A Long-Term Follow-up Study to Evaluate Safety and Tolerability of Olipudase Alfa in Patients Who Completed the DFI12712 or the LTS13632 Study in France
Phase: PHASE2
Conditions: Acid Sphingomyelinase Deficiency
Sponsor: Sanofi

CLINICAL TRIAL PROTOCOL 
A Long-Term follow-up Study to evaluate safety and 
tolerability of olipudase alfa in patients who 
completed the DFI12712 or the LTS13632 Study in 
France 
Protocol number: 
PTA17397 
Compound 
number 
INN 
GZ402665 
Olipudase alfa 
Study phase: 
2 open-label 
Sponsor name: 
Sanofi Winthrop Industrie 
Legal registered 
address: 
82 Avenue Raspail 
94250 Gentilly, FRANCE 
Monitoring team’s 
representative 
name and contact 
information: 
Regulatory agency identifier numbers: 
IND: 
NA 
EudraCT: 
2021-004109-39 
Date: 
01-June-2023 
Total number of 
pages: 55 
Property of the Sanofi Group - strictly confidential 
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NCT:    NCT06949358

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DOCUMENT HISTORY 
 
Document 
Date, version 
Original Protocol 
26-jul-2021, version 1 (electronic1.0) 
Amended Clinical Trial Protocol No. 01 
08-March-2022, version 1 
Amended Clinical Trial Protocol No. 02 
01-June-2023, version 1 
 
Amended Clinical Trial Protocol No. 02 (01-June-2023) 
 
This amended protocol (02) is considered to be nonsubstantial 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 because it does not significantly impact the safety or physical/mental integrity 
of participants, nor the scientific value of the study. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Title 
Changed: “Sanofi-Aventis France” to “Sanofi 
Winthrop Industrie” 
The legal entity of Sanofi will change on 
01-Jul-2023 from Sanofi-Aventis France 
to Sanofi Winthrop Industrie. 

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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ............................................................................................................................................................. 1 
TABLE OF CONTENTS ....................................................................................................................................................................... 3 
LIST OF TABLES ................................................................................................................................................................................. 6 
1 
PROTOCOL SUMMARY .................................................................................................................................................... 7 
1.1 
SYNOPSIS......................................................................................................................................................................... 7 
1.2 
SCHEMA ........................................................................................................................................................................... 8 
1.3 
SCHEDULE OF ACTIVITIES .............................................................................................................................................. 9 
2 
INTRODUCTION .............................................................................................................................................................. 11 
2.1 
STUDY RATIONALE ........................................................................................................................................................ 11 
2.2 
BACKGROUND ............................................................................................................................................................... 12 
2.3 
BENEFIT/RISK ASSESSMENT ........................................................................................................................................ 13 
3 
OBJECTIVE AND ENDPOINTS ....................................................................................................................................... 14 
4 
STUDY DESIGN .............................................................................................................................................................. 15 
4.1.1 
Determination of the end of the study ............................................................................................................................... 15 
5 
STUDY POPULATION ..................................................................................................................................................... 16 
5.1 
INCLUSION CRITERIA .................................................................................................................................................... 16 
5.2 
EXCLUSION CRITERIA ................................................................................................................................................... 16 
5.3 
LIFESTYLE CONSIDERATIONS ...................................................................................................................................... 17 
5.4 
SCREEN FAILURES ........................................................................................................................................................ 17 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT/ADMINISTRATION OF STUDY ADMINISTRATION ........... 17 
6 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................................................. 18 
6.1 
STUDY INTERVENTION ADMINISTERED....................................................................................................................... 18 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ............................................................ 24 
6.3 
STUDY INTERVENTION COMPLIANCE....................................................................................................... 25 
6.4 
DOSE MODIFICATION .................................................................................................................................. 25 
6.5 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY ........................................ 25 
6.6 
TREATMENT OF OVERDOSE...................................................................................................................... 25 

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6.7 
CONCOMITANT THERAPY .......................................................................................................................... 26 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................................ 27 
7.1 
TEMPORARY TREATMENT DISCONTINUATION ....................................................................................... 27 
7.2 
PERMANENT TREATMENT DISCONTINUATION ........................................................................................ 27 
7.3 
CRITERIA FOR PERMANENT TREATMENT DISCONTINUATION.............................................................. 27 
7.3.1 
Handling of the participant after permanent treatment discontinuation ........................................................... 29 
7.3.2 
Procedure and consequence for participant withdrawal from the study ......................................................... 29 
7.4 
LOSS TO FOLLOW-UP ................................................................................................................................. 29 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................................ 31 
8.1 
ASSESSMENTS ............................................................................................................................................ 31 
8.2 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER SAFETY REPORTING ....................... 32 
8.2.1 
Time period and frequency for collecting AE and SAE information ................................................................ 32 
8.2.2 
Method of detecting AEs and SAEs ............................................................................................................... 33 
8.2.3 
Follow-up of AEs and SAEs ........................................................................................................................... 33 
8.2.4 
Regulatory reporting requirements for SAEs.................................................................................................. 33 
8.2.5 
Collection of pregnancy information ............................................................................................................... 33 
8.2.6 
Adverse events of special interest ................................................................................................................. 34 
8.2.7 
Guidelines for reporting product complaints ................................................................................................... 36 
8.3 
PHARMACOKINETICS .................................................................................................................................. 36 
8.4 
BIOMARKERS ............................................................................................................................................... 36 
8.5 
IMMUNOGENICITY ASSESSMENTS ........................................................................................................... 37 
8.6 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................................. 37 
9 
STATISTICAL CONSIDERATIONS .............................................................................................................. 38 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................................... 39 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ......................... 39 
10.1.1 
Regulatory and ethical considerations ........................................................................................................... 39 
10.1.2 
Financial disclosure ....................................................................................................................................... 40 
10.1.3 
Informed consent process ............................................................................................................................. 40 
10.1.4 
Data protection .............................................................................................................................................. 41 
10.1.5 
Committee structure ...................................................................................................................................... 43 
10.1.6 
Dissemination of clinical study data ............................................................................................................... 43 

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10.1.7 
Data quality assurance .................................................................................................................................. 43 
10.1.8 
Source documents ......................................................................................................................................... 44 
10.1.9 
Study closure ................................................................................................................................................. 44 
10.1.10 
Publication policy ........................................................................................................................................... 45 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS .......................................................................................... 45 
10.3 
APPENDIX 3: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ............................... 46 
10.3.1 
Definition of adverse event............................................................................................................................. 46 
10.3.2 
Definition of serious adverse event ................................................................................................................ 47 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................................... 48 
10.3.4 
Reporting of SAEs ......................................................................................................................................... 50 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE .................................................................... 51 
10.5 
APPENDIX 5: COUNTRY-SPECIFIC REQUIREMENTS ............................................................................... 51 
10.6 
APPENDIX 6: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY 
THAT IS DECLARED BY A GOVERNMENTAL AGENCY ............................................................................ 51 
10.7 
APPENDIX 7: ABBREVIATIONS ................................................................................................................... 51 
10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY ................................................................................... 52 
11 
REFERENCE................................................................................................................................................. 53 

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LIST OF TABLES 
 
Table 1 
Dose Escalation for Adults ............................................................................................................ 19 
Table 2 
Dose Escalation for Pediatric Patients ........................................................................................... 20 

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1 
PROTOCOL SUMMARY 
 
1.1 
SYNOPSIS 
 
Protocol title: 
 
A Long-Term follow-up Study to evaluate safety and tolerability of olipudase alfa in the patients 
who completed the DFI12712 or the LTS13632 Study in France. 
 
Rationale: 
No approved treatment is available for ASMD. Clinical studies have been performed to 
demonstrate the efficacy and safety of olipudase alfa in ASMD patients with non-neurologic 
manifestations. In France, one adult patient with ASMD participated in Study DFI12712 and two 
patients in Study LTS13632. The efficacy and safety of olipudase alfa ERT have been 
demonstrated, and the studies DFI12712 and LTS13632 will end once the European marketing 
authorization (EMA) has been granted by the European Commission. The present study intends to 
ensure safety follow-up and treatment continuation for patients who participated in the DFI12712 
study or in the LTS13632 study in France while Sanofi is seeking to obtain reimbursement in 
France. 
This study also intends to fulfill an unmet critical need while Sanofi is seeking reimbursement 
approval of olipudase alfa by providing treatment of the patient in France with ASMD who meets 
the criteria listed in Section 5 . 
 
Objective and endpoints: 
 
The objective of this study is to assess safety and tolerability of olipudase alfa in the patients with 
ASMD who completed the DFI12712 or the LTS13632 study in France until olipudase alfa 
reimbursement is granted in France or until 5 years whichever comes first. 
 
Safety reporting is required. Submission of safety reports to Sanofi is mandatory for the patient to 
be eligible to continue in this study. 
 
Overall design: 
 
This bi-center study in France has an open label, repeated dose design. 
 
This is an open-label study to provide ERT with olipudase alfa to the patients with ASMD who 
completed the DFI12712 or the LTS13632 Study in France until olipudase alfa reimbursement is 
granted in France. 
 
• Study and treatment duration: the period between the patient’s completion of 
StudyDFI12712 or LTS13632 and olipudase alfa reimbursement is available in France. In 
case reimbursement will not be obtained, this study will end 5 years after starting. 

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• Visit frequency: every 2 weeks. 
Study phase: 
 
• open-label extension 
Observations: 
 
• Safety assessments are required in this study. 
Intervention name: 
 
• Olipudase alfa. 
Intervention form: 
 
• Intravenous (IV) infusion. 
Disease studied: 
 
• Acid sphingomyelinase deficiency. 
Study and treatment duration: 
 
• Period between the patient’s completion of Study DFI12712 or LTS13632 and olipudase 
alfa reimbursement becoming available in France. In case reimbursement will not be 
obtained, this study will end 5 years after starting. 
 
Number of participants: 
 
• Up to 3 
Statistical considerations: 
 
Safety analysis will be based on the review of individual values. All AEs reported and safety parameters in 
the study will be listed. Demographic data and concomitant medications will also be listed. 
 
 
Data monitoring/other committee: 
 
• No 
 
1.2 
SCHEMA 
 
Not applicable 

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1.3 
SCHEDULE OF ACTIVITIES 
Treatment perioda 
Post-treatment 
Every 
2 weeks 
(±3 days) 
Every 
3 months 
(±14 days) 
Every 
12 months or 
end of 
treatment 
End of studyb 
(early 
discontinuation) 
Safety follow- 
up phone call 
(15 days after 
last infusion 
visit) 
The informed consent form (ICF) must be signed, inclusion/exclusion criteria must be verified, and a 
participant number must be assigned before the participant’s first study visit. Demographics and 
baseline characteristics (date of first ASMD diagnosis, alcohol and tobacco use history, prior medications 
for 30 days before enrollment, age, sex, height, weight, body mass index [BMI], medical history, and 
specific information on any relevant prior or current medical conditions/surgical procedures ) should be 
confirmed and will be recorded on the case report form (CRF) at the baseline visit (the first olipudase 
alfa infusion visit). The participant number in this study and in Study DF12712 or in LTS13632 will also 
be recorded on the CRF. 
Assessment of AEsc 
 
Concomitant 
treatment 
Abbreviated 
physical 
examinationd 
X 
X 
X 
Weighte, BMI 
X 
X 
Height (for pediatric 
patient) 
X 
Vital sign 
measurementsf 
X 
X 
X 
X 
Liver function g 
X 
X 
X 
ADA (IgG) (and 
specific dosages for 
hypersensitivity) 
X 
X 
X 
Pregnancy testingh 
Every 4 weeks 
Abbreviations: AE = adverse event; β-HCG = beta-human chorionic gonadotropin; BMI = body mass index; CRF = 
case report form; ICF = informed consent form; ADA = anti-drug antibodies 
a Olipudase alfa will be infused once every 2 weeks (±3 days), in reference to the date of the first infusion. The first 
infusion visit is the baseline visit. Unless otherwise specified, study procedures should preferably take place before 
the infusion and at approximately the same time of day at each visit, in reference to the baseline visit. 
b The end of study visit will take place within 2 weeks after the final infusion. 
c Adverse events will be recorded from the time the participant provides signed informed consent through the safety 
follow-up period (15 days after the last olipudase alfa infusion). 
d Only general appearance will be assessed before and after each olipudase alfa infusion. 
e Weight at the previous visit may be used to calculate the dose of olipudase alfa at the current visit. 
f Vital signs will include blood pressure, heart rate, respiratory rate, and temperature. At all visits, vital signs will be 
measured prior to the infusion (within 30 ±10 minutes of infusion start), halfway through the infusion (ie, when half 
the expected infusion duration has elapsed), and at the end of the infusion ±10 minutes. At any visit, the Investigator 
may decide that a longer monitoring period is required. 
g If a re-escalation is needed (in the case the patient missed 3 or more infusions), blood samples will be collected for 
liver function within 24 hours before the infusion and 24 ±3 hours after the end of the infusion at dose escalation 
visits. At any visit, the Investigator may decide that a longer monitoring period is required. 

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h Female participants of childbearing potential: Every 4 weeks a urine pregnancy test (β-HCG) will be performed up 
to 24 hours before the olipudase alfa infusion. If any urine pregnancy test is positive, a serum pregnancy test should 
be performed. 

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2 
INTRODUCTION 
Acid sphingomyelinase deficiency (ASMD) is a rare, potentially life-threatening lysosomal 
storage disease for which only symptomatic treatments currently exist. Patients with ASMD have 
variable impairment of sphingomyelin metabolism due to pathogenic variants in SMPD1, the gene 
encoding acid sphingomyelinase (ASM), that result in expression of defective ASM with reduced 
activity. Because ASM catalyzes the hydrolysis of sphingomyelin to ceramide and 
phosphocholine, reduced ASM activity results in progressive lysosomal accumulation of 
sphingomyelin. This accumulation is mostly in cells of the monocyte/macrophage lineage residing 
in reticuloendothelial tissues, including the spleen, liver, lung, bone marrow, and lymph nodes. 
Neurons may also be affected in severe disease. ASMD is historically known as Niemann-Pick 
disease (NPD), although the nomenclature is evolving and the term ASMD, rather than NPD, is 
becoming more common. 
 
ASMD is an autosomal recessive single-gene disease. It is known to generate a spectrum of 
phenotypes, which have been classified as Type A, Type B, and Type A/B. ASMD Type A is the 
early onset and acute neuropathic form of ASMD, and results in failure to thrive, 
hepatosplenomegaly, rapidly progressive neurologic degeneration, and death, usually before the 
age of 3 years (1). ASMD Type B is usually diagnosed after the age of 2 years, when 
hepatosplenomegaly (the most common disease manifestation in all patients with ASMD) is 
observed. It is characterized by slower progression with little or no neurologic involvement. 
Other, more variable, features include liver dysfunction, pulmonary disease, retinal stigmata, and 
growth retardation. Patients with ASMD Type B can survive into adulthood. ASMD Type A/B 
includes disease manifestations intermediate to those of Type A and Type B. Patients with ASMD 
Type A/B may develop neurologic symptoms in childhood and can have dominant 
neurodegenerative and/or visceral manifestations. Prolonged survival distinguishes Type A/B 
from Type A, though premature death can occur, often from liver and respiratory disease. 
 
2.1 
STUDY RATIONALE 
No approved treatment is available for ASMD. Clinical studies have been performed to 
demonstrate the efficacy and safety of olipudase alfa. In France, one adult patient with ASMD 
participated in Study DFI12712 and two patients with ASMD in the LTS13632 Study. The 
efficacy and safety of olipudase alfa ERT have been demonstrated, and the DFI12712 and the 
LTS13632 studies will end once the European MA has been granted by the European 
Commission. The present study intends to ensure safety follow-up and treatment continuation for 
patients who participated in the DFI12712 or the LTS13632 study in France while Sanofi is 
seeking to obtain reimbursement in France (after the European MA and until reimbursement is 
granted in France). 
This study also intends to fulfill an unmet critical need while Sanofi is seeking regulatory 
approval of olipudase alfa by providing treatment of the patient in France with ASMD who meets 
the criteria listed in Section 5 . In case reimbursement will not be obtained, this study will 
continue for 5 years. 

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2.2 
BACKGROUND 
 
Olipudase alfa is a recombinant human acid sphingomyelinase expressed in Chinese hamster 
ovary cells. The resulting gene product retains the enzymatic activity and lysosomal targeting of 
the native protein. Olipudase alfa is being developed for the treatment of non-central nervous 
system manifestations in patients with a confirmed diagnosis of ASMD. 
 
A review of clinical experience with olipudase alfa is in the Investigator’s Brochure (IB). 
Olipudase alfa is administered by IV infusion every 2 weeks (±3 days). The dose should be based 
on the patient’s weight. During the dose escalation period, patient should be monitored for 3 hours 
after the end of each infusion. Treatment begins with a dose escalation period. The maximum 
administered dose is 3 mg/kg. 
 
Olipudase alfa has been evaluated in 72 patients. ASCEND trial (DFI12712, NCT02004691) is a 
Phase 2/3 double blind, placebo-controlled, randomized, multicenter study, with a primary 
analysis period of 52 weeks and an OLE of less than 4 years. A total of 36 adults with ASMD 
type B patients were included. After 52 weeks of follow-up, the study was declared positive as it 
met the first primary endpoint of DLco (Diffusion capacity of lung for carbon monoxide). The 
DLco was significantly improved versus placebo (p<0.0004). Spleen volume statistically 
decreased (p<0.0001 vs placebo), accompanied by increased platelet count, reflecting correction 
of hypersplenism. Liver volume also significantly decreased (p<0.0001 vs placebo) due to 
clearance of sphingomyelin (supported by histological evidence from serial liver biopsies). 
Olipudase alfa showed a favorable safety and tolerability profile. No patient died and there were 
no permanent discontinuations of olipudase alfa due to adverse events. All serious adverse events 
(SAEs) were considered unrelated to treatment (3 olipudase alfa patients had 5 SAEs and 4 
placebo patients had 11 SAEs). 
IARs, which are expected with ERT, were mild or moderate and easily managed. 8/18 olipudase 
alfa patients (44%) and 6/18 placebo patients (33%) had IARs. Treatment-induced anti-drug 
antibodies (ADAs) occurred in 4/18 olipudase alfa patients (22%) : 2 of these patients had 
transient antibodies and the remaining 2 patients had persistent but low antibody titers No patient 
developed neutralizing antibodies that interfered with cell uptake of enzymes. 
 
ASCEND-Peds trial (DFI13803, NCT02292654) is a Phase 1/2 1-year open-label multi-center 
study to evaluate safety, tolerability, PK, and efficacy of olipudase alfa in pediatric patients with 
ASMD for 64 weeks. The study included 20 children and showed that olipudase alfa is generally 
well-tolerated with significant improvements in clinically relevant disease endpoints. Most AE 
were mild or moderate, including IARs (primarily urticaria, pyrexia, and/or vomiting) in 11 
patients. Three patients had SAE considered related to treatment: one with transient asymptomatic 
alanine and aminotransferase increases, another with urticaria and rash, and a third with an 
anaphylactic ADA+ reaction (who successfully underwent desensitization and reached the 3 
mg/kg maintenance dose). Mean splenomegaly and hepatomegaly significantly improved (p < 
0.0001). Mean % predicted DLco significantly improved by 32.9% (p=0.0053) in patients able to 
perform the test. Mean height Z-scores improved by 0.56 (p < 0.0001). 

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Patients who have completed ASCEND-Peds trial can then be included in the long-term phase 2 
study LTS13632 (NCT02004704). 
 
 
 
 
2.3 
BENEFIT/RISK ASSESSMENT 
 
Information on the known and expected benefits and risks of, and reasonably expected adverse 
events associated with, treatment with olipudase alfa is in the IB and the written subject 
information and informed consent form (ICF). 
 
Considering the measures taken to minimize risk to the patient participating in this study, the 
potential risks identified in association with treatment with olipudase alfa are justified by the 
anticipated benefits that may be afforded to this patient. 

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3 
OBJECTIVE AND ENDPOINTS 
The objective of this study is to assess safety and tolerability of olipudase alfa in patients in 
France with acid sphingomyelinase deficiency (ASMD) who have completed DFI12712 or 
LTS13632 study from market authorization until reimbursement of olipudase alfa in France or 
until 5 years, whichever comes first. 
 
Safety reporting is required. Submission of safety reports to Sanofi is mandatory for the 
participant to be eligible to continue in this study. 

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4 
STUDY DESIGN 
This is an open-label extension, bi-center, French study of safety and tolerability in the patients 
who have previously participated in DFI12712 or LTS13632 study of olipudase alfa in France. 
 
Safety assessments are required. Efficacy, pharmacodynamic, and pharmacokinetic assessments 
are not required. 
 
This study is intended to assure safety follow-up and study treatment continuation for the patients 
who completed the DFI12712 or the LTS13632 study in France while Sanofi is seeking regulatory 
approval of olipudase alfa in France. 
 
4.1.1 Determination of the end of the study 
 
The participants may continue to receive olipudase alfa until the earliest of the participants’ own 
voluntary withdrawal; this study ending; olipudase alfa reimbursement becoming available in 
France; or determination by the participant’s physician that this treatment is no longer appropriate. 
 
The duration of the study is expected to depend on local regulations and on the date when 
olipudase alfa reimbursement becomes available in France. 
 
In case reimbursement will not be obtained, this study will end after 5 years. 

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5 
STUDY POPULATION 
Up to 3 participants are expected to be enrolled in this study. 
 
5.1 
INCLUSION CRITERIA 
 
The patient is eligible to be included in the study only if the following criteria apply: 
I 01. The patient has completed Study DFI12712 (ASCEND) in France, a Phase 2/3, 
multicenter, randomized, double-blind, placebo-controlled, repeat dose study to evaluate 
the efficacy, safety, pharmacodynamics, and pharmacokinetics of olipudase alfa in patients 
with ASMD and has benefited from the drug olipudase alfa or the patient has completed 
Study LTS13632 in France, a Long-Term Study to assess the ongoing safety and efficacy 
of olipudase alfa in patients with ASMD. 
I 02. The patient must provide signed, informed consent prior to performing any study-related 
procedures. Consent of a legally authorized guardian(s) is (are) required for legally minor 
patients as defined by local regulation. If the patient is legally minor, signed written 
consent shall be obtained from parent(s)/legal guardian and assent obtained from patients, 
if applicable 
 
I 03. 
The patient is willing to comply with the clinical protocol. 
I 04. The patient, if female and of childbearing potential, must have a negative pregnancy test 
result [urine beta-human chorionic gonadotropin (β-HCG)] at enrollment. Sexually active 
female patients of childbearing potential and male patients are required to practice true 
abstinence in line with their preferred and usual lifestyle or to use 2 acceptable effective 
methods of contraception, a barrier method such as a condom or occlusive cap (diaphragm 
or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository and an established 
non-barrier method such as oral, injected, or implanted hormonal methods, an intrauterine 
device, or intrauterine system for the entire duration of the treatment period and for at least 
28 days after receiving the last study drug dose. Sterilized or infertile patients (defined as 
having undergone surgical sterilization, ie, vasectomy/bilateral tubectomy, hysterectomy 
and bilateral ovariectomy or as being postmenopausal, defined as at least 12 months of 
amenorrhea prior to enrollment) will be exempted from the requirements to use 
contraception in this study. 
 
 
 
5.2 
EXCLUSION CRITERIA 
 
A patient is excluded from the study if any of the following criteria apply: 
 
   Any patient who has not participated in the Study DFI12712 or the Study LTS13632 

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  A patient who experienced any systemic hypersensitivity reactions to olipudase alfa in 
Study DFI12712 or Study LTS13632 which, in the opinion of the Investigator, could 
indicate that treatment continuation may present an unreasonable risk. 
 
  The patient, in the opinion of the Investigator, is unable to adhere to the requirements of 
the study. 
 
  The patient is unwilling or unable to abstain from alcohol for 1 day prior to and 3 days 
after each olipudase alfa infusion for the duration of the treatment period. 
 
  Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
 
  The patient is concurrently participating in another clinical study of investigational 
treatment. 
 
   Any of the following medical conditions: 
 
• The patient has any new condition or worsening of an existing condition which, in the 
opinion of the Investigator, would make the patient unsuitable for enrollment or could 
interfere with the patient’s participating in or completing the study. 
• Requirement for recurrent dose adjustment of anticoagulation treatment over the last 
6 months. 
• Pregnancy or breastfeeding. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Not applicable 
 
5.4 
SCREEN FAILURES 
 
Not applicable 
 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT/ADMINISTRATION OF 
STUDY ADMINISTRATION 
 
Not applicable 

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6 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention intended to be administered to a 
study participant according to the study protocol. 
 
6.1 
STUDY INTERVENTION ADMINISTERED 
Olipudase alfa is a sterile, nonpyrogenic white to off-white lyophilized cake supplied in 
single-use, 20 cc Type 1 glass vials. Each vial contains approximately 20 mg of extractable 
olipudase alfa. 
The lyophilized powder should be reconstituted with 5.1 mL of sterile water for injection to yield 
a concentration of approximately 4.0 mg/mL olipudase alfa, which will be further diluted in 0.9% 
sodium chloride solution to a specific volume based on the dose to be administered. Detailed 
instructions for the preparation, storage, and administration of olipudase alfa will be given in the 
pharmacy manual and the IB, which will be provided to the Investigator. Physicians seeking 
additional treatment-related information during the course of olipudase alfa treatment should 
communicate with the Sanofi local medical representative. 
Olipudase alfa is administered by IV infusion every 2 weeks (±3 days) in reference to the date of 
the first infusion. The dose should be based on the participant’s weight. For an adult participant 
with a body mass index >30, the dose should be based on weight (mass) in kilograms 
corresponding to a BMI of 30, given the participant’s height. 
Infusions should be supervised by a health care provider with experience in ERT. The potential 
risk of severe infusion-associated reactions (IARs) requires appropriate resuscitation equipment to 
be readily available. During the dose escalation period, the participant should be monitored for 
3 hours after the end of each infusion. There are no restrictions on infusion timing with respect to 
meals. 
The participants will start this study at his/her last dose received in Study DFI12712 or Study 
LTS13632. If more than 1 dose is missed between studies, instructions on dose escalation are 
provided below in this section. 

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• The dose for an adult should be escalated as shown below. 
Table 1 
Dose Escalation for Adults 
Weeka 
Olipudase alfa dose, mg/kg 
0b 
0.1 
2 
0.3 
4b 
0.3 
6 
0.6 
8 
0.6 
10 
1.0 
12 
2.0 
14 
3.0 
≥16 
3.0 
a Weeks do not account for rechallenges. 
b Rechallenges are allowed only once, at Week 0 and at Week 4. 
 
The participant will receive intravenous olipudase alfa over approximately 20 minutes to 4.5 
hours, depending on the dose. The length of the infusion time may be adjusted based on the 
participant’s tolerance of the infusion. 
 
The dose escalation regimen may be adjusted based on the participant’s tolerance of the 
infusion and clinical judgement. 
 
If a mild systemic hypersensitivity reaction occurs,1 rechallenge each is allowed for the doses 
administered at Week 0 (0.1 mg/kg olipudase alfa) and at Week 4 (0.3 mg/kg olipudase alfa). 
 
If a moderate or severe systemic hypersensitivity reaction occurs with the rechallenge, the 
following should take place: 
• The olipudase alfa infusion should immediately be terminated, and appropriate medical 
treatment should be initiated. 
• The event should be clearly documented on the adverse event (AE) form. 
• The Sanofi local medical representative should immediately be informed. 
During dose escalation the following guidelines should be observed (refer to the IB): 
Only AEs not related to the participant’s underlying condition should affect dose escalation. 
 
These guidelines apply to AEs considered related to olipudase alfa treatment. 
• If the participant experiences no AE or a mild AE, escalate to the next dose. 
• If the participant experiences a moderate AE, repeat the same dose at the next infusion. 
• If the participant experiences a severe AE, decrease to the prior dose at the next infusion. 

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If the participant presents on the day of infusion with either an unresolved AE or an acute illness, 
neither of which meets the criteria for permanent discontinuation of treatment, the infusion may 
be withheld or administered at the Investigator’s discretion. 
• The dose for a pediatric patient should be escalated as shown below: 
Table 2 Dose Escalation for Pediatric Patients 
Weeka 
Olipudase alfa dose, mg/kg 
0 
0.03 
2 
0.1b 
4 
0.3c 
6 
0.3c 
8 
0.6d 
10 
0.6d 
12 
1.0d 
14 
2.0d 
≥16 
3.0e 
a Weeks do not account for rechallenges. 
b If the initial dose of 0.03 mg/kg is tolerated (1 rechallenge with 0.03 mg/kg is allowed) 
c If 0.1 mg/kg is tolerated 
d If 2 consecutive doses of 0.3 mg/kg are tolerated 
e If 3.0 mg/kg is not tolerated, the patient should receive the highest tolerated dose for the rest of his/her time in the program. 
 
 
 
Missed doses 
 
A dose is considered missed when it is not administered within 3 days of the scheduled date. 
When a dose of olipudase alfa is missed, administer the next dose as described below as soon as 
possible. Thereafter, infusions should be scheduled every other week from the date of the last 
infusion. 
 
 
Missed doses during the dose escalation period 
• If 1 infusion is missed administer the last tolerated dose before resuming dose escalation 
according to Table 1. 
• If 2 consecutive infusions are missed, administer 1 dose below the last tolerated dose 
(minimal dose 0.3 mg/kg), before resuming dose escalation according to Table 1. 

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• If 3 or more consecutive infusions are missed, resume dose escalation starting at 
0.3 mg/kg, according to Table 1. 
• At the next 2 scheduled infusions after a missed dose, if the dose administered is to be 0.3 
or 0.6 mg/kg, that dose should be administered twice, according to Table 1. 
 
Missed doses when dose escalation is complete 
• If 1 maintenance infusion is missed, administer the same dose and adjust the treatment 
schedule accordingly. 
• If 2 consecutive maintenance infusions are missed, administer 2 mg/kg. At subsequent 
infusions, administer 3 mg/kg. 
• If 3 or more consecutive infusions are missed, resume dose escalation starting at 
0.3 mg/kg, according to Table 1. If 3 or more consecutive infusions are missed, a baseline 
assessment of liver function (AST/ALT) will be required before treatment initiation. 
Please refer to the requirements for safety assessment during dose re-escalation 
(Section 8.1). 
Dose interruption 
 
 
If any of the following AEs occurs dosing should be temporarily stopped, taking into 
consideration the relationship of the AE to treatment with olipudase alfa): 
• Any serious adverse event (SAE), not related to the participant’s underlying condition and 
considered related to treatment with olipudase alfa. 
• Any increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), total 
bilirubin, or alkaline phosphatase (AP) to >3× the baseline value (prior to the start of 
olipudase alfa therapy) and above the upper limit of normal (ULN). 
• Any increase in total bilirubin or AP to >1.5× the baseline value with AST or ALT 
>2× ULN. 
• Any increase in ALT or AST to >3× ULN and >2× the baseline value with fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia (eosinophils 
>ULN). 
• Any serious or severe AE that raises significant concern about the safety of olipudase alfa 
at the administered dose. 
 
When dosing with olipudase alfa is interrupted, safety monitoring of the participant should 
continue. If the AE(s) is/are reversible and results of clinical laboratory tests (including liver 
function tests) approach or reach baseline values, the participant can resume dosing and receive 
the previously-tolerated lower dose (ie, the dose administered at a previous visit without incident). 

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Depending on the participant's response, either dose escalation should continue or the participant 
should go on receiving the previously tolerated dose (ie, the highest tolerated dose). 
 
Management of hypersensitivity and infusion-related reactions 
 
The information in this section is based on clinical trial experience with olipudase alfa and is in 
accordance with the IB. All IARs should be documented on the AE form. 
 
In general, pretreatment is not recommended for prophylactic management of IARs. For a 
participant who experiences moderate to severe or recurrent IARs suggestive of hypersensitivity 
(Section 8.2.6), pretreatment (eg, antihistamines; antipyretics; glucocorticoids) may be considered 
by the Investigator according to his or her clinical judgment. The need for oral or IV cationic 
amphiphilic antihistamines should be carefully considered, given the potential risk of functional 
inhibition of olipudase alfa activity by these drugs. 
 
Mild IARs may be mitigated by reducing the infusion rate (eg, by half) or temporarily interrupting 
the infusion. 
 
A participant reporting signs or experiencing symptoms suggesting hypersensitivity reactions, 
including anaphylactic or anaphylactoid reactions, during infusion of olipudase alfa should be 
treated according to the local SOC. If anaphylaxis or other severe allergic reactions occur, the 
infusion should immediately be terminated, appropriate medical treatment should be initiated, and 
a Sanofi local medical representative informed. 
 
All infusions during dose escalation must take place in a monitored hospital setting. The potential 
risk of severe hypersensitivity IARs during dose escalation mandates the requirement for 
clinicians and appropriate resuscitation equipment to be readily available. 
 
Home infusion 
 
Infusion of olipudase alfa at home may be considered for patients who are tolerating their 
infusions well and have no history of moderate or severe IARs for a few months. The decision to 
have a patient move to home infusion should be made after evaluation and upon recommendation 
by the investigator. A patient’s underlying co-morbidities and ability to adhere to the home 
infusion requirements need to be taken into account when evaluating the patient for eligibility to 
receive home infusion. The following criteria should be considered and documented in medical 
files by investigator: 
• The patient must have no ongoing concurrent condition that, in the opinion of the 
physician, may affect patient’s ability to tolerate the infusion. 
• The patient is considered medically stable. A comprehensive evaluation must be 
completed before the initiation of home infusion. 
• The patient must have received olipudase alfa infusions in a hospital or infusion center for 
a few months and finish dose escalation. Documentation of a pattern of well-tolerated 

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infusions with no IARs, or mild IARs that have been controlled with premedication, is a 
prerequisite for the initiation of home infusion. 
• The participant must be willing and able to comply with home infusion procedures. 
• Any identified risk of noncompliance with monitoring of study requirements, or potential 
for loss to follow -up, should result in a participant’s not being eligible for home infusion 
• Home infusion infrastructure, resources, and procedures, including training, must be 
established and available to the healthcare professional. The healthcare professional must 
be available at all times during the home infusion and a specific time after-infusion, 
depending on patient’s tolerance prior to starting home infusion and determined at the 
discretion of the investigator. 
• If the patient experiences adverse reactions during the home infusion, the infusion process 
should be stopped immediately, and appropriate medical treatment should be initiated. 
Subsequent infusions may need to occur in a hospital or infusion center until no such 
adverse reaction is present. 
• Dose and infusion rate must not be changed without consulting the investigator. 
• Prior to beginning home infusions, the home infusion agency staff, including new staff 
members, must have been trained by the site or sponsor in proper procedures for 
administering infusions, monitoring participants, documenting procedures, and reporting 
to site on a timely basis. Any new staff member must be trained by the site or sponsor 
prior to resuming home infusions. The site must confirm that the home infusion agency 
staff has received training at least equivalent to that provided to new staff members. 
• The home infusion agency staff should be readily available when olipudase alfa is 
administrated and through the post-infusion observation period determined at the 
discretion of the investigator.. 
• The home infusion agency staff must be trained in basic life support (cardiopulmonary 
resuscitation) and should have a process for requesting additional emergency services if 
needed. 
• The home infusion agency must keep source documentation of each infusion, including 
documentation of any AEs. The home infusion agency must be amenable to providing 
specific source documentation to Sanofi and must agree to be monitored. 
 
The Investigator (PI) is responsible for approving initiation of home infusions and is still 
responsible for all study procedures and the participant’s safety, even when delegating infusion 
responsibilities to the home infusion agency during this clinical study. 
It is the Investigator’s responsibility to guide staff in clinical management of the participant in 
case of IARs or hypersensitivity or anaphylactic reactions. The Investigator will be the point of 
contact for home infusion agency staff in the event of questions or emergency situations. 
 
Infusions given in the home setting versus in the clinic will be captured in the electronic case 
report forms (eCRFs) for AEs and exposure. 

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6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY 
 
Sanofi will supply olipudase alfa vials and coordinate packaging and distribution services in 
accordance with the administration schedule. The clinical site should provide syringes and diluent 
bags. 
 
Olipudase alfa will be provided as a sterile lyophilized powder to be reconstituted with sterile 
water for injection and further diluted with 0.9% sodium chloride in an infusion bag and/or 
syringe for administration. 
 
The olipudase alfa label text will meet the national legislation requirements of France and will 
comply with Good Manufacturing Practice. The label text will minimally include the protocol 
number, description of the vial contents, packaging number, storage conditions, Sanofi’s name 
and address, and any required caution statement as mandated by the participating country. Only 
the Investigator should prescribe olipudase alfa. Under no circumstance will olipudase alfa be 
used other than as directed by this protocol. 
 
Olipudase alfa must be kept in a secure area with restricted access. Unreconstituted olipudase alfa 
should be stored under adequate refrigerated conditions at 2°C to 8°C (36°F to 46°F). 
Temperature excursions should be handled as described in the pharmacy manual. 
 
Reconstituted olipudase alfa is stable at 20°C to 25°C for 24 hours plus the duration of the 
infusion, at 0.1 to 3.5 mg/mL. It is recommended that reconstituted olipudase alfa be used 
immediately after reconstitution. 
 
The Investigator or other authorized persons (ie, pharmacists or designees) are responsible for 
storing olipudase alfa provided by Sanofi in a secure and safe place in accordance with local 
regulations, labeling specifications, policies, and procedures. 
 
Control of storage conditions, especially control of temperature (eg, refrigerated storage) and of 
information on in-use stability and instructions for handling olipudase alfa should take place 
according to the rules provided by Sanofi. 
The Investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all study intervention received, and that any discrepancies are 
reported and resolved before use of the study intervention. 
Only the 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. 

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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). 
Sanofi must be promptly informed of any quality issue noticed with the receipt or use of olipudase 
alfa, such as deficiency in condition, appearance, pertaining documentation, labeling, expiration 
date, etc. Some deficiencies may be recorded through a complaint procedure (Section). 
A potential defect in the quality of olipudase alfa 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, to recall olipudase alfa and eliminate potential hazards. 
 
Under no circumstances will the Investigator supply olipudase alfa to a third party (except for 
DTP shipment, for which a courier company has been approved by the Sponsor), allow olipudase 
alfa to be used other than as directed by this clinical trial protocol, or dispose of olipudase alfa in 
any other manner. 
 
6.3 
STUDY INTERVENTION COMPLIANCE 
 
The participants will receive study intervention directly from the Investigator or designee, under 
medical supervision. The date and time of each dose administered in the clinic will be recorded in 
the source documents and recorded. The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention. 
 
6.4 
DOSE MODIFICATION 
 
Dose modification (dose escalation and procedures for missed doses and dose interruption) is 
described in Section 6.1). 
 
6.5 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY 
 
The study will end when olipudase alfa reimbursement becomes available in France. In case 
reimbursement will not be obtained, this study will end 5 years after starting. 
 
6.6 
TREATMENT OF OVERDOSE 
 
In the event of an overdose, of olipudase alfa, the Investigator should: 
• Contact the Sponsor immediately. 
• Evaluate the participant to determine, in consultation with the Sponsor, whether study 
intervention should be interrupted or whether the dose should be reduced. 

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• Closely monitor the participant for any AE/serious adverse event (SAE) and laboratory 
abnormalities. 
• Document appropriately in the report form. 
 
6.7 
CONCOMITANT THERAPY 
 
Based on published in silico and in vitro data, tricyclic antidepressants and some cationic 
amphiphilic drugs, including select antidepressants (eg, imipramine, desipramine, some selective 
serotonin reuptake inhibitors), select antipsychotics (eg, chlorpromazine), and some 
antihistamines (eg, loratadine, desloratadine, astemizole, ebastine, clemastine) may decrease 
olipudase alfa activity. The relevance of this functional inhibition in humans is not known. This 
theoretical interaction should be considered when olipudase alfa is prescribed concomitantly with 
chronic systemic treatment with functional inhibitors of acid sphingomyelinase. 
 
The need for oral or intravenous administration of cationic amphiphilic antihistamines in the 
participant receiving olipudase alfa should be carefully considered. There is no restriction of 
topical antihistamines. 

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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Treatment may be discontinued temporarily or permanently. Any treatment discontinuation 
should be documented. Permanent discontinuation should be a last resort. Sanofi should be 
immediately notified (within 5 business days) if the participant withdraws from the study. Any 
treatment discontinuation should be fully documented in the progress report. 
 
7.1 
TEMPORARY TREATMENT DISCONTINUATION 
 
Treatment discontinuation is temporary when >1 olipudase alfa infusion is not administered, as 
decided by the Investigator. Administration of olipudase alfa should be reinitiated with close, 
appropriate clinical and/or laboratory monitoring, after the Investigator has considered, in his/her 
best medical judgment, that the relationship of olipudase alfa to the event of concern was unlikely, 
and if the participant still meets the enrollment criteria (Section 5). 
 
7.2 
PERMANENT TREATMENT DISCONTINUATION 
 
Treatment discontinuation is permanent when there is a definite decision by the Investigator, 
Sanofi, or the participant to not re-expose the participant to olipudase alfa at any time, or if the 
reimbursement has not been obtained after 5 years. 
 
7.3 
CRITERIA FOR PERMANENT TREATMENT DISCONTINUATION 
 
The participant may withdraw from treatment if he or she decides to do so, at any time and 
irrespective of the reason; withdrawal may also be the decision of the Investigator or of Sanofi, or 
if the reimbursement has not been obtained after 5 years. All efforts will be made to document the 
reasons for discontinuation in the progress report. 
 
The participant should be withdrawn from this study for the following reasons: 
• The participant or their parent(s) / guardian(s) wishes treatment to be withdrawn. 
• The participant has become pregnant or is breastfeeding. 
• The participant is noncompliant with treatment or the requirements of the program. 
In addition, Sanofi may decide to discontinue this study early for any other reason. 
Any clinically significant abnormal laboratory value will be immediately rechecked for 
confirmation before a decision to permanently discontinue treatment with olipudase alfa. 

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Sanofi must be notified of termination of patient participation as soon as possible. If the 
participant is to be discontinued from the study for any reason, safety data should continue to be 
collected for at least 30 days after the last administration of olipudase alfa. 
 
Pregnancy 
 
Pregnancy will always result in treatment discontinuation. There have been no studies of 
olipudase alfa in pregnant women. To ensure participant safety in this study, a female participant 
of childbearing potential must have a serum β-HCG pregnancy test at the time of enrollment and a 
urine β-HCG pregnancy test up to 24 hours before her first olipudase alfa infusion and then once 
every 4 weeks before infusion. The participant must be willing to practice true abstinence in line 
with their preferred and usual lifestyle or to use 2 acceptable effective methods of contraception, a 
barrier method such as a condom or occlusive cap (diaphragm or cervical/vault cap) with 
spermicidal foam/gel/film/cream/suppository and an established non-barrier method such as oral, 
injected, or implanted hormonal methods, an intrauterine device, or intrauterine system for the 
entire duration of the treatment period and for at least 28 days after receiving the last study drug 
dose.. Every effort will be made to prevent pregnancy during this study. Sterilized or infertile 
patients (defined as having undergone surgical sterilization, ie, vasectomy/bilateral tubectomy, 
hysterectomy and bilateral ovariectomy or as being postmenopausal, defined as at least 12 months 
of amenorrhea prior to enrollment) will be exempted from the requirements to use contraception 
in this study 
 
Effective Contraceptive Methods for a Female Participant 
• User-dependent 
- 
Combined (estrogen + progestogen) hormonal contraceptive (oral, intravaginal, or 
transdermal) 
- 
Progestogen-only hormonal contraceptive (oral or injectable). 
• User-independent 
- 
Progestogen-only hormonal contraceptive implant 
- 
Intrauterine device 
- 
Intrauterine hormone-releasing system 
- 
Bilateral tubal occlusion 
- 
Vasectomized partner, if the participant has no other partners and absence of sperm is 
confirmed. 
 
Male Participant 
 
A male participant whose partner is a woman of childbearing potential must agree to the 
following while receiving olipudase alfa and for 15 days after his last infusion: 
• Refrain from donating sperm. 

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• Use a male condom while his partner uses 1 highly effective contraceptive method or 
abstain from heterosexual intercourse. 
 
7.3.1 Handling of the participant after permanent treatment discontinuation 
 
A participant who has received at least 1 olipudase alfa infusion and who is withdrawn from this 
study should receive a safety follow-up telephone call from the clinical site 30 days after the final 
infusion. Any instance of permanent treatment discontinuation must be recorded by the 
Investigator in the progress report when it is considered to be confirmed. 
 
7.3.2 Procedure and consequence for participant withdrawal from the study 
 
The participant may withdraw from this study if he or she decides to do so, at any time and for 
any reason. He or she should preferably withdraw consent in writing. If the participant refuses or 
is physically unavailable to do so, the Investigator should document and sign the reason for the 
participant’s not withdrawing consent in writing. 
 
The reason for withdrawal should be recorded. The participant or their parent(s)/guardian(s) 
should be explicitly asked about the contribution of possible AEs to his or her decision to 
withdraw, and any resulting AE information should be documented and reported to Sanofi. 
 
When the fails to return to the site, the Investigator should make the best effort to recontact him or 
her (eg, contacting the participant’s family or private physician, reviewing available registries or 
health care databases), and to determine his or her health status, including at least his or her vital 
status. Attempts to contact the participant (eg, dates and times of attempted telephone contact; 
receipt for a registered letter) should be documented in the participant’s records. 
 
7.4 
LOSS TO FOLLOW-UP 
 
The 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 the 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, 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 the participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, telephone calls and, if 
necessary, a certified letter sent to the participant’s last known mailing address, or local 

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equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study. 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
Given the nature of this study, reporting of clinical efficacy endpoints is not mandatory, except 
where required by the applicable government health authorities. 
 
8.1 
ASSESSMENTS 
 
Required assessments before enrollment 
 
Not applicable 
 
Assessments after enrollment in case 3 or more missed infusion 
If the patient missed 3 or more infusion, a re-escalation is needed. In this case, liver function tests 
will be performed during dose escalation. 
 
During dose escalation or upon resuming treatment following missed doses, transaminases (ALT 
and AST) levels should be obtained within 72 hours prior to the next scheduled infusion. If either 
the baseline or a pre-infusion transaminase level is >2 times the ULN during dose escalation, then 
additional transaminase levels should be obtained within 72 hours after the end of the infusion. If 
the transaminase levels are elevated above baseline and the ULN, the dose can be adjusted (prior 
dose repeated or reduced) or treatment can be temporarily withheld, based on clinical judgment.. 
Baseline is defined as the following: 
• For dose re-escalation: last value prior to the first re-escalation dose. 

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Antidrug antibody (ADA) testing if indicated for hypersensitivity 
 
If the participant experiences a moderate/severe or recurrent IAR that is suggestive of a 
hypersensitivity reaction, additional blood samples are recommended to be collected and tested 
for anti-olipudase alfa antibody (immunoglobulin G [IgG] and immunoglobulin E [IgE]). For IgE 
anti-olipudase alfa antibody determination, a predose serum sample collected for anti-olipudase 
alfa IgG testing may be used if the IAR occurs at that study visit. If a predose sample was not 
collected on that day, the participant should return to the study site at least 3 days after the event 
for a serum sample to be collected. Investigator will contact Sanofi France Immunosurveillance 
program to receive support on ADA testing. Samples will be sent to LabCorp by the official 
transporter and report results will be made available to the investigator in the dedicated platform. 
Laboratory safety variables 
Safety laboratory tests will be performed at a local laboratory, depending on the site’s laboratory 
and facilities. Serum or urine may be used for pregnancy testing for a female participant of 
childbearing potential. 
 
Only clinically significant laboratory test results will be recorded as AEs in the case report form. 
 
8.2 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER SAFETY 
REPORTING 
 
The definitions of AEs and SAEs are in Appendix 3 (Section 10.3). The definition of an adverse 
event of special interest (AESI) is in Section 8.2.6. 
 
AEs 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 all AEs or AEs that are serious, considered related to the study intervention, or caused the 
participant to discontinue treatment or withdraw from the study (Section 7). 
 
Recording, evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and transmitting SAE reports are discussed in Appendix 3 (Section 10.3). 
 
8.2.1 Time period and frequency for collecting AE and SAE information 
 
All SAEs and AESIs will be recorded and reported to the Sponsor within 24 hours of occurrence, 
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. 
 
The Investigator is not obligated to actively seek information on AEs or SAEs after conclusion of 
the participant’s study participation. However, if the Investigator learns of any SAE, including a 

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death, at any time after the participant has left the study and considers the event to be reasonably 
related to the study intervention or study participation, he or she must promptly notify the 
Sponsor. 
 
8.2.2 Method of detecting AEs and SAEs 
 
Care will be taken not to introduce bias when identifying AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method of inquiring about AEs. 
 
8.2.3 Follow-up of AEs and SAEs 
 
After the initial AE/AESI/SAE report, the Investigator should proactively follow the participant at 
subsequent visits. Further information on follow-up procedures is in Appendix 3 (Section 10.3.3). 
 
8.2.4 Regulatory reporting requirements for SAEs 
Prompt notification of the Sponsor of an SAE is essential so that legal obligations and ethical 
responsibilities toward the participant’s safety and the safety of the study intervention 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, the institutional review boards (IRB)/independent ethics committees 
(IEC), and Investigator. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information in the Investigator Brochure. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to the Investigator as necessary. 
• When receiving an Investigator safety report from the Sponsor describing an SAE, 
SUSAR, or any other specific safety information (eg, summary or listing of SAEs), the 
Investigator will review and file it with the Investigator’s Brochure 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 is expedited to 
regulatory authorities. 
 
8.2.5 Collection of pregnancy information 
Female participant who becomes pregnant 
• The Investigator should collect pregnancy information for a female participant who 
becomes pregnant while receiving olipudase alfa in this study. Pregnancy in a female 
participant or the partner of a male participant during this study will be recorded as an 

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AESI with immediate notification of Sanofi local pharmacovigilance in all cases. It will be 
qualified as an SAE only if it fulfills seriousness criteria. 
• Pregnancy information should be submitted to Sanofi within 24 hours of learning of the 
pregnancy. 
• The pregnancy should be followed to determine its outcome. Information on the status of 
the mother and child should be submitted to Sanofi local pharmacovigilance. 
• Generally, follow-up needs to be no longer than 6 to 8 weeks after the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or the indication for termination. 
• While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy should be reported as an AE or SAE. 
• A spontaneous abortion should always be reported as an SAE. 
Any SAE occurring as a result of a pregnancy after the end of treatment with olipudase alfa which 
the Investigator considers reasonably related to the treatment should be reported to Sanofi. While 
the Investigator is not obligated to actively seek this information from a former participant in this 
study, he or she may learn of an SAE from spontaneous reporting. 
Male participant with partner who becomes pregnant 
• The Investigator will attempt to collect pregnancy information for any woman who 
becomes pregnant while her partner is receiving olipudase alfa in this study. 
• After obtaining signed informed consent from the participant’s partner, the Investigator 
should submit the pregnancy information to Sanofi local pharmacovigilance within 24 
hours of learning of the partner’s pregnancy. 
• The pregnancy should be followed to determine its outcome. Information on the status of 
the mother and child should be submitted to the Sponsor. 
• Generally, follow-up needs to be no longer than 6 to 8 weeks after the estimated delivery 
date. Any termination of the pregnancy will be reported to Sanofi local pharmacovigilance 
regardless of fetal status (presence or absence of anomalies) or the indication for 
termination. 
 
8.2.6 Adverse events of special interest 
 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to olipudase alfa or to this single-center, single-participant study, for 
which ongoing monitoring and rapid communication by the Investigator to Sanofi may be 
appropriate. Such events may require further investigation to characterize and understand them. 
AESIs may be added to or removed from this program with a protocol amendment. 
 
AESIs include: 

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• Pregnancy in a female participant or in a female partner of a male participant. 
• Symptomatic overdose (serious or non-serious) of olipudase alfa 
- 
An overdose (accidental or intentional) of olipudase alfa, defined as an increase of at 
least 30% in the dose administered for the specified duration, or administration of the 
dose for less than half the recommended duration, 
- 
An asymptomatic overdose should be reported as a standard AE. 
• Infusion-associated reactions 
Some AEs may be manifestations of IARs, including hypersensitivity reaction, acute 
phase reaction (APR), and cytokine release syndrome (CRS); however, the original signs 
and symptoms may be reported as AEs. 
IARs are defined as AEs that occur during the infusion or within 24 hours after the start of 
the infusion and are considered as related or possibly related to the treatment by the 
Investigator or Sanofi. An event occurring ≥24 hours after the start of an infusion may be 
judged by the Investigator or Sanofi as an IAR. For this study, IARs may present as 
hypersensitivity reactions, APRs, and CRS. 
If the participant experiences a moderate or severe or recurrent IAR suggestive of a 
hypersensitivity reaction, collection of additional blood samples is recommended for 
determination of anti-olipudase alfa IgE. 
 
• Hypersensitivity reactions 
Infusion-associated hypersensitivity reactions seen with other ERTs are typically 
IgG/IgE-mediated and occur after sensitization. After subsequent exposure to the antigen, 
typically early during the infusion or shortly afterward, a “sensitized” participant may 
experience a broad range of allergic reactions that can be mild to severe or life threatening. 
Anaphylaxis or anaphylactic reaction is a serious IgE-mediated allergic reaction that is 
rapid in onset, and may cause death. Anaphylactoid or nonimmunologic anaphylaxis 
reactions may present with similar serious clinical manifestations to anaphylaxis but 
without prior exposure to the antigen, and are due to nonimmunologic-mediated mast cell 
degranulation. Although mechanistically different, anaphylactic and anaphylactoid 
reactions are treated similarly. 
Common symptoms of hypersensitivity reactions seen with other ERTs include urticaria, 
rash, dyspnea, and, less frequently, orofacial angioedema. Other symptoms of 
hypersensitivity IARs include fever, hypotension, tachycardia, nausea, vomiting, pain, and 
headache. 
• Acute phase reactions 
Symptoms consistent with acute phase reactions (APRs) were reported in 2 adult and 3 
pediatric patients in clinical trials. The main symptoms included pyrexia, nausea, 
vomiting, fatigue, and pain and occurred within 12 to 72 hours after the end of infusion 
during the dose escalation phase. These symptoms were associated with increases in 

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serum/plasma high-sensitivity C-reactive protein and may have been associated with 
various changes in other acute phase reactants including, but not limited to, neutrophils, 
iron, ferritin, fibrinogen, D-dimer, transferrin, albumin, prothrombin time, and partial 
thromboplastin time. Accordingly, APRs will be determined based on combined 
significant laboratory findings and clinical symptoms. 
• Cytokine release syndrome 
Cytokine release syndrome is another type of IAR, attributed to release of excessive 
amounts of cytokines shortly after IV administration of certain therapeutic agents. The 
severe form of CRS is cytokine storm, which may be life-threatening. Nonclinical studies 
of high dose olipudase alfa have suggested the possibility of CRS. Increases were 
observed after a single dose of ≥0.3 mg/kg olipudase alfa in the Phase 1 single-dose study 
for interleukin 8 and interleukin 6, macrophage inflammatory protein 1 alpha component 
(MIP-1α) and beta component (MIP-1β), and other cytokines and biomarkers, based on the 
Myriad Rules-Based Medicine Human Multi-Analyte Profile® antigen panel. Unlike 
immunoglobulin-mediated hypersensitivity reactions, no prior antigen exposure is required 
for development of CRS. 
 
Symptoms of CRS develop soon after exposure and range from mild to severe. Although 
CRS shares some symptoms with other IARs (ie, hypersensitivity reactions and APRs), 
typical symptoms include pyrexia, nausea, vomiting, fatigue, pain, myalgia, and, in severe 
cases, multi-organ system dysfunction or failure, severe headache, and pulmonary edema. 
CRS should be determined based on combined significant laboratory findings and clinical 
symptoms. 
 
8.2.7 Guidelines for reporting product complaints 
 
Any defect in olipudase alfa must be reported by the Investigator as soon as possible. The 
monitoring team will complete a product complaint form within required timelines. 
 
Appropriate information (eg, samples, labels, or documents such as 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. 
 
8.3 
PHARMACOKINETICS 
 
Not applicable 
 
8.4 
BIOMARKERS 
 
Not applicable 

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8.5 
IMMUNOGENICITY ASSESSMENTS 
 
Antibody testing if indicated for hypersensitivity is described in Section 8.1. 
 
8.6 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
 
Not applicable 

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9 
STATISTICAL CONSIDERATIONS 
Safety analysis will be based on the review of individual values. All reported AEs and safety parameters in 
the study will be listed. 
 
Demographic data and the concomitant medications will also be listed. 

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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, IB, 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 the participant. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation, except for changes necessary to eliminate an immediate hazard 
to the participant. 
• 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 (according to Sanofi policy) should be 
returned to the 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 or her 
designated health care 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. 

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- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. If the participant has opted out of being 
notified and the finding has consequences for other individuals, eg, the finding 
relates to a communicable disease, the Investigator should seek independent ethical 
advice before determining next steps. 
- 
If the participant or the participant’s parent(s)/guardian(s) has decided to opt out, 
the Investigator must record in the site medical files that he or she 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), European Medical Device Regulation 2017/745 for 
clinical device research (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 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participant or on the scientific value of the trial) prior to their implementation. 
 
10.1.2 Financial disclosure 
 
The Investigator 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. The Investigator is 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 (according to applicable regulatory requirements), or a person designated by the 
Investigator and under his or her responsibility, should fully inform the participant of all pertinent 
aspects of this study, including the written information given approval/favorable opinion by the 
ethics committee (IRB/IEC). The participant should be informed to the fullest extent possible 
about the study in language and terms he or she can understand. The patient must be informed that 
his or her participant is voluntary. 
 
Participants or their legally authorized representatives will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Privacy and Data Protection requirements including those of the Global Data Protection 
Regulation (GDPR) and of the French law, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 

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The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study, and the date written consent was obtained. The 
authorized person obtaining the informed consent must also sign the informed consent form (ICF). 
 
In case of ICF amendment while the participants are still included in the study, they must provide 
consent again, using the most current version of the ICF. Where participants are no longer in the 
study, those in charge of the amendment must define if those participants must or not reconsent or 
be informed of the amendment (eg, if the processing of personal data is modified, if the Sponsor 
changes, etc.). 
 
A copy of the ICF must be provided to the participant or legally authorized representative(s). 
 
10.1.4 Data protection 
 
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection 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, IRB/IEC members, etc. 
 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participant, the Sponsor takes all appropriate measures to safeguard and prevent access to these 
data by any unauthorized third party. 
 
Protection of participant data 
 
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. 
• The participant will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor or its service providers will be 
identifiable only by the unique identifier; the participant’s name or any information that 
would make the participant identifiable will not be transferred to the Sponsor. 
• The participant or the participant’s parent(s)/guardian(s) must be informed that his or her 
personal study-related data will be used by the Sponsor in accordance with applicable data 
protection laws. The level of disclosure must also be explained to the participant or the 
participant’s parent(s)/guardian(s) as described in the informed consent. 
• The participant or the participant’s parent(s)/guardian(s) must be informed that his or 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 or the participant’s parent(s)/guardian(s) must be informed that his or her 
study-related data will be used for the whole “drug development program”, ie, for this trial 
as well 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 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 (“Sanofi”) or to Sanofi service providers, where needed. 
• 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 of processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. If 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 these data are required to be processed by applicable 
regulations. The same rule applies if 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, 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, 
- 
Sanofi’s Binding Corporate Rules for intragroup transfers. 
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the Commission Nationale de l’Informatique et des Libertés (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to 30 years, unless further 
retention is required by applicable regulations. 

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• To facilitate the maintenance of the Investigator’s personal data, especially if he or she 
contribute to studies sponsored by several pharmaceutical companies, Sanofi participates 
in the Shared Investigator Platform and in the Transcelerate Investigator Registry 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 and 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 access to and 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 
 
Not applicable 
 
 
 
10.1.6 Dissemination of clinical study data 
 
Study participant 
 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. 
 
While making information available, Sanofi continues to protect the privacy of participants in its 
clinical trials 
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 health care organizations 
and professionals and/or any direct or indirect advantages and/or any related information or 
document if required by applicable law, by regulation, or by a code of conduct such as the “FPIA 
Code on Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare 
Professionals and Healthcare Organisations. 
 
10.1.7 Data quality assurance 
• All participant data relating to the study will be recorded on printed or electronic forms 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 

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Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the forms. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
• 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 of the Sponsor. 
 
10.1.8 Source documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on report forms 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 also be available. 
• The Investigator must maintain accurate documentation (source data) that support the 
information entered on report forms. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
on report forms by authorized site personnel are accurate, complete, and verifiable from 
source documents, that the safety and rights of the participant 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. 
 
10.1.9 Study closure 
 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason, at the sole discretion of the Sponsor. The 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: 

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• 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 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigator, the IRB/IEC, and the regulatory authorities of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The Investigator shall 
promptly inform the participant and should assure appropriate participant therapy and/or 
follow-up. 
 
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. 
• 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 
 
The following liver function tests will be performed during dose escalation only if re-escalation is 
needed: 
• ALT 
• AST 
• AP 
• Gamma glutamyl transferase 
• Total and direct bilirubin. 

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Note: Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations. 
 
10.3 
APPENDIX 3: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: DEFINITIONS 
AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING 
 
10.3.1 Definition of adverse event 
• 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 definition of an adverse event 
• Any abnormal laboratory test result (hematology, clinical chemistry, or urinalysis) or other 
result (eg, vital sign measurement), including a result that worsens from baseline, 
considered clinically significant in the medical and scientific judgment of the Investigator 
(ie, not related to progression of underlying disease): 
- 
Symptomatic and/or 
- 
Requiring either corrective treatment or consultation and/or 
- 
Leading to discontinuation of olipudase alfa or dose 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 condition detected or diagnosed after study intervention administration, even though 
it may have been present before the start of the study. 
• Sign, symptom, or the clinical sequela of a suspected drug-drug interaction. 
• Sign, symptom, or the clinical sequela of a suspected overdose of either study intervention 
or a concomitant medication. 
• Signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as AEs or SAEs if they fulfill the definition of an AE or SAE. 
 
Events NOT meeting the definition of an adverse event 

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• Any clinically significant abnormal laboratory findings or other abnormal assessments 
associated with the underlying disease, unless judged by the Investigator to be more severe 
than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected from the participant’s 
condition. 
• Any 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 serious adverse event 
 
An SAE is defined as any adverse event 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 admitted (usually 
involving at least an overnight stay) to the hospital or emergency department for 
observation and/or treatment that would not have been appropriate in a physician’s office 
or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other seriousness criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent or significant disability/incapacity 
- 
The term “disability” means a substantial disruption of a person’s ability to perform 
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. 

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e) Is a congenital anomaly/birth defect 
f) 
Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant medical 
events that 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. 
- 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered a medically important 
event. The list is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
o Allergic bronchospasm 
o Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc) 
o Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase >10 
× ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope; loss of consciousness (except if documented as a consequence of 
blood sampling) 
- 
Bullous cutaneous eruption 
 
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. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the required form. 
• 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. 

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• 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 Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
 
An event is defined as “serious” when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
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 that 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 IB. 
• For each AE/SAE, the Investigator must document in the medical notes that he or 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 Sanofi. 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 Sanofi. 
• The Investigator may change his/her opinion of causality in light of follow-up information, 
and send an SAE follow-up report with the updated causality assessment. 

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• 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, histopathologic examinations, or 
consultation with other health care professionals. 
• If the participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide Sanofi with a copy of any postmortem findings, 
including histopathology.] 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
 
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’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, the site will use the paper SAE data collection tool 
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, the electronic data collection tool will be taken offline to 
prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE or receives updated data on a previously reported 
SAE after the electronic data collection tool has been taken offline, the site can report this 
information on a paper SAE form or to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting will be provided. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method of 
transmitting this information to the Sponsor. 
• Contacts for SAE reporting will be provided. 

Property of the Sanofi group - strictly confidential 
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10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
 
Information on contraception is in Section 7.3. 
 
10.5 
APPENDIX 5: COUNTRY-SPECIFIC REQUIREMENTS 
 
 
 
10.6 
APPENDIX 6: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
 
Not applicable 
 
10.7 
APPENDIX 7: ABBREVIATIONS 
 
 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ASM 
acid sphingomyelinase 
ASMD 
acid sphingomyelinase deficiency 
AST 
aspartate aminotransferase 
CRS 
cytokine release syndrome 
ERT 
enzyme replacement therapy 
IAR 
infusion-associated reaction 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IEC 
independent ethics committee 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IRB 
institutional review board 

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IV 
intravenous 
SUSAR suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
 
 
10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY 
 
Not applicable 

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11 
REFERENCES 
1. Schuchman EH, Desnick RJ. Niemann-Pick disease Types A and B: acid sphingomyelinase 
deficiencies. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio 
A, et al, eds. OMMBID- the Online Metabolic and Molecular Bases of Inherited Diseases. 
New York: McGraw-Hill,2013. Available from: 
http://ommbid.mhmedical.com/content.aspx?bookid=474&Sectionid=45374145 
 
2. XENPOZYME 20 mg, powder for concentrate for solution for infusion (Olipudase alfa) draft 
Summary of Product Characteristics - Marketing Authorization Application 
EMEA/H/C/004850 (Centralized Procedure) [EMA submission dossier 26/10/2021].