies to isatuximab will be performed using a validated 
assay method by or under the supervision of the Sponsor. All samples collected for detection of 
antibodies to isatuximab will also be evaluated for isatuximab serum concentration to enable 
interpretation of the antibody data. Antibodies may be further characterized and/or evaluated for 
their ability to neutralize the activity of the study intervention(s). Samples may be stored for a 


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maximum of 5 years (or according to local regulation
for the study at a facility selected by the Sponsor to enable further analysis of immune responses.
8.10
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS
Not applicable. 
8.11
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH
Future research may help further the understanding of disease subtypes, disease biology, related
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that
predict participant response to treatment. Therefore, data and biological samples will be stored
and used for future research when consented to by participants unless prohibited by local laws or 
IRBs/IECs (in such case, consent for future use of sample will not be included in the local ICF).
For participants who consent to the storage and use of their data and remaining and/or extra
clinical samples, data and samples may be used after the study ends for future research related
either to the drug, the mechanism of action, and the disease or its associated conditions. Such
research may include, but is not limited to, performing assessments on DNA, RNA, proteins or
metabolites. If future research on genetic material is performed, this will also be limited to the
purpose of addressing research questions related to the drug, the mechanism of action, the disease
or its associated conditions.
In the event future research is conducted for other purposes, the study participants will be
informed of those purposes and will be given means to object to those research projects. Data and 
samples will be used in compliance with the information provided to participants in the ICF Part 2 
(future research).
All study participant data and samples will be coded such that no participant direct identifiers will
be linked to them. Coded data and samples may be transferred to a Sponsor site (or a subcontractor 
site), which may be located outside of the country where the study is conducted. The Sponsor 
adopts safeguards for protecting participant confidentiality and personal data (see Section 10.1.4).
The samples will be stored for a maximum of 15 years after the end of the study. Any samples
remaining at the end of retention period will be destroyed. If a participant requests destruction of
his/her samples before the end of the retention period, the Investigator must notify the Sponsor
(or its contract organization) in writing. In such case, samples will be destroyed and related coded
data will be anonymized unless otherwise required by applicable laws.
Study participant coded data will be stored for future research for up to 25 years after the end of
the study. If data are still considered of important scientific value after this period, coded data
already available will be anonymized unless otherwise required by applicable laws (the same will
apply to the data of a study participant who has requested the destruction of his/her samples). A
available to the researchers for a maximum of 2 years after the end of their specific project (end of
project is defined by publication of the results or finalization of the future research project report).


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9
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESES
No formal statistical test will be performed.
9.2
SAMPLE SIZE DETERMINATION
9.2.1
Part A
The primary objective of Part A is to evaluate the safety and tolerability of isatuximab in adults 
with wAIHA based on standard clinical and laboratory parameters and adverse events. A
maximum of 9 participants will be assigned to the IMP in up to three successive cohorts. No
sample size computation was done; sample size is based upon empirical considerations. 
9.2.2
Part B
The primary objective of Part B is to evaluate the efficacy of isatuximab in adults with wAIHA 
based on the Overall response rate (response (R) or complete response (CR)) at Day 85. Sample 
size calculations were performed to ensure reasonable accuracy for the estimation of the response 
rate. The maximal half-width (when a 50% response rate is observed) of the exact two-sided
95% confidence interval using Clopper-Pearson method is displayed for various sample sizes in
Table 6.
Table 6 - Accuracy of the 95% confidence interval
N
Response rate
Lower limit
Upper limit
Half-width
10 
0.5 
0.187 
0.813 
0.313 
12 
0.5 
0.211 
0.789 
0.289 
14 
0.5 
0.230 
0.770 
0.270 
16 
0.5 
0.247 
0.753 
0.253 
A sample size of 14 participants will provide a half-width for the 95% confidence interval of less 
than 0.275 which is deemed reasonable. 
In addition to participants assigned to the IMP in Part B, the assessment of the proof of concept 
will include participants from Part A who received the same dose and number of administrations 
as selected for participants in Part B. Overall, approximately 14 participants assigned to the IMP 
at the selected dose will be included in the primary analysis, comprised of 0 to 6 participants from 
Part A and 8 to 14 participants from Part B. 


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9.3
POPULATIONS FOR ANALYSES
The populations for analyses are defined in Table 7.
Table 7 - Populations for analyses
Population
Description
Screened 
All participants who sign the ICF. 
Efficacy 
All participants exposed to the IMP (regardless of the amount of treatment administered). 
Safety 
All participants exposed to the IMP (regardless of the amount of treatment administered). 
Pharmacokinetic 
All participants exposed to the IMP (regardless of the amount of treatment administered), without any 
major or critical deviations related to IMP administration and for whom the PK data are considered 
sufficient and interpretable. 
Pharmacodynamic 
All participants exposed to the IMP (regardless of the amount of treatment administered), without any 
major or critical deviations impacting PD measurements, and for whom the PD data are considered 
sufficient and interpretable. 
PK/PD population 
All participants included in both the PK and the PD populations. 
ICF: informed consent form, IMP: investigational medicinal product, PD: pharmacodynamic, PK: pharmacokinetic 
9.4
STATISTICAL ANALYSES
The statistical analysis plan will be finalized prior to the database lock and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including primary 
and secondary endpoints.
The impact of a regional or national emergency declared by a governmental agency
(see Section 8) on study conduct will be summarized (eg, study discontinuation or 
discontinuation, delay, or 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.
9.4.1
General considerations
Unless otherwise stated, all statistical analyses of Part B will include participants from Part A 
assigned to six administrations of the IMP at the selected dose for Part B, in addition to 
participants from Part B, and they will be described under Part B in what follows. All data from 
Part A will also be analyzed by dose level group separately.
Descriptive analyses will include summary statistics (using n, mean, standard deviation, inter 
quartile range, median, minimum, and maximum) for quantitative variables or number and 
percentage of participants in each category for qualitative data.
Participants from Cohort 1 in Part A may be retreated after Day 43 under specific conditions. If 
any, these participants will be followed for a total of 24 weeks from the first retreatment dose for 
safety, but the retreatment period will not be included in PK, PD, or efficacy analyses other than 
listings. Safety data post retreatment will be described or listed separately.


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9.4.2
Primary endpoint(s)
9.4.2.1
Part A
Table 8 - Primary endpoint analysis for Part A
Primary endpoint
Statistical analysis methods
Standard clinical and laboratory parameters and adverse 
events. 
Descriptive summaries of Treatment-Emergent Adverse 
Events and Potentially clinically significant abnormalities. 
All the safety analyses will be performed using the safety population from Part A, by dose level 
group. 
The safety evaluation will be based upon the review of the individual values (clinically significant 
abnormalities), descriptive statistics (summary tables, figures) and, if needed, on statistical 
analysis (appropriate estimations, confidence intervals). 
Potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor, according to predefined criteria/thresholds based 
on literature reviews and defined by the Sponsor for clinical laboratory tests and vital signs
(from
BTD-009536
, Appendix 3).
Adverse events will be graded according to the NCI-CTCAE v5.0 and related analyses will be 
provided by grades. For clinical laboratory evaluation, vital signs, and physical examination,
analyses will be provided according to PCSA.
For all safety data, the following observation periods are defined and used for classification of 
AEs and determination of on-treatment PCSA values:
The pre-treatment period is defined as the time between informed consent signature and 
the first IMP administration.
The treatment emergent (TE) period is defined as the period from the first IMP 
administration up to 30 days after the last IMP administration.
The post-treatment period is defined as the time starting after the TE period.
9.4.2.1.1 Adverse events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA;
version in use by the Sponsor at the time of database lock). 
Adverse events will be classified into predefined standard categories according to chronological 
criteria:
Pre-treatment AEs: AEs that occurred, worsened, or became serious during the 
pre-treatment period.


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Treatment-emergent AEs: AEs that occurred, worsened, or became serious during the 
treatment emergent period.
Post-treatment: AEs that occurred, worsened, or became serious during the post-treatment 
period.
Treatment-emergent AEs will be assigned to the dose level group actually received.
The following AEs summaries will be generated with number (%) of participants experiencing at 
least one event by dose level group for the safety population. Multiple occurrences of the same 
event in the same participant will be counted only once in the tables, using the maximum (worst) 
grade by treatment phase. Summaries will be provided for all grades combined and for 
Grade
(including Grade 5):
Overview of TEAEs: number and percentage of participants with any TEAE, any 
Grade
, any serious TEAE, any TEAE leading to death, any TEAE leading to 
permanent intervention discontinuation, any TEAE of special interest (AESI).
Summary of TEAEs by primary SOC, high level group term, high level term, and 
preferred term: number and percentage of participants with at least one TEAE.
Summary of TEAEs by primary SOC and PT: number and percentage of participants with 
at least one TEAE.
TEAEs will also be described according to seriousness, maximum intensity (ie, grade),
relation to the IMP and action taken.
Number and percentage of participants experiencing treatment emergent AESI will be 
presented by AESI category and PT.
Post-treatment AEs: overview, summary of AEs and serious AEs by primary SOC and PT.
All AEs reported in the study will be listed, sorted by participant and onset date. Participants 
presenting TEAEs will be listed sorted by primary SOC and PT. Any deaths, serious adverse 
events of special interest and other significant AEs, any AEs leading to permanent intervention
discontinuation, will be listed.
9.4.2.1.2 Laboratory data
For parameters with laboratory ranges and/or abnormality criteria (PCSA), analysis will be 
performed using all post-baseline assessments done during the TE period, including all unplanned 
and rechecked values. Counts of participants with PCSAs according to baseline status will be 
presented by dose level group. The same type of summary tables will be provided for out-of-
normal laboratory range values.
Descriptive statistics of values and changes from baseline at each scheduled visit and graphs over 
time of key laboratory parameters will be provided for the intervention period and the follow-up 
period overall.


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9.4.2.1.3 Vital signs and physical examinations
For all parameters with PCSA definition, counts of participants with PCSAs will be presented by 
dose level group, regardless of the baseline status. All post-baseline assessments done during the 
TE period, including all unplanned and rechecked values, will be taken into account.
Descriptive statistics of vital signs, ie, heart rate (HR), systolic and diastolic blood pressures (SBP 
and DBP), will be provided by dose level group on the value and change from baseline at each 
scheduled visit for the intervention period and the follow-up period overall.
In addition, graphs over time may be provided for heart rate and blood pressures.
9.4.2.2
Part B
Table 9 - Primary endpoint analysis for Part B
Primary endpoint
Statistical analysis methods
Overall response rate (response (R) or complete response (CR)) 
at Day 85: 
from baseline and an absence of transfusion in the last 7 
days and absence of rescue medications in the past 4 
weeks, without biochemical resolution of hemolysis.  
 g/dL (men), no evidence of hemolysis (normal 
bilirubin, LDH, haptoglobin, and reticulocytes), and 
absence of transfusion in the last 7 days and absence of 
rescue medication in the past 4 weeks 
The proportion of overall response will be computed at 
Day 85 together with its exact 95% confidence interval 
using Clopper-Pearson method. 
Participants whose response at Day 85 is not evaluable, 
whatever the reason (eg, early discontinuation), will be 
considered as non-responders.  
The primary analysis will be conducted in the efficacy population, which will be used as the
denominator for computation of the response rate.
Sensitivity analysis
The overall response rate (including the breakdown for complete response and response) will be 
described at each scheduled visit of the intervention period. 
The estimation of the response rate at D85 and its exact 95% confidence interval using Clopper-
Pearson method will also be computed in participants who had an evaluable response at this visit.
Additional sensitivity analyses and subgroup analyses (eg, for primary wAIHA and SLE-
associated wAIHA) may be performed and will be detailed in the SAP.


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9.4.3
Secondary endpoint(s)
9.4.3.1
Part A (Cohorts 2 and 3 only)
9.4.3.1.1 Analysis of efficacy
The following analysis of clinical response and fatigue will be conducted in the efficacy 
population of Part A for Cohorts 2 and 3 only. Response data will be listed for participants from 
all cohorts. 
Overall response rate at Day 85
The overall response rate (including the breakdown for complete response and response) will be 
described by dose level group at each visit of the intervention period including Day 85 and using 
the same approach for participants with a non-evaluable response as in Section 9.4.2.2.
Time to response and durability of response
The proportion of participants with durable hemoglobin response by Day 169 will be computed 
together with its exact 95% confidence interval.
The proportion of overall response will be computed at Day 169. Participants whose response at 
Day 169 is not evaluable, whatever the reason (eg, early discontinuation), will be considered as 
non-responders.
The overall response rate (including the breakdown for complete response and response) will be 
described by dose level group at each visit of the follow-up period.
The time to response (CR or R) will be computed as the time between the start of treatment until 
the first documented response (in days) and described by summary statistics (using n, mean, 
standard deviation, interquartile range, median, minimum, and maximum)
The time to loss of response (in days) will be computed as the time between the first documented 
response (CR or R) and the first documented loss of response (ie, neither R nor CR as detailed in 
Section 3) and described by summary statistics (using n, mean, standard deviation, interquartile 
range, median, minimum, and maximum). For participants still showing a response at the end of 
the follow-up period, the end date will be the last date where the response is assessed.
Depending on the number of responses, the time to response and the time to loss of response will 
be listed or described by dose level group in the subset of participants who achieved a response 
during the intervention period as well as in the subset of participants who achieved a response 
during the study including the follow-up period (if different).
The time to loss of CR (in days) will be computed as the time between the first documented CR 
and the first documented loss of CR (as detailed in Section 3) and described by summary statistics 
(using n, mean, standard deviation, interquartile range, median, minimum, and maximum). For 
participants still showing a CR at the end of the follow-up period, the end date will be the last date 
where the response is assessed. 


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Depending on the number of CRs, the time to loss of CR will be listed or described by dose level 
group in the subset of participants who achieved a CR during the intervention period as well as in 
the subset of participants who achieved a CR during the study including the follow-up period 
(if different).
The proportion of participants requiring rescue therapy (any wAIHA-directed therapy other than 
prednisone or transfusion) or splenectomy will also be described by dose level group.
Fatigue
Descriptive statistics of the FACIT-fatigue scale score will be provided for the value at each 
scheduled visit of the intervention and follow-up periods (including Day 85 and Day 169) and on 
the change from baseline by dose level group.
9.4.3.2
Part B
9.4.3.2.1 Analysis of safety
All the safety analyses will be performed using the safety population. Statistical analysis of safety 
data will be conducted following the same approach as described in Section 9.4.2.1.
9.4.3.2.2 Secondary efficacy endpoints
Analysis of secondary efficacy endpoints will be conducted in the efficacy population. Subgroup 
analyses (eg, for primary wAIHA and SLE-associated wAIHA) may be performed and will be 
detailed in the SAP.
Time to response and durability of response
The proportion of overall response at Day 169 and its exact 95% confidence interval using 
Clopper-Pearson method, the time to response and durability of response, and the proportion of 
participants requiring rescue therapy or splenectomy will be summarized, using the same 
approach and definitions as in Section 9.4.3.1.1.
Fatigue
Descriptive statistics of the FACIT-fatigue scale score will be provided for the value at each 
scheduled visit of the intervention and follow-up periods (including Day 85 and Day 169) and on 
the change from baseline.
In addition, a mixed-effect model for repeated measures will be implemented providing estimates
and 95% confidence intervals at Day 85 and Day 169 for the change from baseline: the full model 
specifications will be provided in the SAP.


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9.4.3.3
Parts A and B
9.4.3.3.1 Other secondary efficacy endpoints
Markers of hemolysis
To evaluate the effect of isatuximab on markers of hemolysis, the values and change from 
baseline at each scheduled visit in LDH, haptoglobin, reticulocytes, and total bilirubin will be 
described.
Hemoglobin
Descriptive statistics and graphs of hemoglobin values and change from baseline over time for 
each scheduled visit will be provided.
9.4.3.3.2 Analysis of pharmacokinetic parameters
Descriptive statistics (eg, mean, geometric mean, median, SD, SEM, CV, minimum, and 
maximum) for the pharmacokinetic parameters of isatuximab will be provided by dose level,
under the responsibility of the Sanofi Pharmacokinetics, Dynamics and Metabolism (PKDM)
department.
9.4.3.3.3 Immunogenicity
Anti-Drug Antibodies (ADA) incidence will be described. Individual ADA sample status
(positive, negative or inconclusive) will be listed. 
9.4.4
Tertiary/exploratory endpoint(s)
The analysis described below will be performed for Parts A and B.
9.4.4.1
Pharmacodynamic analysis
PD biomarkers (eg, levels of circulating immune cells, immunoglobulin levels, vaccine antibody 
titers, bone marrow plasma cells) will be described or plotted in the Pharmacodynamic
population. Additional details will be provided in the SAP.
9.4.4.2
Pharmacokinetic/pharmacodynamic analysis
The analysis of PK/PD relationship (eg, relationship of PK parameters to hemoglobin levels and 
levels of plasmablasts and NK cells) will be described and reported separately.
9.4.5
Other safety analyse(s)
Any other safety analyses will be detailed in the SAP.


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9.4.6
Other analyse(s)
Not applicable.
9.5
INTERIM ANALYSES
No formal interim analysis is planned. For Part A, a descriptive summary may be provided on key 
parameters of interest after each cohort for decision making on the dose.
The study analysis will be conducted in two steps. The first step analysis will be conducted when 
all participants in Part B have completed Day 85 (and including 30 days after the last IMP 
administration) or withdrawn from the intervention period. The final analysis will be conducted at 
the end of the study.
9.6
COMMITTEES OR OTHER REVIEW BOARDS
For details on Dose Selection Committee refer to Appendix 1 (Section 10.1.5).


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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 Good Clinical Practice (GCP) Guidelines.
-
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR).
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. Determining whether an incidental finding should be 
returned to a participant and, if it meets the appropriate criteria, to ensure the finding is
returned (an incidental finding is a previously undiagnosed medical condition that is 
discovered unintentionally and is unrelated to the aims of the study for which the tests 
are being performed). The following should be considered when determining the return 
of an incidental finding:
-
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and
-
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
-
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps.


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-
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings.
-
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.
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
ie, changes
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation.
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.
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. 
egally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory samples or
new extra samples for optional exploratory research. The Investigator or authorized designee will 


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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 consent 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 consent.
For a regional or national emergency declared by a governmental agency, contingency procedures 
many implemented for the duration of the emergency (See Section 8).
The participant or their legally authorized representative may 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).
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
applicable laws and regulations including the GDPR (General Data Protection Regulation). The 
study Sponsor is the Sanofi company responsible for ensuring compliance with this matter, when 
processing data from any individual who may be included in the Sanofi databases, including 
Investigators, nurses, experts, service providers, Ethics Committee members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to the
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party.
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 African American population for the FDA or on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan).
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 to the Sponsor.
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 as described in the informed consent.
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.


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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.
Participants must be informed that their study-
as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results.
Protection of data related to professionals involved in the study 
Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). 
In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list.
Personal data can be communicated to the following recipients: 
-
Personnel within Sanofi or partners or service providers involved in the study 
-
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency
Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably: 
-
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers,
-
-group transfers. 
Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
with
any competent local regulatory authority.


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Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations.
In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project. 
Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact).
10.1.5 Committee structure
Dose Selection Committee
The dose selection committee will determine the dose for Part A, Cohorts 2 and 3, and Part B. The 
committee will also determine whether to open Cohort 3. The committee will be comprised of 
(at a minimum) the Study Medical Manager, Clinical Research Director, Pharmacokineticist, 
Statistician, Global Safety Officer, and overall study Principal Investigator.
10.1.6 Dissemination of clinical study data
Sanofi shares information about clinical trials and results on publically 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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Professionals involved in the study or in the drug development program
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
10.1.7 Data quality assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
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 
physically or electronically signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
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 CRF 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.


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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
Data reported on the CRF or 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.
10.1.9 Study and site start and closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The Sponsor or designee reserves the right to close a 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
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up.


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Dose limiting toxicity (DLT) and study stopping rules
DLT rules for Part A
A DLT in Part A is defined as a Grade 3 or higher AE, unless clearly attributable to 
wAIHA or clearly unrelated to the study drug
If 1 DLT occurs in any cohort, the dose for the next cohort cannot be increased
If >1 DLT occurs in any cohort, the dose for the next cohort must be reduced
DLT rules for Part B 
A DLT in Part B is defined as a Grade 4 or higher AE, unless clearly attributable to 
wAIHA or clearly unrelated to the study drug
If >1 DLT occurs in Part B, a dosing and enrollment hold will occur. The hold may be 
lifted if the benefit/risk ration of the study is still deemed to be favorable by applicable 
competent authorities
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.
10.2
APPENDIX 2: CLINICAL LABORATORY TESTS
Required laboratory tests are detailed in Table 10.
Because of the likelihood of hemolysis in samples obtained from patients with wAIHA, 
hematology and hemolysis parameters (CBC, haptoglobin, LDH, total bilirubin, and 
reticulocyte count) which are critical to study endpoints should be performed in local 
laboratories. The remaining parameters should be performed at the central laboratory 
(Labcorp). It is important that samples for central and local analysis are obtained at the 
same time. Local laboratory results for the hematology and hemolysis parameters above 
must be entered into the eCRF. Additionally, local laboratory results performed in cases 
where the parameter could not be processed centrally or when used to make a study 
intervention decision or response evaluation must also be entered into the eCRF
Protocol-specific requirements for inclusion or exclusion of participants are detailed in
Section 5 of the protocol.


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Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.
Pregnancy testing, blood typing, and the Direct Antiglobulin Test (DAT) will be 
performed locally.
Table 10 - Protocol-required laboratory assessments
Laboratory assessments
Parameters
Hematology (local lab) 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
MCV 
 
MCH 
 
Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Markers of hemolysis: 
LDH 
Haptoglobin 
Total bilirubin 
 
       Direct Antiglobulin Test 
Clinical chemistry 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose (non-fasting) 
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total and direct bilirubin 
 
Total protein 
Coagulation 
 
 
PT/INR 
 
PTT 
Other tests 
 
Ferritin (Screening only) 
 
FSH (screening only, when applicable) 
 
Serology (screening only): HIV antibody, hepatitis B surface antigen (HBsAg), anti-HBs, 
anti-HBc (total and IgM, followed by HBV DNA in case of anti-HBc positivity), and hepatitis 
C virus antibody, hepatitis C virus RNA (if positive anti-HCV Ab) 
 
SARS-CoV-2 molecular test 


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Laboratory assessments
Parameters
 
Quantitative immunoglobulins (IgA, IgG, IgM) 
Measles, mumps, tetanus, diphtheria titers 
Routine urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick 
Microscopic examination (if blood or protein is abnormal) 
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
10.3.1 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
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:
-
Symptomatic and/or 
-
Requiring either corrective treatment or consultation, and/or 
-
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 
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"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
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 disease/disorder being studied or expected progression, signs, or symptoms of the 
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.
10.3.2 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
b) Is life-threatening
-
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.
c) 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 t
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 d
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.


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d) Results in persistent disability/incapacity
-
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.
e) Is a congenital anomaly/birth defect
f)
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.
10.3.3 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 CRF.
It is not acceptable for the Investigator
records to the Sponsor in lieu of completion of the AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are requested by 
the 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 the
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.


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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
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 the 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 the 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 the Sponsor to
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
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.


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10.3.4 Reporting of SAEs
SAE reporting to the Sponsor via an electronic data collection tool
The primary mechanism for reporting an SAE to the 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 the 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 in 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)
A woman is considered fertile following menarche and until becoming post-menopausal 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.


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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 sit
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:
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 below.
Table 11 - 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 ovulation 
-
(oral, intravaginal, or transdermal) 
Progestogen-only hormone contraception associated with inhibition of ovulation 
-
(oral or injectable) 
Highly effective methods that are user independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
-
Intrauterine device (IUD) 
-
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 


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Vasectomized partner 
Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has been confirmed. If not and less than 1 year after 
vasectomy, additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days. 
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 treatment. 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. 
COLLECTION OF PREGNANCY INFORMATION:
Male participants with partners who become pregnant 
The Investigator will attempt to collect preg
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive the study intervention.
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
egnancy. 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.
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. 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 while participating in this study. The initial 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. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. 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 for medical reasons
will be reported as an AE or SAE. 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such. 


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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.
10.5
APPENDIX 5: GENETICS
Use/Analysis of DNA
Genetic 
study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood
sample will be collected for DNA analysis from consenting participants.
DNA samples will be used for research related to anti-CD38 antibodies or wAIHA and
related diseases. They may also be used to develop tests/assays including diagnostic tests 
related to anti-CD38 antibodies or wAIHA. Genetic research may consist of the analysis of 
one or more candidate genes or the analysis of genetic markers throughout the genome 
(as appropriate).
DNA samples will be analyzed for
. Additional analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to isatuximab or study interventions of this class to understand 
study disease or related conditions.
The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary.
The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality.
The samples will be retained while research on isatuximab or other anti-CD38 antibodies
continues but no longer than 5 years or other period as per local requirements.




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10.7
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS
For participants enrolled in France:
I 04. Applicable for both Part A and Part B: Participants who have previously failed to maintain a 
sustained response after treatment with rituximab (or other anti-CD20 monoclonal antibodies). 
The last dose of the anti-CD20 antibody must have been administered at least 12 weeks before 
enrollment.
10.8
APPENDIX 8: ABBREVIATIONS
ADCC:
antibody-dependent cell-mediated cytotoxicity
AE:
adverse event
AESI:
adverse event of special interest
CR:
complete response
HSCT:
hematopoietic stem cell transplantation
IR:
infusion reaction
MedDRA:
medical dictionary for regulatory activities
NIMP:
noninvestigational medicinal product
PCSA:
potentially clinically significant abnormality
PD:
pharmacodynamics
PK:
pharmacokinetics
R:
response
RRMM:
relapsed refractory multiple myeloma
SLE:
systemic lupus erythematosus
TEAE:
treatment-emergent adverse event
TMDD:
target-mediated drug disposition 
Vmax:
maximum elimination rate


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10.9
APPENDIX 9: PROTOCOL AMENDMENT HISTORY
AMENDED PROTOCOL 05 (02 Dec 2021)
This amended protocol (amendment 05) 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
Changes in retreatment criteria for Cohort 1 and clarification of clinical laboratory testing.
Protocol amendment summary of changes table
AMENDED PROTOCOL 04 (31 August 2021)
This amended protocol (amendment 04) 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
Changes in response to ANSM (French National Agency for Medicines and Health Products 
Safety) feedback and alignment with other wAIHA studies
Protocol amendment summary of changes table
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis; 3 Objectives and 
Endpoints; 9.4.2.2 Part 2 
Absence of rescue medication for the past 4 
weeks added as part of the definition of the 
endpoint for response and complete response  
Alignment with other wAIHA 
studies 
1.1 Synopsis; 3 Objectives and 
Endpoints 
endpoints 
Clarification 
1.1 Synopsis; 3 Objectives and 
Endpoints 
Additional durability of response endpoint added 
Alignment with other wAIHA 
studies 
1.3 Schedule of Activities 
Baseline chemistry and urinalysis on Day 1 added 
Correction 
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis; 4.1 Overall Design; 
6.6 Dose Modification; 6.6.1 
Retreatment Criteria 
Retreatment criteria for cohort 1 participants  
Cohort 1 retreatment criteria too 
restrictive. 
1.3 Schedule of activities, footnote p; 
10.2 Appendix 2: Clinical Laboratory 
Tests 
Clarification regarding use of local laboratories 
Clarification 


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Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities; 
3 Objectives and Endpoints 
Quality of life questionnaires (PGIS, PGIC, CGI-E, 
CGI-I, CGI-S) added for Part B participants 
Alignment with other wAIHA 
studies 
5.1 Inclusion criteria I04; 
10.7 Country-specific requirements 
For both Parts A and B, participants enrolled in 
France must have previously failed to maintain a 
sustained response to rituximab or other anti-
CD20 monoclonal antibodies 
ANSM request 
5.1 Inclusion criteria I07 
Male contraception use extended to 5 months after 
the last isatuximab dose 
ANSM request 
5.2 Exclusion criteria E12 
WBC and neutrophil cutoffs added instead of 
utilizing investigator judgement  
ANSM request 
8.3.4 Regulatory reporting 
requirements for SAEs 
Updated reporting guidelines for SUSARs 
ANSM request 
8.5.2 Pharmacokinetic and 
immunogenicity bioanalytical 
method; 10.2 Appendix 2: Clinical 
laboratory tests  
Covance acquired by Labcorp, name changed 
accordingly 
Correction 
9.4.3 Secondary endpoints 
Clarifications as to the statistical methods and 
definitions of endpoints 
Clarification 
10.1.4 Data protection 
Additional language regarding protection of data 
related to professionals involved in the study 
Updated standard language 
10.1.6 Dissemination of clinical 
study data 
Additional language regarding professionals 
involved in the study or in the drug development 
program 
Updated standard language 
10.1.9 Study and site start and 
closure 
Updated dose limiting toxicity and study stopping 
rules 
ANSM request 
10.10 Appendix 10: Questionnaires 
Appendix containing the questionnaires to be used 
in this study added 
Addition 
AMENDED PROTOCOL 03 (05 May 2021)
This amended protocol (amendment 03) is considered to be not 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
Correction of inclusion criteria value.
Protocol amendment summary of changes table
Section # and Name
Description of Change
Brief Rationale
5.1 Inclusion criteria, criterion I02, b 
Haptoglobin value corrected from 
mg/dL to 
 mg/dL  
The original value of 
 
was an error; the lower limit of 


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Section # and Name
Description of Change
Brief Rationale
quantification for the assay is 
typically 10 mg/dL 
AMENDED PROTOCOL 02 (01 March 2021)
This amended protocol (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
Health authority feedback as well as clarifications and corrections
Protocol amendment summary of changes table
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of activities 
LDH, haptoglobin, total bilirubin, and reticulocytes 
will be collected during screening 
Correction 
1.3 Schedule of activities, footnote l 
Bone marrow biopsies/aspirates may only be 
performed for participants in Part B; clarification as 
to when the procedure can be performed 
To limit performance of bone 
marrow biopsies/aspirates to 
when the final dose is established
1.3 Schedule of activities, footnote 
m 
Antidrug antibody titers will be collected after the 
end of study only for participants who have 
positive ADA at the end of the study and 
experienced an AE during the study potentially 
related to ADA  
Alignment with other internal 
studies 
1.3 Schedule of activities, footnote r 
The decision to collect samples for RNAseq will be 
determined by the Sponsor prior to the start of Part 
B. If collected, it will be collected for participants in 
Part B only 
Feasibility constraints may not 
allow for the collection of these 
samples 
1.3 Schedule of activities, footnote s 
If the Day 3 visit is performed at home, a sample 
for RNAseq will not be collected 
Operational complexity in 
processing and shipping this 
sample if collected at the 
 
2.3.2 Infections, COVID-19, and 
other risks 
Additional information on the impact of isatuximab 
on vaccine titers and SARS-CoV-2 vaccination 
MHRA guidance on COVID-19 
vaccination for clinical trials 
5.1 Inclusion criteria, criterion I07 
Mention of the use of a male condom plus 
spermicide removed  
To align with the Clinical Trial 
Facilitation Group contraception 
guidelines 
5.2 Exclusion criteria, criterion E05 
Active HCV infection defined as positive HCV RNA 
and positive anti-HCV 
ve 
anti-
 
5.2 Exclusion criteria 
E15 and E16 added 
Hungarian health authority 
request 
6.5 Concomitant therapy 
Guidance on SARS-CoV-2 vaccination added 
Clarification 


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Section # and Name
Description of Change
Brief Rationale
8.11 Use of biological samples and 
data for future research 
Section added 
Correction 
10.1.9 Study and site start and 
closure 
Additional criteria for study hold/termination 
Paul Ehrlich Institute request 
10.2 Appendix 2: Clinical laboratory 
tests 
Clarification that blood typing is to be performed 
locally  
Clarification 
10.4 Appendix 4: Contraceptive 
guidance and collection of 
pregnancy information, Table 11 
Double barrier method removed as an acceptable 
contraception method 
To align with the Clinical Trial 
Facilitation Group contraception 
guidelines 
10.6 Appendix 6: Liver safety 
Clarification that the workup for elevated liver tests 
may be performed centrally or locally 
Clarification 
Throughout 
Clarification that the bone marrow biopsy may be a 
biopsy or aspirate 
Clarification 
Throughout 
Additional corrections to typography and 
formatting 
 
AMENDED PROTOCOL 01 (19 October 2020)
This amended protocol (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.
OVERALL RATIONALE FOR THE AMENDMENT
This amendment is in response to feedback from the U.S. FDA.
Protocol amendment summary of changes table
Section # and Name
Description of Change
Brief Rationale
Section 6.1 Study Intervention(s) 
Administered;  
Section 2.3 Benefit/Risk 
Assessment 
In the prior version of the protocol, pre-medication for 
infusion reactions would only be instituted if deemed 
necessary by the Investigator/Sponsor. Pre-medications 
for infusion reactions will now be given prior to the first 
two doses of isatuximab for all participants. 
Additional safety measure 
Section 5.1 Inclusion Criteria 
Length of contraception extended to 5 months after the 
last isatuximab dose for women of childbearing potential 
Alignment with SARCLISA 
U.S. Package Insert 
Section 2.3 Benefit/Risk 
Assessment 
Potential risk of neutropenia clarified; language regarding 
potential risk of tumorigenicity, embryo-fetal toxicity, and 
interference with serum protein electrophoresis and 
immunofixation tests added 
Alignment with SARCLISA 
U.S. Package Insert 


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10.10 APPENDIX 10: QUESTIONNAIRES


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11
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13. Jain A, Gupta DK. Daratumumab for refractory warm autoimmune hemolytic anemia. Ann 
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of current challenges and opportunities. BioDrugs. 2018;32(5):425-40.
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TABLE OF CONTENTS
STATISTICAL TECHNICAL DOCUMENT .....................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................................3 
1 
STATISTICAL AND ANALYTICAL PROCEDURES ......................................................................4 
1.1 
INTRODUCTION..............................................................................................................................4 
1.2 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL............................4 
1.2.1 
................................................................................4 
1.2.2 
......................................................................................5 
1.2.3 
...................................................................................................................................5 
1.2.4 
.................................................................................5 
1.2.5 
......................................................................................6 
1.2.6 
...................................................................6 
1.2.7 
..............................................................................................6 
1.3 
DATA HANDLING CONVENTIONS ................................................................................................6 
2 
SOFTWARE DOCUMENTATION ...................................................................................................9 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ADA:
anti-drug antibodies
AE:
adverse event
AUC:
area under the plasma concentration versus time curve
Cmax:
maximum plasma concentration observed
CTCAE:
common terminology criteria for adverse events
CV:
coefficient of variation
IMP:
investigational medicinal product
LLOQ:
lower limit of quantification
MedDRA:
Medical Dictionary for Regulatory Authorities
NCI:
National Cancer Institute
PCSA:
potentially clinically significant abnormality
PD:
pharmacodynamic
PK:
pharmacokinetic
PKDM:
Pharmacokinetics, Dynamics and Metabolism
PT:
preferred term
SD:
standard deviation
SEM:
standard error of the mean
SOC:
system organ class
TEAE:
treatment-emergent adverse event
ULOQ:
upper limit of quantification
WHO-DD:
World Health Organization Drug Dictionary


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1
STATISTICAL AND ANALYTICAL PROCEDURES
1.1
INTRODUCTION
The purpose of this document is to provide additional technical details.
A comprehensive and detailed description of strategy and statistical technique used to perform the 
analysis of data was provided in Section 9 of the protocol (Amended Clinical Trial Protocol, 
Version 06, dated 28-Mar-2022).
Modifications from analyses specified in the protocol are defined in Section 1.2.
Details for analyses defined in the protocol and additional analyses are further specified in 
Section 1.3.
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA version currently in effect at the time of database lock, version 26.0 or later).
Previous and concomitant medication records will be coded according to the World Health 
Organization Drug Dictionary (WHO-DD version currently in effect at the time of database lock, 
version 2023MAR B3 or later).
For laboratory variables, analyses according to National Cancer Institute (NCI) grading will be 
made according to the NCI common terminology criteria for AEs (CTCAE) version currently in 
effect at the time of database lock. In addition, for laboratory variables for which NCI-CTCAE 
scale is not applicable, and vital sign variables, potentially clinically significant abnormality 
(PCSA) analyses will be performed based on the PCSA list from BTD-0090536 version 3.0 dated 
3).
1.2
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL
This study stopped early and, as a result, Part B was not performed. Therefore, all protocol 
defined analyses planned for Part B will not be presented. 
1.2.1
M
4
Inter quartile range will not be included in descriptive analyses. Standard error of the mean (SEM)
will be provided instead. Hence, unless otherwise specified, descriptive statistics will be provided 
using number of observations, mean, standard deviation (SD), SEM, minimum, maximum and 
median for quantitative variables.
Because of the likelihood of hemolysis in samples obtained, it has been deemed sufficient to 
analyze all laboratory assessments (including the primary efficacy endpoint) using local 
laboratory assessments primarily and if not available using central laboratory assessments.


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1.2.2
An additional listing of all AEs will be generated. This detailed listing means the following 
protocol defined summaries and listings will not be presented: 
Treatment-emergent AEs (TEAEs) described according to seriousness, maximum intensity 
(ie, grade), relation to the investigational medicinal product (IMP) and action taken.
Summary of post-treatment AEs.
Participants presenting TEAEs listed sorted by primary system organ class (SOC) and 
preferred term (PT).
An additional summary of COVID19 related TEAEs will be generated by study intervention 
group with number (%) of participants experiencing at least one treatment emergent COVID19 
related AE, sorted by the internationally agreed SOC order and decreasing frequency of PTs.
1.2.3
4.2.1.2 Laboratory 
examinations
In addition to the protocol defined outputs the following listings will be presented:
Listing of participants with combined PCSAs for liver function Safety population.
Listing of laboratory data.
Vital signs - Listing of participants with post-baseline abnormality (PCSA).
With the addition of the detailed listing of laboratory data noted above, which will include flags 
for PCSAs and abnormalities based on normal ranges, the protocol defined summary of out-of-
normal laboratory range values will not be presented. 
With the addition of the vital signs listing of participants with post-baseline abnormality (PCSA)
noted above, the protocol defined descriptive statistics of vital signs will not be presented.
1.2.4
f
In addition to the populations for analyses defined in the protocol Table 7, the population without 
trial impact (disruption) due to COVID19 is defined as any participant: 
without any critical or major deviation related to COVID19 
The pharmacodynamic (PD) and pharmacokinetic (PK)/PD populations will not be considered 
due to the study stopping early and the fact that consequently the PD and PK/PD analyses will not 
be performed.


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1.2.5
Due to the study stopping early, the protocol defined anti-drug antibodies (ADA) incidence will 
not be presented. Instead, a listing of ADA data will be provided. 
1.2.6
4 Tertiary/exploratory endpoint(s)
Due to the study stopping early, the analyses described within Section 9.4.4 of the protocol for 
Part A will not be performed.
1.2.7
Due to the study stopping early, the study analyses will now be conducted as one step (as Part B is 
no longer applicable), at the end of the study.
1.3
DATA HANDLING CONVENTIONS
This section describes the rules and conventions used in the presentation and analysis of data.
The data will be analyzed following the Sanofi guideline for reporting of Phase 1b/2 studies 
-009094 v4.0). In the statistical appendices and in-text tables, the following 
treatment labels will be used:
Isatuximab 140 mg SC Q2W x2
Isatuximab 280 mg SC Q2W x6
Isatuximab 560 mg SC Q2W x6
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened. Only the data associated with the final re-screen for a participant will be considered 
for the definition of analysis populations.
As permitted in the protocol, one participant in Cohort 1 who met retreatment criteria and agreed 
to be retreated, was retreated as part of Cohort 2. The retreatment period will not be included for 
any analyses other than listings and will be reported separately. Furthermore, only the data 
associated with the first treatment period will be considered for the definition of analysis 
populations. For the retreated participant, the treatment-emergent period is defined as the period 
from the first IMP administration of the considered study period up to the last IMP administration 
of the considered study period + 30 days or up to the next study period (excluded), whatever 
occurred first. For the retreated participant, the following treatment label will be used when 
applicable:
Isatuximab 280 mg Retreated SC Q2W x6


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For parameters with evaluations before administration and in cases of rechecked value(s) for one 
participant, only the last observation will be used as baseline in descriptive statistics and 
derivations of other parameter values. 
After baseline, only observations planned in the protocol will be used in descriptive statistics.
For clinical laboratory parameters with nonnumeric values, the imputed values used for the 
descriptive statistics and/or the flags will be determined by considering the following rules:
be X + 10[-number of digits of the considered parameter in 
the database]
If not otherwise stated in the statistical section of the protocol:
Missing data other than protocol-planned baseline values will not be replaced.
Descriptive statistics for quantitative parameters will be provided using number of non-
missing observations, mean, SD, SEM, minimum, maximum and median.
Descriptive statistics for qualitative parameters will be provided using frequencies (N) and 
percent (%).
Laboratory and vital signs variables
For the following laboratory variables, descriptive statistics and individual plots for results and 
changes from baseline (absolute or percent change, as applicable) will be provided by planned 
visit and time and presented by study intervention group.
Hemoglobin (g/L)
Markers of hemolysis
-
LDH (µkat/L)
-
Haptoglobin (mg/L)
-
Reticulocytes (%)
-
Total bilirubin
The variables will be converted into standard international units.
For all laboratory variables, listings will be provided. For vital sign variables, a listing of 
participants with PCSA will be provided.
Data below the lower limit of quantitation/detection limit (LLOQ) will be treated as LLOQ/2 and 
values above the upper limit of quantification (ULOQ) will be treated as ULOQ in descriptive 
statistics.


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Pharmacokinetic analysis
For ease of presentation, mean values will be arithmetic mean unless specified otherwise. Plasma 
concentration values below the plasma assay limit will be treated as zero in calculating mean 
values. Mean values below the LLOQ will be reported as LLOQ in the tables and not plotted in 
the figures if after maximum plasma concentration observed (Cmax). Mean calculations and their 
associated statistics will be generated from unrounded numbers and may differ slightly from those 
values that would be determined using the rounded numbers displayed in the tables. Values 
expressed in all tables will be for ease of presentation and will not be meant to imply accuracy to 
more than 3 significant figures.
Area under the plasma concentration versus time curve (AUC) values extrapolated to infinity by 
more than 30% will be excluded from any PK statistical analysis.
Plasma concentrations and PK parameters of Isatuximab will be summarized by descriptive 
statistics (such as arithmetic mean, geometric mean, SD, SEM, coefficient of variation (CV[%]), 
median, minimum, maximum, and number of observations), for each study intervention group. 
These descriptive statistics will be performed under the responsibility of the Pharmacokinetics, 
Dynamics and Metabolism (PKDM) department at Sanofi.
Handling missing data for adverse events
In case of missing or inconsistent information, an AE will be counted as a TEAE, unless it can 
clearly be ruled out that it is not a TEAE (eg, by partial dates or other information).
If the start date (or time) of an AE is incomplete or missing, then the AE will be considered as a 
TEAE unless a partial date (or time) or comment shows it as a pre- or post-treatment event.
If the relationship to study drug is missing, the AE will be assessed as unrelated if it started before 
administration of study medication; in all other cases it will be assumed to be related.
If the severity is missing for one of the treatment-emergent occurrences of an AE, the severity will 
be imputed with the maximal severity of the other occurrences. If the severity is missing for all 
the occurrences, the severity 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.


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2
SOFTWARE DOCUMENTATION
The analysis of clinical data will be performed under the responsibility of the Sanofi Biostatistics 
Department, using SAS® (SAS Institute, NC USA). Statistical analysis of PK parameters will be 
performed by the Sanofi PKDM Department, using DatAssist_NCA 1.0 and Phoenix 8.2.