Conditions: Sphingomyelin Lipidosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
The primary objective of this study was to obtain data regarding the safety of olipudase alfa in participants with acid sphingomyelinase deficiency (ASMD) who were exposed to long term treatment with olipudase alfa.

The secondary objectives of this study were to obtain data regarding the efficacy of olipudase alfa and to characterize olipudase alfa pharmacodynamics (PD) and pharmacokinetics (PK) following long-term administration.

Detailed description:
LTS13632 is a multicenter, nonrandomized, open-label, long-term extension study of participants with ASMD who have previously participated in a study of olipudase alfa. (DFI13803 for pediatric participants and DFI13412 for adult participants).

The maximum study duration per participant was 9 years or until olipudase alfa becomes commercially accessible. Notwithstanding the above, every pediatric participant were treated in LTS13632 study for at least 3 years to comply with the requirements agreed in the olipudase alfa Pediatric Investigational Plan.

Arms:
arm 1: GZ402665 administered intravenously once every 2 weeks at the dose each participant was receiving at the end of their previous olipudase alfa study, for 9 years or until olipudase alfa becomes commercially accessible, whichever comes first, unless the participant decides to enter another olipudase alfa clinical trial within the 9-year period prior to when olipudase alfa is commercially accessible.

Interventions: intervention 1: GZ402665
Intervention descriptions: intervention 1: Pharmaceutical form: Powder for concentrate for solution for infusion

Route of administration: intravenous infusion

Protocol document:
Prot_000.pdf: 


Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 2
NAMES AND ADDRESSES OF
COORDINATING 
INVESTIGATOR
Name:
Address:
Tel:
Fax:
E-mail:
MONITORING TEAM’S 
REPRESENTATIVE
Name:
Address:
Tel:
Fax:
E-mail:
SPONSOR
Company:
Address:
Sanofi Genzyme 
50 Binney Street
Cambridge, MA 02142 USA
OTHER EMERGENCY 
TELEPHONE NUMBERS
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
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Page 3
PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Country/Countries 
impacted by 
amendment
Date, Version
Amended Clinical Trial Protocol 07
All
15-Apr-2022, Version 1 (electronic 10.0)
Amended Clinical Trial Protocol 06
All
29-Jan-2021, Version 1 (electronic 9.0)
Amended Clinical Trial Protocol 05
All
18-Aug-2020, Version 1 (electronic 8.0)
Amended Clinical Trial Protocol 04
All
31-Jul-2019, Version 1 (electronic 6.0)
Amended Clinical Trial Protocol 03
All
25-Apr-2018, Version 1 (electronic 5.0)
Protocol Amendment 03
All
25-Apr-2018, Version 1 (electronic 1.0)
Amended Clinical Trial Protocol 02
All
25-Apr-2017, Version 1 (electronic 4.0)
Protocol Amendment 02 
All
25-Apr-2017, Version 1 (electronic 1.0)
Amended Clinical Trial Protocol 01
All
23-Mar-2016, Version 1 (electronic 3.0)
Protocol Amendment 01
All
23-Mar-2016, Version 2 (electronic 3.0)
Clinical Trial Protocol
All
02-Apr-2013, Version 1 (electronic 1.0)
Amended Clinical Trial Protocol 07 (15-Apr-2022)
This amended protocol (07) is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
The primary reasons for this amendment are described below:
x
To allow the continuity of treatment with olipudase alfa in the time frame between local 
Regulatory approval and commercial accessibility by clarifying the duration of study 
treatment. 
x
To comply with the requirements agreed in the olipudase alfa Pediatric Investigational 
Plan (PIP).
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Protocol amendment summary of changes table
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial 
Summary - Study Design  
Language updated: 
x
Patients will receive olipudase alfa every 2 weeks 
for 9 years or until olipudase alfa becomes 
commercially accessible (see maximum duration 
below), whichever comes first, unless the patient 
decides to enter another olipudase alfa clinical trial 
within the 9-year period prior to when olipudase alfa 
is commercially accessible.  
x
The term “commercially accessible” is defined as 
when olipudase alfa is commercially accessible to 
each patient on an individual basis 
(eg, reimbursement being in place). The duration of 
study treatment with olipudase alfa between local 
Regulatory approval and commercial accessibility 
should not exceed 90 days. Therefore, as described 
below, after local Regulatory approval, the patient 
can continue in the LTS13632 study for a maximum 
of 127 days. 
x
This duration will ensure a maximum 90 days of 
study treatment with olipudase alfa for patients after 
local Regulatory approval and a safety follow up 
phone call 30 to 37 days after the last dose of study 
treatment. 
x
Notwithstanding the above, every pediatric patient 
will be treated with olipudase alfa in the LTS13632 
study for at least 3 years. 
x
The patient can switch immediately after the end of 
study treatment to commercial treatment without 
any gap in order to ensure continuity of treatment 
with olipudase alfa. 
x
To allow the continuity 
of treatment with 
olipudase alfa in the 
time frame between 
local Regulatory 
approval and 
commercial 
accessibility 
x
 To comply with the 
agreed PIP 
Clinical Trial 
Summary - Duration of Study 
Period 
(Per Patient) 
Language updated: 
x
The maximum study duration per patient is 9 years 
or until olipudase alfa becomes commercially 
accessible (see maximum duration below), 
whichever comes first, unless the patient decides to 
enter another olipudase alfa clinical trial within the 
9-year period prior to when olipudase alfa is 
commercially accessible.  
x
The term “commercially accessible” is defined as 
when olipudase alfa is commercially accessible to 
each patient on an individual basis 
(eg, reimbursement being in place). The duration of 
study treatment with olipudase alfa between the 
local Regulatory approval and commercial 
accessibility should not exceed 90 days. Therefore, 
as described below, after local Regulatory approval, 
the patient can continue in the LTS13632 study for 
a maximum of 127 days.  
x
This will ensure 90 days of study treatment with 
x
To allow the continuity 
of treatment with 
olipudase alfa in the 
time frame between 
Regulatory approval 
and commercial 
accessibility 
x
To comply with the 
agreed PIP 
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Page 5
Section # and Name 
Description of Change 
Brief Rationale 
olipudase alfa for patients after local Regulatory 
approval and a safety follow up phone call 30 to 
37 days after the last dose of study treatment.  
x
Notwithstanding the above, every pediatric patient 
will be treated in the LTS13632 study for at least 
3 years.  
x
The patient can switch immediately after the end of 
study treatment to commercial treatment without 
any gap in order to ensure continuity of treatment 
with olipudase alfa. An EOT visit after the last 
administered dose of study treatment and a safety 
follow-up phone call 30 to 37 days after the last 
administered dose of study treatment will also apply 
in case the patient switches immediately after the 
end of study treatment to commercial treatment. 
Section 4.2 Study Rationale 
Language updated and order of paragraphs rearranged for 
readability: 
x
The current study is an open-label, long-term 
treatment study planned for 9 years, or until 
olipudase alfa becomes commercially accessible 
(see maximum duration below), whichever comes 
first, unless the patient decides to enter another 
olipudase alfa clinical trial within the 9-year period 
prior to when olipudase alfa is commercially 
accessible. 
x
The term “commercially accessible” is defined as 
when olipudase alfa is commercially accessible to 
each patient on an individual basis 
(eg, reimbursement being in place). The duration of 
study treatment with olipudase alfa between local 
Regulatory approval and commercial accessibility 
should not exceed 90 days. Therefore, as described 
below, after local Regulatory approval, the patient 
can continue in the LTS13632 study for a maximum 
of 127 days.  
x
This will ensure 90 days of study treatment with 
olipudase alfa for patients after local Regulatory 
approval and a safety follow up phone call  30 to 37 
days after the last dose of study treatment. 
x
Notwithstanding the above, every pediatric patient 
will be treated in the LTS13632 study for at least 3 
years to comply with the agreed PIP. 
x
The patient can switch immediately after the end of 
study treatment to commercial treatment without 
any gap in order to ensure continuity of treatment 
with olipudase alfa. 
x
To allow the continuity 
of treatment with 
olipudase alfa in the 
time frame between 
Regulatory approval 
and commercial 
accessibility. 
x
To comply with the 
agreed PIP 
Section 6 Study Design 
Language updated and sub-headers (Treatment Period and 
DMC) added for readabillity: 
x
Enrolled patients will receive an IV infusion of 
olipudase alfa every 2 weeks for 9 years, or until 
x
To allow the continuity 
of treatment with 
olipudase alfa in the 
time frame between 
Regulatory approval 
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Section # and Name 
Description of Change 
Brief Rationale 
olipudase alfa becomes commercially accessible 
(see maximum duration below), whichever comes 
first, unless the patient decides to enter another 
olipudase alfa clinical trial within the 9-year period 
prior to when olipudase alfa commercially 
accessible.  
x
The term “commercially accessible” is defined as 
when olipudase alfa is commercially accessible to 
each patient on an individual basis 
(eg, reimbursement being in place). The duration of 
study treatment with olipudase alfa between local 
Regulatory approval and commercial accessibility 
should not exceed 90 days. Therefore, as described 
below, after local Regulatory approval, the patient 
can continue in the LTS13632 study for a maximum 
of 127 days. 
x
This will ensure 90 days of study treatment with 
olipudase alfa for patients after local Regulatory 
approval and a safety follow up phone call 30 to 37 
days after the last dose of study treatment. 
x
Notwithstanding the above, every pediatric patient 
will be treated in the LTS13632 study for at least 3 
years.  
x
The patient can switch immediately after the end of 
study treatment to commercial treatment without 
any gap in order to ensure continuity of treatment 
with olipudase alfa. 
and commercial 
accessibility. 
x
To comply with the 
agreed PIP 
Section 6.1.1 Treatment 
period
Language updated and sub-headers (Treatment Period  and 
Schedule of Assessments) added for readability: 
x
During the treatment period, patients will receive an 
IV infusion of olipudase alfa every 2 weeks for 9 
years or until olipudase alfa becomes commercially 
accessible (see maximum duration below), 
whichever comes first, unless the patient decides to 
enter another olipudase alfa clinical trial within the 
9-year period prior to when olipudase alfa is 
commercially accessible.  
x
The term “commercially accessible” is defined as 
when olipudase alfa is commercially accessible to 
each patient on an individual basis 
(eg, reimbursement being in place). The duration of 
study treatment with olipudase alfa between local 
Regulatory approval and commercial accessibility 
should not exceed 90 days.  
x
Notwithstanding the above, every pediatric patient 
will be treated in the LTS13632 study for at least 3 
years.  
x
The patient can switch immediately after the end of 
study treatment to commercial treatment without 
any gap in order to ensure continuity of treatment 
with olipudase alfa. 
x
To allow the continuity 
of treatment with 
olipudase alfa in the 
time frame between 
Regulatory approval 
and commercial 
accessibility. 
x
To comply with the 
agreed PIP 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1.2 Post treatment 
period 
Language updated: 
For patients completing or discontinuing/withdrawing from the 
study, there will be a post-treatment period consisting of an 
end of treatment (EOT) visit 2 weeks (±7 days) after the last 
administered dose of study treatment and a safety follow-up 
phone call 30 to 37 days after the last administered dose of 
study treatment. 
An end-of-treatment visit and a safety follow up phone call will 
also apply in case the patient switches immediately after the 
end of study treatment to commercial treatment. 
To reflect amendment-specific 
changes. 
Section 6.3 Duration of Study 
Participation 
Language updated: 
x
Treatment period of 9 years or until olipudase alfa 
becomes commercially accessible (see maximum 
duration below), whichever comes first, unless the 
patient decides to enter another olipudase alfa 
clinical trial within the 9-year period prior to when 
olipudase alfa is commercially accessible.  
x
The term “commercially accessible” is defined as 
when olipudase alfa is commercially accessible to 
each patient on an individual basis 
(eg, reimbursement being in place). The duration of 
study treatment with olipudase alfa between local 
Regulatory approval and commercial accessibility 
should not exceed 90 days. Therefore, as described 
below, after local Regulatory approval, the patient 
can continue in the LTS13632 study for a maximum 
of 127 days. 
x
This will ensure 90 days of study treatment with 
olipudase alfa for patients after local Regulatory 
approval and a safety follow up phone call 30 to 37 
days after the last dose of study treatment. The 
patient can switch immediately after the end of 
study treatment to commercial treatment without 
any gap in order to ensure continuity of treatment 
with olipudase alfa.  
x
Notwithstanding the above, every pediatric patient 
will be treated in the LTS13632 study for at least 3 
years.  
x
To allow the continuity 
of treatment with 
olipudase alfa in the 
time frame between 
Regulatory approval 
and commercial 
accessibility. 
x
To comply with the 
agreed PIP 
Section 6.3 Duration of Study 
Participation 
Language updated for clarification: 
Follow up period concluded with a safety follow up phone call 
30 to 37 days after the patient’s last infusion in the LTS13632 
study. A safety follow-up phone call will also apply in case the 
patient switches immediately after the end of study treatment 
to commercial treatment. 
To reflect amendment-specific 
changes. 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary – 
Study Design and Duration 
Of Study Period (per patient); 
Section 6 Study Design; 
Section 6.1.1 Treatment 
Period; Section 6.3 Duration 
of study participation 
Removal of the following text: 
 
If marketing approval was not available, extension of follow up 
beyond 9 years would be considered with sponsor’s approval, 
in accordance with local regulations. 
Olipudase alfa is in the process 
of being submitted worldwide, so 
the statement regarding 
marketing approval not being 
available is no longer applicable. 
Section 4.2 Study Rationale 
Removal of the following text: 
 
If marketing approval was not available, extension of follow up 
beyond 9 years would be considered with sponsor’s and 
health authorities’ approval, in accordance with local 
regulations. 
Olipudase alfa is in the process 
of being submitted worldwide, so 
the statement regarding 
marketing approval not being 
available is no longer applicable. 
Section 11.1.1 
Section number has been updated. 
Formatting 
Section 17.2 - Appendix B 
Protocol Amendment History  
 
The numbering of this section has been updated. Due to 
addition of amendment history for Amended Clinical Trial 
Protocol 06 (29-Jan-2021) as sub-section 17.2.1, all further 
sub-sections were re-numbered accordingly. 
To conform with the usual 
process for amendment history. 
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CLINICAL TRIAL SUMMARY
COMPOUND: olipudase alfa 
(recombinant human acid sphingomyelinase / 
GZ402665)  
STUDY No: GZ402665 (LTS13632) 
TITLE
A long-term study to assess the ongoing safety and efficacy of olipudase alfa in 
patients with acid sphingomyelinase deficiency 
INVESTIGATOR/TRIAL LOCATION
Multinational, multicenter 
PHASE OF DEVELOPMENT
2 
STUDY OBJECTIVE(S) 
 
Primary objective 
The primary objective of this study is to obtain data regarding the safety of 
olipudase alfa in patients with acid sphingomyelinase deficiency (ASMD) who 
are exposed to long-term treatment with olipudase alfa. 
Secondary objective(s)  
The secondary objectives of this study are to obtain data regarding the efficacy 
of olipudase alfa and to characterize olipudase alfa pharmacodynamics (PD) 
and pharmacokinetics (PK) following long-term administration. 
STUDY DESIGN 
This is a multinational, multicenter, nonrandomized, open-label, long-term 
treatment study of patients who have previously participated in a study of 
olipudase alfa. 
x
Patients will receive olipudase alfa every 2 weeks for 9 years or until 
olipudase alfa becomes commercially accessible (see maximum 
duration below), whichever comes first, unless the patient decides to 
enter another olipudase alfa clinical trial within the 9-year period prior 
to when olipudase alfa is commercially accessible.  
x
The term “commercially accessible” is defined as when olipudase alfa 
is commercially accessible to each patient on an individual basis 
(eg, reimbursement being in place). The duration of study treatment 
with olipudase alfa between local Regulatory approval and commercial 
accessibility should not exceed 90 days. Therefore, as described 
below, after local Regulatory approval, the patient can continue in the 
LTS13632 study for a maximum of 127 days.  
x
This will ensure 90 days of study treatment with olipudase alfa for 
patients after local Regulatory approval and a safety follow up phone 
call 30 to 37 days after the last dose of study treatment.  
x
Notwithstanding the above, every pediatric patient will be treated in 
the LTS13632 study for at least 3 years.  
x
The patient can switch immediately after the end of study treatment to 
commercial treatment without any gap in order to ensure continuity of 
treatment with olipudase alfa.  
Patients will start this study at the same dose they were receiving at the end of 
their primary study, provided that they have not missed more than 1 biweekly 
dose between studies. During the study, for pediatric patients who will reach 
adult age (18 years old) will receive the adult infusion volume. 
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STUDY POPULATION  
Main selection criteria 
 
Inclusion criteria  
To enter this study, patients must have fulfilled the following criteria: 
x
The patient completed the treatment period of a previous study of 
olipudase alfa with an acceptable safety profile in the opinion of the 
investigator and sponsor. 
x
The patient and/or the patient's parent(s)/legal guardian(s) is willing 
and able to provide signed written informed consent. 
x
The patient who is female and of childbearing potential must have 
a negative urine pregnancy test for beta human chorionic 
gonadotropin (β-HCG). 
x
Female patients of childbearing potential and sexually mature male 
patients must be willing to practice true abstinence in line with their 
preferred and usual lifestyle or use 2 acceptable effective methods of 
contraception up to 15 days following their last dose of study drug. 
 
Exclusion criteria 
Exclusion criteria related to study methodology: 
x
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 
participating in or completing the study. 
x
The patient, in the opinion of the investigator, is unable to adhere to 
the requirements of the study. 
x
The patient is unwilling or unable to abstain from the use of alcohol for 
1 day prior to and 3 days after each olipudase alfa infusion for the 
duration of the treatment period. 
x
The patient is unwilling or unable to avoid, for 10 days before and 
3 days after liver biopsies, medications or herbal supplements that are 
potentially hepatotoxic (eg, 3-hydroxy-3-methylglutaryl coenzyme A 
reductase inhibitors, erythromycin, valproic acid, antidepressants, 
kava, echinacea) or may cause or prolong bleeding 
(eg, anticoagulants, ibuprofen, aspirin, garlic supplements, ginkgo, 
ginseng) (only patients who previously participated in the DFI13412 
study). 
Exclusion criteria related to the current knowledge of the compound and 
condition: 
x
The patient requires medication(s) that may decrease olipudase alfa 
activity (eg, fluoxetine, chlorpromazine; tricyclic antidepressants 
[eg, imipramine, desipramine]). 
Total expected number of patients 
Approximately 25 patients. 
5 adult patients rolled over from study DFI13412 and approximately 20 pediatric 
patients expected to roll over from study DFI13803 
STUDY TREATMENT(s) 
 
Investigational medicinal product(s) 
 
Formulation 
Olipudase alfa (recombinant human acid sphingomyelinase; GZ402665) 
Sterile lyophilized powder administered by intravenous (IV) infusion following 
reconstitution and dilution. 
During clinical development of olipudase alfa, incremental changes were made 
to the olipudase alfa manufacturing process. The different processes are 
referred to as Process B, C(
) and C(
).  
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Route(s) of administration 
IV infusion. 
Dose regimen 
Patients will receive an IV infusion of olipudase alfa every 2 weeks (± 3 days).  
Home infusion may be possible.  Patients must meet specific eligibility 
requirements.  In addition, the investigator and the sponsor must agree that 
home infusion is appropriate. Quarterly visits will occur at the site. If the site visit 
is not possible during a regional or national emergency declared by a 
governmental agency such as the COVID-19 pandemic due to site closure or 
extenuating circumstances that prevent an in-person site visit and home infusion 
is already approved for the eligible patient, quarterly visits will be done at 
home.Patients will continue their current dose if they have not missed more than 
1 dose between studies.  Dose reintroduction regimens may be required for 
patients who have missed more than 1 dose between studies or during this 
study, depending on their usual dose.  For patients receiving home infusions 
who have missed 2 or fewer doses, the investigator can decide whether 
reintroduction should occur at the hospital/study site or via home infusion. For 
patients who have missed 3 or more doses ≥0.6 mg/kg, reintroduction of 
olipudase alfa should occur at the hospital/study site.  If the site visit is not 
possible, During a regional or national emergency declared by a governmental 
agency, such as the COVID-19 pandemic, due to site closure or extenuating 
circumstances that prevent an in-person site visit, reintroduction may be done 
via home infusion in compliance with applicable country-specific regulations. 
ENDPOINT(S) 
 
Primary endpoints 
Data pertaining to the safety and tolerability of olipudase alfa 
x
Assessment of adverse events (AEs)/treatment-emergent adverse 
events (TEAEs), including infusion-associated reactions (IARs) and 
Adverse Events of Special Interest (AESI). 
x
Complete Physical examinations. 
x
Extended Neurologic examinations. 
x
Abbreviated Physical Exam 
x
Weight. 
x
Height (pediatric patients only). 
x
Vital sign measurements. 
x
Clinical laboratory tests. 
x
Electrocardiograms (ECGs). 
x
Doppler echocardiography. 
x
Safety biomarkers. 
x
Liver biopsy (only patients who previously participated in the 
DFI13412 study). 
x
Liver ultrasound with Doppler (only patients who previously 
participated in DFI13803). 
x
Immune response assessments. 
Secondary endpoints (efficacy) 
x
Abdominal magnetic resonance imaging (MRI) to evaluate 
improvements in spleen and liver volume. 
x
Pulmonary imaging (high-resolution computed tomography [HRCT]. 
and chest X-ray [at selected sites]). 
x
Pulmonary function test. 
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x
Hematology (hemoglobin and platelet count). 
x
Lipid profile. 
x
Health outcome questionnaires (adult and Pediatric). 
x
Hand X-ray for bone age and bone maturation (pediatric patients). 
x
Linear patient growth by height Z-score (pediatric patients). 
Other endpoints 
x
Physician’s global assessment of change. 
x
Cognitive and adaptive function (pediatric patients who performed the 
assessments in DFI13803) 
x
Cycle ergometry. 
x
Efficacy biomarkers. 
x
Bone disease assessments (only patients who previously participated 
in the DFI13412 study). 
x
Bone biomarkers. 
x
Tanner staging (pediatric patients). 
x
Photographs (optional). 
 
Pharmacokinetics 
Plasma parameters, including Cmax, AUClast, AUC0-∞, t1/2z, CL and Vss. 
Pharmacodynamics 
x
Sphingomyelin in liver tissue (only in adults) and plasma. 
x
Metabolites levels in plasma and dried blood spot (DBS). 
ASSESSMENT SCHEDULE 
Patients will be enrolled directly from their previous study.  (Note: The term 
“pediatric patients only” means patients coming from the original pediatric trial, 
DFI13803.  Some of these patients will reach adult age [18 years old] while in 
this study.  These patients will be adults by age, but they will remain part of the 
“pediatric patient” cohort.) 
In case of more than 3 infusions missed between trials, assessments 
(eg, efficacy biomarkers, sphingomyelin and metabolites) may be repeated at 
study entry. 
Patients who require dose reintroduction will have these assessments at each 
infusion until reaching their usual dose of olipudase alfa: 
x
Before infusion: vital sign measurements, liver function tests (LFTs), 
hematology, and safety biomarkers. 
x
Immediately after infusion: vital sign measurements. 
x
24 hours after infusion: vital sign measurements, LFTs, and safety 
biomarkers. 
x
48 hours  after infusion: vital sign measurements, LFTs and safety 
biomarkers. The 48 hours post-infusion assessments will no longer be 
assessed after the cutoff date for a planned second database lock of 
the study for regulatory submissions in 2021. 
During the dose escalation period, for transaminases assessed after 
infusion, if any AST or ALT value is >2x baseline and >ULN, the test should 
be repeated prior to the next scheduled infusion. Depending on the test 
results, the dose can be adjusted (repeated or reduced) or treatment can 
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be withheld to allow additional transaminase monitoring, based on the 
physician’s clinical judgment. 
Baseline is defined as the following:  
x
For initial dose escalation: last values prior to first dose of olipudase 
alfa 
x
For dose re-escalation: last values prior to the first re-escalation dose 
Safety will be monitored continuously.  Safety and efficacy assessments will 
occur regularly every 3, 6, 9, and 12 months.  In the first 5 years, 
pharmacodynamic (PD) evaluations will occur every 3 months then every 6 
months after the cutoff date for a planned second database lock of the study for 
purpose of regulatory submissions in 2021. After 5 years, PD evaluations will 
occur every 12 months. PK evaluation will occur every 12 months only in the 
first 5 years and upon introduction of Process C(
) or Process C(
) at any 
time during the study. 
For patients completing or discontinuing/withdrawing from the study, there will 
be a post treatment period consisting of an end-of-treatment (EOT) visit 2 weeks 
(±7 days) after the last administered dose of olipudase alfa and a safety 
follow-up phone call 30 to 37 days after the last administered dose. 
STATISTICAL CONSIDERATIONS
Sample size determination
Sample size is determined by the number of patients who complete the 
treatment phase of a previous clinical study of olipudase alfa, sign the informed 
consent form of the LTS13632 study, and meet the eligibility criteria. It is 
expected that the sample size for this study will be approximately 25. 
Analysis populations
The safety set will include all enrolled patients who received at least 1 dose 
(partial or total) of olipudase alfa in the current study. 
Analysis of safety
Safety analyses will include a summary of treatment duration, the total number 
of infusions received, and the total amount of olipudase alfa received.  
Frequencies (number and percentage) of patients with 1 or more 
treatment-emergent AEs will be summarized by the Medical Dictionary for 
Regulatory Activities System Organ Class (SOC) and preferred term (PT). All 
treatment-emergent AEs, all treatment-emergent AEs potentially related to 
olipudase alfa, all treatment-emergent AEs leading to treatment discontinuation 
and study discontinuation, all treatment-emergent AEs that are infusion-
associated reactions, all treatment--emergent serious adverse events (SAEs) 
(including treatment-related SAEs), and all AEs with fatal outcomes (including 
fatal treatment-emergent AEs) will be summarized.  Other safety variables, 
including laboratory parameters and vital sign measurements, will be 
summarized by study visit and by dose. 
The PK analysis will include all patients who receive at least 1 infusion of study 
drug after PK analysis informed consent and have evaluable PK data.   
Other analysis populations, such as for pharmacogenomics, if any, will be 
defined in the SAP. 
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Analysis of secondary endpoints
Summary statistics for the values, nominal change from baseline, and percent 
change from baseline will be presented for efficacy assessments at various 
study time points.  The association between changes in efficacy parameters and 
total amount of drug received will be examined. 
Plasma concentration-time data will be analyzed using actual dosing and 
sampling times by noncompartmental methods. Pharmacokinetic parameters 
will be calculated for each patient and summarized by dose level and study 
week. As data permit, PK parameters may also be evaluated across dose level 
at each manufacturing scale.  Metabolite levels will be summarized by dose 
level and time point using descriptive statistics.
DURATION OF STUDY PERIOD 
(per patient) 
x
The maximum study duration per patient is 9 years or until olipudase 
alfa becomes commercially accessible (see maximum duration 
below), whichever comes first, unless the patient decides to enter 
another olipudase alfa clinical trial within the 9-year period prior to 
when olipudase alfa is commercially accessible. 
x
The term “commercially accessible” is defined as when olipudase alfa 
is commercially accessible to each patient on an individual basis 
(eg, reimbursement being in place). The duration of study treatment 
with olipudase alfa between  local Regulatory approval and 
commercial accessibility should not exceed 90 days. Therefore, as 
described below, after local Regulatory approval, the patient can 
continue in the LTS13632 study for a maximum of 127 days. 
x
This will ensure 90 days of study treatment with olipudase alfa for 
patients after local Regulatory approval and a safety follow up phone 
call 30 to 37 days after the last dose of study treatment. 
x
Notwithstanding the above, every pediatric patient will be treated in 
the LTS13632 study for at least 3 years.  
x
The patient can switch immediately after the end of study treatment to 
commercial treatment without any gap in order to ensure continuity of 
treatment with olipudase alfa. An EOT visit after the last administered 
dose of study treatment and a safety follow-up phone call 30 to 37 
days after the last administered dose of study treatment will also apply 
in case the patient switches immediately after the end of study 
treatment to commercial treatment. 
STUDY COMMITTEES
Independent data monitoring committee (DMC). 
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1
STUDY FLOW CHARTS
Table 1 and Table 3 are the study flow charts for adult patients coming from study DFI13412, 
corresponding to the period Year 1 to Year 5 and beyond Year 5, respectively. Complementary 
flow charts have been added for the changes to be effective after the cutoff date for a planned 
second database lock of the study for purpose of regulatory submissions in 2021 (Table 2 and 
Table 4). Table 5, Table 7, and Table 9 are the study flow charts for pediatric patients  coming 
from the pediatric study DFI13803 and correspond to Year 1, Year 2 through Year 5, and beyond 
Year 5,  respectively. Complementary flow charts have been added for the changes to be effective 
after the cutoff date for a planned second database lock of the study for purpose of regulatory 
submissions in 2021 (Table 6, and Table 10). Table 11 and Table 12 are the pharmacokinetic (PK)
sampling schedules for adults and pediatric patients, respectively.
Patients will be enrolled directly from their previous study after providing informed consent.
In case of more than 3 infusions missed between trials, assessments (eg, efficacy biomarkers, 
sphingomyelin and metabolites) may be repeated at study entry.  The investigator, after discussion 
with the sponsor, may order individualized assessments before the patient receives the first infusion
in this study.
Dose reintroduction regimens may be required for patients who have missed more than 1 dose 
between studies or during this study (LTS13632), depending on their usual dose. For patients 
receiving home infusions who have missed 2 or fewer doses, the investigator can decide whether 
reintroduction should occur at the hospital/study site or via home infusion. For patients who miss 
3 or more doses ≥0.6 mg/kg, reintroduction of olipudase alfa should occur at the study site. If the 
site visit is not possible during a regional or national emergency declared by a governmental 
agency such as the COVID-19 pandemic due to site closure or extenuating circumstances that 
prevent an in-person site visit, reintroduction can occur via home infusion in compliance with 
applicable country-specific regulations.
Patients who require dose reintroduction will have these assessments at each infusion until 
reaching their usual dose of olipudase alfa:
x
Before infusion: vital sign measurements, liver function tests (LFTs), hematology, and 
safety biomarkers.
x
Immediately after infusion: vital sign measurements.
x
24 hours after infusion: vital sign measurements, LFTs, hematology, and safety 
biomarkers.
x
48 hours after infusion: vital sign measurements, LFTs, hematology, and safety 
biomarkers. 
The 48 hours post-infusion assessments will no longer be assessed after the cutoff date for 
a planned second database lock of the study for purpose of regulatory submissions in 
2021.
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During the dose escalation period, for transaminases assessed after infusion, if any AST or 
ALT value is >2x baseline and >ULN, the test should be repeated prior to the next 
scheduled infusion. Depending on the test results, the dose can be adjusted (repeated or 
reduced) or treatment can be withheld to allow additional transaminase monitoring, based 
on the physician’s clinical judgment.
Baseline is defined as the following: 
x
For initial dose escalation: last values prior to first dose of olipudase alfa
x
For dose re-escalation: last values prior to the first re-escalation dose
For a new manufacturing scale, if treatment is not interrupted, PK sample collection will take 
place at the patient’s last infusion under the current manufacturing scale and at the first infusion 
under the new manufacturing scale. For introduction of drug product from Process C(
), if
treatment is not interrupted, PK sample collection will take place at the second infusion under 
Process C(
). If introduction of Process C(
) occurs, sample collection of anti olipudase alfa 
antibody (IgG) will be monthly for the first 6 months after introducing the drug product from 
Process C(
) then quarterly after that.
If a PK or IgG sample collection for the planned introduction of drug product from Process C(
) 
was erroneously taken, the future sample collection will be adjusted to the blood volume per each 
age cohort in order to avoid excessive blood withdrawal. For specific details, please refer to Study 
Manual. See Section 9.3.8 for time points and additional information. 
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1.1
FLOW CHART FOR ADULTS: YEAR 1 THROUGH YEAR 5
Table 1 - Study flow chart for former patients from the DFI13412 study - Year 1 through Year 5 - only applicable  before the implementation of 
changes that will occur after the cutoff date of the second database lock
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study. The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every  
2-week visit 
(±3 days)a 
Every  
3-month visit 
(±14 days)a 
Every  
6-month visit 
(±14 days)a 
Every  
9-month visit 
(±14 days)a 
Every 12 month 
visit 
(±14 days)a 
Patient 
discontinuation, 
or withdrawalb 
Safety follow-
up phone callc 
Note: The informed consent form must be signed and the inclusion/exclusion criteria must be verified prior to the patient‘s first visit. 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time the patient 
signs the written informed consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.  Concomitant medications that the patient is taking when the written informed consent is signed 
and up to 30 days prior should be reported in this study. 
Complete physical examination 
 
 
X 
 
X 
X 
 
Extended neurological examination 
 
 
 
 
X 
X 
 
Abbreviated physical examination 
X 
X 
 
X 
 
 
 
Before and after each infusion 
Weightd  
Before each infusion 
X 
 
Height 
 
 
 
X 
X 
 
Vital sign measurements (blood pressure, heart rate, 
respiratory rate, temperature)e  
Before and 1 hour (±10 minutes) after each infusion. 
X 
 
Clinical laboratory tests (clinical chemistry, 
hematology, LFTs, coagulation, urinalysis) 
 
X 
X 
X 
X 
X 
 
Hemoglobin level and platelet countf 
 
 
X 
 
X 
X 
 
Urine E-HCG pregnancy test (only women of 
childbearing potential) 
Every 4 weeks 
X 
 
Electrocardiograme, g 
 
 
X 
 
X 
X 
 
Doppler echocardiography 
 
 
 
 
X 
X 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study. The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every  
2-week visit 
(±3 days)a 
Every  
3-month visit 
(±14 days)a 
Every  
6-month visit 
(±14 days)a 
Every  
9-month visit 
(±14 days)a 
Every 12 month 
visit 
(±14 days)a 
Patient 
discontinuation, 
or withdrawalb 
Safety follow-
up phone callc 
Safety biomarkers (hsCRP, iron, ferritin, cardiac 
troponin I, IL-6, IL-8, calcitonin, plasma ceramide) 
 
X 
X 
X 
X 
X 
 
Abdominal MRI (liver and spleen volumes)  
 
 
X 
(first 2 years)h  
 
X 
X 
 
Chest HRCT  
 
 
 
 
X 
X 
 
Chest X-rayi 
 
 
 
 
X 
X 
 
Pulmonary function tests (FVC,FEV1,DLCO,TLC)j  
 
 
X 
(first 2 years)h  
 
X 
X 
 
Cycle ergometryj 
 
 
X (first 2 years) 
 
X 
X 
 
Physician global assessment 
 
 
X (first 2 years) 
 
X 
X 
 
Efficacy biomarkers 
(serum chitotriosidase, CCL18)  
 
X 
X 
X 
X 
X 
 
Bone biomarkers (alkaline phosphatase, 
C-telopeptide) 
 
X 
X 
X 
X 
X 
 
Fasting lipids (total cholesterol, HDL, LDL, VLDL, 
triglycerides, ApoB, ApoA1, lipoprotein[a]) 
 
X 
(first 2 years) 
X 
X 
(first 2 years) 
X 
X 
 
Metabolite levels in plasma 
 
X 
X 
X 
X 
X 
 
Metabolite levels in dried blood spot 
 
X 
X 
X 
X 
X 
 
Patient photographs (optional) 
 
 
 
X 
 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of the disease. 
 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Lumbar spine and bilateral femur MRI 
 
 
 
 
X 
X 
 
Lumbar spine and bilateral femur DXA 
 
 
 
 
X 
X 
 
Adult health outcome questionnaires (BFI, BPI-SF, 
SFCRQ-SAS, SF-36, NPB-HAQv2) 
 
 
X 
(first 2 years) 
 
X 
X 
 
Pharmacokineticse, k  
 
 
 
 
X 
 
 
See Section 1.6 and Table 11  
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study. The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every  
2-week visit 
(±3 days)a 
Every  
3-month visit 
(±14 days)a 
Every  
6-month visit 
(±14 days)a 
Every  
9-month visit 
(±14 days)a 
Every 12 month 
visit 
(±14 days)a 
Patient 
discontinuation, 
or withdrawalb 
Safety follow-
up phone callc 
Sphingomyelin in liver tissue (liver biopsy) 
A liver biopsy will be performed after at least 3 years in the study for patients who previously 
participated in the DFI13412 study 
 
 
Immune response assessments 
Anti-olipudase alfa antibody (IgG) 
Quarterly 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to 
Process C(
), collection will be monthly for the first 6 months after starting the new process, and 
quarterly after that. 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
Anti-olipudase alfa antibody (IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR 
suggestive of a hypersensitivity reaction 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
Anti-olipudase alfa antibody (IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR 
suggestive of a hypersensitivity reaction 
 
 
Serum tryptase and complement activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
 
Skin testing 
If necessary 
 
 
a
Patients will receive olipudase alfa every 2 weeks (±3 days). Quarterly visits will occur at the site. If the site visit is not possible during a regional or national emergency declared by a 
governmental agency such as the COVID-19 pandemic due to site closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the 
eligible patient, quarterly visits will be done at home. Quarterly visit specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site 
visits become available. In such a case, some of the quarterly visit assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of 
life instruments). Telehealth visits are an acceptable alternative to site visits If the site visit is not possible during a regional or national emergency declared by a governmental agency such as 
the COVID-19 pandemic due to site closure or extenuating circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific 
regulations.  
b
All patients will have a visit 2 weeks (±7 days) after the last dose of study treatment. For the end of study/early discontinuation visit, NPB HAQ, abdominal MRI, HRCT, chest X-ray, pulmonary 
function tests, cycle ergometry, and Doppler echocardiography will not be repeated if they had been done within 3 months prior.  DXA and bone MRI will not be repeated if they were done 
within 6 months prior. 
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment. 
d
Weight at previous onsite visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits unless quarterly visit occurs at home.  Body mass index 
(BMI) will be calculated. 
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e
At time points when multiple assessments are scheduled, the order will be: vital sign measurements, electrocardiogram, pharmacokinetics (PK). 
f
As indicated, an additional sample will be collected for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart from the sample collected for clinical laboratory tests. 
g
Patients must rest in the supine position for 510 minutes prior to and during all electrocardiograms. 
h
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to Process C(
), an abdominal MRI and pulmonary function tests (PFTs) will be performed at 
the first 6-month visit after the change, but only if that 6-month visit is not a 12-month visit at which the assessment is already scheduled. 
i
Only at selected sites. 
j
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
k
Pharmacokinetic testing will only occur yearly and during the study period, for the switch from Process B to Process C or from Process C(
) to the updated manufacturing process C(
).  For 
introduction of process C(
), if treatment is not interrupted, PK sample collection will take place at the patient’s last infusion under the current manufacturing scale and at the first infusion of 
Process C(
) IMP.  In case reintroduction of olipudase alfa coincides with introduction of Process C(
), PK samples will be collected at the infusion at which patients receive their usual dose 
of olipudase alfa under Process C(
).  For schedule of PK assessment in adults, see Section 1.6, Table 11. 
ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; BFI=Brief Fatigue Inventory; BPI-SF=Brief Pain Inventory- Short Form; CCL18=chemokine 
(CC-motif) ligand 18; DLCO=diffusing capacity of the lung for carbon monoxide; DXA=dual-energy X-ray absorptiometry; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; 
HDL=high-density lipoprotein; HRCT=high-resolution computed tomography; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-associated reaction; Ig=immunoglobulin; IL=interleukin; 
LDL=low-density lipoprotein; LFT=liver function test; MRI=magnetic resonance imaging; NPB-HAQv2=Niemann-Pick B Health Assessment Questionnaire, version 2; SF=short form; 
SFCRQ-SAS=Chronic Respiratory Disease Questionnaire Self-administered Standardized; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
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Table 2 - Study flow chart for former patients from the DFI13412 study - Year 1 through Year 5 - only applicable after the cutoff date for a planned 
second database lock of the study for purpose of regulatory submissions in 2021
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study. The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every  
2-week visit 
(±3 days)a  
Every  
3-month visit 
(±14 days)a 
Every  
6-month visit 
(±14 days)a  
Every  
9-month visit 
(±14 days)a  
Every 12 month 
visit 
(±14 days)a  
Patient 
discontinuation, 
or withdrawalb 
Safety follow-
up phone callc 
Note: The informed consent form must be signed and the inclusion/exclusion criteria must be verified prior to the patient‘s first visit. 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time the patient 
signs the written informed consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.  Concomitant medications that the patient is taking when the written informed consent is signed 
and up to 30 days prior should be reported in this study. 
Complete physical examination 
 
 
X 
 
X 
X 
 
Extended neurological examination 
 
 
 
 
X 
X 
 
Abbreviated physical examination 
X 
X 
 
X 
 
 
 
Before and after each infusion 
Weightd 
Before each infusion 
X 
 
Height 
 
 
 
X 
X 
 
Vital sign measurements (blood pressure, heart rate, 
respiratory rate, temperature)e  
Before and 1 hour (±10 minutes) after each infusion. 
X 
 
Clinical laboratory tests (clinical chemistry, 
hematology, LFTs, coagulation, urinalysis) 
 
X 
X 
X 
X 
X 
 
Hemoglobin level and platelet countf 
 
 
X 
 
X 
X 
 
Urine E-HCG pregnancy test (only women of 
childbearing potential) 
Every 4 weeks 
X 
 
Electrocardiograme, g  
 
 
X 
 
X 
X 
 
Doppler echocardiography 
 
 
 
 
X 
X 
 
Safety biomarkers (hsCRP, iron, ferritin, cardiac 
troponin I, IL-6, IL-8, calcitonin) 
 
X 
X 
X 
X 
X 
 
Abdominal MRI (liver and spleen volumes)  
 
 
X 
 
X 
X 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study. The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every  
2-week visit 
(±3 days)a  
Every  
3-month visit 
(±14 days)a 
Every  
6-month visit 
(±14 days)a  
Every  
9-month visit 
(±14 days)a  
Every 12 month 
visit 
(±14 days)a  
Patient 
discontinuation, 
or withdrawalb 
Safety follow-
up phone callc 
(first 2 years)h  
Chest HRCT  
 
 
 
 
X 
X 
 
Chest X-rayi 
 
 
 
 
X 
X 
 
Pulmonary function tests (FVC,FEV1,DLCO,TLC)j  
 
 
X 
(first 2 years)h  
 
X 
X 
 
Cycle ergometryj 
 
 
X (first 2 years) 
 
X 
X 
 
Physician global assessment 
 
 
X (first 2 years) 
 
X 
X 
 
Efficacy biomarkers 
(serum chitotriosidase, CCL18)  
 
X 
X 
X 
 
Bone biomarkers (alkaline phosphatase, 
C-telopeptide) 
 
X 
X 
X 
 
Fasting lipids (total cholesterol, HDL, LDL, VLDL, 
triglycerides, ApoB, ApoA1, lipoprotein[a]) 
 
X 
(first 2 years) 
X 
X 
(first 2 years) 
X 
X 
 
Metabolite levels in plasma (ceramide, lyso-
sphingomyelin)  
 
X 
X 
X 
 
Patient photographs (optional) 
 
 
 
X 
 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of the disease. 
 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Lumbar spine and bilateral femur MRI 
 
 
 
 
X 
X 
 
Lumbar spine and bilateral femur DXA 
 
 
 
 
X 
X 
 
Adult health outcome questionnaires (BFI, BPI-SF, 
SFCRQ-SAS, SF-36, NPB-HAQv2) 
 
 
X 
(first 2 years) 
 
X 
X 
 
Pharmacokineticsk 
 
 
 
 
X 
 
 
See Section 1.6 and Table 11  
Sphingomyelin in liver tissue (liver biopsy) 
A liver biopsy will be performed after at least 3 years in the study for patients who previously 
participated in the DFI13412 study 
 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study. The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every  
2-week visit 
(±3 days)a  
Every  
3-month visit 
(±14 days)a 
Every  
6-month visit 
(±14 days)a  
Every  
9-month visit 
(±14 days)a  
Every 12 month 
visit 
(±14 days)a  
Patient 
discontinuation, 
or withdrawalb 
Safety follow-
up phone callc 
Immune response assessments 
Anti-olipudase alfa antibody (IgG) 
Quarterly 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to 
Process C(
), collection will be monthly for the first 6 months after starting the new process, and 
quarterly after that. 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
Anti-olipudase alfa antibody (IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR 
suggestive of a hypersensitivity reaction 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
Anti-olipudase alfa antibody (IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR 
suggestive of a hypersensitivity reaction 
 
 
Serum tryptase and complement activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
 
Skin testing 
If necessary 
 
 
 
ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; BFI=Brief Fatigue Inventory; BPI-SF=Brief Pain Inventory- Short Form; CCL18=chemokine (CC-motif) ligand 18; 
DLCO=diffusing capacity of the lung for carbon monoxide; DXA=dual-energy X-ray absorptiometry; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; HDL=high-density lipoprotein; 
HRCT=high-resolution computed tomography; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-associated reaction; Ig=immunoglobulin; IL=interleukin; LDL=low-density lipoprotein; LFT=liver function test; 
MRI=magnetic resonance imaging; NPB-HAQv2=Niemann-Pick B Health Assessment Questionnaire, version 2; SF=short form; SFCRQ-SAS=Chronic Respiratory Disease Questionnaire Self-administered 
Standardized; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
a
Patients will receive olipudase alfa every 2 weeks (±3 days). Quarterly visits will occur at the site. If the site visit is not possible during a regional or national emergency declared by a 
governmental agency such as the COVID-19 pandemic due to site closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the 
eligible patient, quarterly visits will be done at home. Quarterly visit specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site visits 
become available. In such a case, some of the quarterly visit assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of life 
instruments). Telehealth visits are an acceptable alternative to site visits if the site visit is not possible during a regional or national emergency declared by a governmental agency such as the 
COVID-19 pandemic due to site closure or extenuating circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific regulations.  
b
All patients will have a visit 2 weeks (±7 days) after the last dose of study treatment. For the end of study/early discontinuation visit, NPB HAQ, abdominal MRI, HRCT, chest X-ray, pulmonary 
function tests, cycle ergometry, and Doppler echocardiography will not be repeated if they had been done within 3 months prior.  DXA and bone MRI will not be repeated if they were done 
within 6 months prior. 
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment. 
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d
Weight at previous on-site visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits unless quarterly visit occurs at home.  Body mass index 
(BMI) will be calculated. 
e
At time points when multiple assessments are scheduled, the order will be: vital sign measurements, electrocardiogram, pharmacokinetics (PK). 
f
As indicated, an additional sample will be collected for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart from the sample collected for clinical laboratory tests. 
g
Patients must rest in the supine position for 5-10 minutes prior to and during all electrocardiograms. 
h
Upon a manufacturing scale change, an abdominal MRI and pulmonary function tests (PFTs) will be performed at the first 6-month visit after the change, but only if that 6-month visit is not a 
12-month visit at which the assessment is already scheduled. 
i
Only at selected sites. 
j
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
k
Pharmacokinetic testing will only occur yearly and upon introduction of Process C(
) or Process C(
).  For Process C(
), if treatment is not interrupted, PK sample collection will take place 
at the patient’s last infusion under the current manufacturing scale and at the first infusion under Process C(
). For the switch from Process C(
) to Process C(
), if treatment is not 
interrupted, PK sample collection will take place at the second infusion under 
  In case reintroduction of olipudase alfa coincides with introduction of a drug product from Process 
C(
) or Process C(
), PK samples will be collected at the infusion at which patients receive their usual dose of olipudase alfa under Process C(
) or Process C(
).  For schedule of PK 
assessment in adults, see Section 1.6, Table 11. 
 
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1.2
FLOWCHART FOR ADULTS: BEYOND YEAR 5
Table 3 - Study flow chart for former patients from DFI13412 - beyond Year 5 - only applicable  before the implementation of changes that will occur 
after the cutoff date of the second database lock
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every  
2-week visit 
(±3 days)a
Every  
3-month visit 
(±14 days)a
Every  
6-month visit 
(±14 days)a 
Every  
9-month visit 
(±14 days)a 
Every 12 month visit 
(±14 days)a 
Study completion, 
patient 
discontinuation, or 
withdrawalb
Safety 
follow-up 
phone callc 
Note: The informed consent form must be signed and the inclusion/exclusion criteria must be verified prior to the patient‘s first visit. 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time the patient signs the written 
informed consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.  Concomitant medications that the patient is taking when the written informed consent is signed and up to 30 days 
prior should be reported in this study. 
Complete physical examination 
 
 
 
 
X 
X 
 
Extended neurological examination 
 
 
 
 
X 
X 
 
Abbreviated physical examination 
X 
 
 
 
 
 
 
Before and after each infusion 
Weightd
 
X 
X 
X 
X 
X 
 
Height 
 
 
 
X 
X 
 
Vital sign measurements (blood 
pressure, heart rate, respiratory 
rate, temperature)e
Before and 1 hour (±10 minutes) after each infusion. 
X 
 
Clinical laboratory tests (clinical 
chemistry, hematology, LFTs, 
coagulation, urinalysis) 
 
X 
 
X 
X 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every  
2-week visit 
(±3 days)a
Every  
3-month visit 
(±14 days)a
Every  
6-month visit 
(±14 days)a 
Every  
9-month visit 
(±14 days)a 
Every 12 month visit 
(±14 days)a 
Study completion, 
patient 
discontinuation, or 
withdrawalb
Safety 
follow-up 
phone callc 
Hematology, Hemoglobin level and 
platelet count 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to Process C(
), 
2 samples will be taken during an infusion 3 months after introducing the new process, one for deferential 
hematology and the other for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart. 
 
 
Urine E-HCG pregnancy test (only 
women of childbearing potential) 
Every 4 weeks 
X 
 
Electrocardiograme, f
 
 
 
 
X 
X 
 
Safety biomarkers (hsCRP, iron, 
ferritin, calcitonin, plasma 
ceramide) 
 
X 
X 
X 
 
Abdominal MRI (liver and spleen 
volumes)  
 
 
 
X 
X 
 
Chest HRCT  
 
 
 
 
X 
X 
 
Pulmonary function tests 
(FVC,FEV1,DLCO,TLC)g 
 
 
 
X 
X 
 
Physician global assessment 
 
 
 
X 
X 
 
Efficacy biomarkers 
(serum chitotriosidase, CCL18) 
 
 
 
 
X 
X 
 
Fasting lipids (total cholesterol, 
HDL, LDL, VLDL, triglycerides, 
ApoB, ApoA1, lipoprotein[a]) 
 
 
X 
X 
 
Metabolite levels in plasma  
 
 
 
 
X 
X 
 
Patient photographs (optional) 
 
 
 
X 
 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of the disease. 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every  
2-week visit 
(±3 days)a
Every  
3-month visit 
(±14 days)a
Every  
6-month visit 
(±14 days)a 
Every  
9-month visit 
(±14 days)a 
Every 12 month visit 
(±14 days)a 
Study completion, 
patient 
discontinuation, or 
withdrawalb
Safety 
follow-up 
phone callc 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Adult health outcome 
questionnaires (BFI, BPI SF, 
SFCRQ SAS, SF-36) 
 
 
 
 
X 
X 
 
Pharmacokineticsh
 
 
 
 
 
 
 
Immune response assessments 
Anti olipudase alfa antibody (IgG) 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to Process C(
), 
collection will be monthly for the first 6 months after introducing the new process and quarterly after that. 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
Anti-olipudase alfa antibody (IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
Anti-olipudase alfa antibody (IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
 
Serum tryptase and complement 
activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
 
Skin testing 
If necessary 
 
 
a
Patients will receive olipudase alfa every 2 weeks (±3 days). Quarterly visits will occur at the site. If the site visit is not possible during a regional or national emergency declared by a 
governmental agency such as the COVID-19 pandemic due to site closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the 
eligible patient, quarterly visits will be done at home. Quarterly visit specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site 
visits become available. In such a case, some of the quarterly visit assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of 
life instruments).  Telehealth visits are an acceptable alternative to site visits. If the site visit is not possible during a regional or national emergency declared by a governmental agency such 
as the COVID-19 pandemic due to site closure or extenuating circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific 
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Page 28
regulations.  
b
All patients will have a visit 2 weeks (±3 days) after the last dose of study treatment. For the end of study/early discontinuation visit, all “beyond Year 5” assessments will not be repeated if 
they had been done within 6 months prior.   
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment. 
d
Weight at previous on-site visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits unless quarterly visit occurs at home.  Body mass index 
(BMI) will be calculated. 
e
At time points when multiple assessments are scheduled, the order will be: vital sign measurements then electrocardiogram. 
f
Patients must rest in the supine position for 5-10 minutes prior to and during all electrocardiograms. 
g
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
h
Beyond 5 years, pharmacokinetic testing will only occur upon introduction of Process C(
) or Process C(
).  For Process C(
), if treatment is not interrupted, PK sample collection will take 
place at the patient’s last infusion under Process B and at the first infusion under Process C(
). For the switch from Process C(
) to Process C(
), if treatment is not interrupted, PK sample 
collection will take place at the second infusion under Process C(
).  In case reintroduction of olipudase alfa coincides with introduction of a drug product from Process C(
) or Process 
C(
), PK samples will be collected at the infusion at which patients receive their usual dose of olipudase alfa under the new process.  For schedule of PK assessment in adults, see 
Section 1.6, Table 11. 
ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; BFI=Brief Fatigue Inventory; BPI-SF=Brief Pain Inventory- Short Form; DLCO=diffusing capacity of 
the lung for carbon monoxide; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; HDL=high-density lipoprotein; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-
associated reaction; Ig=immunoglobulin; IL=interleukin; LDL=low-density lipoprotein; LFT=liver function test; MRI=magnetic resonance imaging; SF=short form; SFCRQ-SAS=Chronic Respiratory 
Disease Questionnaire Self-administered Standardized; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
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Table 4 - Study flow chart for former patients from DFI13412 - beyond Year 5 - only applicable after the cutoff date for a planned second database 
lock of the study for purpose of regulatory submissions in 2021
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 
2-week visit 
(±3 days)a
Every 
3-month visit
(±14 days)a
Every 
6-month visit
(±14 days)a 
Every 
9-month visit
(±14 days)a 
Every 12 month visit
(±14 days)a 
Study completion, 
patient 
discontinuation, or 
withdrawalb
Safety
follow-up
phone callc
Note: The informed consent form must be signed and the inclusion/exclusion criteria must be verified prior to the patient‘s first visit. 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time the patient signs the written 
informed consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.  Concomitant medications that the patient is taking when the written informed consent is signed and up to 30 days 
prior should be reported in this study. 
Complete physical examination 
 
 
 
 
X 
X 
 
Extended neurological examination 
 
 
 
 
X 
X 
 
Abbreviated physical examination 
X 
 
 
 
 
 
 
Before and after each infusion 
Weightd
 
X 
X 
X 
X 
X 
 
Height 
 
 
 
X 
X 
 
Vital sign measurements (blood 
pressure, heart rate, respiratory 
rate, temperature)e
Before and 1 hour (±10 minutes) after each infusion. 
X 
 
Clinical laboratory tests (clinical 
chemistry, hematology, LFTs, 
coagulation, urinalysis) 
 
 
X 
 
X 
X 
 
Hematology, hemoglobin level and 
platelet count 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to Process C(
), 
2 samples will be taken during an infusion 3 months after introducing Process C(
) or Process C(
), one for 
deferential hematology and the other for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart. 
 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 
2-week visit 
(±3 days)a
Every 
3-month visit
(±14 days)a
Every 
6-month visit
(±14 days)a 
Every 
9-month visit
(±14 days)a 
Every 12 month visit
(±14 days)a 
Study completion, 
patient 
discontinuation, or 
withdrawalb
Safety
follow-up
phone callc
Urine E-HCG pregnancy test (only 
women of childbearing potential) 
Every 4 weeks 
X 
 
Electrocardiograme, f
 
 
 
 
X 
X 
 
Safety biomarkers (hsCRP, iron, 
ferritin, calcitonin, plasma) 
 
 
X 
 
X 
X 
 
Abdominal MRI (liver and spleen 
volumes)  
 
 
 
 
X 
X 
 
Chest HRCT  
 
 
 
 
X 
X 
 
Pulmonary function tests 
(FVC,FEV1,DLCO,TLC)g
 
 
 
X 
X 
 
Physician global assessment 
 
 
 
X 
X 
 
serum chitotriosidase, CCL18 
 
 
 
 
X 
X 
 
Fasting lipids (total cholesterol, 
HDL, LDL, VLDL, triglycerides, 
ApoB, ApoA1, lipoprotein[a]) 
 
 
X 
X 
 
Metabolite levels in plasma 
(ceramide, lyso-sphingomyelin)
 
 
X 
X 
 
Patient photographs (optional) 
 
 
 
X 
 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of the disease. 
 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Adult health outcome 
questionnaires (BFI, BPI SF, 
SFCRQ SAS, SF-36) 
 
 
 
 
X 
X 
 
Pharmacokineticsh
 
 
 
 
 
 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 
2-week visit 
(±3 days)a
Every 
3-month visit
(±14 days)a
Every 
6-month visit
(±14 days)a 
Every 
9-month visit
(±14 days)a 
Every 12 month visit
(±14 days)a 
Study completion, 
patient 
discontinuation, or 
withdrawalb
Safety
follow-up
phone callc
Immune response assessments 
Anti olipudase alfa antibody (IgG) 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to Process C(
), 
Collection will be monthly for the first 6 months after introducing the new process, and quarterly after that. 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
Anti-olipudase alfa antibody (IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
Anti-olipudase alfa antibody (IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
 
Serum tryptase and complement 
activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
 
Skin testing 
If necessary 
 
 
 
ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; BFI=Brief Fatigue Inventory; BPI-SF=Brief Pain Inventory- Short Form; DLCO=diffusing capacity of 
the lung for carbon monoxide; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; HDL=high-density lipoprotein; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-
associated reaction; Ig=immunoglobulin; IL=interleukin; LDL=low-density lipoprotein; LFT=liver function test; MRI=magnetic resonance imaging; SF=short form; SFCRQ-SAS=Chronic Respiratory 
Disease Questionnaire Self-administered Standardized; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
a
Patients will receive olipudase alfa every 2 weeks (±3 days). Quarterly visits will occur at the site. If the site visit is not possible during a regional or national emergency declared by a 
governmental agency such as the COVID-19 pandemic due to site closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the 
eligible patient, quarterly visits will be done at home. Quarterly visit specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site 
visits become available. In such a case, some of the quarterly visit assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of 
life instruments).  Telehealth visits are an acceptable alternative to site visits, if the site visit is not possible during a regional or national emergency declared by a governmental agency such as 
the COVID-19 pandemic due to site closure or extenuating circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific 
regulations.  
b
All patients will have a visit 2 weeks (±3 days) after the last dose of study treatment. For the end of study/early discontinuation visit, all “beyond Year 5” assessments will not be repeated if 
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Page 32
they had been done within 6 months prior.   
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment. 
d
Weight at previous on-site visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits unless quarterly visit occurs at home.  Body mass index 
(BMI) will be calculated. 
e
At time points when multiple assessments are scheduled, the order will be: vital sign measurements then electrocardiogram. 
f
Patients must rest in the supine position for 5-10 minutes prior to and during all electrocardiograms. 
g
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
h
Beyond 5 years, upon introduction of Process C(
) or Process C(
), for Process C(
), if treatment is not interrupted, PK sample collection will take place at the patient’s last infusion under 
the Process B and at the first infusion under Process C(
). For the switch from Process C(
) to Process C(
), if treatment is not interrupted, PK sample collection will take place at the 
second infusion under Process C(
).  In case reintroduction of olipudase alfa coincides with introduction of Process C(
) or Process C(
), PK samples will be collected at the infusion at 
which patients receive their usual dose of olipudase alfa under the new process.  For schedule of PK assessment in adults, see Section 1.6, Table 11. 
 
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1.3
FLOW CHART FOR PEDIATRIC (FORMER DFI13803) PATIENTS: YEAR 1
The term “pediatric patients” means patients coming from the original pediatric trial, DFI13803. Some of these patients will reach adult age 
(18 years old) while in this study.  These patients will be adults by age, but they will remain part of the “pediatric patient” cohort.
Table 5 - Study flow chart for former DFI13803 patients - Year 1 - only applicable before the implementation of changes that will occur after the cutoff 
date of the second database lock
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
W14a 
QV  
(±14 days) 
W26a 
QV 
(±14 days) 
W38a 
QV  
(±14 days) 
W52a 
QV 
(±14 days) 
Study completion, 
patient 
discontinuation, or 
withdrawalb 
Safety 
follow-up 
phone callc 
Note: The informed consent form must be signed and the inclusion/exclusion criteria must be verified prior to the patient‘s first visit. 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time the patient signs the written informed 
consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.  Concomitant medications that the patient is taking when the written informed consent is signed and up to 30 days prior 
should be reported in this study. 
Complete physical 
examination 
 
X 
 
X 
 
X 
 
Extended neurological 
examinationd 
 
 
 
X 
 
X 
 
Abbreviated physical 
examination 
X 
 
X 
 
X 
 
 
 
Before and after each infusion 
 
Weighte 
Before each infusion 
X 
 
Height 
 
X 
 
X 
 
 
X 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
W14a 
QV  
(±14 days) 
W26a 
QV 
(±14 days) 
W38a 
QV  
(±14 days) 
W52a 
QV 
(±14 days) 
Study completion, 
patient 
discontinuation, or 
withdrawalb 
Safety 
follow-up 
phone callc 
Vital sign measurements 
(blood pressure, heart rate, 
respiratory rate, 
temperature)f  
Before and 1 hour (±10 minutes) after each infusion. 
X 
 
Clinical laboratory tests 
(clinical chemistry, LFTs, 
hematology, coagulation, 
urinalysis) 
 
X 
X 
X 
X 
X 
 
Hemoglobin level and 
platelet countg 
 
X 
 
X 
 
X 
 
Urine E-HCG pregnancy 
test (only women of 
childbearing potential) 
Every 4 weeks 
X 
 
Electrocardiogramf, h  
 
X 
 
X 
 
X 
 
Doppler echocardiography 
 
 
 
X 
 
X 
 
Safety biomarkers (hsCRP, 
iron, ferritin, cardiac 
troponin I, IL-6, IL-8, 
calcitonin, plasma 
ceramide) 
 
X 
X 
X 
X 
X 
 
Abdominal MRI (liver and 
spleen volumes) 
 
X 
 
X 
 
X 
 
Chest HRCT  
 
 
 
X 
 
X 
 
Chest X-rayi 
 
 
 
X 
 
X 
 
Pulmonary function tests 
(FVC,FEV1,DLCO,TLC)j, k  
 
X 
 
X 
 
X 
 
Physician global 
assessment 
 
X  
 
X 
 
X 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
W14a 
QV  
(±14 days) 
W26a 
QV 
(±14 days) 
W38a 
QV  
(±14 days) 
W52a 
QV 
(±14 days) 
Study completion, 
patient 
discontinuation, or 
withdrawalb 
Safety 
follow-up 
phone callc 
Efficacy biomarkers 
(serum chitotriosidase, 
CCL18)  
 
X 
X 
X 
X 
X 
 
Bone biomarkers (alkaline 
phosphatase, 
C-telopeptide)k  
 
X 
X 
X 
X 
X 
 
Fasting lipids (total 
cholesterol, HDL, LDL, 
VLDL, triglycerides, ApoB, 
ApoA1, lipoprotein[a] ) 
 
X 
X 
X 
X 
X 
 
Metabolite levels in plasma 
 
X 
X 
X 
X 
X 
 
Metabolite levels in dried 
blood spotk 
 
X 
X 
X 
X 
X 
 
Patient photographs 
(optional) 
 
 
 
X 
 
X 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of the disease. 
X 
 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Liver ultrasound with 
Doppler 
 
X 
 
X 
 
X 
 
Hand X-ray for bone age 
 
X  
 
X 
 
X 
 
Tanner staging 
 
X 
 
X 
 
X 
 
Cognitive and adaptive 
function (for patients who 
performed the assessment 
in DFI13803 (DP-3 and 
ABAS) 
 
X  
 
X 
 
X 
 
Linear patient growth by 
height Z-score 
 
X 
 
X 
 
X 
 
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15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 36
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
W14a 
QV  
(±14 days) 
W26a 
QV 
(±14 days) 
W38a 
QV  
(±14 days) 
W52a 
QV 
(±14 days) 
Study completion, 
patient 
discontinuation, or 
withdrawalb 
Safety 
follow-up 
phone callc 
Pediatric health outcome 
questionnaires (PedsQL, 
PedsQL Multidimensional 
Fatigue Scale, PedsQL 
Pediatric Pain 
Questionnaire) 
 
X 
 
X 
 
X 
 
Pharmacokineticsf, l  
 
 
 
X 
 
 
 
See Section 1.6 and Table 12 
 
 
Immune response assessments 
 
 
Anti-olipudase alfa antibody 
(IgG) 
Quarterly 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to Process C(
), 
collection will be monthly for the first 6 months after introducing the new process, and quarterly after that. 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
 
 
Anti-olipudase alfa antibody 
(IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
Anti-olipudase alfa antibody 
(IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
 
Serum tryptase and 
complement activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
 
Skin testing 
If necessary 
 
 
a
Patients from DFI13803 are to follow the pediatric schedule of events in the LTS13632 study.  The pediatric schedule of events is based on pediatric patients receiving 64 weeks of treatment 
in the prior DFI13803 study. The adult schedule of events is based on adult patients receiving 26 weeks of treatment in the prior DFI13412 study. Patients will receive olipudase alfa every 
2 weeks (±3 days). Quarterly visits will occur at the site. If the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 
pandemic due to site closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the eligible patient, quarterly visits will be done at 
home. Quarterly visit specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site visits become available. In such a case, some of 
the quarterly visit assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of life instruments). Telehealth visits are an 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
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Version number: 1
Property of the Sanofi Group - strictly confidential
Page 37
acceptable alternative to site visits if the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 pandemic due to site 
closure or extenuating circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific regulations. 
b
All patients will have a visit 2 weeks (±7 days) after the last dose of study treatment.  For the end of study/early discontinuation visit, abdominal MRI, HRCT, chest X-ray, pulmonary function 
tests (PFTs) , Doppler echocardiography, hand X-ray, and pediatric health outcome questionnaires will not be repeated if they had been done within the prior 3 months. 
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment. 
d
If possible, the neurological examination should be performed by the same neurologist who performed it in the DFI13803 study. If possible, the same neurologist should perform the 
neurological examination throughout the study. 
e
Weight at previous on-site visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits.  Body mass index (BMI) will be calculated. 
f
At time points when multiple assessments are scheduled, the order will be: vital sign measurements, electrocardiogram, pharmacokinetics (PK). 
g
As indicated, an additional sample will be collected for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart from the sample collected for clinical laboratory tests. If drug 
product from a manufacturing scale change or an updated manufacturing process is administered, 2 samples will be taken during an infusion 3 months after introducing the new scale or the 
updated manufactured process one for deferential hematology and the other for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart. 
h
Patients must rest in the supine position for 5-10 minutes prior to and during all electrocardiograms. 
i
Only at selected sites 
j
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
k
Only for patients for whom it was done in DFI13803. 
l
Pharmacokinetic testing will only occur yearly and upon introduction of a manufacturing scale change from Process B to Process C(
) or from Process C(
) to the updated manufacturing 
process C(
).  For Process C(
), if treatment is not interrupted, PK sample collection will take place at the patient’s last infusion under Process B and at the first infusion under Process 
C(
). For the switch from Process C(
) to Process C(
), if treatment is not interrupted, PK sample collection will take place at the second infusion under Process C(
).  In case 
reintroduction of olipudase alfa coincides with introduction of Process C
) or Process C(
), PK samples will be collected at the infusion at which patients receive their usual dose of 
olipudase alfa under the new process. For schedule of PK assessment in children, see Section 1.6, Table 12. 
ABAS=Adaptive Behavior Assessment System; ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; CCL18=chemokine (CC-motif) ligand 18; 
DLCO=diffusing capacity of the lung for carbon monoxide; DP-3=Development Profile-Third Edition; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; HDL=high-density 
lipoprotein; HRCT=high-resolution computed tomography; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-associated reaction; Ig=immunoglobulin; IL=interleukin; LDL=low-density 
lipoprotein; LFT=liver function test; MRI=magnetic resonance imaging; PedsQL=Pediatric Quality of Life; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
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Property of the Sanofi Group - strictly confidential
Page 38
Table 6 - Study flow chart for former DFI13803 patients - Year 1 - only applicable after the cutoff date for a planned second database lock of the 
study for purpose of regulatory submissions in 2021
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
W14a 
QV  
(±14 days) 
W26a 
QV 
(±14 days) 
W38a 
QV  
(±14 days) 
W52a 
QV 
(±14 days) 
Study completion, 
patient 
discontinuation, or 
withdrawalb 
Safety 
follow-up 
phone callc 
Note: The informed consent form must be signed and the inclusion/exclusion criteria must be verified prior to the patient‘s first visit. 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time the patient signs the written informed 
consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.  Concomitant medications that the patient is taking when the written informed consent is signed and up to 30 days prior 
should be reported in this study. 
Complete physical 
examination 
 
X 
 
X 
 
X 
 
Extended neurological 
examinationd 
 
 
 
X 
 
X 
 
Abbreviated physical 
examination 
X 
 
X 
 
X 
 
 
 
Before and after each infusion 
 
Weighte 
Before each infusion 
X 
 
Height 
 
X 
 
X 
 
 
X 
 
Vital sign measurements 
(blood pressure, heart rate, 
respiratory rate, 
temperature)f 
Before and 1 hour (±10 minutes) after each infusion. 
X 
 
Clinical laboratory tests 
(clinical chemistry, LFTs, 
hematology, coagulation, 
urinalysis) 
 
X 
X 
X 
X 
X 
 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 39
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
W14a 
QV  
(±14 days) 
W26a 
QV 
(±14 days) 
W38a 
QV  
(±14 days) 
W52a 
QV 
(±14 days) 
Study completion, 
patient 
discontinuation, or 
withdrawalb 
Safety 
follow-up 
phone callc 
Hemoglobin level and 
platelet countg 
 
X 
 
X 
 
X 
 
Urine E-HCG pregnancy 
test (only women of 
childbearing potential) 
Every 4 weeks 
X 
 
Electrocardiogramf, h  
 
X 
 
X 
 
X 
 
Doppler echocardiography 
 
 
 
X 
 
X 
 
Safety biomarkers (hsCRP, 
iron, ferritin, cardiac 
troponin I, IL-6, IL-8, 
calcitonin,) 
 
X 
X 
X 
X 
X 
 
Abdominal MRI (liver and 
spleen volumes) 
 
X 
 
X 
 
X 
 
Chest HRCT  
 
 
 
X 
 
X 
 
Chest X-rayi 
 
 
 
X 
 
X 
 
Pulmonary function tests 
(FVC,FEV1,DLCO,TLC)j 
 
X 
 
X 
 
X 
 
Physician global 
assessment 
 
X  
 
X 
 
X 
 
serum chitotriosidase, 
CCL18 
 
 
X 
 
X 
X 
 
Bone biomarkers (alkaline 
phosphatase, 
C-telopeptide)  
 
 
X 
 
X 
X 
 
Fasting lipids (total 
cholesterol, HDL, LDL, 
VLDL, triglycerides, ApoB, 
ApoA1, lipoprotein[a]) 
 
X 
X 
X 
X 
X 
 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 40
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
W14a 
QV  
(±14 days) 
W26a 
QV 
(±14 days) 
W38a 
QV  
(±14 days) 
W52a 
QV 
(±14 days) 
Study completion, 
patient 
discontinuation, or 
withdrawalb 
Safety 
follow-up 
phone callc 
Metabolite levels in plasma 
(ceramide, lyso-
sphingomyelin)  
 
 
X 
 
X 
X 
 
Patient photographs 
(optional) 
 
 
 
X 
 
X 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of the disease. 
X 
 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Liver ultrasound with 
Doppler 
 
X 
 
X 
 
X 
 
Hand X-ray for bone age 
 
X  
 
X 
 
X 
 
Tanner staging 
 
X 
 
X 
 
X 
 
Cognitive and adaptive 
function (for patients who 
performed the assessment 
in DFI13803 (DP-3 and 
ABAS) 
 
X  
 
X 
 
X 
 
Linear patient growth by 
height Z-score 
 
X 
 
X 
 
X 
 
Pediatric health outcome 
questionnaires (PedsQL, 
PedsQL Multidimensional 
Fatigue Scale, PedsQL 
Pediatric Pain 
Questionnaire) 
 
X 
 
X 
 
X 
 
Pharmacokineticsf, k 
 
 
 
X 
 
 
 
See Section 1.6 and Table 12  
 
 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 41
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
W14a 
QV  
(±14 days) 
W26a 
QV 
(±14 days) 
W38a 
QV  
(±14 days) 
W52a 
QV 
(±14 days) 
Study completion, 
patient 
discontinuation, or 
withdrawalb 
Safety 
follow-up 
phone callc 
Immune response assessments 
 
 
Anti-olipudase alfa antibody 
(IgG) 
Quarterly 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to Process C(
), 
collection will be monthly for the first 6 months after introducing the drug product from the new process and quarterly 
after that. 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
 
 
Anti-olipudase alfa antibody 
(IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
Anti-olipudase alfa antibody 
(IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
 
Serum tryptase and 
complement activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
 
Skin testing 
If necessary 
 
 
a
Patients from DFI13803 are to follow the pediatric schedule of events in the LTS13632 study.  The pediatric schedule of events is based on pediatric patients receiving 64 weeks of treatment 
in the prior DFI13803 study. The adult schedule of events is based on adult patients receiving 26 weeks of treatment in the prior DFI13412 study. Patients will receive olipudase alfa every 
2 weeks (±3 days). Quarterly visits will occur at the site If the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 
pandemic due to site closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the eligible patient, quarterly visits will be done at 
home. Quarterly visit specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site visits become available. In such a case, some of 
the quarterly visit assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of life instruments). Telehealth visits are an 
acceptable alternative to site visits if the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 pandemic due to site 
closure or extenuating circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific regulations. 
b
All patients will have a visit 2 weeks (±7 days) after the last dose of study treatment.  For the end of study/early discontinuation visit, abdominal MRI, HRCT, chest X-ray, pulmonary function 
tests (PFTs) , Doppler echocardiography, hand X-ray, and pediatric health outcome questionnaires will not be repeated if they had been done within the prior 3 months. 
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment 
d
If possible, the neurological examination should be performed by the same neurologist who performed it in the DFI13803 study. If possible, the same neurologist should perform the 
neurological examination throughout the study. 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 42
e
Weight at previous on-site visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits.  Body mass index (BMI) will be calculated. 
f
At time points when multiple assessments are scheduled, the order will be: vital sign measurements, electrocardiogram, pharmacokinetics (PK). 
g
As indicated, an additional sample will be collected for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart from the sample collected for clinical laboratory tests. If drug 
product from a manufacturing scale change or an updated manufacturing process is administered, 2 samples will be taken during an infusion 3 months after introducing the new scale or the 
updated manufactured process one for deferential hematology and the other for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart. 
h
Patients must rest in the supine position for 5-10 minutes prior to and during all electrocardiograms. 
i
Only at selected sites 
j
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
k
Pharmacokinetic testing will only occur yearly and upon introduction of a manufacturing scale change from Process B to Process C(
) or from Process C(
) to the updated manufacturing 
process C(
).  For Process C(
), if treatment is not interrupted, PK sample collection will take place at the patient’s last infusion under Process B and at the first infusion under Process 
C(
). For the switch from Process C(
) to Process C(
), if treatment is not interrupted, PK sample collection will take place at the second infusion under Process C(
).  In case 
reintroduction of olipudase alfa coincides with introduction of a drug product from Process C(
) or Process C(
), PK samples will be collected at the infusion at which patients receive their 
usual dose of olipudase alfa under the new process.  For schedule of PK assessment in children, see Section 1.6, Table 12. 
ABAS=Adaptive Behavior Assessment System; ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; CCL18=chemokine (CC-motif) ligand 18; 
DLCO=diffusing capacity of the lung for carbon monoxide; DP-3=Development Profile-Third Edition; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; HDL=high-density 
lipoprotein; HRCT=high-resolution computed tomography; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-associated reaction; Ig=immunoglobulin; IL=interleukin; LDL=low-density 
lipoprotein; LFT=liver function test; MRI=magnetic resonance imaging; PedsQL=Pediatric Quality of Life; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 43
1.4
FLOW CHART FOR PEDIATRIC (FORMER DFI13803) PATIENTS: YEAR 2 THROUGH YEAR 5
The term “pediatric patients” means patients coming from the original pediatric trial, DFI13803.  Some of these patients will reach adult age 
(18 years old) while in this study. These patients will be adults by age, but they will remain part of the “pediatric patient” cohort.
Table 7 - Study flow chart for former DFI13803 patients - Year 2 through Year 5 - only applicable  before the implementation of changes that will 
occur after the cutoff date of the second database lock
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to 
assessments not linked to the time of the infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated 
physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Patient 
discontinuation, 
or withdrawalb 
Safety 
follow-up 
phone callc 
Visit/timing 
Every 
2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
 
 
Year 2 
W66 
W80 
W92 
W104 
 
 
Year 3 
W118 
W132 
W144 
W156 
 
 
Year 4 
W170 
W184 
W196 
W208 
 
 
Year 5 
W222 
W236 
W248 
W260 
 
 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time the 
patient signs the written informed consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.   
Complete physical examination 
 
X 
 
X 
 
X 
 
Extended neurological examinationd 
 
 
 
X 
 
X 
 
Abbreviated physical examination 
X 
 
X 
 
X 
 
 
Before and after each infusion 
 
 
Weighte  
Before each infusion 
X 
 
Height 
 
X 
X 
 
X 
 
Vital sign measurements (blood pressure, heart rate, 
respiratory rate, temperature)f  
Before and 1 hour (±10 minutes) after each infusion. 
X 
 
Clinical laboratory tests (clinical chemistry, 
hematology, LFTs, coagulation, urinalysis) 
 
X 
X 
X 
X 
X 
 
Hemoglobin level and platelet countg 
 
X 
 
X 
 
X 
 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 44
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to 
assessments not linked to the time of the infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated 
physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Patient 
discontinuation, 
or withdrawalb 
Safety 
follow-up 
phone callc 
Visit/timing 
Every 
2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
 
 
Year 2 
W66 
W80 
W92 
W104 
 
 
Year 3 
W118 
W132 
W144 
W156 
 
 
Year 4 
W170 
W184 
W196 
W208 
 
 
Year 5 
W222 
W236 
W248 
W260 
 
 
Urine E-HCG pregnancy test (only women of 
childbearing potential) 
Every 4 weeks 
X 
 
Electrocardiogramf,h 
 
X 
 
X 
 
X 
 
Doppler echocardiography 
 
 
 
X 
 
X 
 
Safety biomarkers (hsCRP, iron, ferritin, cardiac 
troponin I, IL-6, IL-8, calcitonin, plasma ceramide) 
 
X 
X 
X 
X 
X 
 
Abdominal MRI (liver and spleen volumes)i  
 
X  (Year 2 only)  
 
X 
 
X 
 
Chest HRCT  
 
 
 
X 
 
Xi 
 
Chest X-ray j 
 
 
 
X 
 
Xi 
 
Pulmonary function tests 
(FVC,FEV1,DLCO,TLC)i, k 
 
X 
(Year 2 only) 
 
X 
 
X 
 
Physician global assessment 
 
X 
(Year 2 only) 
 
X 
 
X 
 
Efficacy biomarkers 
(serum chitotriosidase, CCL18)  
 
X 
X 
X 
X 
X 
 
Bone biomarkers (alkaline phosphatase, 
C-telopeptide)l  
 
X 
X 
X 
X 
X 
 
Fasting lipids (total cholesterol, HDL, LDL, VLDL, 
triglycerides, ApoB, ApoA1, lipoprotein[a]) 
 
X 
X 
(Year 2 only) 
X 
X 
(Year 2 only) 
X 
 
Metabolite levels in plasma 
 
X 
X 
X 
X 
X 
 
Metabolite levels in dried blood spotl 
 
X 
X 
X 
X 
X 
 
Patient photographs (optional) 
 
 
 
X 
 
 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of 
the disease. 
 
 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 45
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to 
assessments not linked to the time of the infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated 
physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Patient 
discontinuation, 
or withdrawalb 
Safety 
follow-up 
phone callc 
Visit/timing 
Every 
2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
 
 
Year 2 
W66 
W80 
W92 
W104 
 
 
Year 3 
W118 
W132 
W144 
W156 
 
 
Year 4 
W170 
W184 
W196 
W208 
 
 
Year 5 
W222 
W236 
W248 
W260 
 
 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Liver ultrasound with Doppler 
 
X 
(Year 2 only) 
 
X 
 
X 
 
Hand X-ray for bone age 
 
X 
 
X 
 
X 
 
Tanner staging 
 
X 
 
X 
 
X 
 
Cognitive and adaptive function (for patients who 
performed the assessments in DFI13803) (DP-3 and 
ABAS)  
 
X 
(Year 2 only) 
 
X 
 
X 
 
Linear patient growth by height Z-score 
 
X 
 
X 
 
X 
 
Pediatric health outcome questionnaires (PedsQL, 
PedsQL Multidimensional Fatigue Scale, PedsQL 
Pediatric Pain Questionnaire) 
 
X 
(Year 2 only) 
 
X 
 
X 
 
Pharmacokineticsf, m  
 
 
 
X 
 
 
 
 
See Section 1.6 and Table 12  
 
 
Immune response assessments 
Anti-olipudase alfa antibody (IgG) 
Quarterly 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to 
Process C(
), collection will be monthly for the first 6 months after introducing the new process, 
and quarterly after that. 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
Anti-olipudase alfa antibody (IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR 
suggestive of a hypersensitivity reaction 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
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Property of the Sanofi Group - strictly confidential
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to 
assessments not linked to the time of the infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated 
physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Patient 
discontinuation, 
or withdrawalb 
Safety 
follow-up 
phone callc 
Visit/timing 
Every 
2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
 
 
Year 2 
W66 
W80 
W92 
W104 
 
 
Year 3 
W118 
W132 
W144 
W156 
 
 
Year 4 
W170 
W184 
W196 
W208 
 
 
Year 5 
W222 
W236 
W248 
W260 
 
 
Anti-olipudase alfa antibody (IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR 
suggestive of a hypersensitivity reaction 
 
 
Serum tryptase and complement activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
 
Skin testing 
If necessary 
 
 
a
Patients from DFI13803 are to follow the pediatric schedule of events in the LTS13632 study.  The pediatric schedule of events is based on pediatric patients receiving 64 weeks of treatment 
in the prior DFI13803 study.  The adult schedule of events is based on adult patients receiving 26 weeks of treatment in the prior DFI13412 study. All patients will have a visit 2 weeks 
(±3 days) after the last Quarterly visits will occur at the site. If the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 
pandemic due to site closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the eligible patient, quarterly visits will be done at 
home. Quarterly visit specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site visits become available. In such a case, some of 
the quarterly visit assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of life instruments). Telehealth visits are an 
acceptable alternative to site visits, If the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 pandemic due to site 
closure or extenuating circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific regulations. 
b
All patients will have a visit 2 weeks (±7 days) after the last dose of study treatment.  For the end of study/early discontinuation visit, abdominal MRI, HRCT, chest X-ray, pulmonary function 
tests (PFTs), Doppler echocardiography, hand X-ray, and pediatric health outcome questionnaires will not be repeated if they had been done within 3 months prior. 
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment. 
d
If possible, the neurological examination should be performed by the same neurologist who performed it in the DFI13803 study.  If possible, the same neurologist should perform the 
neurological examination throughout the study. 
e
Weight at previous on-site visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits unless quarterly visit occurs at home.  Body mass index 
(BMI) will be calculated. 
f
At time points when multiple assessments are scheduled, the order will be: vital sign measurements, electrocardiogram, pharmacokinetics (PK). 
g
As indicated, an additional sample will be collected for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart from the sample collected for clinical laboratory tests. If drug 
product from a manufacturing scale change or an updated manufacturing process is administered, 2 samples will be taken during an infusion 3 months after introducing the new scale or the 
updated manufactured process one for deferential hematology and the other for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart. 
h
Patients must rest in the supine position for 5-10 minutes prior to and during all electrocardiograms. 
i
Upon a manufacturing scale change that occurs beyond Year 2, an abdominal MRI and pulmonary function tests will be performed at the first 6-month visit after the change, but only if that 
6-month visit is not a 12-month visit at which the assessment is already scheduled.  Pulmonary function tests will be performed for patients who had a baseline assessment in the DFI13803 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 47
study. 
j
Only at selected sites. 
k
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
l
Only for patients for whom it was done in DFI13803. 
m Pharmacokinetic testing will only occur yearly and upon introduction of a manufacturing scale change from Process B to Process C(
) or from Process C(
) to the updated manufacturing 
process C(
),.  For Process C(
), if treatment is not interrupted, PK sample collection will take place at the patient’s last infusion under process B and at the first infusion under Process 
C(
). For the switch from Process C(
) to Process C(
), if treatment is not interrupted, PK sample collection will take place at the second infusion under Process C(
).  In case 
reintroduction of olipudase alfa coincides with introduction of a drug product from Process C(
) or Process C(
), PK samples will be collected at the infusion at which patients receive their 
usual dose of olipudase alfa under the new process.  For schedule of PK assessment in children, see Section 1.6, Table 12. 
ABAS=Adaptive Behavior Assessment System; ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; CCL18=chemokine (CC-motif) ligand 18; 
DLCO=diffusing capacity of the lung for carbon monoxide; DP-3=Development Profile-Third Edition; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; HDL=high-density 
lipoprotein; HRCT=high-resolution computed tomography; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-associated reaction; Ig=immunoglobulin; IL=interleukin; LDL=low-density 
lipoprotein; LFT=liver function test; MRI=magnetic resonance imaging; PedsQL=Pediatric Quality of Life; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
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Amended Clinical Trial Protocol No. 07
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Version number: 1
Property of the Sanofi Group - strictly confidential
Page 48
Table 8 - Study flow chart for former DFI13803 patients - Year 2 through Year 5 - only applicable after the cutoff date for a planned second database
lock of the study for purpose of regulatory submissions in 2021
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to 
assessments not linked to the time of the infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated 
physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Patient 
discontinuation, 
or withdrawalb 
Safety 
follow-up 
phone callc 
Visit/timing 
Every 
2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
 
 
Year 2 
W66 
W80 
W92 
W104 
 
 
Year 3 
W118 
W132 
W144 
W156 
 
 
Year 4 
W170 
W184 
W196 
W208 
 
 
Year 5 
W222 
W236 
W248 
W260 
 
 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time the 
patient signs the written informed consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.   
Complete physical examination 
 
X 
 
X 
 
X 
 
Extended neurological examinationd 
 
 
 
X 
 
X 
 
Abbreviated physical examination 
X 
 
X 
 
X 
 
 
Before and after each infusion 
 
 
Weighte  
Before each infusion 
X 
 
Height 
 
X 
X 
 
X 
 
Vital sign measurements (blood pressure, heart rate, 
respiratory rate, temperature)f 
Before and 1 hour (±10 minutes) after each infusion. 
X 
 
Clinical laboratory tests (clinical chemistry, hematology, 
LFTs, coagulation, urinalysis) 
 
X 
X 
X 
X 
X 
 
Hemoglobin level and platelet countg 
 
X 
 
X 
 
X 
 
Urine E-HCG pregnancy test (only women of 
childbearing potential) 
Every 4 weeks 
X 
 
Electrocardiogramf, h 
 
X 
 
X 
 
X 
 
Doppler echocardiography 
 
 
 
X 
 
X 
 
Safety biomarkers (hsCRP, iron, ferritin, cardiac 
troponin I, IL-6, IL-8, calcitonin, plasma ceramide) 
 
X 
X 
X 
X 
X 
 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 49
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to 
assessments not linked to the time of the infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated 
physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Patient 
discontinuation, 
or withdrawalb 
Safety 
follow-up 
phone callc 
Visit/timing 
Every 
2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
 
 
Year 2 
W66 
W80 
W92 
W104 
 
 
Year 3 
W118 
W132 
W144 
W156 
 
 
Year 4 
W170 
W184 
W196 
W208 
 
 
Year 5 
W222 
W236 
W248 
W260 
 
 
Abdominal MRI (liver and spleen volumes)i 
 
X  (Year 2 only)  
 
X 
 
X 
 
Chest HRCT  
 
 
 
X 
 
Xi 
 
Chest X-ray j 
 
 
 
X 
 
Xi 
 
Pulmonary function tests 
(FVC,FEV1,DLCO,TLC)i, k 
 
X 
(Year 2 only) 
 
X 
 
X 
 
Physician global assessment 
 
X 
(Year 2 only) 
 
X 
 
X 
 
Efficacy biomarkers 
(serum chitotriosidase, CCL18)  
 
 
X 
 
X 
X 
 
Bone biomarkers (alkaline phosphatase, C-telopeptide)  
 
 
X 
 
X 
X 
 
Fasting lipids (total cholesterol, HDL, LDL, VLDL, 
triglycerides, ApoB, ApoA1, lipoprotein[a]) 
 
X 
X 
(Year 2 only) 
X 
X 
(Year 2 only) 
X 
 
Metabolite levels in plasma (ceramide, lyso-
sphingomyelin)  
 
 
X 
 
X 
X 
 
Patient photographs (optional) 
 
 
 
X 
 
 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of 
the disease. 
 
 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Liver ultrasound with Doppler 
 
X 
(Year 2 only) 
 
X 
 
X 
 
Hand X-ray for bone age 
 
X 
 
X 
 
X 
 
Tanner staging 
 
X 
 
X 
 
X 
 
Cognitive and adaptive function (for patients who 
performed the assessments in DFI13803) (DP-3 and 
ABAS)  
 
X 
(Year 2 only) 
 
X 
 
X 
 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 50
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to 
assessments not linked to the time of the infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated 
physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Patient 
discontinuation, 
or withdrawalb 
Safety 
follow-up 
phone callc 
Visit/timing 
Every 
2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
 
 
Year 2 
W66 
W80 
W92 
W104 
 
 
Year 3 
W118 
W132 
W144 
W156 
 
 
Year 4 
W170 
W184 
W196 
W208 
 
 
Year 5 
W222 
W236 
W248 
W260 
 
 
Linear patient growth by height Z-score 
 
X 
 
X 
 
X 
 
Pediatric health outcome questionnaires (PedsQL, 
PedsQL Multidimensional Fatigue Scale, PedsQL 
Pediatric Pain Questionnaire) 
 
X 
(Year 2 only) 
 
X 
 
X 
 
Pharmacokineticsl 
 
 
 
X 
 
 
 
 
See Section 1.6 and Table 12  
 
 
Immune response assessments 
Anti-olipudase alfa antibody (IgG) 
Quarterly 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to 
Process C(
), collection will be monthly for the first 6 months after introducing the new process, 
and quarterly after that. 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
Anti-olipudase alfa antibody (IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR 
suggestive of a hypersensitivity reaction 
 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
 
Anti-olipudase alfa antibody (IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR 
suggestive of a hypersensitivity reaction 
 
 
Serum tryptase and complement activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
 
Skin testing 
If necessary 
 
 
a
Patients from DFI13803 are to follow the pediatric schedule of events in the LTS13632 study.  The pediatric schedule of events is based on pediatric patients receiving 64 weeks of treatment 
in the prior DFI13803 study.  The adult schedule of events is based on adult patients receiving 26 weeks of treatment in the prior DFI13412 study. All patients will have a visit 2 weeks 
(±3 days) after the last Quarterly visits will occur at the site. If the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 
pandemic due to site closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the eligible patient, quarterly visits will be done at 
home. Quarterly visit specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site visits become available. In such a case, some of 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 51
the quarterly visit assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of life instruments). Telehealth visits are an 
acceptable alternative to site visits, If the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 pandemic due to site 
closure or extenuating circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific regulations. 
b
All patients will have a visit 2 weeks (±7 days) after the last dose of study treatment.  For the end of study/early discontinuation visit, abdominal MRI, HRCT, chest X-ray, pulmonary function 
tests (PFTs), Doppler echocardiography, hand X-ray, and pediatric health outcome questionnaires will not be repeated if they had been done within 3 months prior. 
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment. 
d
If possible, the neurological examination should be performed by the same neurologist who performed it in the DFI13803 study.  If possible, the same neurologist should perform the 
neurological examination throughout the study. 
e
Weight at previous on-site visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits unless quarterly visit occurs at home.  Body mass index 
(BMI) will be calculated. 
f
At time points when multiple assessments are scheduled, the order will be: vital sign measurements, electrocardiogram, pharmacokinetics (PK). 
g
As indicated, an additional sample will be collected for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart from the sample collected for clinical laboratory tests During 
the study period, for the switch from Process B to Process C(
) or from Process C(
) to the updated manufacturing process C(
) , 2 samples will be taken during an infusion 3 months after 
introducing Process C(
) or Process C(
), one for deferential hematology and the other for hemoglobin and platelet count at least 24 hours and up to 2 weeks apart. 
h
Patients must rest in the supine position for 5-10 minutes prior to and during all electrocardiograms. 
i
During the study period, for the switch from Process B to Process C or from Process C(
) to the updated manufacturing process C(
), that occurs beyond Year 2, an abdominal MRI and 
pulmonary function tests will be performed at the first 6-month visit after the change, but only if that 6-month visit is not a 12-month visit at which the assessment is already scheduled.  
Pulmonary function tests will be performed for patients who had a baseline assessment in the DFI13803 study. 
j
Only at selected sites. 
k
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
l
Pharmacokinetic testing will only occur yearly and upon introduction of a manufacturing scale change from Process B to Process C(
) or from Process C(
) to the updated manufacturing 
process C(
),.  For Process C(
), if treatment is not interrupted, PK sample collection will take place at the patient’s last infusion under process B and at the first infusion under Process 
C(
). For the switch from Process C(
) to Process C(
), if treatment is not interrupted, PK sample collection will take place at the second infusion under Process C(
).  In case 
reintroduction of olipudase alfa coincides with introduction of a drug product from Process C(
) or Process C(
), PK samples will be collected at the infusion at which patients receive their 
usual dose of olipudase alfa under the new process.  For schedule of PK assessment in children, see Section 1.6, Table 12. 
ABAS=Adaptive Behavior Assessment System; ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; CCL18=chemokine (CC-motif) ligand 18; 
DLCO=diffusing capacity of the lung for carbon monoxide; DP-3=Development Profile-Third Edition; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; HDL=high-density 
lipoprotein; HRCT=high-resolution computed tomography; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-associated reaction; Ig=immunoglobulin; IL=interleukin; LDL=low-density 
lipoprotein; LFT=liver function test; MRI=magnetic resonance imaging; PedsQL=Pediatric Quality of Life; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 52
1.5
FLOW CHART FOR PEDIATRIC (FORMER DFI13803) PATIENTS: BEYOND YEAR 5
Table 9 - Study flow chart for former DFI13803 patients - Year 5 and beyond - only applicable before the implementation of changes that will occur 
after the cutoff date of the second database lock
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
Study 
completion, 
patient 
discontinuation 
or withdrawalb
Safety 
follow-
up 
phone 
callc
Year 6 
W274 
W288 
W300 
W312 
Year 7 
W326 
W340 
W352 
W364 
Year 8 
W378 
W392 
W404 
W416 
Year 9 
W430 
W444 
W456 
W468 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time 
the patient signs the written informed consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.   
Complete physical examination 
 
 
 
X 
 
X
 
Extended neurological examinationd
 
 
 
X 
 
X
 
Abbreviated physical examination 
X 
 
 
 
 
 
 
Before and after each infusion 
 
 
Weighte
Before each infusion 
X
 
Height 
 
X 
X 
 
X 
 
Vital sign measurements (blood pressure, heart rate, respiratory 
rate, temperature)f 
Before and 1 hour (±10 minutes) after each infusion. 
X
 
Clinical laboratory tests (clinical chemistry, hematology, LFTs, 
coagulation, urinalysis) 
 
X 
 
X 
 
X 
 
Hematology hemoglobin level and platelet count 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) 
to Process C(
), 2 samples will be taken during an infusion 3 months after introducing the 
new process, one for deferential hematology and the other for hemoglobin and platelet count 
at least 24 hours and up to 2 weeks apart.. 
 
 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 53
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
Study 
completion, 
patient 
discontinuation 
or withdrawalb
Safety 
follow-
up 
phone 
callc
Year 6 
W274 
W288 
W300 
W312 
Year 7 
W326 
W340 
W352 
W364 
Year 8 
W378 
W392 
W404 
W416 
Year 9 
W430 
W444 
W456 
W468 
Urine E-HCG pregnancy test (only women of childbearing 
potential) 
Every 4 weeks 
X 
 
Electrocardiogramf, g
 
 
 
X 
 
X 
 
Safety biomarkers (hsCRP, iron, ferritin, calcitonin, plasma 
ceramide) 
 
X 
 
X 
 
X 
 
Abdominal MRI (liver and spleen volumes)i 
 
 
 
X 
 
X 
 
Chest HRCT 
 
 
 
X 
 
X 
 
Pulmonary function tests 
(FVC,FEV1,DLCO,TLC)h
 
 
 
X 
 
X 
 
Physician global assessment 
 
 
 
X 
 
X 
 
Efficacy biomarkers 
(serum chitotriosidase, CCL18)  
 
 
 
X 
 
X 
 
Fasting lipids (total cholesterol, HDL, LDL, VLDL, triglycerides, 
ApoB, ApoA1, lipoprotein[a]) 
 
 
 
X 
 
X 
 
Metabolite levels in plasma 
 
 
 
X 
 
X 
 
Patient photographs (optional) 
 
 
 
X 
 
 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of the disease. 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Hand X-ray for bone age 
 
 
 
X 
 
X 
 
Tanner staging 
 
 
 
X 
 
X 
 
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Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 54
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks 
(±3 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
QVa 
(±14 days) 
Study 
completion, 
patient 
discontinuation 
or withdrawalb
Safety 
follow-
up 
phone 
callc
Year 6 
W274 
W288 
W300 
W312 
Year 7 
W326 
W340 
W352 
W364 
Year 8 
W378 
W392 
W404 
W416 
Year 9 
W430 
W444 
W456 
W468 
Linear patient growth by height Z score 
 
X 
 
X 
 
X 
 
Pediatric health outcome questionnaires (PedsQL, PedsQL 
Multidimensional Fatigue Scale, PedsQL Pediatric Pain 
Questionnaire) 
 
 
 
X 
 
X 
 
Pharmacokineticsi
 
 
 
 
 
 
 
Immune response assessments 
Anti olipudase alfa antibody (IgG) 
During the study period, for the switch from Process B to Process C(
) or from Process C(
) to Process C
), 
collection will be monthly for the first 6 months after introducing new process 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
Anti-olipudase alfa antibody (IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
Anti-olipudase alfa antibody (IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
Serum tryptase and complement activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
Skin testing 
If necessary 
 
a
Patients from DFI13803 are to follow the pediatric schedule of events in the LTS13632 study.  The pediatric schedule of events is based on pediatric patients receiving 64 weeks of treatment in 
the prior DFI13803 study.  The adult schedule of events is based on adult patients receiving 26 weeks of treatment in the prior DFI13412 study. All patients will have a visit 2 weeks (±3 days).  
Quarterly visits will occur at the site If the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 pandemic due to site 
99&/,1


Amended Clinical Trial Protocol No. 07
15-Apr-2022
LTS13632 - olipudase alfa
Version number: 1
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closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the eligible patient, quarterly visits will be done at home. Quarterly visit 
specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site visits become available. In such a case, some of the quarterly visit 
assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of life instruments). Telehealth visits are an acceptable alternative to 
site visits, If the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 pandemic due to site closure or extenuating 
circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific regulations. 
b
All patients will have a visit 2 weeks (±7 days) after the last dose of study treatment.  For the end of study/early discontinuation visit, all “beyond Year 5” assessments will not be repeated if they 
had been done within 6 months prior. 
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment. 
d
If possible, the neurological examination should be performed by the same neurologist who performed it in the DFI13803 study.  If possible, the same neurologist should perform the 
neurological examination throughout the study. 
e
Weight at previous on-site visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits unless quarterly visit occurs at home.  Body mass index 
(BMI) will be calculated. 
f
At time points when multiple assessments are scheduled, the order will be: vital sign measurements then electrocardiogram. 
g
Patients must rest in the supine position for 5-10 minutes prior to and during all electrocardiograms. 
h
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
i
Beyond 5 years, pharmacokinetic testing will only occur upon introduction of Process C(
) or the Process C(
).  For Process C(
), if treatment is not interrupted, PK sample collection will 
take place at the patient’s last infusion under Process B and at the first infusion under Process C(
). During the study period, for the switch from Process C(
) to Process C(
), if treatment is 
not interrupted, PK sample collection will take place at the second infusion under Process C(
).  In case reintroduction of olipudase alfa coincides with introduction of drug product from 
Process C(
) or Process C(
), PK samples will be collected at the infusion at which patients receive their usual dose of olipudase alfa under the new process.  For schedule of PK 
assessment in adults, see Section 1.6, Table 11. 
ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; DLCO=diffusing capacity of the lung for carbon monoxide; FEV1=forced expiratory volume in 
1 second; FVC=forced vital capacity; HDL=high-density lipoprotein; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-associated reaction; Ig=immunoglobulin; IL=interleukin; 
LDL=low-density lipoprotein; LFT=liver function test; MRI=magnetic resonance imaging; PedsQL=Pediatric Quality of Life; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
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Table 10 - Study flow chart for former DFI13803 patients - Year 5 and beyond - only applicable after the cutoff date for a planned second database 
lock of the study for purpose of regulatory submissions in 2021
Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks
(±3 days) 
QVa
(±14 days) 
QVa
(±14 days) 
QVa
(±14 days) 
QVa
(±14 days) 
Study completion, 
patient discontinuation 
or withdrawalb
Safety
follow-up
phone 
callc
Year 6 
W274 
W288 
W300 
W312 
Year 7 
W326 
W340 
W352 
W364 
Year 8 
W378 
W392 
W404 
W416 
Year 9 
W430 
W444 
W456 
W468 
Adverse events 
Collect continuously throughout the study.  Adverse events that started during the previous study and are ongoing at the time 
the patient signs the written informed consent should be reported in this study. 
Concomitant medications 
Collect continuously throughout the study.   
Complete physical examination 
 
 
 
X 
 
X
 
Extended neurological examinationd
 
 
 
X 
 
X
 
Abbreviated physical examination 
X 
 
 
 
 
 
 
Before and after each infusion 
 
 
Weighte
Before each infusion 
X
 
Height 
 
X 
X 
 
X 
 
Vital sign measurements (blood pressure, heart rate, respiratory 
rate, temperature)f
Before and 1 hour (±10 minutes) after each infusion. 
X
 
Clinical laboratory tests (clinical chemistry, hematology, LFTs, 
coagulation, urinalysis) 
 
X 
 
X 
 
X 
 
Hematology, hemoglobin level and platelet count 
During the study period, for the switch from Process B to Process C(
) or from 
Process C(
) to Process C(
), 2 samples will be taken during an infusion 
3 months after introducing the new process, one for deferential hematology and 
the other for hemoglobin and platelet count at least 24 hours and up to 2 weeks 
apart. 
 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks
(±3 days) 
QVa
(±14 days) 
QVa
(±14 days) 
QVa
(±14 days) 
QVa
(±14 days) 
Study completion, 
patient discontinuation 
or withdrawalb
Safety
follow-up
phone 
callc
Year 6 
W274 
W288 
W300 
W312 
Year 7 
W326 
W340 
W352 
W364 
Year 8 
W378 
W392 
W404 
W416 
Year 9 
W430 
W444 
W456 
W468 
Urine E-HCG pregnancy test (only women of childbearing 
potential) 
Every 4 weeks 
X 
 
Electrocardiogramf, g
 
 
 
X 
 
X 
 
Safety biomarkers (hsCRP, iron, ferritin, calcitonin) 
 
X 
 
X 
 
X 
 
Abdominal MRI (liver and spleen volumes) 
 
 
 
X 
 
X 
 
Chest HRCT 
 
 
 
X 
 
X 
 
Pulmonary function tests
(FVC,FEV1,DLCO,TLC)h
 
 
 
X 
 
X 
 
Physician global assessment 
 
 
 
X 
 
X 
 
Efficacy biomarkers 
(serum chitotriosidase, CCL18)  
 
 
 
X 
 
X 
 
Fasting lipids (total cholesterol, HDL, LDL, VLDL, triglycerides, 
ApoB, ApoA1, lipoprotein[a]) 
 
 
 
X 
 
X 
 
Metabolite levels in plasma (ceramide, lyso-sphingomyelin) 
 
 
 
X 
 
X 
 
Patient photographs (optional) 
 
 
 
X 
 
 
 
Photographs (eg, abdominal) will be taken on patients who volunteer to provide visual context of the disease. 
Olipudase alfa infusion 
X 
X 
X 
X 
X 
 
 
Hand X-ray for bone age 
 
 
 
X 
 
X 
 
Tanner staging 
 
 
 
X 
 
X 
 
Linear patient growth by height Z score 
 
X 
 
X 
 
X 
 
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Study period
Treatment
Post treatment
Note: The visit schedule is calculated in reference to the first infusion of the patient’s previous study.  The ±14 day window applies only to assessments not linked to the time of the 
infusion.  For infusions and assessments closely linked to the time of the infusion (eg, abbreviated physical exams, vital signs), the Q2W visit window of ±3 days remains. 
Visit/timing 
Every 2 weeks
(±3 days) 
QVa
(±14 days) 
QVa
(±14 days) 
QVa
(±14 days) 
QVa
(±14 days) 
Study completion, 
patient discontinuation 
or withdrawalb
Safety
follow-up
phone 
callc
Year 6 
W274 
W288 
W300 
W312 
Year 7 
W326 
W340 
W352 
W364 
Year 8 
W378 
W392 
W404 
W416 
Year 9 
W430 
W444 
W456 
W468 
Pediatric health outcome questionnaires (PedsQL, PedsQL 
Multidimensional Fatigue Scale, PedsQL Pediatric Pain 
Questionnaire) 
 
 
 
X 
 
X 
 
Pharmacokineticsi
 
 
 
 
 
 
 
Immune response assessments 
Anti olipudase alfa antibody (IgG) 
If introduction of a drug product from Process C(
) or Process C(
) occurs, collection will be monthly for the 
first 6 months after introducing the drug product from the new process 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
IL-6, IL-8, and calcitonin 
In case of suspected cytokine release syndrome 
 
Immune response assessment in case of IAR suggestive of hypersensitivity reaction 
Anti-olipudase alfa antibody (IgG) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
Neutralizing antibodies 
In patients who develop anti-olipudase alfa antibody (IgG) 
 
Anti-olipudase alfa antibody (IgE) 
At least 3 days after or prior to the next infusion in case of a moderate/severe or recurrent IAR suggestive of a 
hypersensitivity reaction 
 
Serum tryptase and complement activation 
Within 1 to 3 hours of a moderate/severe or recurrent IAR suggestive of a hypersensitivity reaction 
 
Skin testing 
If necessary 
 
a
Patients from DFI13803 are to follow the pediatric schedule of events in the LTS13632 study.  The pediatric schedule of events is based on pediatric patients receiving 64 weeks of treatment in 
the prior DFI13803 study.  The adult schedule of events is based on adult patients receiving 26 weeks of treatment in the prior DFI13412 study. All patients will have a visit 2 weeks (±3 days).  
Quarterly visits will occur at the site. If the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 pandemic due to site 
closure or extenuating circumstances that prevent an in-person site visit and home infusion is already approved for the eligible patient, quarterly visits will be done at home. Quarterly visit 
specific assessments that need a site visit will not be done at that time and will be done as unscheduled as soon as site visits become available. In such a case, some of the quarterly visit 
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assessments may be done by home nurse (eg, lab sampling) and by the site through the phone (eg, Health-related quality of life instruments). Telehealth visits are an acceptable alternative to 
site visits, if the site visit is not possible during a regional or national emergency declared by a governmental agency such as the COVID-19 pandemic due to site closure or extenuating 
circumstances that prevent an in-person site visit, in accordance with institutional policy and with applicable country-specific regulations. 
b
All patients will have a visit 2 weeks (±7 days) after the last dose of study treatment.  For the end of study/early discontinuation visit, all “beyond Year 5” assessments will not be repeated if they 
had been done within 6 months prior. 
c
All patients will have a final safety follow-up phone call 30 to 37 days after the last dose of study treatment. 
d
If possible, the neurological examination should be performed by the same neurologist who performed it in the DFI13803 study.  If possible, the same neurologist should perform the 
neurological examination throughout the study. 
e
Weight at previous on-site visit may be used to calculate drug dosage at current visit.  Weight is not required at home infusion visits unless quarterly visit occurs at home.  Body mass index 
(BMI) will be calculated. 
f
At time points when multiple assessments are scheduled, the order will be: vital sign measurements then electrocardiogram. 
g
Patients must rest in the supine position for 5-10 minutes prior to and during all electrocardiograms. 
h
Assessments should be performed at the same time (±2 hours) to ensure consistency. 
i
Beyond 5 years, pharmacokinetic testing will only occur upon the introduction of a drug product from Process C(
) or Process C(
).  For Process C(
), if treatment is not interrupted, PK 
sample collection will take place at the patient’s last infusion under Process B and at the first infusion under Process C(
).  During the study period, for the switch from Process C(
) to 
Process C(
), if treatment is not interrupted, PK sample collection will take place at the second infusion under Process C(
).  In case reintroduction of olipudase alfa coincides with 
introduction of drug product from Process C(
) or Process C(
), PK samples will be collected at the infusion at which patients receive their usual dose of olipudase alfa under the new 
process.  For schedule of PK assessment in adults, see Section 1.6, Table 11. 
ApoA1=apolipoprotein A1; ApoB=apolipoprotein B; β-HCG=beta human chorionic gonadotropin; DLCO=diffusing capacity of the lung for carbon monoxide; FEV1=forced expiratory volume in 
1 second; FVC=forced vital capacity; HDL=high-density lipoprotein; hsCRP=high-sensitivity C-reactive protein; IAR= infusion-associated reaction; Ig=immunoglobulin; IL=interleukin; 
LDL=low-density lipoprotein; LFT=liver function test; MRI=magnetic resonance imaging; PedsQL=Pediatric Quality of Life; TLC=total lung capacity; VLDL=very low-density lipoprotein. 
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1.6
STUDY FLOW CHART: PHARMACOKINETIC SAMPLING
For both adult and pediatric patients, PK testing will only occur yearly (up to 5 years) and upon 
the introduction of a drug product from Process C(
) or Process C(
) at any time during the 
study.  For Process C(
), if treatment is not interrupted, PK collection will take place at the 
patient’s last infusion under the current manufacturing scale and at the first infusion Process 
C(
). For introduction of drug product from Process C(
), if treatment is not interrupted, PK 
sample collection will take place at the second infusion under the Process C(
).  In case 
reintroduction of olipudase alfa coincides with introduction of drug product from Process C(
) or 
Process C(
), PK samples will be collected at the infusion at which patients receive their usual 
dose of olipudase alfa under the new process. For introduction of drug product from Process 
C(
), if treatment is not interrupted, PK sample collection will take place at the second infusion 
under Process C(
). 
If a PK sample collection for the planned introduction of drug product from an updated 
manufacturing process was erroneously taken, the future sample collection will be adjusted 
according to the blood volume allowed per each age cohort in order to avoid excessive blood 
withdrawal. For specific details, please refer to Study Manual.
Table 11 - Pharmacokinetic sampling in adults
Week
Before
infusiona
End of 
infusion
Hours after infusionb
1 
4 
8 
24 
48 
96 
12-month visit (up to 5 years) 
X 
X 
X 
X 
X 
X 
X 
X 
If a manufacturing scale change or 
an updated manufacturing process 
occurs  
X 
X 
X 
X 
X 
X 
X 
X 
a
Pre-infusion sample to be collected within 24 hours before infusion start. 
b
Sample collections are to be within ±10 minutes for those <8 hours from infusion end and ±3 hours for those ≥8 hours after infusion end. 
Table 12 - Pharmacokinetic sampling in pediatric patients
Visit 
Age 
Time from end of infusiona
12-month visit 
or if 
introduction of 
a drug 
product from 
a 
manufacturing 
scale change 
or an updated 
manufacturing 
process 
occurs  
Adolescent 
Pre-infusionb 
End of 
infusion 
2 h 
6 h 
24 h 
48 h 
96 h 
X 
X 
X 
X 
X 
X 
X 
 
Pre infusionb 
End of 
infusion 
0-30 min 
2-4 h 
6-12 h 
24-36 h 
84-96 h 
Child 
X 
 
X 
X 
X 
X 
X 
Infant/early 
child 
X 
 
X 
 
X 
X 
X 
a
Sample collections are to be within ±10 minutes for those <8 hours from infusion end and ±3 hours for those ≥8 hours after infusion end. 
b
Pre-infusion sample to be collected within 24 hours before infusion start. 
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2
TABLE OF CONTENTS
AMENDED CLINICAL TRIAL PROTOCOL NO. 07.......................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................................................3 
CLINICAL TRIAL SUMMARY ........................................................................................................................9 
1 
STUDY FLOW CHARTS ...............................................................................................................15 
1.1 
FLOW CHART FOR ADULTS: YEAR 1 THROUGH YEAR 5 .......................................................17 
1.2 
FLOWCHART FOR ADULTS: BEYOND YEAR 5 .........................................................................25 
1.3 
FLOW CHART FOR PEDIATRIC (FORMER DFI13803) PATIENTS: YEAR 1.............................33 
1.4 
FLOW CHART FOR PEDIATRIC (FORMER DFI13803) PATIENTS: YEAR 2 THROUGH 
YEAR 5 ..........................................................................................................................................43 
1.5 
FLOW CHART FOR PEDIATRIC (FORMER DFI13803) PATIENTS: BEYOND YEAR 5 ............52 
1.6 
STUDY FLOW CHART: PHARMACOKINETIC SAMPLING .........................................................60 
2 
TABLE OF CONTENTS ................................................................................................................61 
2.1 
LIST OF TABLES...........................................................................................................................67 
3 
LIST OF ABBREVIATIONS ..........................................................................................................69 
4 
INTRODUCTION AND RATIONALE.............................................................................................71 
4.1 
INTRODUCTION............................................................................................................................71 
4.2 
STUDY RATIONALE......................................................................................................................73 
5 
STUDY OBJECTIVES ...................................................................................................................74 
5.1 
PRIMARY.......................................................................................................................................74 
5.2 
SECONDARY ................................................................................................................................74 
6 
STUDY DESIGN ............................................................................................................................75 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................75 
6.1.1 
Treatment period............................................................................................................................76 
6.1.2 
Post treatment period.....................................................................................................................76 
6.2 
INTERIM ANALYSIS......................................................................................................................77 
6.3 
DURATION OF STUDY PARTICIPATION ....................................................................................77 
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6.3.1 
Determination of end of clinical trial (all patients) ..........................................................................77 
6.4 
STUDY COMMITTEES..................................................................................................................78 
7 
SELECTION OF PATIENTS..........................................................................................................79 
7.1 
INCLUSION CRITERIA..................................................................................................................79 
7.2 
EXCLUSION CRITERIA ................................................................................................................79 
7.2.1 
Exclusion criteria related to study methodology ............................................................................79 
7.2.2 
Exclusion criteria related to the current knowledge of the compound and condition.....................79 
8 
STUDY TREATMENTS .................................................................................................................80 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................80 
8.1.1 
Treatments administered ...............................................................................................................80 
8.1.2 
Route and method of administration..............................................................................................81 
8.1.3 
Dosing considerations....................................................................................................................81 
8.1.4 
Dose adjustments ..........................................................................................................................82 
8.1.5 
Dosing delays or missed doses .....................................................................................................82 
8.1.6 
Dose stopping criteria ....................................................................................................................83 
8.1.7 
Study interruption criteria ...............................................................................................................83 
8.1.8 
Treatment discontinuation..............................................................................................................83 
8.2 
BLINDING PROCEDURES............................................................................................................84 
8.3 
PACKAGING AND LABELING ......................................................................................................84 
8.4 
STORAGE CONDITIONS AND SHELF LIFE................................................................................84 
8.5 
RESPONSIBILITIES ......................................................................................................................84 
8.5.1 
Treatment accountability and compliance......................................................................................85 
8.5.2 
Return and/or destruction of treatments ........................................................................................85 
8.6 
CONCOMITANT MEDICATION.....................................................................................................85 
8.6.1 
Treatment of infusion-associated reactions ...................................................................................86 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................87 
9.1 
ENDPOINTS ..................................................................................................................................87 
9.1.1 
Primary endpoint............................................................................................................................87 
9.1.2 
Secondary endpoints (efficacy)......................................................................................................88 
9.1.3 
Other endpoints..............................................................................................................................89 
9.1.4 
Safety assessments.......................................................................................................................90 
9.1.5 
Complete physical examination .....................................................................................................90 
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9.1.6 
Extended neurological examination...............................................................................................90 
9.1.6.1 
Extended neurological examination in adults ................................................................................90 
9.1.6.2 
Extended neurological examination in pediatric patients...............................................................90 
9.1.7 
Abbreviated physical examination .................................................................................................91 
9.1.8 
Vital sign measurements................................................................................................................91 
9.1.9 
Clinical laboratory tests..................................................................................................................91 
9.1.10 
Electrocardiograms ........................................................................................................................92 
9.1.11 
Echocardiogram with Doppler........................................................................................................92 
9.1.12 
Liver biopsy for sphingomyelin in liver tissue (only patients who previously participated in 
the DFI13412 study).......................................................................................................................93 
9.1.13 
Liver ultrasound with Doppler (only patients who previously participated in the DFI13803 
study) .............................................................................................................................................93 
9.1.14 
Safety biomarkers ..........................................................................................................................93 
9.1.15 
Immune response assessments ....................................................................................................94 
9.2 
EFFICACY ASSESSMENTS .........................................................................................................95 
9.2.1 
Abdominal magnetic resonance imaging.......................................................................................95 
9.2.2 
Pulmonary imaging ........................................................................................................................95 
9.2.2.1 
High-resolution computed tomography..........................................................................................95 
9.2.2.2 
Chest X ray ....................................................................................................................................96 
9.2.3 
Pulmonary function tests................................................................................................................96 
9.2.4 
Hematology....................................................................................................................................97 
9.2.5 
Fasting lipid profile .........................................................................................................................97 
9.2.6 
Health outcome questionnaires .....................................................................................................97 
9.2.6.1 
Adults .............................................................................................................................................97 
9.2.6.2 
Pediatric patients............................................................................................................................98 
9.2.6.3 
Additional questionnaires.............................................................................................................100 
9.2.7 
Hand X-ray (only patients who previously participated in the DFI13803 study) ..........................100 
9.2.8 
Tanner staging (only patients who previously participated in the DFI13803 study) ....................100 
9.2.9 
Linear growth by height by Z-score (only patients who previously participated in the 
DFI13803 study)...........................................................................................................................100 
9.3 
OTHER ASSESSMENTS ............................................................................................................100 
9.3.1 
Physician global assessment of change......................................................................................101 
9.3.2 
Cognitive and adaptive function (for pediatric patients who performed the assessments in 
the DFI13803 study).....................................................................................................................101 
9.3.3 
Cycle ergometry...........................................................................................................................101 
9.3.4 
Efficacy biomarkers......................................................................................................................102 
9.3.5 
Bone disease assessments .........................................................................................................102 
9.3.6 
Bone biomarkers..........................................................................................................................102 
9.3.7 
Patient photographs.....................................................................................................................102 
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9.3.8 
Pharmacokinetics.........................................................................................................................102 
9.3.8.1 
Pharmacokinetics handling procedure.........................................................................................103 
9.3.8.2 
Bioanalytical method....................................................................................................................103 
9.3.8.3 
Pharmacokinetic sampling and parameters in adults ..................................................................103 
9.3.8.4 
Pharmacokinetic sampling and parameters in pediatric patients ................................................105 
9.3.9 
Pharmacodynamic assessments .................................................................................................106 
9.3.9.1 
Liver biopsy for sphingomyelin in liver tissue (only patients who previously participated in 
the DFI13412 study......................................................................................................................106 
9.3.9.2 
Metabolite levels in plasma and dried blood spot (all patients) ...................................................106 
9.3.9.3 
Plasma ceramide (all patients).....................................................................................................106 
9.4 
APPROPRIATENESS OF MEASUREMENTS ............................................................................106 
9.5 
SAMPLED BLOOD VOLUME ......................................................................................................106 
9.6 
FUTURE USE OF SAMPLES ......................................................................................................113 
10 
STUDY PROCEDURES ..............................................................................................................114 
10.1 
VISIT SCHEDULE........................................................................................................................114 
10.2 
STUDY PROCEDURES ..............................................................................................................114 
10.2.1 
Home infusions ............................................................................................................................114 
10.2.2 
Alcohol consumption....................................................................................................................115 
10.2.3 
Pregnancy and contraception ......................................................................................................115 
10.2.3.1 Pregnancy....................................................................................................................................116 
10.2.3.2 Contraception...............................................................................................................................116 
10.3 
DEFINITION OF SOURCE DATA................................................................................................117 
10.4 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.....................................117 
10.4.1 
Temporary treatment discontinuation with investigational medicinal product(s) .........................117 
10.4.2 
Permanent treatment discontinuation with investigational medicinal product(s) .........................118 
10.4.3 
List of criteria for permanent treatment discontinuation...............................................................118 
10.4.4 
Handling of patients after permanent treatment discontinuation .................................................119 
10.4.5 
Procedure and consequence for patient withdrawal from study..................................................119 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................120 
10.5.1 
Definitions of adverse events.......................................................................................................121 
10.5.1.1 Adverse event ..............................................................................................................................121 
10.5.1.2 Serious adverse event .................................................................................................................121 
10.5.1.3 Adverse event of special interest.................................................................................................122 
10.5.1.4 Definitions for criteria of adverse events......................................................................................124 
10.5.2 
Guidelines for reporting adverse events ......................................................................................126 
10.5.2.1 General guidelines .......................................................................................................................126 
10.5.2.2 Instructions for reporting serious adverse events ........................................................................126 
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10.5.2.3 Guidelines for reporting adverse events of special interest.........................................................127 
10.5.2.4 Guidelines for management of specific laboratory abnormalities ................................................128 
10.5.2.5 Summary of adverse event reporting...........................................................................................128 
10.6 
PREGNANCY REPORTING........................................................................................................129 
10.7 
OBLIGATIONS OF THE SPONSOR ...........................................................................................129 
10.8 
ADVERSE EVENTS MONITORING............................................................................................129 
11 
STATISTICAL CONSIDERATIONS............................................................................................130 
11.1 
GENERAL CONSIDERATIONS ..................................................................................................130 
11.1.1 
Final analysis ...............................................................................................................................130 
11.2 
DETERMINATION OF SAMPLE SIZE.........................................................................................130 
11.3 
DISPOSITION OF PATIENTS .....................................................................................................130 
11.4 
ANALYSIS POPULATIONS.........................................................................................................131 
11.5 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...........................................................131 
11.6 
STATISTICAL METHODS ...........................................................................................................131 
11.6.1 
Extent of investigational medicinal product exposure..................................................................131 
11.6.2 
Analyses of efficacy endpoints.....................................................................................................131 
11.6.2.1 Multiplicity considerations ............................................................................................................132 
11.6.3 
Analyses of safety data................................................................................................................132 
11.6.3.1 Adverse events ............................................................................................................................132 
11.6.3.2 Laboratory data and vital sign measurements.............................................................................133 
11.6.3.3 Immune response assessments ..................................................................................................133 
11.6.4 
Analyses of pharmacokinetic and pharmacodynamic variables ..................................................134 
11.6.5 
Analyses of quality of life and cognitive variables........................................................................134 
11.7 
INTERIM ANALYSIS....................................................................................................................134 
12 
ETHICAL AND REGULATORY STANDARDS...........................................................................135 
12.1 
ETHICAL PRINCIPLES ...............................................................................................................135 
12.2 
LAWS AND REGULATIONS .......................................................................................................135 
12.3 
INFORMED CONSENT ...............................................................................................................135 
12.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.............................136 
13 
STUDY MONITORING.................................................................................................................137 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................137 
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13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................137 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................138 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS AND ADDITIONAL 
REQUEST....................................................................................................................................138 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................138 
14 
ADMINISTRATIVE EXPECTATIONS .........................................................................................140 
14.1 
CURRICULUM VITAE..................................................................................................................140 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................140 
14.3 
CONFIDENTIALITY .....................................................................................................................140 
14.4 
PROPERTY RIGHTS...................................................................................................................141 
14.5 
DATA PROTECTION...................................................................................................................141 
14.6 
INSURANCE COMPENSATION..................................................................................................141 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................142 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................142 
14.8.1 
Decided by the sponsor ...............................................................................................................142 
14.8.2 
Decided by the investigator..........................................................................................................143 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................143 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................143 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................144 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................145 
17 
APPENDICES..............................................................................................................................147 
17.1 
APPENDIX A: COUNTRY SPECIFIC REQUIREMENTS............................................................147 
17.2 
APPENDIX B: PROTOCOL AMENDMENT HISTORY................................................................147 
17.2.1 
Amended Clinical Trial Protocol 06 (29-Jan-2021)......................................................................147 
17.2.2 
Amended Clinical Trial Protocol 05 (18-Aug-2020) .....................................................................152 
17.2.3 
Amended protocol 04 (31-Jul-2019) ............................................................................................155 
17.2.4 
Amended protocol 03 based on Protocol Amendment 03 (25 April 2018) ..................................159 
17.2.5 
Amended protocol 02 based on Protocol Amendment 02 (25 April 2017) ..................................162 
17.2.6 
Amended protocol 01 based on Protocol Amendment 01 (23 March 2016)................................164 
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2.1
LIST OF TABLES
Table 1 - Study flow chart for former patients from the DFI13412 study - Year 1 through Year 5 - only 
applicable  before the implementation of changes that will occur after the cutoff date of the second 
database lock ................................................................................................................................................17 
Table 2 - Study flow chart for former patients from the DFI13412 study - Year 1 through Year 5 - only 
applicable after the cutoff date for a planned second database lock of the study for purpose of regulatory 
submissions in 2021......................................................................................................................................21 
Table 3 - Study flow chart for former patients from DFI13412 - beyond Year 5 - only applicable  before the 
implementation of changes that will occur after the cutoff date of the second database lock ......................25 
Table 4 - Study flow chart for former patients from DFI13412 - beyond Year 5 - only applicable after the 
cutoff date for a planned second database lock of the study for purpose of regulatory submissions in 2021
.......................................................................................................................................................................29 
Table 5 - Study flow chart for former DFI13803 patients - Year 1 - only applicable before the 
implementation of changes that will occur after the cutoff date of the second database lock ......................33 
Table 6 - Study flow chart for former DFI13803 patients - Year 1 - only applicable after the cutoff date for a 
planned second database lock of the study for purpose of regulatory submissions in 2021........................38 
Table 7 - Study flow chart for former DFI13803 patients - Year 2 through Year 5 - only applicable  before 
the implementation of changes that will occur after the cutoff date of the second database lock ................43 
Table 8 - Study flow chart for former DFI13803 patients - Year 2 through Year 5 - only applicable after the 
cutoff date for a planned second database lock of the study for purpose of regulatory submissions in 2021
.......................................................................................................................................................................48 
Table 9 - Study flow chart for former DFI13803 patients - Year 5 and beyond - only applicable before the 
implementation of changes that will occur after the cutoff date of the second database lock ......................52 
Table 10 - Study flow chart for former DFI13803 patients - Year 5 and beyond - only applicable after the 
cutoff date for a planned second database lock of the study for purpose of regulatory submissions in 2021
.......................................................................................................................................................................56 
Table 11 - Pharmacokinetic sampling in adults.............................................................................................60 
Table 12 - Pharmacokinetic sampling in pediatric patients...........................................................................60 
Table 13 - Quality of life assessments ..........................................................................................................99 
Table 14 - Approximate number of plasma samples in adult patients ........................................................103 
Table 15 - List of pharmacokinetic parameters and definitions...................................................................104 
Table 16 - Approximate number of plasma samples by pediatric age cohort .............................................105 
Table 17 - Approximate sampled blood volume in patients ages 12 to <18 years in the first 5 years........107 
Table 18 - Additional approximate sampled blood volume in patients ages 12 to <18 years with 
an olipudase alfa manufacturing scale change ...........................................................................................108 
Table 19 - Additional approximate sampled blood volume in patients ages 12 to <18 years with the 
olipudase alfa updated manufacturing process...........................................................................................108 
Table 20 - Approximate sampled blood volume in patients ages 12 to <18 years beyond 5 years............108 
Table 21 - Approximate sampled blood volume in patients in the child cohort (6 to <12 years)  and in 
patients ages 3 to <6 years in the first 5 years............................................................................................109 
Table 22 - Additional approximate sampled blood volume in patients in the child cohort (6 to <12 years) 
and ages 3 to <6 years with an olipudase alfa manufacturing scale change..............................................110 
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Table 23 - Additional approximate sampled blood volume in patients in the child cohort (6 to <12 years) 
and ages 3 to <6 years with an olipudase alfa manufacturing process update ..........................................110 
Table 24 - Approximate sampled blood volume in patients in the child cohort (6 to <12 years) and in 
patients ages 3 to <6 years - beyond 5 years .............................................................................................110 
Table 25 - Approximate sampled blood volume in patients from birth to ≤2 years of age in the first 5 years
.....................................................................................................................................................................111 
Table 26 - Additional approximate sampled blood volume in patients from birth to ≤2 years of age with an 
olipudase alfa manufacturing scale change ................................................................................................112 
Table 27 - Additional approximate sampled blood volume in patients from birth to ≤2 years of age with an 
olipudase alfa manufacturing process update.............................................................................................112 
Table 28 - Approximate sampled blood volume in patients from birth to ≤2 years of age- beyond 5 years
.....................................................................................................................................................................112 
Table 29 - Approximate sampled blood volume per infusion following moderate, severe, or recurrent IARs 
suggestive of hypersensitivity reactions ......................................................................................................113 
Table 30 - Summary of adverse event reporting instructions......................................................................128 
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3
LIST OF ABBREVIATIONS
ABAS:
Adaptive Behavior Assessment System
ACE:
angiotensin converting enzyme
AE:
adverse event
AP:
alkaline phosphatase
Apo:
apolipoprotein
APR:
acute phase reaction
ASM:
acid sphingomyelinase
ASMD:
acid sphingomyelinase deficiency
ASMKO:
acid sphingomyelinase knock out
AUC0-∞:
area under the concentration-time curve from time 0 to infinity
AUClast:
area under the concentration-time curve
BFI:
Brief Fatigue Inventory
BMD:
bone mineral density
BMI:
body mass index
BPI:
Brief Pain Inventory
CCL-18:
chemokine (CC-motif) ligand 18
Ceoi:
concentration at the end of infusion
CL:
apparent total body clearance
Cmax:
maximum concentration observed
CO2:
carbon dioxide
CRF:
case report form
CRS:
cytokine release syndrome
CS:
clinically significant
DBS:
dried blood spot
DLCO:
diffusing capacity of the lung for carbon monoxide
DMC:
Data Monitoring Committee
DNA:
deoxyribonucleic acid
DP-3:
Development Profile-Third Edition
DXA:
dual-energy X-ray absorptiometry
ECHO:
echocardiogram
EOT:
end of treatment
FEV1:
forced expiratory volume in the first 1 second
FVC:
forced vital capacity
HDL:
high-density lipoprotein
HRCT:
high resolution computed tomography
IAR:
infusion associated reaction
ICH:
International Council on Harmonisation
IEC:
independent ethics committee
IL:
interleukin
ILD:
interstitial lung disease
IMP:
investigational medicinal product
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IRB:
institutional review board
IV:
intravenous
LDL:
low-density lipoprotein
LFT:
liver function test
MIP:
macrophage inflammatory protein
MRI:
magnetic resonance imaging
NCS:
not clinically significant
NE:
not evaluable
NPB-HAQ:
Niemann-Pick B Health Assessment Questionnaire version 2
NPD:
Niemann-Pick disease
O2:
oxygen
PCSA:
potentially clinically significant abnormality
PD:
pharmacodynamic
PedsQL:
Pediatric Quality of Life
PFT:
pulmonary function test
PIP:
pediatric investigational plan
PK:
pharmacokinetic
PT:
preferred term
SAE:
serious adverse event
SF:
Short Form
SF-36:
Short Form-36
SFCRQ SAS:
Chronic Respiratory Disease Questionnaire Self-administered Standardized
SOC:
system organ class
t1/2z:
terminal half-life associated with the terminal slope (λz)
tmax:
time to reach maximum concentration
VLDL:
very low-density lipoprotein
Vss:
apparent volume of distribution at steady-state
β-HCG:
beta-human chorionic gonadotropin
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4
INTRODUCTION AND RATIONALE
4.1
INTRODUCTION
Human acid sphingomyelinase deficiency (ASMD) is a serious, rare, life threatening lysosomal 
storage disorder for which only palliative treatment exists. Patients with ASMD are unable to 
metabolize sphingomyelin properly due to mutations in SMPD1, the gene encoding acid 
sphingomyelinase (ASM), whose transcription and translation results in a defective (ASM) 
enzyme. Inactivity of ASM leads to the lysosomal accumulation of sphingomyelin and, 
secondarily, increases in cholesterol and other related lipids, mostly in the organs, such as the 
spleen, liver, lung, and bone marrow.
Historically, ASMD has been diagnosed as Niemann-Pick Disease (NPD) and of either Type A or
Type B disease. Type A (NPD A) is characterized as the early-onset and acute neuropathic form 
of (NPD) and results in failure to thrive, hepatosplenomegaly, rapidly progressive neurological 
degeneration, and death, usually before the age of 3 years (1). Niemann-Pick disease Type B
(NPD B) is a milder disease with little or no neurological involvement that may already have 
manifestations in childhood.  The most common disease manifestation is hepatosplenomegaly. 
Other more variable features include liver dysfunction, pulmonary disease, retinal stigmata, and 
growth retardation.  Niemann-Pick disease Type B is usually diagnosed in childhood after 
organomegaly is observed, typically after the age of 2 years. Most patients diagnosed with Type B
disease live into adulthood.  Being an autosomal recessive single gene disease, ASMD is 
acknowledged to generate a spectrum of phenotypes. Accordingly, cases classified as intermediate 
to the A and B extremes have been reported. Patients with this intermediate form (NPD A/B) may 
develop neurologic symptoms during childhood and have a chronic neurodegenerative disease 
course.
Sanofi Genzyme is developing a potential enzyme replacement therapy for ASMD with olipudase 
alfa, a recombinant human acid sphingomyelinase, for the treatment of the non-neurological 
manifestations of ASMD.  This recombinantly-derived enzyme is expressed in Chinese hamster 
ovarian cells transfected with olipudase alfa complementary DNA that encodes a 627-residue 
peptide chain.  The resulting gene product retains the enzymatic activity and lysosomal targeting 
of the native protein.
Proof of concept for olipudase alfa therapy has been demonstrated in the acid sphingomyelinase 
knock-out (ASMKO) mouse (2), which exhibits both systemic and neurological features of 
ASMD.  Repeat intravenous (IV) bolus administration of olipudase alfa to ASMKO mice led to 
dose-dependent reductions of sphingomyelin in visceral organs and in the lungs to a lesser extent, 
but was unable to prevent neurologic decline and prolong survival (3, 4). However, chronic 
dosing in the ASMKO animal model is limited because the mice succumb to the neurologic 
disease resulting from the natural progression of complete ASMD in approximately 6 to 8 months.
Pharmacodynamic (PD), pharmacokinetic (PK), and toxicological studies conducted in the 
ASMKO mouse found significant reductions of sphingomyelin in the liver, lung, kidney, and 
spleen at olipudase alfa doses ranging from 0.1 to 5.0 mg/kg in a time-dependent manner; 
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however, toxicity was observed in ASMKO mice given single high-dose boluses of olipudase alfa 
(≥10 mg/kg).  The same single, high doses did not cause toxic effects in normal mice, Sprague 
Dawley rats, or cynomolgus monkeys, suggesting that catabolites of sphingomyelin, and not 
olipudase alfa itself, were the cause of the toxic effects.  Subsequent “debulking” studies in 
ASMKO mice demonstrated that a slow reduction in the sphingomyelin load over time using 
multiple low doses of olipudase alfa (4 doses of 3.0 mg/kg of olipudase alfa administered over 
8 days) followed by a high dose (20 mg/kg 3 days later) prevented the toxicity associated with the 
single initial high doses.  These findings suggest that the observed toxicity is related to the rate of 
substrate degradation and that step-wise removal of substrate likely mitigates toxicity. 
Furthermore, repeat high doses of olipudase alfa (30 mg/kg every 2 weeks for 7 doses) 
administered after a 7-day debulking period (3 mg/kg on Days 1, 3, 5, and 7) also did not cause 
toxicity.
During clinical development of olipudase alfa, incremental changes were made to the olipudase 
alfa manufacturing process. The different processes are referred to as Process B, C(
) and C(
). 
In a completed Phase 1 study (5), the safety, PK, and PD profiles of single, ascending doses of 
olipudase alfa were evaluated. Single doses of 0.03, 0.1, 0.3, 0.6, and 1.0 mg/kg of olipudase alfa 
were infused sequentially by dose cohort in 11 adult patients with ASMD. Study results found 
dose-related increases in ceramide, bilirubin, high-sensitivity C-reactive protein (hsCRP), and 
other acute phase reactants in patients that peaked 24 to 48 hours postdose and resolved by 
Day 14.  Reported adverse events (AEs) involving constitutional symptoms (pain, fever, nausea, 
and vomiting) were consistent with first-dose-related toxicity and occurred in a dose-dependent 
fashion as was previously observed in the ASMKO mouse.  Serious adverse events (SAEs) related 
to olipudase alfa treatment were not reported. The sponsor terminated the study subsequent to 
a single patient dosed at 1.0 mg/kg of olipudase alfa presenting with hyperbilirubinemia and 
an acute-phase reaction (APR) with clinical symptoms. Of note, this patient was subsequently 
confirmed to have Gilbert’s syndrome. Because there were no other signs of liver toxicity or 
hemolysis, the observed hyperbilirubinemia may have been secondary to specific inhibition of 
bilirubin uptake into hepatocytes and/or glucuronide conjugation of bilirubin within hepatocytes.
In a completed Phase 1b, open-label, multicenter ascending-dose study in 5 adult patients with 
ASMD, the safety and tolerability of olipudase alfa were evaluated during a 26-week treatment 
period (6). Patients received an initial IV dose of 0.1 mg/kg of olipudase alfa, then the dose was 
escalated in a stepwise manner to a final target IV dose of 3.0 mg/kg.  All patients remained at 
3.0 mg/kg for the remainder of the treatment period. Upon completion of the study, all patients 
enrolled into an open-label, long-term treatment study. Results from this trial demonstrated that 
the progressive, within-patient olipudase alfa dose escalation regimen was well tolerated in adult 
ASMD patients. No serious or severe AEs or deaths were reported in the study.  Related AEs 
consisted predominantly of infusion-associated reactions (IARs), most of which were mild in 
severity with all patients recovering without sequelae. At the end of the 6-month treatment period, 
a positive response to treatment with olipudase alfa was observed in several individual efficacy 
parameters. This included mean decreases in spleen and liver volumes by 25.3% and 17.1%, 
respectively; decreased interstitial lung disease (ILD) scores; increased percent predicted diffusing 
capacity of the lung for carbon monoxide (DLCO); reduction in serum chitotriosidase, chemokine 
(CC-motif) ligand 18 (CCL-18), and angiotensin-converting enzyme (ACE); a positive trend 
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towards a less proatherogenic lipid profile; and, trends for improvement in quality of life 
assessments for fatigue and pain.
Other clinical studies of olipudase alfa are planned or ongoing.  These include:
x
A Phase 1/2, multicenter, open-label, ascending-dose study to evaluate the safety, 
tolerability, PK, PD, and exploratory efficacy of olipudase alfa in pediatric patients aged 
<18 years with ASMD.
x
A Phase 2/3, multicenter, randomized, double-blinded, placebo-controlled repeat-dose 
study to evaluate the efficacy, safety, PD, and PK of olipudase alfa in patients 
with ASMD.
A complete summary of nonclinical and clinical experience with olipudase alfa can be found in 
the investigator’s brochure.
4.2
STUDY RATIONALE
Cumulative data from preclinical and human studies conducted to date with olipudase alfa 
demonstrate both the safety and tolerability of repeat dosing of olipudase alfa.  This study will 
provide long-term data on olipudase alfa in pediatric and adult patients with ASMD.
This study is being conducted to allow patients with ASMD to continue the olipudase alfa 
treatment they were receiving at the end of their primary study after that study is completed. 
Individual dose adjustments are allowed in this study, but may also be recommended based on 
results from completed or ongoing studies of olipudase alfa. The primary objective of this study is 
to obtain safety data in pediatric and adult patients with ASMD who are exposed to long-term 
treatment with olipudase alfa. Secondary objectives are to obtain efficacy, PK, and PD data.
Treatment Period
x
The current study is an open-label, long-term treatment study planned for 9 years, or until
olipudase alfa becomes commercially accessible (see maximum duration below), whichever 
comes first, unless the patient decides to enter another olipudase alfa clinical trial within the 
9-year period prior to when olipudase alfa is commercially accessible.
x
The term “commercially accessible” is defined as when olipudase alfa is commercially 
accessible to each patient on an individual basis (eg, reimbursement being in place). The 
duration of study treatment with olipudase alfa between local Regulatory approval and 
commercial accessibility should not exceed 90 days. Therefore, as described below, after 
local Regulatory approval, the patient can continue in the LTS13632 study for a maximum of 
127 days.
x
This will ensure 90 days of study treatment with olipudase alfa for patients after local 
Regulatory approval and a safety follow up phone call 30 to 37 days after the last dose of 
study treatment. 
x
Notwithstanding the above, every pediatric patient will be treated in the LTS13632 study for 
at least 3 years to comply with the agreed PIP. 
x
The patient can switch immediately after the end of study treatment to commercial treatment 
without any gap in order to ensure continuity of treatment with olipudase alfa.
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5
STUDY OBJECTIVES
5.1
PRIMARY
The primary objective of this study is to obtain data regarding the safety of olipudase alfa in 
patients with ASMD who are exposed to long-term treatment with olipudase alfa.
5.2
SECONDARY
The secondary objectives of this study are to obtain data regarding the efficacy of olipudase alfa 
and to characterize olipudase alfa PD and PK following long-term administration.
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6
STUDY DESIGN
This is a multinational, multicenter, nonrandomized, open-label, long-term treatment study of 
approximately 25 patients who have previously participated in a study of olipudase alfa. 5 adult 
patients rolled over from study DFI13412 into LTS13632 study and approximately 20 pediatric 
patients are expected to roll over from study DFI13803. Patients will be enrolled directly into this 
study from their previous study.
Treatment Period
x
Enrolled patients will receive an IV infusion of olipudase alfa every 2 weeks for 9 years, or 
until olipudase alfa becomes commercially accessible (see maximum duration below), 
whichever comes first, unless the patient decides to enter another olipudase alfa clinical trial 
within the 9-year period prior to when olipudase alfa commercially accessible. 
x
The term “commercially accessible” is defined as when olipudase alfa is commercially 
accessible to each patient on an individual basis (eg, reimbursement being in place). The 
duration of study treatment with olipudase alfa between local Regulatory approval and 
commercial accessibility should not exceed 90 days. Therefore, as described below, after local 
Regulatory approval, the patient can continue in the LTS13632 study for a maximum of 
127 days.
x
This will ensure 90 days of study treatment with olipudase alfa for patients after local 
Regulatory approval and a safety follow up phone call 30 to 37 days after the last dose of 
study treatment. 
x
Notwithstanding the above, every pediatric patient will be treated in the LTS13632 study for 
at least 3 years. 
x
The patient can switch immediately after the end of study treatment to commercial treatment 
without any gap in order to ensure continuity of treatment with olipudase alfa. 
Data Monitoring Committee
A chartered, independent data monitoring committee (DMC) will provide ongoing expert, 
independent review of safety data to ensure the protection and safety of the patients, as described 
in Section 6.4.
6.1
DESCRIPTION OF THE PROTOCOL
The study consists of 2 periods, treatment and posttreatment.
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6.1.1
Treatment period
Treatment Period
x
During the treatment period, patients will receive an IV infusion of olipudase alfa every 
2 weeks for 9 years or until olipudase alfa becomes commercially accessible (see maximum 
duration below), whichever comes first, unless the patient decides to enter another olipudase 
alfa clinical trial within the 9-year period prior to when olipudase alfa is commercially 
accessible. 
x
The term “commercially accessible” is defined as when olipudase alfa is commercially 
accessible to each patient on an individual basis (eg, reimbursement being in place). The 
duration of study treatment with olipudase alfa between local Regulatory approval and 
commercial accessibility should not exceed 90 days. 
x
Notwithstanding the above, every pediatric patient will be treated in the LTS13632 study for 
at least 3 years. 
x
The patient can switch immediately after the end of study treatment to commercial treatment 
without any gap in order to ensure continuity of treatment with olipudase alfa. 
In the first 5 years, safety and efficacy assessments will occur at regular 3, 6, or 12 month 
intervals then only selected assessments will occur every 6 or 12 months after 5 years.  
Schedule of Assessments 
In the first 5 years, pharmacodynamic (PD) evaluations will occur every 3 months then every 
6 months after the cutoff date for a planned second database lock of the study for purpose of 
regulatory submissions in 2021. After 5 years, PD evaluations will occur every 12 months. 
PK evaluations will occur every 12 months only in the first 5 years and upon introduction of 
Process C(
) or Process C(
) at any time during the study. Beyond 5 years, pharmacokinetic 
testing will only occur upon the introduction of Process C(
) or Process C(
).  For Process 
C(
), if treatment is not interrupted, PK sample collection will take place at the patient’s last 
infusion under the current manufacturing scale and at the first infusion under Process C(
).  For 
introduction of Process C(
), if treatment is not interrupted, PK sample collection will take place 
at the second infusion under Process C(
).  In case reintroduction of olipudase alfa coincides 
with introduction of drug product from Process C(
) or Process C(
), PK samples will be 
collected at the infusion at which patients receive their usual dose of olipudase alfa under the new 
process. For schedule of PK assessment in adults, see Section 1.6, Table 11.
6.1.2
Post treatment period
For patients completing or discontinuing/withdrawing from the study, there will be a 
posttreatment period consisting of an end-of-treatment (EOT) visit 2 weeks (±7 days) after the last 
administered dose of study treatment and a safety follow-up phone call 30 to 37 days after the last 
administered dose of study treatment.
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An EOT visit and a safety follow-up phone call will also apply in case the patient switches 
immediately after the end of study treatment to commercial treatment.
6.2
INTERIM ANALYSIS
No formal interim analysis is planned for this study. A formal summary of data or interim CSR 
may be produced to support regulatory approval(s) and/or other submission/application 
requirement(s). 
6.3
DURATION OF STUDY PARTICIPATION
The length of a patient's participation will be from the time the informed consent form is signed 
until the last planned assessment/visit.  The approximate maximum study duration per patient is as 
follows:
x
Treatment period of 9 years or until olipudase alfa becomes commercially accessible (see 
maximum duration below), whichever comes first, unless the patient decides to enter 
another olipudase alfa clinical trial within the 9-year period prior to when olipudase alfa is 
commercially accessible. 
x
The term “commercially accessible” is defined as when olipudase alfa is commercially 
accessible to each patient on an individual basis (eg, reimbursement being in place). The 
duration of study treatment with olipudase alfa between local Regulatory approval and 
commercial accessibility should not exceed 90 days. Therefore, as described below, after 
local Regulatory approval, the patient can continue in the LTS13632 study for a maximum 
of 127 days.
x
This will ensure 90 days of study treatment with olipudase alfa for patients after local 
Regulatory approval and a safety follow up phone call 30 to 37 days after the last dose of 
study treatment. 
x
The patient can switch immediately after the end of study treatment to commercial 
treatment without any gap in order to ensure continuity of treatment with olipudase alfa. 
x
Notwithstanding the above, every pediatric patient will be treated in the LTS13632 study 
for at least 3 years.  
x
Follow up period concluded with a safety follow up phone call 30 to 37 days after the 
patient’s last infusion in the LTS13632 study. A safety follow-up phone call will also 
apply in case the patient switches immediately after the end of study treatment to 
commercial treatment.
6.3.1
Determination of end of clinical trial (all patients)
The study will be considered to be complete when the last patient has his/her last contact with 
his/her study site.
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6.4
STUDY COMMITTEES
An independent DMC, composed of members independent from the sponsor and the study 
investigators, is implemented in order to monitor patient safety by conducting formal reviews of 
accumulated safety data.  The DMC will provide the sponsor with appropriate recommendations 
on the conduct of the clinical trial to ensure the protection and safety of the patients enrolled in the
study (ie, exposure to study drug). All activities and responsibilities of the DMC are described in 
the DMC charter in compliance with applicable guidance (7).
Data monitoring committee meetings will occur at regular intervals as outlined in the DMC 
charter specific to this study.  The report of a potential dose-limiting toxicity to the sponsor or the 
occurrence of any safety-related issues identified by the sponsor's medical monitor or global 
safety officer that pose a medical concern, for example a fatal event, will result in the DMC 
holding an ad hoc review of the safety data and providing its recommendations to the sponsor 
regarding further patient treatment.
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7
SELECTION OF PATIENTS
7.1
INCLUSION CRITERIA
To enter this study, patients must have fulfilled the following criteria:
I 01.
The patient completed the treatment period of a previous study of olipudase alfa with 
an acceptable safety profile in the opinion of the investigator and sponsor.
I 02.
The patient and the patient's parent(s)/legal guardian(s) is willing and able to provide 
signed written informed consent.
I 03.
The patient who is female and of childbearing potential must have a negative urine 
pregnancy test for beta-human chorionic gonadotropin (β-HCG) (see Section 9.1.9).
I 04.
Female patients of childbearing potential and sexually mature male patients must be 
willing to practice true abstinence in line with their preferred and usual lifestyle or use 
2 acceptable effective methods of contraception up to 15 days following their last dose of 
study drug (see Section 10.2.3.2).
7.2
EXCLUSION CRITERIA
Patients who have met all the above inclusion criteria listed in Section 7.1 will be assessed for the 
following exclusion criteria:
7.2.1
Exclusion criteria related to study methodology
E 01. 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 participating in or completing the study.
E 02. The patient, in the opinion of the investigator, is unable to adhere to the requirements of 
the study.
E 03. The patient is unwilling or unable to abstain from the use of alcohol for 1 day prior to and 
3 days after each olipudase alfa infusion for the duration of the treatment period.
E 04. The patient is unwilling or unable to avoid, for 10 days before and 3 days after liver 
biopsies, medications or herbal supplements that are potentially hepatotoxic 
(eg, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, erythromycin, valproic 
acid, antidepressants, kava, echinacea) or may cause or prolong bleeding 
(eg, anticoagulants, ibuprofen, aspirin, garlic supplements, ginkgo, ginseng) (only patients 
who previously participated in the DFI13412 study).
7.2.2
Exclusion criteria related to the current knowledge of the compound and condition
E 05. The patient requires medication(s) that may decrease olipudase alfa activity (eg, fluoxetine, 
chlorpromazine; tricyclic antidepressants [eg, imipramine, desipramine]).
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8
STUDY TREATMENTS
8.1
INVESTIGATIONAL MEDICINAL PRODUCT(S)
The study drug, olipudase alfa, is a sterile, white to off-white lyophilized cake supplied in 
single-use, 20 cc Type 1 glass vials. Each vial contains 20 milligrams of extractable olipudase 
alfa.
The study drug will be reconstituted with 5.1 mL of sterile water for injection to yield 
a concentration of 4.0 mg/mL of olipudase alfa.  The study drug will be further diluted in
0.9% sodium chloride for injection solution to a specific volume based on dose.
Detailed instructions on olipudase alfa preparation, storage, and administration are provided in the 
corresponding manual.
Refer to Section 8.5 for product handling and complaints reporting.
8.1.1
Treatments administered
Patients will receive olipudase alfa every 2 weeks (±3 days). Home infusions may be possible. To 
be eligible for home infusions, patients must meet the criteria in Section 10.2.1.
Patients will start this study at the same dose they were receiving at the end of their primary study, 
provided that they have not missed more than 1 biweekly dose between studies.  
All patients will have a visit 2 weeks (±3 days).  Quarterly visits will occur at the site. If the site 
visit is not possible due to site closure or extenuating circumstances that prevent an in-person site 
visit (eg, during COVID-19 pandemic) and home infusion is already approved for the eligible 
patient, quarterly visits will be done at home. Quarterly visit specific assessments that need a site 
visit will not be done at that time and will be done as unscheduled as soon as site visits become 
available. In such a case, some of the quarterly visit assessments may be done by home nurse 
(eg, lab sampling) and by the site through the phone (eg, Health-related quality of life 
instruments). Telehealth visits are an acceptable alternative to site visits, if site visits are not 
possible during a regional or national emergency declared by a governmental agency such as the 
COVID-19 pandemic due to site closure or extenuating circumstances that prevent an in-person 
site visit, in accordance with institutional policy and with applicable country-specific regulations.
Dose reintroduction regimens may be required for patients who have missed more than 1 dose 
between studies or during this study (LTS13632), depending on their usual dose.  For patients 
receiving home infusions who have missed 2 or fewer doses, the investigator can decide whether 
reintroduction should occur at the hospital/study site or via home infusion. For patients who have 
missed 3 or more doses ≥0.6 mg/kg, reintroduction of olipudase alfa should occur at the
hospital/study site. If the site visit is not possible during a regional or national emergency declared 
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by a governmental agency such as the COVID-19 pandemic due to site closure or extenuating 
circumstances that prevent an in-person site visit, reintroduction may be done via home infusion. 
Olipudase alfa reintroduction guidance will depend on the patient’s usual dose and the number of 
missed infusions: 
x
If a patient misses 1 dose, continue at the dose previous to the missed dose.
x
If a patient misses 2 doses:
-
If the previous dose was >0.6 mg/kg, the next dose must be 1 level below the last dose,
-
If the previous dose was ≤0.6 mg/kg, the next dose must be equal to the last dose.
x
If a patient misses 3 or more doses:
-
If the previous dose was >0.6 mg/kg, the next dose must be 0.3 mg/kg (0.3 mg/kg 
should be repeated at the subsequent infusion, similar to dose escalation schedule in 
the original study). Details will be provided in the study manual
-
If the previous dose was ≤0.6 mg/kg, the next dose must be equal to the last dose,
-
If a patient has missed 3 or more doses ≥0.6 mg/kg, reintroduction of olipudase alfa for 
patients receiving infusions at home should occur at the hospital/study site. 
-
If the site visit is not possible during a regional or national emergency declared by a 
governmental agency such as the COVID-19 pandemic due to site closure or 
extenuating circumstances that prevent an in-person site visit, reintroduction may be 
done via home infusion, if the patient has previously been approved for home infusion.
8.1.2
Route and method of administration
Patients will receive IV olipudase alfa over the same time period as in their original study. The 
length of the infusion time may be adjusted based on the patient’s tolerance of the infusion.
During the study, pediatric patients who reach adult age (18 years old) will receive the adult 
infusion volume.
See Section 8.1.5 for information on dose adjustments following dosing delays or missed doses.
8.1.3
Dosing considerations
Patients will receive the same olipudase alfa dose every 2 weeks, provided they have not missed 
more than 1 biweekly dose between studies.
Dosing will be based on an individual patient’s mass (ie, weight) as outlined in Section 8.1.1. For 
patients who participated in the DFI13412 study and who had a body mass index (BMI) >30, the 
dose will be based on the mass (in kilograms) corresponding to a BMI of 30 given the specific 
patient’s height.
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8.1.4
Dose adjustments
Dose adjustments may also be considered at any time in consultation with the sponsor but may be 
recommended based on current safety or efficacy analysis results obtained from completed or 
ongoing studies of olipudase alfa.
8.1.5
Dosing delays or missed doses
Dose reintroduction regimens may be required for patients who have missed more than 1 dose 
between studies or during this study (LTS13632), depending on their usual dose. For patients 
receiving home infusions who have missed 2 or fewer doses, the investigator can decide whether 
reintroduction should occur at the hospital/study site via home infusion. For patients who have 
missed 3 or more doses ≥0.6 mg/kg, reintroduction of olipudase alfa should occur at the 
hospital/study site.  If the site visit is not possible due to site closure or extenuating circumstances 
that prevent an in-person site visit (eg, during COVID-19 pandemic), reintroduction may be done 
via home infusion, if the patient has previously been approved for home infusion. 
Patients who require dose reintroduction will have these assessments at each infusion until 
reaching their usual dose of olipudase alfa:
x
Before infusion: vital sign measurements, liver function tests (LFTs), hematology tests and 
safety biomarkers.
x
Immediately after infusion: vital sign measurements.
x
24 hours after infusion: vital sign measurements, LFTs, hematology and safety biomarkers
x
48 hours after infusion: vital sign measurements, LFTs and safety biomarkers. 
The 48 hours post-infusion assessments will no longer be assessed after the cutoff date for 
a planned second database lock of the study for purpose of regulatory submissions in 
2021.
During the dose escalation period, for transaminases assessed after infusion, if any AST or 
ALT value is >2x baseline and >ULN, the test should be repeated prior to the next scheduled 
infusion. Depending on the test results, the dose can be adjusted (repeated or reduced) or 
treatment can be withheld to allow additional transaminase monitoring, based on the 
physician’s clinical judgment.
Baseline is defined as the following: 
x
For initial dose escalation: last values prior to first dose of olipudase alfa
x
For dose re-escalation: last values prior to the first re-escalation dose
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8.1.6
Dose stopping criteria
If any of the following AEs occur, dosing will be temporarily stopped for the specific patient who 
experienced the AE:
x
Any SAE, not related to the patient’s underlying condition and considered related to the 
study treatment.
x
Any increase in AST, ALT, total bilirubin, or alkaline phosphatase (AP) >3x baseline 
(prior to olipudase alfa therapy, ie, baseline value from the primary study) and > the upper 
limit of normal (ULN).
x
Any increase in total bilirubin or AP >1.5x baseline, in the presence of AST or 
ALT > 2 x ULN.
x
Any increase in ALT or AST >3 x ULN combined with an increase in ALT or 
AST >2x baseline (prior to olipudase alfa therapy), with symptoms of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia (>ULN).
x
Any AE that, in the opinion of the investigator or sponsor, raises significant concern 
regarding the safety of olipudase alfa at the administered dose.
8.1.7
Study interruption criteria
If either of these criteria are met,
x
2 patients develop the same severe AE that is not related to their underlying condition, or
x
A death occurs that is assessed as related or possibly related to olipudase alfa, an ad hoc 
DMC meeting will be held to review the safety data and provide its recommendations to 
the sponsor regarding further patient treatment.
After consideration of DMC recommendations, final decisions regarding discontinuation of study 
drug for all or selected clinical trial patients will be made by the Sponsor.
In the event a significant safety concern arises, the Sponsor may immediately decide to 
discontinue study drug dosing in all clinical trial patients prior to receipt of DMC 
recommendation.
If the study is temporarily or permanently halted, the Sponsor will notify the health authorities of 
the halt by a substantial amendment in regions where this applies.
8.1.8
Treatment discontinuation
A patient’s study treatment may be discontinued at any time at the patient’s request or at the 
discretion of the investigator or sponsor.  The following may be justifiable reasons for the 
investigator or sponsor to discontinue a patient from treatment:
x
The patient was erroneously included in the study (ie, was found to not have met the 
inclusion/exclusion criterion).
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x
The patient is unable to comply with the requirements of the protocol.
x
The patient participates in another interventional investigational study
x
In the opinion of the investigator, the patient is no longer deriving clinical benefit.
x
Pregnancy 
Patients who received at least 1 dose of investigational product and who are withdrawn from the
study will be asked to complete all discontinuation assessments prior to withdrawal (as detailed in 
Section 1.1 and Section 1.2 [adults] and Section 1.4 and Section 1.5 [pediatric patients]) and will 
receive a safety follow up telephone call from the study site 30 to 37 days after the final 
administration of olipudase alfa.
The investigator will document the reason(s) for treatment discontinuation/study withdrawal on 
the case report form (CRF).
8.2
BLINDING PROCEDURES
Not applicable. This is a single-arm, open-label study design.
8.3
PACKAGING AND LABELING
Olipudase alfa is packaged and labeled according to Good Manufacturing Practices and local 
regulatory specifications and requirements.  Refer to the corresponding manual for additional 
details.
8.4
STORAGE CONDITIONS AND SHELF LIFE
All clinical trial material must be kept in a secure area with restricted access and be stored under 
adequate refrigerated temperature conditions (2°C to 8°C [36°F to 46°F]).  Temperature 
excursions will be handled as described in the corresponding manual.
It is recommended that the reconstituted product be used immediately after reconstitution.  
Additional stability data are provided in the corresponding manual.
8.5
RESPONSIBILITIES
The investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
investigational medicinal product (IMP) will be responsible for ensuring that the study drug used 
in the clinical trial is securely maintained as specified by the sponsor and in accordance with 
applicable regulatory requirements.
All IMP will be dispensed in accordance with the investigator's prescription and it is the 
investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained.
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Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
sponsor.  Some deficiencies may be recorded through a complaint procedure.
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
sponsor.  In this case, the investigator will be responsible for promptly addressing any request 
made by the sponsor in order to recall IMP and eliminate potential hazards.
Under no circumstances will the investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner.
8.5.1
Treatment accountability and compliance
Compliance to the treatment regimen will be monitored in terms of the percentage of scheduled 
infusions the patient receives through the treatment period. No infusions should be missed. 
Noncompliance is defined as missing 2 consecutive infusions or 4 total infusions per each 
12-month period throughout the treatment period. As they are identified, the investigator should 
discuss noncompliant patients on a case by case basis with the sponsor’s medical monitor 
(or designee).
8.5.2
Return and/or destruction of treatments
Reconciliation of study drug must be performed at the site by the investigator and the monitoring 
team using treatment log forms and documented on center study drug inventory countersigned by 
the investigator and the monitoring team.
If appropriate, a written authorization for destruction will be provided by the sponsor clinical trial 
team once the reconciliation is achieved.  Investigational medicinal product destruction may be 
performed at the site depending on study drug specificities and local requirements; alternatively, 
study drug may be returned to the sponsor for destruction.
8.6
CONCOMITANT MEDICATION
Medications and therapeutic procedures received by the patient in the 30 days prior to their 
providing written and signed informed consent or assent until the final visit for this study will be 
recorded on the concomitant medication CRF, as appropriate.
Prior and concomitant medications will be coded according to the World Health Organization 
Drug Dictionary.
x
Prior medications will be defined as medications that were taken prior to the first infusion 
of olipudase alfa.
x
Concomitant medications will be defined as medications that are taken after providing 
informed consent in this study.
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During the study, prohibited medications include those that may decrease olipudase alfa activity 
(eg, chlorpromazine, tricyclic anti-depressants [eg, imipramine or desipramine]). See the most 
recent version of the study manual for a list of concomitant medications that may decrease 
olipudase alfa activity.
Cationic amphiphilic antihistamines, such as loratadine, desloratadine, astemizole, ebastine, 
terfenadine, and clemastine, may decrease olipudase alfa activity. Therefore, the need for their use 
in oral or IV administration should be carefully considered. There is no restriction on topical
antihistamines.
Certain medications and herbal supplements can be hepatotoxic or can cause or prolong bleeding, 
and should not be taken within 10 days before and 3 days after the biopsy procedure (only patients 
who previously participated in the DFI13412 study). Potentially hepatotoxic medications or herbal 
supplements include, but are not limited to, 3-hydroxy-3-methylglutaryl-coenzyme A reductase 
inhibitors, erythromycin, valproic acid, antidepressants, kava, and echinacea. Medications that 
may cause or prolong bleeding include, but are not limited to, anticoagulants, ibuprofen, aspirin, 
garlic supplements, ginkgo, and ginseng.
These lists of prohibited medications and herbal supplements may be incomplete. The investigator 
may also prohibit medications and products not listed here. Therefore, the investigator must 
review all medications and products for every patient. For more information on medications and 
herbal supplements that may decrease olipudase alfa activity or may be hepatotoxic, refer to the 
most recent version of the study manual.
Pretreatment in general is not recommended for prophylactic management of IARs.  For patients 
who experience moderate to severe or recurrent IARs (as defined in Section 10.5.1.3.2) suggestive 
of hypersensitivity, pretreatment regimens (eg, antihistamines, antipyretics, glucocorticoids) may 
be prescribed by the investigator as per clinical judgment.  In particular, the need for cationic 
amphiphilic antihistamines administered orally or IV should be carefully considered given the 
potential risk for functional inhibition of olipudase alfa activity by such drugs.
8.6.1
Treatment of infusion-associated reactions
For management of mild IARs, infusion rate reductions (eg, reduced to half the rate) or temporary 
interruptions may mitigate the reaction.  For moderate to severe or recurrent IARs, the 
investigator may consider the use of pretreatment medications (eg, antihistamines, antipyretics, 
and/or glucocorticoids), if the symptoms are suggestive of hypersensitivity reaction, in addition to 
infusion rate reductions, interruptions, or discontinuation.  In particular, the need for cationic 
amphiphilic antihistamines administered orally or IV should be carefully considered given the 
potential risk for functional inhibition of olipudase alfa activity by such drugs.
Patients experiencing symptoms suggestive of hypersensitivity reactions, including anaphylactic 
or anaphylactoid reactions, during olipudase alfa infusion should be managed according to the 
general standards of care consistent with the treatment of such reactions. If anaphylaxis or other 
severe allergic reactions occur, immediate discontinuation of the infusion should be considered, 
and appropriate medical treatment should be initiated.  Because of the potential for severe IARs, 
appropriate medical personnel and equipment to perform resuscitation must be readily available in 
the event of a hypersensitivity reaction.
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9
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT
The term “pediatric patients only” means patients coming from the original pediatric trial, 
DFI13803.  Some of these patients will reach adult age (18 years old) while in this study. These 
patients will be adults by age, but they will remain part of the “pediatric patient” cohort.
9.1
ENDPOINTS
9.1.1
Primary endpoint
Primary safety endpoints pertaining to the safety and tolerability of olipudase alfa, as described in 
Section 9.1.4 through Section 9.1.15, include:
x
Assessment of AEs/treatment-emergent AEs (TEAEs), including IARs (eg, cytokine 
release syndrome [CRS], APRs), and adverse events of special interest [AESIs]).
x
Complete physical examinations.
x
Extended neurological examinations.
x
Abbreviated physical examinations.
x
Weight.
x
Height (pediatric patients only).
x
Vital sign measurements.
x
Clinical laboratory tests:
-
Clinical chemistry,
-
LFTs,
-
Hematology,
-
Coagulation studies,
-
Urinalysis,
-
Urine pregnancy test (women of childbearing potential only).
x
ECGs.
x
Echocardiogram with Doppler.
x
Liver biopsy (only patients who previously participated in the DFI13412 study).
x
Liver ultrasound with Doppler (only patients who previously participated in DFI13803).
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x
Safety biomarkers:
-
High-sensitivity C-reactive protein (hsCRP),
-
Iron,
-
Ferritin,
-
Cardiac troponin I,
-
Interleukin (IL) 6,
-
IL 8,
-
Calcitonin,
-
Plasma ceramide.
x
Immune response assessments.
A site physician will assess safety findings as normal, abnormal but not clinically significant 
(NCS), or abnormal and clinically significant (CS).  Any abnormal findings that meet the 
definition of an AE per Section 10.5.1 will be recorded on the AE CRF.
The analysis of safety is described in Section 11.6.3.
9.1.2
Secondary endpoints (efficacy)
Secondary endpoints (efficacy), as described in Section 9.2.1 through Section 9.2.9 include:
x
Abdominal magnetic resonance imaging (MRI) to evaluate improvements in spleen and 
liver volume.
x
Pulmonary imaging:
-
High resolution computed tomography (HRCT),
-
Chest X-rays (at selected sites).
x
Pulmonary function tests (PFTs).
x
Hematology:
-
Hemoglobin,
-
Platelet count.
x
Lipid profile:
-
Total cholesterol,
-
High-density lipoprotein (HDL),
-
Low-density lipoprotein (LDL),
-
Very low-density lipoprotein (VLDL),
-
Triglycerides,
-
Apolipoprotein B (ApoB),
-
Apo A,
-
Lipoprotein(a).
x
Hand X-ray (pediatric patients only).
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x
Linear patient growth by height Z-score (pediatric patients only).
x
Adult health outcome questionnaires:
-
Brief Fatigue Inventory (BFI),
-
Brief Pain Inventory Short Form (BPI-SF),
-
Chronic Respiratory Disease Questionnaire Self-administered Standardized 
(SFCRQ SAS),
-
Short Form 36 (SF-36),
-
Niemann-Pick B Health Assessment Questionnaire (NPB-HAQv2), version 2.
x
Pediatric health outcome questionnaires:
-
Pediatric Quality of Life (PedsQL),
-
PedsQL Multidimensional fatigue scale,
-
PedsQL Pediatric Pain Questionnaire.
x
An additional questionnaire about home infusion experience may be added for patients 
who received home infusion treatment for at least one year.
Efficacy analyses are described in Section 11.6.2.
9.1.3
Other endpoints
Other endpoints, as described in Section 9.3.1 through Section 9.3.9, include:
x
Physician global assessment of change.
x
Cognitive and adaptive function (for pediatric patients who performed the assessments in 
DFI13803):
-
Development Profile-Third Edition (DP-3),
-
Adaptive Behavior Assessment System (ABAS).
x
Cycle ergometry to evaluate exercise capacity.
x
Efficacy biomarkers, including, but not limited to:
-
Serum chitotriosidase,
-
CCL18
x
Bone disease assessments (only patients who previously participated in the DFI13412 
study):
-
Lumbar spine MRI for bone marrow burden score,
-
Bilateral femur MRI for bone marrow burden score,
-
Lumbar spine by dual-energy X-ray absorptiometry (DXA) for bone mineral density 
(BMD) T-score and Z-score,
-
Bilateral femurs by DXA for BMD T-score and Z-score.
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x
Bone biomarkers:
-
AP,
-
C-telopeptide levels.
x
Tanner staging (pediatric study DFI13803 patients only).
x
Photographs (optional).
x
Pharmacokinetics.
x
Pharmacodynamics (metabolite levels in plasma and/or dried blood spot (DBS) 
[eg, sphingomyelin, lysosphingomyelin]). 
x
Plasma ceramide.
x
Sphingomyelin levels in liver tissue obtained by liver biopsy (only patients who previously 
participated in the DFI13412 study).
Efficacy analyses are described in Section 11.6.2.
Pharmacokinetic parameters and pharmacodynamics (PD) will be assessed as described in 
Section 9.3.8 and Section 9.3.9, respectively.  Pharmacokinetic and PD analyses are described in 
Section 11.6.4.
9.1.4
Safety assessments
See Section 10.5.1 for more details about AEs.
9.1.5
Complete physical examination
A complete physical examination will be performed prior to infusion at the time points specified 
in Section 1.1 through Section 1.5. A complete physical examination will include assessment of 
the patient’s general appearance, general neurological status, skin, head, eyes, ears, nose, throat, 
lymph nodes, heart, lungs, abdomen, and extremities/joints.
9.1.6
Extended neurological examination
9.1.6.1
Extended neurological examination in adults
The neurological examination in adults will include, but is not limited to, mental status, cranial 
nerves, muscle strength, sensation, deep-tendon reflexes, coordination, and gait.
9.1.6.2
Extended neurological examination in pediatric patients
The neurological examination in pediatric patients will include, but is not limited to, mental 
status, posture, cranial nerves, motor system including muscle atrophy, tone and power, reflexes, 
sensory system, coordination, gait, and age-appropriate responses.  If possible, the neurological 
examination should be performed by the same neurologist who performed it in the DFI13803 
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study.  Also, if possible, the neurological examination should be performed by the same 
neurologist throughout the study.
9.1.7
Abbreviated physical examination
An abbreviated physical examination of the patient’s general appearance only will be performed 
before and after infusion at the time points specified in Section 1.1 through Section 1.5 Patients 
will be assessed for body weight, height, and calculated BMI at the time points specified in 
Section 1.1 through Section 1.5.
9.1.8
Vital sign measurements
Vital sign measurements will be obtained before and after infusions at the time points specified in 
the flow charts in Section 1.1 through Section 1.5. Patients must be in a supine position for
approximately 5 to 10 minutes before their vital signs are measured. Vital sign measurements will 
include systolic and diastolic blood pressure (mm Hg), heart rate (beats/minute), respiratory rate 
(breaths/minute), and temperature (°F or °C).
For patients who have a dose reintroduction, vital signs will be measured at each visit before 
(within 30 minutes) the infusion, immediately after the infusion, and at 24 and 48 hours 
postinfusion until the patients are back on their usual dose of olipudase alfa (Section 8.1.5).
9.1.9
Clinical laboratory tests
Pediatric patient blood volumes by age cohort are provided in Section 9.5.
The clinical laboratory data consist of blood analyses (clinical chemistry, LFTs, hematology, 
coagulation studies) urinalysis, and for women of childbearing potential only, a urine pregnancy 
test.  Values will be converted into standard international units and then analyzed. International 
units will be used in all listings and tables.
Acute phase reactions and CRS are associated with changes in specific clinical laboratory 
parameters (Section 10.5.1.3.2).
The following clinical laboratory test results will be assessed by the site as specified in 
Section 1.1 through Section 1.5.
x
Clinical chemistry: Sodium, potassium, calcium, chloride, blood urea nitrogen, creatinine, 
lactate dehydrogenase, total protein, albumin, glucose, cholesterol, phosphorus, and 
creatine kinase.
x
Liver function tests: ALT, AST, AP, gamma-glutamyl-transferase, total bilirubin, and 
direct bilirubin.
x
Hematology: Complete blood count with differential and platelet count, including 
hematocrit, hemoglobin, and red blood cell, white blood cell, platelet, neutrophil, 
lymphocyte, monocyte, eosinophil, and basophil counts.
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x
Coagulation studies: Prothrombin time (Protime), partial thromboplastin time, 
international normalized ratio, and D-dimer.
x
Urinalysis: Dipstick for glucose, protein, hemoglobin, leukocytes, ketones, and bilirubin.
x
Urine pregnancy test (women of childbearing potential only) (Note: If a urine pregnancy 
test is positive, study drug dosing should be withheld until results are confirmed with a 
serum β-hCG test.)
Laboratory reports will be made available to the investigator in a timely manner to ensure 
appropriate clinical review.
9.1.10 Electrocardiograms
Standard 12-lead, digitized electrocardiograms (ECGs) will be conducted as a singlet as specified 
in Section 1.1 through Section 1.5.
Electrocardiograms will be performed while the patient remains in a supine position for 
approximately 5 to 10 minutes prior to and while conducting the ECG.  The following parameters 
will be assessed: heart rate; cardiac rhythm; respiratory rate; pulse rate; QRS, QT, and QTc 
intervals; QRS-axis; R-voltage V6; S-voltage V1; left ventricular hypertrophy criteria; right 
ventricular hypertrophy criteria; and, repolarization changes.  Interpretation will include 
an assessment of heart rate, cardiac rhythm, intervals, axis, conduction defects, and overall cardiac 
impression for each patient.
A specialist trained in the interpretation of this test at each study site will review the ECGs 
according to site-specific procedures for safety.  Where possible, the same examiner should 
perform all such reviews.  Electrocardiograms of completed patients may be read by a central 
reviewer for data analysis.
Details for ECG procedures are provided in the corresponding manual.
9.1.11 Echocardiogram with Doppler
A standard 2-dimensional and M-mode echocardiogram (ECHO) with Doppler will be conducted
at the time points specified in Section 1.1 through Section 1.5. The ECHO may be conducted up 
to 24 hours before the infusion.
Examination will include, but not be limited to: ventricular cavity size, valve characterization, 
ejection fraction, ventricular wall thickness, regional wall motion, diastolic function, and 
pericardium characterization. Pulmonary blood pressure and blood flow will be determined by 
Doppler ultrasound.
A specialist trained in the interpretation of this test at each study site will review the ECHOs 
according to site-specific procedures for safety.  Where possible, the same examiner should 
perform all such reviews.
Details for ECHO procedures are provided in the corresponding manual.
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9.1.12 Liver biopsy for sphingomyelin in liver tissue (only patients who previously 
participated in the DFI13412 study)
A liver biopsy will be performed after at least 3 years in the study.  
Liver biopsy samples will be evaluated for sphingomyelin accumulation.  Sphingomyelin 
accumulation in liver will be quantified by computer morphometry of high resolution light 
microscopy images.  Sphingomyelin will also be quantified using liquid chromatography-tandem 
mass spectrometry (LC/MS/MS).  Liver tissue samples will also be evaluated using 
histopathological methods.
Sample processing, storage, and shipment guidelines are provided in the corresponding manual.
Certain medications and herbal supplements can be hepatotoxic or can cause or prolong bleeding, 
and should not be taken within 10 days before and 3 days after the biopsy procedure. Prohibited 
medications and products that are not to be taken within 10 days before and 3 days after the 
biopsy are discussed in Section 8.6.
9.1.13 Liver ultrasound with Doppler (only patients who previously participated in the 
DFI13803 study)
Liver ultrasound Doppler will be performed to document hepatic blood flow characteristics, 
principally portal vein pressure, and blood flow direction.  The structures to be examined include 
the hepatic portal vein, the main hepatic artery, and the main hepatic vein.  Additional structures 
that may be examined include the network of intrahepatic portal veins, the main and intrahepatic 
arteries, the hepatic veins, the main and intrahepatic portal veins, the intrahepatic portion of the 
inferior vena cava, collateral venous pathways, and transjugular intrahepatic portosystemic shunts.  
Liver ultrasound Doppler will be performed using methods that are compatible with the standard 
institutional procedures of the investigational site.
9.1.14 Safety biomarkers
Safety biomarkers including, but not limited to, hsCRP, iron, ferritin, cardiac troponin I, IL-6,
IL-8, plasma ceramide and calcitonin will be assessed as specified in the study flow charts in 
Section 1.1 through Section 1.5.  Ceramide is also a PD biomarker (Section 9.3.9.3).
The percent neutrophils (acute-phase reactants), total bilirubin, and direct bilirubin are considered 
safety biomarkers, although they are assessed as part of the routine clinical laboratory tests 
(Section 9.1.9).
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9.1.15 Immune response assessments
Samples will be collected as specified in Section 1.1 through Section 1.5 for the evaluation of 
anti-olipudase alfa IgG antibodies.   If introduction of a drug product from Process C(
) or from 
Process C(
) occurs, testing will occur monthly for the first 6 months after introducing the drug 
product from Process C(
) or Process C(
).  If seroconversion occurs, patients will also be 
tested for neutralizing antibodies to olipudase alfa.
In the event that a patient reports an IAR that is suggestive of a hypersensitivity reaction (as 
described in Section 10.5.1.3.2.1) and is of:
x
Moderate intensity,
x
Severe intensity, or, 
x
Is recurrent (of any intensity grade), additional blood samples will be collected and sent to 
the sponsor for anti-olipudase alfa antibody (IgG and IgE), tryptase activity, and 
complement activation testing as described below.  Skin testing may also be performed if 
a hypersensitivity reaction is suspected.
x
For IgE anti-olipudase alfa antibody testing the same predose serum sample drawn for 
anti-olipudase alfa IgG testing may be used if the IAR occurs at that study visit.  If 
a predose sample was not drawn on that day, the patient should return to the study site at 
least 3 days after the event for a serum sample to be drawn.  Testing is conducted for 
research purposes to gain additional information as to individual patients’ responses to 
study treatment and for aiding in the clinical management of patient safety.
x
Blood samples will be drawn within 1 to 3 hours of an IAR for serum tryptase activity 
testing (serum) and complement activation testing (plasma), when clinically indicated.
x
Refer to the corresponding manual for guidelines on the collection and shipping of 
samples.
x
If necessary, following consultation between the investigator and the sponsor, skin testing 
may be performed in patients who experience an IAR that meets the following criteria:
-
The IAR has moderate or severe intensity or is recurrent, and,
-
The patient has persistent and intractable symptoms of hypersensitivity suggestive of 
an IgE-mediated hypersensitivity reaction as described in Section 10.5.1.3.2.1,
-
See also the corresponding manual for skin testing procedures.
x
Cytokine release syndrome: If a patient experiences an AE of moderate or severe intensity 
that is suggestive of CRS (as described in Section 10.5.1.3.2.3, an additional blood sample 
for IL-6, IL-8, and calcitonin will be drawn immediately (if a sample has not already been 
obtained within the previous 30 minutes).
Refer to the corresponding manuals for comprehensive lists of panel tests and guidelines on the 
collection and shipment of samples.
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9.2
EFFICACY ASSESSMENTS
The efficacy assessments (secondary endpoints) are described in Section 9.2.1 through 
Section 9.2.9.  These include improvements in spleen and liver volume (as measured by 
abdominal MRI), pulmonary imaging by HRCT and chest X-ray (at selected sites) (for ILD
scores), PFTs, hematology, lipid profiles, adult health outcome questionnaires, pediatric health 
outcome questionnaires, and for pediatric patients only, hand X-rays, Tanner staging, and linear 
growth by height Z-score.
Refer to the study flow charts in Section 1.1 through Section 1.6 for the timing of these 
assessments throughout the study.  Efficacy analyses are described in Section 11.6.2.
9.2.1
Abdominal magnetic resonance imaging
Spleen and liver volumes will be assessed by abdominal MRI to quantify the degree of 
splenomegaly and hepatomegaly at the time points specified in Section 1.1 through Section 1.5.
Upon a manufacturing scale change, an abdominal MRI will be performed at the first 6-months 
visit after the change if that 6-months visit is not a 12-months visit where the assessment is 
already scheduled.  Patients are required to fast from solid foods (liquids, such as water, milk, and 
juice, are allowed) for 6 hours prior to the MRI to reduce the effect of a meal.
The MRIs will be collected and read centrally by a third party blinded to patient number and study 
visit.  Procedures for MRI are detailed in the corresponding manual.
9.2.2
Pulmonary imaging
9.2.2.1
High-resolution computed tomography
High-resolution computed tomography scans of the chest will be obtained as specified in 
Section 1.1 through Section 1.5 to quantify the degree of possible ILD.
High-resolution computed tomography will be performed using methods that are compatible with 
the standard institutional procedures of the investigational site.  Images will be collected centrally 
by a medical imaging core laboratory where they will be digitized and coded and read by a third 
party blinded to patient number and study visit.  The mean density will be calculated at each lung 
level using standard HRCT software.  The lung fields will be assessed by a central reader and 
scored subjectively for the degree of ILD (0 = normal, 1 = mild, 2 = moderate, or 3 = severe) (8).
The bilateral lung boundaries are determined from the following 4 pre-defined levels on the 
HRCT images (8).
x
Level 1 includes the aortic arch.
x
Level 2 includes the carina.
x
Level 3 is midway between the carina and 1 centimeter above the hemidiaphragm.
x
Level 4 is 1 centimeter above the hemidiaphragm.
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A qualitative assessment will be made of the ILD, ground glass appearance, reticular, nodular 
density, and pleura thickening of the right and left lungs for each pre-defined level above 
according to the following criteria:
x
0 = No disease.
x
1 = Mild (affecting 1% to 25% of the lung volume).
x
2 = Moderate (affecting 26% to 50% of the lung volume).
x
3 = Severe (affecting 51% to 100% of the lung volume).
x
NE = Not evaluable.
Procedures for HRCT scans are detailed in the corresponding manual.
9.2.2.2
Chest X ray
A chest X-ray (posterior-anterior and lateral views) will be performed at selected sites as indicated 
in Section 1.1 through Section 1.5.
A study site physician, such as the investigator, a pulmonologist, or a radiologist, should review 
the chest X-ray in a timely manner to determine whether there are any safety concerns and for
clinical management of the patient.  Chest X-rays will be collected at the site and sent to a 
medical imaging core laboratory where they will be digitized (if not already done at the site), 
coded, and read by a third-party reader blinded to patient number and study visit.  The lung fields 
will be scored subjectively for the degree of ILD (8):
x
0 = No infiltrative lung disease.
x
1 = Mild (affecting 1% to 25% of the lung volume).
x
2 = Moderate (affecting 26% to 50% of the lung volume).
x
3 = Severe (affecting 51% to 100% of the lung volume).
Procedures for chest X-ray scoring are detailed in the corresponding manual.
9.2.3
Pulmonary function tests
Pulmonary function tests will be performed in all patients previously enrolled in the DFI13412 
study, and in patients for whom it was done in the DFI13803 study, to measure lung volumes, air 
flow, and gas exchange for evidence of ILD at the time points specified in the study flow charts in 
Section 1.1 through Section 1.5.  Completion of PFTs may depend on patient age or cooperation, 
or both.
Upon a manufacturing scale change, PFTs will be performed at the first 6-month visit after the 
change if that 6-month visit is not a 12-month visit where the assessment is already scheduled.  
The pulmonary function test (PFT) administration protocol is standardized across sites in 
accordance with American Thoracic Society/European Respiratory Society guidelines (9, 10).
Pulmonary function testing will include, but will not be limited to, assessment of forced vital 
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capacity (FVC), forced expiratory volume in the first 1 second (FEV1) of the FVC maneuver, and 
total lung capacity.  Diffusing capacity of carbon monoxide (DLCO) will be used to measure gas 
exchange across the alveolocapillary membrane.  Pulmonary function tests should occur at the 
same time of day across study visits (±2 hours of the time of day of the first assessment).
Patients who routinely take bronchodilators must withhold bronchodilators before routine PFTs as 
follows:
x
Short-acting inhaled or oral bronchodilators (eg, albuterol) - 8 hours.
x
Medium-acting inhaled bronchodilators (eg, atrovent) - 12 hours.
x
Long-acting inhaled or oral bronchodilators (eg, salmeterol) - 24 hours.
The equipment will be part of the institution’s quality control/assurance program with regard to 
validation and calibration.  The equipment is calibrated the day of the testing.  A log will be kept 
and a copy will be submitted to the sponsor at the completion of the study.  Where possible, the 
same equipment will be used for all measurements.
A specialist trained in the interpretation of this test should review the PFTs in a timely manner for 
clinical management of the patient.
9.2.4
Hematology
Hemoglobin and platelet counts will be assessed as safety and as efficacy parameters, as ASMD 
results in hematologic disorders.  An additional blood sample will be obtained for hemoglobin and 
platelet count at least 24 hours and up to 2 weeks apart from the sample collected for clinical 
laboratory tests at the time points specified in Section 1.1 through Section 1.5.
9.2.5
Fasting lipid profile
A fasting lipid profile will be assessed as an efficacy parameter, as ASMD results in the 
progressive accumulation of lipids.
Blood will be collected prior to infusion for fasting lipids (including, but not limited to, total 
cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), VLDL-cholesterol (VLDL-C),
triglycerides, ApoB, apolipoprotein A1, and lipoprotein [a]) at the time points specified in 
Section 1.1 through Section 1.5.
9.2.6
Health outcome questionnaires
9.2.6.1
Adults
The following health-related quality of life instruments will be completed by patients according to 
the time points specified in Section 1.1 and Section 1.2.
x
The BFI is a validated, self-administered questionnaire that was originally developed to 
assess fatigue severity in cancer patients (11).  The BFI has 9 items and uses numeric 
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rating scales from 0 to 10.  Patients are asked in 3 items to rate the severity of their fatigue 
at its worst, usual, and now during normal waking hours.  The amount that fatigue has 
interfered with different aspects of the patient's life during the preceding 24 hours
(including general activity, mood, walking ability, normal work, relations with other 
people, and enjoyment of life) is assessed in 6 items.
x
The BPI-SF is a validated, self-administered questionnaire designed to measure a patient’s 
perceived level of pain.  The BPI-SF measures the patient’s intensity of pain (sensory 
dimension), the interference of pain in the patient’s life (reactive dimension), and asks the 
patient about pain relief, pain quality, and the patient’s perception of the cause of pain 
(12, 13). The BPI-SF consists of 15 items that use a numeric rating scale to assess pain 
severity and pain interference in the past 24 hours.
x
The Chronic Respiratory Disease Questionnaire Self-Administered Standardized 
(SFCRQ-SAS) is a validated, self-administered questionnaire designed to evaluate health 
related quality of life in adult patients with chronic airflow limitation, chronic respiratory 
disease, and cystic fibrosis (14).  The CRQ-SAS has 20 items and evaluates 4 dimensions 
of respiratory impairment, including dyspnea, fatigue, emotional function, and the patient's 
feeling of control over the disease (mastery).
x
The SF-36 is a 36-item, validated, multidimensional, generic health-related quality of life 
measure that has been validated for adults in numerous healthy and ill populations 
internationally (15).  The SF-36 consists of 8 scales, including physical functioning, role 
physical, bodily pain, mental health, role emotional, social functioning, vitality, and 
general health.  The questionnaire also includes 2 summary measures of physical health 
and mental health derived from scale aggregates.
x
The NPB-HAQ, version 2 is a disease-specific questionnaire that covers various aspects of 
fatigue, pain, respiratory, abdominal complaints, and quality of life, and questions specific 
to ASMD symptoms and physical activity.  The questionnaire also includes items to gather 
information on patient utilization of care and caregiver support (completed up to 5 years).
9.2.6.2
Pediatric patients
For pediatric patients, health outcome measures will be evaluated as specified in Section 1.3
through Section 1.5 using the assessment tools in Table 13 summarized by age range.  Completion 
of questionnaires may depend on patient age or cooperation, or both.
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Table 13 - Quality of life assessments
Assessment
Scale
Quality of life-general 
PedsQL Core Scales 
Young child (5-7 years of age) 
Child (8-12 years of age) 
Teen (13-18 years of age) 
Young adult (18-25 years of age) 
 
Parent report for: 
Infants (1-12 months of age) 
Infants (13-24 months of age) 
Toddlers (2-4 years of age) 
Young child (5-7 years of age) 
Child (8-12 years of age) 
Teen (13-18 years of age) 
Young adult (18-25 years of age) 
Fatigue 
PedsQL Multidimensional Fatigue Scale, Standard version for: 
Young child (5-7 years of age) 
Child (8-12 years of age) 
Teen (13-18 years of age) 
Young adult (18-25 years of age) 
 
Parent report for: 
Toddlers (2-4 years of age) 
Young child (5-7 years of age) 
Child (8-12 years of age) 
Teen (13-18 years of age) 
Young adult (18-25 years of age) 
Pain 
PedsQL Pediatric Pain Questionnaire: 
Young child (5-7 years of age) 
Child (8-12 years of age) 
Teen (13-18 years of age) 
 
Parent report for: 
Young child (5-7 years of age) 
Child (8-12 years of age) 
Teen (13-18 years of age) 
PedsQL = Pediatric Quality of Life 
The PedsQL scale is a brief, standardized, generic assessment instrument that systematically 
assesses patients’ and parents’ perceptions of health-related quality of life in pediatric patients 
with chronic health conditions (16).  The PedsQL consists of a 23-item core measure including 
a self-report for children aged 5 to 18 years and for young adults aged 18 to 25 years. A report for 
parents of patients from birth to 25 years of age is also available.
The PedsQL Multidimensional Fatigue Scale consists of 18 questions, 6 regarding general fatigue, 
6 regarding sleep/rest fatigue, and 6 regarding cognitive fatigue.  It also includes a self-report for 
children aged 5 to 18 years and for young adults aged 18 to 25 years.  A report for parents of 
patients aged 2 to 25 years is also available.
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The PedsQL Pediatric Pain Questionnaire consists of 3 questions that include a child self-report 
for patients aged 5 to18 years and a proxy report for parents of patients aged 5 to 18 years.  These 
same questionnaires will be used for patients aged 18 to 25 years because questionnaires are not 
available for young adults.
Refer to the study operations manual for further details.
9.2.6.3
Additional questionnaires
A questionnaire about home infusion experience may be added at any time before the end of the 
study for patients who received home infusion treatment for at least one year.
9.2.7
Hand X-ray (only patients who previously participated in the DFI13803 study)
Patients will have an X-ray performed on their left hand, fingers, and wrist as indicated in 
Section 1.3 through Section 1.5.
The X-rays will be collected at the site and sent to a medical imaging core laboratory where they 
will be digitized (if not already done at the site), coded, and read by a third party blinded to 
patient number and study visit. Bone age (maturation) will be calculated using the 
Greulich & Pyle Atlas (17).
9.2.8
Tanner staging (only patients who previously participated in the DFI13803 study)
Patient puberty stage will be evaluated according to Tanner staging (18, 19).  Tanner stage for 
genitals (male, stage I though V), breasts (females, stage I though V), and pubic hair (both 
genders, stage I through V) will be documented at the time points specified in Section 1.3 through
Section 1.5.
9.2.9
Linear growth by height by Z-score (only patients who previously participated in the 
DFI13803 study)
Growth in pediatric patients will be assessed by height Z-scores.
9.3
OTHER ASSESSMENTS
Other assessments are described in Section 9.3.1 through Section 9.3.9.  The assessments will 
include physician global assessment of change, cognitive and adaptive function (for pediatric 
patients who performed the assessments in the DFI13803 study), cycle ergometry, efficacy 
biomarkers, bone disease assessments, bone biomarkers, photographs (optional), PK, and PD.  
Pharmacokinetic parameters and PD will be assessed as described in Section 9.3.8
and Section 9.3.9, respectively.
Refer to the study flow chart in Section 1.1 through Section 1.6 for the timing of these 
assessments throughout the study.
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9.3.1
Physician global assessment of change
The physician's global assessment of the patient’s progress will be evaluated prior to infusion at 
the time points specified in the study flow chart in Section 1.1 through Section 1.5.
The investigator will evaluate the patient’s current clinical status compared to baseline in the 
first study before the patient received the first dose of olipudase alfa by marking 1 of the 
following 7 categories: marked improvement, moderate improvement, mild improvement, no 
change, mild worsening, moderate worsening, or marked worsening.
9.3.2
Cognitive and adaptive function (for pediatric patients who performed the 
assessments in the DFI13803 study)
Cognitive function will be evaluated using the DP-3 assessment tool.  Adaptive function will be 
evaluated using the ABAS. These assessments will be performed only for pediatric patients who 
performed the assessments in DFI13803.  Completion of these assessments may depend on patient 
age or cooperation, or both.
Assessment time points are specified in Section 1.3 and Section 1.4. Refer to the study operations 
manual for further details.
9.3.3
Cycle ergometry
Cycle ergometry will be performed at the time points specified in Section 1.1.  Completion of the 
assessment may depend upon patient cooperation.
Cardiopulmonary status will be assessed using a stationary 1-wheeled cycle as an ergometer to 
measure a person's work output under controlled conditions.  Patients will be asked to ride the 
cycle at increasing workload levels until they can no longer proceed.  Patients will breathe 
through a tube connected to a 1-way valve for continuous measurements of oxygen (O2) uptake, 
carbon dioxide (CO2) output, and tidal volume throughout the test.  Heart rate, respiratory rate, 
and digital O2 saturation will also be continuously monitored.  Steady-state levels for each 
workload will be calculated for O2 uptake, CO2 output, tidal volume, ventilation, and respiratory 
exchange ratio.  The maximum workload achieved will be recorded and expressed as percent 
predicted.  In addition, percent predicted maximum will be calculated for O2 uptake, heart rate, 
and tidal volume. Note that cycle ergometry assessments must occur at the same time for each 
assessment (ie, ±2 hours of the time of day of the first assessment).
Procedures for cycle ergometry assessments are detailed in the corresponding manual.
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9.3.4
Efficacy biomarkers
Blood samples for efficacy biomarkers will be collected prior to infusion at the time points 
specified in Section 1.1 through Section 1.5. Biomarkers will include, but not be limited to, serum 
chitotriosidase, CCL-18.
Processing, storage, and shipment guidelines for samples to be sent to the sponsor are provided in 
the corresponding manual.
9.3.5
Bone disease assessments
Bone disease assessments will be obtained only for patients who previously participated in the 
DFI13412 study as specified in Section 1.1 through Section 1.5.  Magnetic resonance imaging of 
the lumbar spine and both femurs will be used to determine bone marrow burden scores (20, 21).
Dual-energy X-ray absorptiometry of the lumbar spine and both femurs will provide total BMD 
measurements, BMD T-scores, and Z-scores.  The assessments may be performed on the same 
day as the spleen and liver volume MRIs.
All bone images will be sent to a central reviewer for blinded analysis of potential bone disease.  
See the corresponding manual for further details.
9.3.6
Bone biomarkers
Serum bone-specific alkaline phosphatase and C-telopeptide levels will be evaluated as indicated 
in Section 1.1 through Section 1.5.
9.3.7
Patient photographs
Photographs (eg, abdominal) will be taken as specified in Section 1.1 through Section 1.5 of
patients who volunteer to provide visual context of the disease.
9.3.8
Pharmacokinetics
For both adult and pediatric patients, PK testing will only occur yearly for the first 5 years and 
upon the introduction of Process C(
) or Process C(
) at any time during the study.  For Process 
C(
), if treatment is not interrupted, PK sample collection will take place at the patient’s last 
infusion under the current manufacturing scale and at the first infusion Process C(
). For 
introduction of drug product from Process C(
),if treatment is not interrupted, PK sample 
collection will take place at the second infusion under Process C(
).  In case reintroduction of 
olipudase alfa coincides with introduction of a drug product from Process C(
) or Process C(
), 
PK samples will be collected at the infusions at which patients receive their usual dose of 
olipudase alfa under the new process.
Blood samples for pediatric patients are drawn at different intervals than samples in adult patients 
(Section 1.6, Table 12 and Table 11, respectively) and in different volumes (Section 9.5).
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9.3.8.1
Pharmacokinetics handling procedure
Special procedures for collection, storage, and shipment are provided in the corresponding 
manual.
9.3.8.2
Bioanalytical method
Plasma will be separated from blood samples and analyzed for plasma concentrations of olipudase 
alfa using a validated enzyme-linked immunosorbent method.
9.3.8.3
Pharmacokinetic sampling and parameters in adults
9.3.8.3.1 Sampling time in adults
Pharmacokinetic sampling will occur at the time points listed in Section 1.1 and Section 1.6.
Specific time points are detailed in Table 11. If a patient receives only a partial infusion (eg, due 
to a safety concern), PK sampling will be repeated the next time the patient receives that dose. If 
a repeat is required, all PK time points will be repeated.
Windows around PK blood samples are ±10 minutes for collection times less than 8 hours and 
±3 hours for collection times of 8 hours or longer post infusion.
Blood samples may be drawn for PK assessments using an indwelling catheter from an arm that is 
not used for dose administration. The exact time of dose administration (start and stop times of 
infusion), rate of infusion, and dose will be recorded along with exact sampling times.
If a manufacturing scale change occurs, serial blood samples for PK will be collected at all of the 
same time points with the last infusion of olipudase alfa produced at the original scale and with 
the first infusion of olipudase alfa produced at the new scale. For introduction of drug product 
from Process C(
), PK sample collection will only take place at the second infusion under 
Process C(
).
9.3.8.3.2 Number of pharmacokinetic samples in adults
Table 14 shows the approximate number of plasma samples in adults.
Table 14 - Approximate number of plasma samples in adult patients
Collection 
Number of samples
Yearly collection (5 years) 
8  
Change in manufacturing scale 
Last infusion on old scale 
8 
First infusion on new scale 
8 
Updated manufacturing process 
Second infusion on updated process 
8 
Total by patient 
64 
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9.3.8.3.3 Pharmacokinetics parameters in adults
The following PK parameters will be calculated using noncompartmental methods from plasma 
olipudase alfa concentrations.  The parameters will include, but may not be limited to, those listed 
in Table 15.
Table 15 - List of pharmacokinetic parameters and definitions
Parameters
Drug/Analyte
Definition/Calculation
Cmax 
olipudase alfa 
Maximum plasma concentration observed 
Ceoi 
olipudase alfa 
Concentration at the end of infusion 
tmax 
olipudase alfa 
Time to reach Cmax 
AUClast 
olipudase alfa 
Area under the plasma concentration-versus-time curve calculated using the 
trapezoidal method from time zero to the real time 
AUC0-∞ 
olipudase alfa 
Area under the plasma concentration-versus-time curve extrapolated to infinity 
according to the following equation:  
z
C
AUC
AUC
last
last


 
 
Values with a percentage of extrapolation > 20% will not be taken into account 
in the descriptive statistics 
t1/2z 
olipudase alfa 
Terminal half-life associated with the terminal slope (λz) determined according to 
the following equation: 
z
1/2Z
0.693
 
t
O
 
 
where λz is the slope of the regression line of the terminal phase of the plasma 
concentration-versus-time curve, in semilogarithmic scale.  Half-life is calculated 
by taking the regression of at least 3 points. 
CL 
olipudase alfa 
Apparent total body clearance of a drug from the plasma calculated using the 
following equation: 
AUC
D
CL
ose
 
 
Vss 
olipudase alfa 
Apparent volume of distribution at steady state using the following equation: 
AUC
AUMC
 x 
CL
 
Vss  
 
Note: The analyte and matrix for all PK parameters are olipudase alfa and plasma, respectively. 
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9.3.8.4
Pharmacokinetic sampling and parameters in pediatric patients
9.3.8.4.1 Sampling time in pediatric patients
Pharmacokinetic sampling will occur at the time points listed in Section 1.3 through Section 1.6.
Specific time points are detailed in Table 12 for each age group.  To minimize the amount of 
blood drawn, post dose time points have been selected for sparse sampling of PK parameters.
If a patient receives only a partial infusion (eg, due to a safety concern), PK sampling will be 
repeated the next time the patient receives that dose. If a repeat is required, all PK time points will 
be repeated.
In adolescent patients, windows around PK blood samples are ±10 minutes for collection times 
<8 hours and ±3 hours for collection times ≥8 hours post infusion.
Depending on patient age, blood samples may be drawn for PK assessments using an indwelling 
catheter from an arm that is not used for olipudase alfa infusions. The exact time of olipudase alfa 
infusions (start and stop times of infusion), rate of infusion, time of infusion rate changes, and 
dose will be recorded along with exact sampling times.
9.3.8.4.2 Number of pharmacokinetic samples in pediatric patients
Table 16 shows the approximate number of plasma samples by age cohort.
Table 16 - Approximate number of plasma samples by pediatric age cohort
Collection
Adolescent cohort
Child cohort
Infant/early child 
cohort
Yearly collection (5 years) 
7 
6  
5 
Change in manufacturing scale 
Last infusion on old scale 
7 
6 
5 
First infusion on new scale 
7 
6 
5 
Updated manufacturing process 
Second infusion on updated 
process 
7 
6 
5 
 
 
 
 
Total by patient 
56 
48 
40 
 
9.3.8.4.3 Pharmacokinetics parameters in pediatric patients
Plasma concentration-time data will be analyzed by noncompartmental methods, nonlinear mixed 
effects modeling or by population-based analysis, based upon patient age and data suitability.  
Where appropriate, PK parameters calculated using noncompartmental methods from plasma 
olipudase alfa concentrations may include those listed in Table 15.
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9.3.9
Pharmacodynamic assessments
Only patients who previously participated in the DFI13412 study will have PD assessments for 
clearance of sphingomyelin accumulation in liver tissue.  All patients will be assessed for 
metabolite levels in plasma and/or DBS, as well as plasma ceramide.
9.3.9.1
Liver biopsy for sphingomyelin in liver tissue (only patients who previously 
participated in the DFI13412 study
Liver biopsy samples will be evaluated for sphingomyelin accumulation and liver pathology in the 
patients who previously participated in the DFI13412 study who were at least 18 years old when 
they entered in the study.  Patients who were younger than 18 years old when they entered the 
study will not have liver biopsies.  See Section 9.1.12 for details about liver biopsies.
9.3.9.2
Metabolite levels in plasma and dried blood spot (all patients)
Metabolite levels (eg, sphingomyelin, lyso-sphingomyelin) in plasma and/or DBS will be 
quantified by the sponsor (or designee) using samples collected as detailed in the study flow chart 
in Section 1.1 through Section 1.5. Procedure, preparation, and sample shipment guidelines for 
plasma and DBS sampling are provided in the corresponding manual.
9.3.9.3
Plasma ceramide (all patients)
Plasma ceramide will be quantified at the time points shown in the flow chart in Section 1.1
through Section 1.5.  Plasma ceramide is also being tested as a safety biomarker.
9.4
APPROPRIATENESS OF MEASUREMENTS
The safety, efficacy, and PK/PD measurements in this trial are accepted methods for assessing 
patient safety and outcomes.
9.5
SAMPLED BLOOD VOLUME
For all pediatric patients, no more than 7 mL/kg of blood will be collected during any 8-week 
period.  Additional blood samples may be collected at the investigator’s discretion for patient 
safety monitoring.
If a PK or IgG sample collection for the planned introduction of drug product from Process C(
) 
was erroneously taken, the future sample collection will be adjusted according to the blood 
volume allowed per each age cohort in order to avoid excessive blood withdrawal. For specific 
details, please refer to Study Manual.
Table 17 shows the approximate sampled blood volume in patients ages 12 to <18 years old in the 
first 5 years.
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Table 17 - Approximate sampled blood volume in patients ages 12 to <18 years in the first 5 years
Assessment
Volume (mL) 
per sample
Number of samples 
per year
Total (mL) per year
Liver function, clinical chemistry, and 
lipid profile 
5.0 
4 
20.0 
Hematology 
2.0 
4 
8.0 
Coagulation 
3.6 
4 
14.4 
Safety biomarkers 
6.5 
4 
26.0 
Efficacy biomarkers 
10.0 
4 
40.0 
Serum bone-specific AP and  
C-telopeptide 
2.5 
4 
10.0 
Metabolites in plasma and/or DBS 
3.2 
4 
12.8 
Anti-olipudase alfa IgG and neutralizing 
antibodies in IgG-positive patients 
3.5 
4 
14.0 
Olipudase alfa pharmacokinetics 
1.5 
7 
10.5 
Approximate total per year 
155.7 
Approximate total per 5 years 
778.5 
AP=alkaline phosphatase 
Table 18, Table 19 show the additional approximate sampled blood volume in patients ages 12 to
<18 years old with an olipudase alfa manufacturing scale change or manufacturing process update 
respectively. Not all of the patients will be exposed to both changes; therefore, blood volume 
would be calculated individually. To avoid excessive blood volume withdrawn, if similar 
assessment is regularly scheduled (IgG, PK or hematology and coagulation) in the same month, 
priority is given to manufacturing scale or updated manufacturing process update assessments and 
the regular similar assessments may be canceled.
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Table 18 - Additional approximate sampled blood volume in patients ages 12 to <18 years with 
an olipudase alfa manufacturing scale change
Assessment
Volume (mL) 
per sample
Number of samples
Total (mL)
Anti-olipudase alfa IgG and neutralizing 
antibodies in IgG-positive patients 
3.5 
1 sample per month 
for 6 months 
21.0 
Olipudase alfa pharmacokinetics - prior to 
manufacturing scale change 
1.5 
7 
10.5 
Olipudase alfa pharmacokinetics - post 
manufacturing scale change 
1.5 
7 
10.5 
Approximate additional volume per study 
42.0 
 
Table 19 - Additional approximate sampled blood volume in patients ages 12 to <18 years with the 
olipudase alfa updated manufacturing process
Assessment
Volume (mL) 
per sample
Number of samples
Total (mL)
Anti-olipudase alfa IgG and neutralizing 
antibodies in IgG-positive patients 
3.5 
1 sample per month 
for 6 months 
21.0 
Olipudase alfa pharmacokinetics – Second 
infusion on updated process 
1.5 
7 
10.5 
Hematology samples 3 months after first 
infusion on updated process 
2 
1 
2 
Coagulation and platelet samples 3 months 
after first infusion on updated process 
3.6 
1 
3.6 
Approximate additional volume per study 
37.1 
 
Table 20 shows the approximate sampled blood volume in patients ages 12 to <18 years old 
beyond 5 years.
Table 20 - Approximate sampled blood volume in patients ages 12 to <18 years beyond 5 years
Assessment
Volume (mL) 
per sample
Number of samples 
per year
Total (mL) per year
Liver function, clinical chemistry, 
and lipid profile 
5 
2 
10.0 
Hematology 
3.6 
2 
7.2 
Safety biomarkers 
6.5 
2 
13.0 
Efficacy biomarkers 
10 
1 
10.0 
Metabolites in plasma and/or 
DBS 
3.2 
1 
3.2 
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Assessment
Volume (mL) 
per sample
Number of samples 
per year
Total (mL) per year
Approximate total per year, 
beyond 5 years 
 
 
43.4 
Approximate total per 4 years, 
beyond 5 years 
  
  
173.6 
 
Table 21 shows the approximate sampled blood volume in the child cohort (6 to <12 years old) 
and in patients ages 3 to <6 years old in the first 5 years.
Table 21 - Approximate sampled blood volume in patients in the child cohort (6 to <12 years) 
and in patients ages 3 to <6 years in the first 5 years
Assessment
Volume (mL) 
per sample
Number of samples 
per year
Total (mL) per year
Liver function, clinical chemistry, and 
lipid profile 
4.0 
4 
16.0 
Hematology 
1.2 
4 
4.8 
Coagulation 
2.8 
4 
11.2 
Safety biomarkers 
6.2 
4 
24.8 
Efficacy biomarkers 
5.1 
4 
20.4 
Serum bone-specific AP and  
C-telopeptide 
2.2 
4 
8.8 
Metabolites in plasma and/or DBS 
1.5 
4 
6.0 
Anti-olipudase alfa IgG and neutralizing 
antibodies in IgG-positive patients 
1.1 
4 
4.4 
Olipudase alfa pharmacokinetics 
1.5 
6 
9.0 
Approximate total per year 
105.4 
Approximate total per 5 years 
527.0 
AP=alkaline phosphatase 
Table 22 and Table 23 show the additional approximate sampled blood volume in patients in the 
child cohort (6 to <12 years) and ages 3 to <6 years with an olipudase alfa manufacturing scale 
change to Process C(
) or manufacturing process update to Process C(
) respectively. Not all of 
the patients will be exposed to both changes; therefore blood volume would be calculated 
individually. To avoid excessive blood volume withdrawn, if similar assessment is regularly 
scheduled (IgG, PK or hematology and coagulation) in the same month, priority is given to 
manufacturing scale or updated manufacturing process update assessments and the regular 
assessment may be canceled.
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Table 22 - Additional approximate sampled blood volume in patients in the child cohort (6 to 
<12 years) and ages 3 to <6 years with an olipudase alfa manufacturing scale change
Assessment
Volume (mL) 
per sample
Number of samples
Total (mL)
Anti-olipudase alfa IgG and neutralizing 
antibodies in IgG positive patients 
2.2 
1 sample per month 
for 6 months 
13.2 
Olipudase alfa pharmacokinetics – prior to 
manufacturing scale change 
1.5 
6 
9.0 
Olipudase alfa pharmacokinetics – post 
manufacturing scale change 
1.5 
6 
9.0 
Approximate additional volume per study 
31.2 
 
Table 23 - Additional approximate sampled blood volume in patients in the child cohort (6 to 
<12 years) and ages 3 to <6 years with an olipudase alfa manufacturing process update
Assessment
Volume (mL) 
per sample
Number of samples
Total (mL)
Anti-olipudase alfa IgG and neutralizing 
antibodies in IgG-positive patients 
2.2 
1 sample per month 
for 6 months 
13.2 
Olipudase alfa pharmacokinetics – Second 
infusion on updated process 
1.5 
6 
9.0 
Hematology samples 3 months after first 
infusion on updated process 
1.2 
1 
1.2 
Coagulation and platelet samples 3 months 
after first infusion on updated process 
2.8 
1 
2.8 
Approximate additional volume per study 
26.2 
 
Table 24 shows the approximate sampled blood volume in the child cohort (6 to <12 years old) 
and in patients ages 3 to <6 years old beyond 5 years.
Table 24 - Approximate sampled blood volume in patients in the child cohort (6 to <12 years) and in 
patients ages 3 to <6 years - beyond 5 years
Assessment
Volume (mL) 
per sample
Number of samples 
per year
Total (mL) per year
Liver function, clinical chemistry, 
and lipid profile 
4 
2 
8.0 
Hematology 
2.8 
2 
5.6 
Safety biomarkers 
6.2 
2 
12.4 
Efficacy biomarkers 
5.1 
1 
5.1 
Metabolites in plasma and/or DBS 
1.5 
1 
1.5 
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Assessment
Volume (mL) 
per sample
Number of samples 
per year
Total (mL) per year
Approximate total per year, beyond 
5 years 
 
 
32.6 
Approximate total per 4 years, 
beyond 5 years 
  
  
130.4 
Table 25 shows the approximate sampled blood volume in patients from birth to ≤2 years old in 
the first 5 years.
Table 25 - Approximate sampled blood volume in patients from birth to ≤2 years of age in the first 
5 years
Assessment
Volume (mL) 
per sample
Number of samples 
per year
Total (mL) per year
Liver function, clinical chemistry, and 
lipid profile 
4.0 
4 
16.0 
Hematology 
1.2 
4 
4.8 
Coagulation 
2.8 
4 
11.2 
Safety biomarkers 
4.0 
4 
16.0 
Efficacy biomarkers 
3.7 
4 
14.8 
Serum bone-specific AP and  
C-telopeptide 
2.2 
4 
8.8 
Metabolites in plasma and/or DBS 
1.5 
4 
6.0 
Anti-olipudase alfa IgG and neutralizing 
antibodies in IgG-positive patients 
1.1 
4 
4.4 
Olipudase alfa pharmacokinetics 
1.5 
5 
7.5 
Approximate total per year 
89.5 
Approximate total per 5 years 
447.5 
AP=alkaline phosphatase 
Table 26 and Table 27 show the additional approximate sampled blood volume in patients from 
birth to ≤2 years of age with an olipudase alfa manufacturing scale change or manufacturing 
process update respectively. Not all of the patients will be exposed to both changes; therefore 
blood volume would be calculated individually. To avoid excessive blood volume withdrawn, if 
similar assessment is regularly scheduled (IgG, PK or hematology and coagulation) in the same 
month, priority is given to manufacturing scale or updated manufacturing process update 
assessments and the regular assessment may be canceled.
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Table 26 - Additional approximate sampled blood volume in patients from birth to ≤2 years of age 
with an olipudase alfa manufacturing scale change
Assessment
Volume (mL) 
per sample
Number of samples
Total (mL)
Anti-olipudase alfa IgG and neutralizing antibodies in 
IgG-positive patients 
1.1 
1 sample per month 
for 6 months 
6.6 
Olipudase alfa pharmacokinetics – prior to 
manufacturing scale change 
1.5 
5 
7.5 
Olipudase alfa pharmacokinetics – post 
manufacturing scale change 
1.5 
5 
7.5 
Approximate additional volume per study 
21.6 
 
Table 27 - Additional approximate sampled blood volume in patients from birth to ≤2 years of age 
with an olipudase alfa manufacturing process update
Assessment
Volume (mL) 
per sample
Number of samples
Total (mL)
Anti-olipudase alfa IgG and neutralizing antibodies in 
IgG-positive patients 
1.1 
1 sample per month 
for 6 months 
6.6 
Olipudase alfa pharmacokinetics – Second infusion 
on updated process 
1.5 
5 
7.5 
Hematology samples 3 months after first infusion on 
updated process 
1.2 
1 
1.2 
Coagulation and platelet samples 3 months after first 
infusion on updated process 
2.8 
1 
2.8 
Approximate additional volume per study 
18.1 
 
Table 28 shows the approximate sampled blood volume in patients from birth to ≤2 years old 
beyond 5 years.
Table 28 - Approximate sampled blood volume in patients from birth to ≤2 years of age- beyond 
5 years
Assessment
Volume (mL) 
per sample
Number of samples 
per year
Total (mL) per 
year
Liver function, clinical chemistry, and lipid profile 
4 
2 
8 
Hematology 
2.8 
2 
5.6 
Safety biomarkers 
4 
2 
8 
Efficacy biomarkers 
3.7 
1 
3.7 
Metabolites in plasma and/or DBS 
1.5 
1 
1.5 
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Assessment
Volume (mL) 
per sample
Number of samples 
per year
Total (mL) per 
year
Approximate total per year, beyond 5 years 
 
 
26.8 
Approximate total per 4 years, beyond 5 years 
  
  
107.2 
 
Additional blood samples may be required for IgE, serum tryptase, and complement activation 
following moderate, severe, or recurrent mild IARs suggestive of hypersensitivity reactions.  
Additional blood volumes are provided in Table 29.
Table 29 - Approximate sampled blood volume per infusion following moderate, severe, or 
recurrent IARs suggestive of hypersensitivity reactions
Type
Volume (mL) per sample
IgE antibodies 
3.5 
Serum tryptase 
3.5 
Complement 
2.0 
Total per infusion 
9.0 
 
9.6
FUTURE USE OF SAMPLES
For patients who have consented to it, left over samples following testing may be used for other 
research purposes (excluding genetic analysis) related to ASMD. These samples will be stored for 
15 years after end of the study in compliance with applicable country-specific regulations.
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioassay method, or to identify new drug targets or biomarkers.
These samples will remain labeled with the same identifiers as the ones used during the study 
(ie, subject ID).  They will be transferred to a Sanofi site (or a subcontractor site) which can be 
located outside of the country where the study is conducted.  The sponsor has included safeguards 
for protecting subject confidentiality and personal data (Section 14.3 and Section 14.5,
respectively).
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10
STUDY PROCEDURES
10.1
VISIT SCHEDULE
Section 1.1 through Section 1.5 summarize the schedules of study events for all patients enrolled 
into this study.  Individual assessments are described in Section 9.
10.2
STUDY PROCEDURES
Infusions will take place at the study site, or for some patients, at home.
10.2.1 Home infusions
Home infusion may be possible.  Patients must meet the eligibility requirements outlined below.  
In addition, the investigator and the sponsor must agree that home infusion is appropriate.  
To receive home infusions, the following criteria must be met:
x
The investigator must agree in writing that home infusion is appropriate for the patient.
x
The patient, or the pediatric patient’s parent(s) or legal guardian(s), must be willing and 
able to comply with home infusion procedures.
x
The patient must, in the investigator’s (or designee’s) opinion, have been clinically stable 
with no history of moderate or severe IARs for at least 6 months, and must be on a stable 
olipudase alfa dose.  No infusion rate increases will be allowed while a patient is receiving 
home infusions.
x
The patient must have no ongoing (not yet recovered) SAEs that, in the opinion of the 
investigator, may affect the patient’s ability to tolerate the infusion.
x
Home infusion infrastructure, resources, and procedures must be established and available 
according to applicable regional regulations.
x
For patients experiencing an IAR while being infused at home, the investigator should 
assess whether or not it is safe for the patient to continue to be treated via home infusion or 
return to the study site for their following infusion and when the patient would be ready to 
resume home infusion. In case home infusion continues, the investigator will guide the 
home infusion staff on the measures to be followed for subsequent infusion to manage the 
IAR (eg, infusion interruption, premedication, change the infusion rate, etc. See Treatment 
of infusion-associated reactions in Section 8.6.1.
x
If recurrent IARs or hypersensitivity reactions occur, the investigator should assess 
whether or not it is safe for the patient to continue to be treated via home infusion.
x
If a severe hypersensitivity reaction or an anaphylaxis reaction occurs, during an infusion 
given at home, treatment will be discontinued immediately, and appropriate medical 
treatment will be initiated. The patient will return to the study site for further management 
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until the investigator agrees with the sponsor that it is safe for the patient to continue to be 
treated via home infusion. See Section 8.6 for details on severe hypersensitivity and 
anaphylaxis management.
x
For the switch from Process C(
) IMP to Process C(
) IMP, if the site visit is possible, 
the patient should  receive the first infusion at the site. However, if the site visit is not 
possible during a regional or national emergency declared by a governmental agency such 
as the COVID-19 pandemic due to site closure or extenuating circumstances that prevent 
an in-person site visit, the first infusion of the Process C(
) IMP is allowed during home 
infusion for eligible patients in agreement between the Sponsor and the Investigator in 
compliance with applicable country-specific regulations.
x
Prior to beginning home infusions, the home infusion staff, including new staff members, 
must have been appropriately trained and/or licensed, if applicable, on proper procedures 
to prepare and administer infusions, monitor patients, document procedures, and report to 
site on a timely basis.
x
The home infusion staff must have access to and be trained on proper use of safety 
equipment, including, but not limited to, cardiopulmonary resuscitation equipment.
x
Home infusion staff must keep source documentation of the infusion, including 
documentation of any AEs.  Home infusion staff must be amenable to providing specific 
source documentation to Sanofi Genzyme and agree to be monitored.  The Principal 
Investigator is still responsible for all study procedures and patient’s safety even when 
delegating infusion responsibilities to the home care company.
x
An additional questionnaire about home infusion experience may be added any time 
before end of the study for patients who received home infusion treatment for total time of 
at least of one year.
10.2.2 Alcohol consumption
Patients must be willing to abstain from the use of alcohol for 1 day prior to and 3 days after each 
study drug infusion (see Section 7.2).
Patients will be counseled to limit alcohol consumption during the study:
x
Male patients to a maximum of 30 grams of alcohol per day (2 drinks/day).
x
Female patients to a maximum of 15 grams of alcohol per day (1 drink/day).
Patients who do not limit alcohol can be discontinued from the study according to investigator’s 
discretion.
10.2.3 Pregnancy and contraception
Female patients of childbearing potential are required to have a negative urine β-HCG pregnancy 
test before enrolling in the trial and every 4 weeks prior to undergoing visit specific assessments 
and receiving olipudase alfa.
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10.2.3.1 Pregnancy
Pregnancy will lead to treatment discontinuation in all cases.  No studies of olipudase alfa have 
been conducted in pregnant women.  To ensure patient safety for this study, all female patients of 
childbearing potential must have a negative urine β-HCG pregnancy test every 4 weeks.
Female patients of childbearing potential and sexually mature male patients must be willing to 
practice true abstinence, or use 2 acceptable, effective methods of contraception.  Every effort will 
be made to prevent pregnancy during this study.  In all cases, the sponsor must be notified of all 
terminations to treatment as soon as possible and, if applicable, the date of withdrawal from the 
study must be recorded in the CRF and in the patient’s medical record.  If possible, all tests and 
evaluations listed for the end of study visit will be carried out.  If a patient fails to return for the 
necessary visits, then every effort must be made to contact the patient and determine the reason(s), 
which will be recorded on the CRF.
Female patients will be instructed to notify the investigator immediately if they discover they are 
pregnant.  Male patients will be instructed to notify the investigator immediately if they discover 
that their sexual partner is pregnant.
If the investigator learns of a report of pregnancy at any time after signing the informed consent,
the investigator should follow the instructions in Section 10.5.2.3.1 for female patients on the 
study to contact Global Pharmacovigilance and Epidemiology (GPE) within 24 hours. For female 
partners of male patients on the study, the pregnancy form will be used to report the pregnancy to 
Global Pharmacovigilance and Epidemiology (GPE) within 24 hours. Follow-up of the pregnancy 
is mandatory until the outcome has been determined. The progress of the pregnancy must be 
followed until the outcome of the pregnancy is known (ie, delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, additional follow-up
information may be requested.
The investigator will be asked to obtain follow-up information after the gestational period to 
obtain maternal/fetal/neonatal outcome and any other relevant information.
Follow-up information may be requested at additional time points. All study related visits/contacts 
involving a known pregnancy should include pregnancy status assessment until pregnancy 
outcome is known.
If a female patient is discontinued because of pregnancy, pregnancy will be documented as the 
reason for study discontinuation.  Spontaneous abortions and stillbirths are reported as SAEs, and 
the investigator should follow the instructions in Section 10.5.2.2.
10.2.3.2 Contraception
Female patients of childbearing potential and sexually mature male patients are required to
practice true abstinence in line with their preferred and usual lifestyle or 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 
nonbarrier method such as oral, injected, or implanted hormonal methods, an intrauterine device, 
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or an intrauterine system for the duration of the study, and for at least 15 days after the last dose 
of study drug.
Female patients will be considered capable of bearing children unless they have not yet had 
menarche, had a hysterectomy or bilateral oophorectomy, or have undergone menopause (ie, are 
≥50 years old without menses for ≥1 year or are <50 years old with confirmed ovarian failure).
10.3
DEFINITION OF SOURCE DATA
Source data includes all information in original records and certified copies of original records of 
clinical findings, observations, or other activities necessary for the reconstruction and evaluation 
of the trial.  Source data are contained in source documents.
Source documents are original documents, data and records (eg, hospital records, clinical and 
office charts, laboratory reports and notes, memoranda, patient diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcripts 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, X-rays, patient files, and records kept at the pharmacy, at the 
laboratories, and at medical-technical departments) involved in the clinical study. Source 
documentation must be maintained to support information provided in the CRF.
All protocol-required information collected during the study must be recorded by the investigator 
or other study personnel in the source documentation for the study. The source documentation 
will be used to enter the protocol-required information into the CRF. No data should therefore be 
directly entered into the CRF.
10.4
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort.  Any IMP discontinuation should be fully documented in the source and CRF.  In any 
case, the patient should remain in the study as long as possible.
Pregnancy will lead to treatment discontinuation in all cases.  Sexually active female patients of 
childbearing potential and sexually active male patients who permanently discontinue must use 
2 forms of contraception for at least 15 days after their last dose.
10.4.1 Temporary treatment discontinuation with investigational medicinal product(s)
Temporary treatment discontinuation, decided by the investigator, corresponds to more than 
1 dose not administered to the patient.  Dose reintroduction regimens may be required for patients 
who have missed more than 1 dose between studies, depending on their usual dose.
For patients receiving home infusions who have missed 2 or fewer doses, the investigator can 
decide whether reintroduction should occur at the hospital/study site or via home infusion. For 
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patients who miss 3 or more doses ≥0.6 mg/kg, reintroduction of olipudase alfa should occur at 
the hospital/study site. If the site visit is not possible due to site closure or extenuating 
circumstances that prevent an in-person site visit (eg, during COVID-19 pandemic), 
reintroduction may be done via home infusion. 
The investigator, in consultation with the sponsor, will determine whether the patient will be 
redosed.  Reintroducing patients to olipudase alfa treatment will take into account the patient’s 
usual dose, the number of missed infusions, and the patient’s ability to tolerate the dose.
Upon reintroduction of treatment, certain assessments will be repeated at infusions 
(Section 8.1.5). The investigator will decide if additional specific assessments may be required 
before the patient can begin the reintroduction regimen.
Olipudase alfa reintroduction guidance is described in Section 8.1.1. Reintroduction of olipudase 
alfa treatment will be done with appropriate monitoring at the discretion of the investigator and 
confirmation that the patient still meets the study criteria (Section 7.1 and Section 7.2).
The duration of all temporary treatment discontinuations should be recorded by the investigator in 
the appropriate screens of the CRF.
10.4.2 Permanent treatment discontinuation with investigational medicinal product(s)
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the investigator, sponsor, or the patient not to re-expose the patient to the 
IMP at any time.
10.4.3 List of criteria for permanent treatment discontinuation
Patients may withdraw from treatment at any time and irrespective of the reason.  The investigator 
may also decide to withdraw a patient from treatment.
Patients should discontinue the IMP for the following reasons:
x
Unacceptable toxicity.
x
The need for intervention or therapy precluded by protocol, and determination by the 
investigator that it is medically necessary to do so.
x
The patient was unable to comply with the requirements of the protocol.
x
The patient wishes to be withdrawn from treatment.
x
The patient was erroneously included in the study (failed to satisfy all study criteria in 
Section 7).
x
The patient participated in another investigational study without the prior written 
authorization from the sponsor.
x
The patient is no longer deriving clinical benefit, in the opinion of the investigator.
x
Pregnancy.
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In addition, the sponsor may decide to discontinue the trial prematurely for any other reason.
Any relevant abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of the IMP for the concerned 
patient.
Patients who received at least 1 dose of study drug and who are withdrawn from the study will be 
asked to complete all discontinuation assessments before withdrawal (as detailed in Section 1.1,
Section 1.2, Section 1.4 and Section 1.5).  They will also receive a safety follow-up telephone call 
from the study site 30 to 37 days after the final administration of study drug.  If a patient fails to 
return for the necessary visits, every effort must be made to contact the patient to determine the 
reason(s).  The investigator will document the reason(s) for treatment discontinuation/study 
withdrawal on the CRF and in the patient’s medical record.  In all cases, the sponsor must be 
notified of all study terminations as soon as possible.
10.4.4 Handling of patients after permanent treatment discontinuation
Patients or parent/legal guardians who decide to discontinue participation in the study should be 
contacted by the study investigator in order to obtain information about the reason(s) for 
discontinuation and collection of any potential AEs.
When possible, all tests and evaluations listed in Section 1.1, Section 1.2, Section 1.4 and 
Section 1.5 for the post treatment withdrawal visit should be carried out within 2 weeks of the last 
olipudase alfa infusion.  If a patient fails to return for the necessary visits, every effort must be 
made to contact the patient and determine the reason(s) and record the reason(s) on the CRF.
In all cases, the sponsor must be notified of all study terminations as soon as possible and the 
reason for and date of withdrawal from the study must be recorded in the CRF and in the patient’s 
medical record.
10.4.5 Procedure and consequence for patient withdrawal from study
Patients may withdraw from the study before study completion if they decide to do so, at any time 
and irrespective of the reason.  Preferably the patient should withdraw consent in writing and, if 
the patient refuses or is physically unavailable, the site should document and sign the reason for 
the patient’s failure to withdraw consent in writing.
The reason for withdrawal should be captured.  Patients who withdraw should be explicitly asked 
about the contribution of possible AEs to their decision to withdraw consent, and any AE 
information elicited should be documented.
Patients who withdraw should be asked to come back for the end of study visit and will receive 
the safety follow phone call.
For patients who fail to return to the site, the investigator should make the best effort to contact 
the patient (eg, contacting patient’s family or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, including at least his/her vital status.  
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Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contact, receipt for sending a registered letter).
The statistical analysis plan (SAP) will specify how these patients lost to follow-up for their 
primary endpoints will be considered.
10.5
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING
The investigator is the primary person responsible for making all clinically relevant decisions on 
safety issues.
Any abnormal findings that meet the definition of an AE per Section 10.5.1 will be recorded on 
the CRF.  The investigator will continue to monitor the patient until the parameter returns to 
baseline or until the investigator determines that follow-up is no longer medically necessary.
All AEs (as described in Section 10.5.1) regardless of seriousness or relationship to study 
treatment will be collected from the time of written informed consent until the patient completes 
participation in the study as defined in Section 6.3.1.  Adverse events that started during the 
previous study which are ongoing at the time the patient signs the written informed consent 
should be reported in this study.
All SAEs (as described in Section 10.5.1.2) and any AESI requiring immediate notification 
(as described in Section 10.5.2.3.1) including those ongoing at the time of study completion) will 
be monitored until resolution, stabilization of the condition, or until it is mutually agreed upon by 
both the investigator and the sponsor safety physician to discontinue.
If, at any time after the patient has completed participation in the study (as defined in 
Section 6.3.1), the investigator or study staff becomes aware of an SAE that they believe is 
possibly related or related to IMP, then the event and any known details should be reported 
promptly to the sponsor.  Follow the reporting instructions in Section 10.5.2.2.
All AEs diagnosed by the investigator will be reported per applicable regulations and guidelines.  
Definitions for AEs, SAEs, AESI; and instructions for AE monitoring and reporting, are provided 
in Section 10.5 through Section 10.8. All AEs will be coded using the version of Medical 
Dictionary for Regulatory Activities (MedDRA) currently in effect at the time of the considered 
database lock.
The investigator is responsible for reviewing and signing all laboratory reports. Any abnormal 
findings that meet the definition of an AE per Section 10.5.1 will be recorded on the CRF. The 
investigator will continue to monitor the patient until the parameter returns to baseline or until the 
investigator determines that follow-up is no longer medically necessary.
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10.5.1 Definitions of adverse events
10.5.1.1 Adverse event
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have 
a causal relationship with this treatment.
10.5.1.2 Serious adverse event
An SAE is any untoward medical occurrence that at any dose:
x
Results in death, or
x
Is life-threatening (Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the patient 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), or
x
Requires inpatient hospitalization or prolongation of existing hospitalization, or
x
Results in persistent or significant disability/incapacity, or
x
Is a congenital anomaly/birth defect.
x
Is a medically important event.
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or may require 
intervention (ie, specific measures or corrective treatment) to prevent one of the other outcomes 
listed in the definition above.
Note: The following list of medically important events is intended to serve as a guideline for 
determining which conditions have to be considered as medically important events.  The list is not 
intended to be exhaustive:
x
Intensive treatment in an emergency room or at home for:
-
Allergic bronchospasm,
-
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),
-
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).
x
Development of drug dependency or drug abuse.
x
Suicide attempt or any event suggestive of suicidality.
x
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling).
x
Bullous cutaneous eruptions.
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x
Cancers diagnosed during the study.
x
Chronic neurodegenerative diseases if newly diagnosed and not part of the ASMD 
spectrum.
10.5.1.3 Adverse event of special interest
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor may be appropriate.  Such events may require further investigation in
order to characterize and understand them.  Adverse events of special interest may be added or 
removed during a study by protocol amendment.  Reporting guidelines and follow-up instructions 
are provided below.
AESIs include pregnancy, IARs (hypersensitivity reactions, APRs, and CRSs).
10.5.1.3.1Pregnancy
Pregnancy of a female patient entered in the study, and pregnancy occurring in a female partner of 
a male patient entered in this study.  See Section 10.2.3.1 for details.
10.5.1.3.2Infusion-associated reactions
Some AEs may be manifestations of IARs, including hypersensitivity reaction, APR, and CRS.  
However, original signs and symptoms must be reported as AEs.  In the CRF, investigators are 
asked to identify whether a specific AE represents a clinical manifestation of the IAR.
Infusion-associated reactions are defined as AEs that occur during the infusion or within up to 
24 hours after the start of infusion and are considered as related or possibly related to the study
treatment by the investigator or the sponsor.  An event occurring ≥24 hours after the start of 
an infusion may be judged an IAR at the discretion of the investigator or sponsor.  For this study 
of olipudase alfa, IARs may present as different types of reactions, such as hypersensitivity 
reactions, APRs, and CRS.
10.5.1.3.2.1
Hypersensitivity reactions
Infusion-associated hypersensitivity reactions seen with other enzyme replacement therapies are 
typically immunoglobulin-mediated (IgG/IgE) and occur after sensitization. After subsequent 
exposure to the antigen typically early into or shortly after the infusion, a “sensitized” patient 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 (22). Anaphylactoid, or non-immunologic anaphylaxis, reactions may 
present with similar serious clinical manifestations as anaphylaxis, but without prior exposure to 
the drug and are due to nonimmunologic-mediated mast cell degranulation.  Although 
mechanistically different, anaphylactic and anaphylactoid reactions are treated similarly.
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Common symptoms of hypersensitivity reactions seen with other enzyme replacement therapy 
include urticaria, rash, dyspnea, and less frequently, angioedema. Other symptoms of 
hypersensitivity IARs, APRs, and CRS include fever, hypotension, tachycardia, nausea, vomiting, 
pain, and headache.
There were no IARs suggestive of hypersensitivity in the Phase 1b trial (6).
10.5.1.3.2.2
Acute phase reactions
Acute phase reactions are considered a type of IAR.  Acute phase reactions were observed in the 
Phase 1 single-dose study (5) and the Phase 1b repeat-dose study (6) in 2 patients during dose 
escalation.  The patients successfully completed the trial.  Typically, APRs occurred within 12 to
72 hours after olipudase alfa infusion and were indicative of an inflammatory response as they 
were associated with elevations in hsCRP and changes acute phase reactants including, but not 
limited to, neutrophils, iron, ferritin, fibrinogen, D-dimer, transferrin, albumin, prothrombin time,
and partial thromboplastin time. Typical AEs that were reported by the patient included, but were 
not limited to, pyrexia, nausea, vomiting, fatigue, and pain; and were concurrent with the changes 
in specific laboratory parameters. Accordingly, APRs will be determined based on combined 
significant laboratory findings and clinical symptoms.
10.5.1.3.2.3
Cytokine release syndrome
Cytokine release syndrome is another type of IAR, attributed to the release of excessive amounts 
of cytokines shortly after the 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.  There were no events characterized as cytokine 
release syndrome in either the Phase 1 single- or the Phase 1b repeat-dose trials with olipudase 
alfa (5, 6). The Phase 1 single-dose study demonstrated increases in IL-8 and IL-6; macrophage 
inflammatory protein 1, alpha component (MIP-1α); macrophage inflammatory protein 1, beta 
component (MIP-1β); and other cytokines and biomarkers (based Myriad Rules-Based Medicine 
Human Multi-Analyte Profile® antigen panel) after a single dose of ≥0.3 mg/kg of olipudase alfa 
(5). In the Phase 1b trial, increases in mean IL-6 and IL-8 values were associated with the 
first administrations of olipudase alfa at doses 0.6 mg/kg through 2.0 mg/kg and tended to be 
concurrent with acute phase responses (6). Unlike immunoglobulin-mediated hypersensitivity 
reactions, no prior antigen exposure is required for the 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), symptoms typical of CRS 
include pyrexia, nausea, vomiting, fatigue, pain, myalgia, and in severe cases, multiorgan system 
dysfunction or failure, severe headache, and pulmonary edema.  Cytokine release syndrome will 
be determined based on combined significant laboratory findings and clinical symptoms.
10.5.1.3.3Symptomatic overdose (serious or nonserious) of study drug
An overdose (accidental or intentional) of study drug is defined as an increase of at least 30% of 
the dose to be administered in the specified duration or if the dose is administered in less than half 
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the recommended duration of administration.  An asymptomatic overdose will be reported as 
a standard AE.
10.5.1.3.4Laboratory values
The following laboratory values and symptoms will be considered AESIs (see also dose stopping 
criteria in Section 8.1.6), as follows:
x
Any increase in AST, ALT, total bilirubin, or AP >3x baseline (prior to olipudase alfa 
therapy) and > ULN.
x
Any increase in total bilirubin or AP >1.5x baseline in the presence of AST or 
ALT > 2x ULN.
x
Any increase in ALT or AST >3x the ULN combined with an increase in ALT or 
AST >2x baseline (prior to olipudase alfa therapy) with symptoms of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia (> ULN).
10.5.1.3.5Other significant events
Any AE that, in the opinion of the investigator or sponsor, raises significant concern regarding the 
safety of olipudase alfa at the administered dose will be considered an AESI.
10.5.1.4 Definitions for criteria of adverse events
10.5.1.4.1Relationship to study treatment
Assessment of the association between the AE and study exposure is important for regulatory 
reporting.  This assessment is to be made in blinded studies and also for known comparators.  For 
each AE/SAE the investigator is to determine whether there is a reasonable possibility 
demonstrated by evidence which suggests a causal relationship between the study treatment and 
the AE according to the categories below:
x
Not related: There is no suspicion of a causal relationship between exposure and the AE.
x
Unlikely related: There is no evidence for a causal relationship between exposure and the 
AE; however, such a relationship cannot be ruled out.
x
Possibly related: There is some evidence supporting the possibility of a causal relationship 
between exposure and the AE.
x
Related: There is strong evidence that there is a causal relationship between exposure and 
the AE.
A relationship to the investigational product must be assigned for each AE/SAE recorded, even if 
there is only limited information at the time. The investigator may change his/her opinion of 
causality in light of follow-up information, amending the AE/SAE report accordingly.
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10.5.1.4.2Severity of adverse event scoring
Note that “severity” is not the same as “seriousness,” which is defined in Section 10.5.1.2.
Intensity:
x
Mild = no modification of daily activities and does not require mandatory 
corrective/symptomatic treatment.
x
Moderate = hinders normal daily activities and/or requires mandatory 
corrective/symptomatic treatment.
x
Severe = prevents daily activities and requires mandatory corrective/symptomatic 
treatment.
10.5.1.4.3Outcome
Outcome describes the status of the AE.  The investigator will provide information regarding the 
patient outcome of each AE.  Definitions for possible results of an AE include:
x
Fatal: The termination of life as a result of an AE.
x
Not recovered/not resolved: The patient has not recuperated, or the AE has not improved.
x
Recovering/resolving: The patient is recuperating, or the AE is improving.
x
Recovered/Resolved: The patient has recuperated, or the AE has resolved.
x
Recovered with sequelae/resolved with sequelae: The AE has resolved, but the patient has 
been left with symptoms or pathology.
x
Unknown: Not known, not observed, not recorded, or refused.
10.5.1.4.4Action taken regarding the investigational product
The investigator will be required to provide the action taken regarding investigational product 
(eg, active, comparator) in response to the AE. Options include:
x
Dose increased: Increase in the frequency, strength, or amount of investigational product 
administered.
x
Dose not changed: No change in administration of the investigational product.
x
Dose reduced: Reduction in the frequency, strength, or amount of investigational product 
administered.
x
Drug (investigational product) interrupted: Temporary interruption in administration of the 
investigational product.
x
Drug (investigational product) withdrawn: Administration of the investigational product 
terminated (no further dosing).
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x
Not applicable: Determination of a value is not relevant in the current context. “Not 
applicable” can be used only if the:
-
AE occurred before the first IMP dose,
-
Patient has died; or, 
-
AE occurred after the last scheduled infusion.
x
Unknown: Not known, not observed, not recorded, or refused.
10.5.2 Guidelines for reporting adverse events
10.5.2.1 General guidelines
See Table 30 for an overview of AE reporting instructions.
x
All AEs, regardless of seriousness or relationship to study treatment spanning from the 
signature of the informed consent form until the end of the study are to be recorded on the 
corresponding CRF.
x
Except for IARs, whenever possible, diagnosis or single syndrome will be reported instead 
of symptoms.  For IARs, all symptoms must be separately recorded.
x
The investigator will specify the date of onset, intensity, action taken with respect to IMP, 
corrective treatment/therapy given, additional investigations performed, outcome, and 
his/her opinion as to whether there is a reasonable possibility that the AE was caused by 
the IMP.
x
The investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients.
x
Laboratory, vital sign measurements, or ECG abnormalities are to be recorded as AEs 
only if:
-
Symptomatic, and/or,
-
Requiring either corrective treatment or consultation, and/or,
-
Leading to IMP discontinuation or modification of dosing, and/or,
-
Fulfilling a seriousness criterion, and/or,
-
Defined as an AESI (Section 10.5.1.3).
10.5.2.2 Instructions for reporting serious adverse events
In the case of occurrence of an SAE, the investigator must immediately:
x
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the CRF; the system will automatically send a notification to the monitoring team after 
approval of the investigator within the CRF or after a standard delay.  If automatic 
notification is not available, paper SAE notifications must be sent manually to the local 
Pharmacovigilance and Epidemiology office.
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x
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol.  
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the sponsor.  For laboratory results, include the laboratory normal ranges.
x
All further data updates should be recorded in the CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE.  In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification.
x
A back-up plan (using a paper CRF process) is available and should be used when the 
electronic CRF system does not work.
Any SAE brought to the attention of the investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility should be 
reported to the monitoring team.
10.5.2.3 Guidelines for reporting adverse events of special interest
10.5.2.3.1Reporting of adverse events of special interest with immediate notification
For AESIs the sponsor will be informed within 24 hours as per the SAE notification instructions 
described in Section 10.5.2.2 even if not fulfilling a seriousness criterion, using the corresponding 
screens in the CRF.
x
Pregnancy
-
Pregnancy occurring in a female patient included in the clinical trial.  Pregnancy will 
be recorded as an AESI with immediate notification in all cases.  It will be qualified as 
an SAE only if it fulfills the SAE criteria,
-
In the event of pregnancy, study drug should be discontinued,
-
Follow-up of the pregnancy is mandatory until the outcome has been determined.
x
Infusion-associated reaction (see Section 10.5.1.3.2), which include:
-
Hypersensitivity reactions,
-
Acute-phase reaction,
-
Cytokine release syndrome.
x
Symptomatic overdose with IMP:
-
No doses greater than 3.0 mg/kg every other week have been administered to patients. 
In the event of overdose, the infusion should be terminated immediately. The patient 
should be monitored closely for the development of IARs, including seizures (which 
may occur at high doses of polysorbate 80), and should be treated appropriately at the 
investigator’s discretion,
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-
Note: An overdose (accidental or intentional) of study drug is defined as an increase of 
at least 30% of the dose to be administered in the specified duration, or if the dose is 
administered in less than half the recommended duration of administration. The 
circumstances (ie, accidental or intentional) will be clearly specified in the verbatim 
and symptoms, if any, entered on separate AE forms (Section 10.5.2.5).
x
The following laboratory values and symptoms (see also dose stopping criteria in 
Section 8.1.6) as follows: 
-
Any increase in AST, ALT, total bilirubin, or AP >3x baseline (prior to olipudase alfa 
therapy, [ie, baseline in the previous study (DFI13412 or DFI13803)]) and > ULN,
-
Any increase in total bilirubin or AP >1.5x baseline in the presence of AST or 
ALT > 2x ULN,
-
Any increase in ALT or AST >3x the ULN combined with an increase in ALT or 
AST >2x baseline (prior to olipudase alfa therapy) with symptoms of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia (>ULN).
x
Any AE that, in the opinion of the investigator or sponsor, raises significant concern 
regarding the safety of olipudase alfa at the administered dose
10.5.2.3.2Reporting of adverse events of special interest without immediate notification
x
Asymptomatic overdose with IMP (see Section 10.5.2.3.1 for the definition of 
an overdose).
10.5.2.4 Guidelines for management of specific laboratory abnormalities
Not applicable.
10.5.2.5 Summary of adverse event reporting
Table 30 - Summary of adverse event reporting instructions
Event category
Reporting 
timeframe
Specific events in this 
category
Case report form completion
AE form 
Safety 
complementary 
form 
Other specific 
forms 
Adverse event 
(non-SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious adverse event 
(non-AESI or AESI) 
Expedited 
(within 24 hours) 
Any AE meeting seriousness 
criteria per Section 10.5.1.2 
Yes 
Yes 
No 
Adverse event of 
special interest  
Expedited  
(within 24 hours) 
Symptomatic overdose 
Yes 
Yes 
No 
Pregnancy 
Yes 
Yes 
Yes 
Infusion associated reactions 
(IAR)/hypersensitivity reactions 
Laboratory values per 
Section 10.5.1.3 and 
Section 10.5.2.3 
Yes 
Yes 
No 
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10.6
PREGNANCY REPORTING
Female patients will be instructed to notify the investigator immediately if they discover they are 
pregnant.  Pregnant female patients will be discontinued from the study.
Male patients will be instructed to notify the investigator immediately if they discover that their 
sexual partner is pregnant.
If the investigator learns of a report of pregnancy at any time after signing the informed consent, 
the investigator should follow the instructions in Section 10.5.2.3.1 to contact the sponsor within 
24 hours.  The investigator will be asked to complete the AE form, the safety complementary 
form, and the pregnancy form.  The patient will be followed until the outcome of the pregnancy is 
known.  The investigator will be responsible for this follow-up.
If not otherwise established, the investigator will inform the patient that the sponsor is required to 
gather information regarding the course and outcome of the pregnancy after exposure to a study 
product.  The progress of the pregnancy must be followed until the outcome of the pregnancy is 
known (ie, delivery, elective termination, or spontaneous abortion).  If the pregnancy results in the 
birth of a child, additional follow-up information may be requested.
The investigator will be asked to obtain follow-up information no later than 2 months after the 
gestational period to obtain maternal/fetal/neonatal outcome and any other relevant information.  
Follow-up information may be requested at additional time points.  All study-related 
visits/contacts involving a known pregnancy should include pregnancy status assessment until 
pregnancy outcome is known.
Please note that pregnancy is an AESI, not an AE or SAE.  All information received will be 
assessed for any AEs and SAEs and processed per study guidelines.  If the patient is discontinued 
because of pregnancy, pregnancy will be documented as the reason for study discontinuation.  
Spontaneous abortions and stillbirths are reported as SAEs.
10.7
OBLIGATIONS OF THE SPONSOR
During the course of the study, the sponsor will report in an expedited manner:
x
All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction), to the health authorities, independent ethics 
committees (IECs)/institutional review boards (IRBs) as appropriate, and to the 
investigators.
x
All SAEs that are expected and at least reasonably related to the IMPs to the health 
authorities according to local regulations.
The sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report.
10.8
ADVERSE EVENTS MONITORING
All events will be managed and reported in compliance with all applicable regulations and will be 
included in the final clinical study report.
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11
STATISTICAL CONSIDERATIONS
An SAP will be written and finalized prior to database lock to give guidance to the statistical 
analysis.  It will be in compliance with the International Council on Harmonisation (ICH) and 
Food and Drug Administration’s Guidance for Industry: Statistical Principles for Clinical Trials.
11.1
GENERAL CONSIDERATIONS
The sponsor or its designee will perform the statistical analysis of the data from this study.  The 
analysis will be performed using the SAS® statistical software system Version 9.3 or higher.
Important CRF data, as well as any outcomes derived from the data, will be displayed in patient 
data listings.  Categorical variables will be summarized using frequencies and percentages, and 
continuous variables will be summarized using descriptive statistics (number of patients with
observation, mean, standard deviation, median, minimum, and maximum).
11.1.1 Final analysis
The final analysis will be performed at the completion of the treatment period.  This analysis will 
include safety, efficacy, PK, and PD data.  Analyses of change will be based upon changes from 
baseline prior to olipudase alfa therapy (ie, baseline in the previous study [DFI13412 or 
DFI13803]) through study completion.  The final statistical analyses will be performed when the 
entire database is locked and signed off, in accordance with the standard operating procedures of 
the sponsor or designee.
11.2
DETERMINATION OF SAMPLE SIZE
Sample size will be determined by the number of patients who complete the treatment phase of 
a previous clinical study of olipudase alfa, sign the informed consent form for the LTS13632 
study, and meet the eligibility criteria.  It is expected that the sample size for this study will be 
approximately 25.
11.3
DISPOSITION OF PATIENTS
Enrolled patients are defined as patients who signed informed consent forms.
Patient enrollment will be summarized for the enrolled patient set by study site, including 
frequency and percentage of patients who received at least 1 infusion (total or partial) of study 
treatment.
All patients who receive an infusion (total or partial) of olipudase alfa (safety population) will be 
included in the summary of patient disposition.  The number and percentage of patients who either 
complete the study or withdraw from the study, and/or withdraw from treatment, along with the 
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reasons for their withdrawal, and who completed or discontinued the posttreatment safety 
follow up will be presented.
11.4
ANALYSIS POPULATIONS
The safety set will include all enrolled patients who received at least 1 infusion (partial or total) of 
olipudase alfa in the current study.
The PK analysis includes all patients who receive at least 1 infusion of study drug after PK 
analysis informed consent and have evaluable PK data.  Other analysis populations, such as for 
pharmacogenomics, if any, will be defined in the SAP.
Subgroup analyses may be conducted for safety and efficacy endpoints in subpopulations of the 
safety set.  Subpopulations may be defined by parameters including, but not limited to, age, 
gender, genotype, exposure to study treatment, pre-dose (trough) plasma concentration of 
olipudase alfa, and concomitant therapies.  Further details will be provided in the SAP.
Throughout the study, “baseline” refers to the baseline in the previous study (DFI13412 or 
DFI13803).
11.5
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Demographic and baseline characteristics will be summarized using descriptive statistics for the 
safety set.
11.6
STATISTICAL METHODS
All analysis will be done on the safety set unless specified otherwise.
11.6.1 Extent of investigational medicinal product exposure
The extent of study treatment exposure will be assessed and summary statistics will be presented.
11.6.2 Analyses of efficacy endpoints
Efficacy assessments are described in Section 9.2.
Summary statistics for the values, nominal change from baseline, and percent change from 
baseline will be presented for efficacy assessments at various study time points.  The baseline 
value is defined to be the latest assessment value prior to the first dose of study treatment in the 
primary study.  For selected parameters, the mean (95% confidence interval) or median 
(interquartile range) may be plotted over time.  Categorical variables will be summarized using 
frequencies and percentages at various study time points.
The association between changes in efficacy parameters and total amount of drug received may be 
examined.
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11.6.2.1 Multiplicity considerations
Not applicable.
11.6.3 Analyses of safety data
Safety assessments are described in Section 9.1.4 through Section 9.1.15.  All safety analyses will 
be performed on the safety set (defined in Section 11.4).  No formal inferential testing will be 
performed.  Summaries will be descriptive in nature.
The following definitions will be applied to laboratory parameters, ECGs, and vital sign 
measurements.
x
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the sponsor according to predefined 
criteria/thresholds based on literature review and defined by the sponsor for clinical 
laboratory tests and vital signs.
x
PCSA criteria will determine which patients had at least 1 PCSA during the treatment 
period, taking into account all evaluations performed during the treatment period, 
including unscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the treatment PCSA percentage.
x
Treatment period: the treatment period used for quantitative analysis is defined as the time 
from first dose to the last dose of IMP +14 Days.
11.6.3.1 Adverse events
The definitions in Section 10.5.1 will be used for AEs.  Pretreatment AEs will be listed and 
presented separately from treatment-emergent AEs.
All AEs will be coded using the most recent version of the MedDRA.  Adverse event incidence 
tables will present by system organ class (SOC) (sorted by internationally agreed order) and 
preferred term (PT) sorted in alphabetical order for each treatment group, and the number and 
percentage of patients experiencing an AE.  Multiple occurrences of the same event in the same 
patient will be counted only once in the tables within a treatment phase.  The denominator for 
computation of percentages is the safety population within each treatment group.
All treatment-emergent AEs, all treatment-emergent AEs potentially related to olipudase alfa, all 
treatment-emergent AEs leading to treatment discontinuation and study discontinuation, all 
treatment-emergent AEs that are IARs, all treatment-emergent SAEs (including treatment-related 
SAEs), and all AEs with fatal outcomes (including fatal treatment-emergent AEs) will be 
summarized.
Detailed listings of AEs, SAEs, AESIs, related AEs, and discontinuations due to AEs will be 
provided.  These will include the olipudase alfa dose of the infusion prior to or during the 
occurrence of the AE, where applicable.
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For the overall analyses of AEs, the number of AEs and annualized rate, and the number and 
proportion of patients experiencing specific AEs will be tabulated according to the olipudase alfa 
dose level of the infusion prior to or during the occurrence of the AE.
Separate analyses of AEs will also be conducted by demographic characteristics (eg, age and sex).  
Adverse events of special interest, such as IARs, and SAEs will be analyzed similarly.
11.6.3.1.1Adverse events of special interest
Detailed listings for AESIs, including IAR, APR, and CRS will be provided.
11.6.3.1.2Deaths
The following deaths summary will be generated:
x
Treatment-emergent AE leading to death (death as an outcome on the AE CRF page as 
reported by the investigator) by primary SOC and PT showing number and percent of 
patients sorted by internationally agreed order of SOC and alphabetic order of PT.
11.6.3.2 Laboratory data and vital sign measurements
11.6.3.2.1Physical examinations, vital sign measurements, electrocardiograms, and 
echocardiograms
Observed values and changes from baseline (as applicable) will be summarized descriptively 
overall and by highest tolerated dose and/or by dose received prior to evaluation.  Outlier 
summaries for the ECG parameters (eg, QTc) will be created for the safety set.
11.6.3.2.2Clinical laboratory tests
Observed values and changes from baseline to study time points will be summarized descriptively 
overall and by highest tolerated dose and/or by dose received prior to evaluation.  All laboratory 
values will be classified as normal, above normal, or below normal based on normal ranges 
provided by the laboratory.  Frequencies of CS abnormal values and shifts from baseline to study 
time points will be summarized.  Patient listings of biomarkers will be provided.
11.6.3.3 Immune response assessments
Immune response assessments will be analyzed in the safety set.  The presence, absence, and titers 
of serum anti-olipudase alfa IgG antibodies will be summarized.  The data will be summarized 
over time overall and by the dose level of the infusion prior to or during the evaluation.
Levels of acute phase reactants, serum tryptase, complement activation, neutralizing antibodies, 
and anti-olipudase alfa antibodies (IgG and IgE) obtained in response to an IAR, and skin testing 
results (if available), will be presented in patient listings, if applicable.
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11.6.4 Analyses of pharmacokinetic and pharmacodynamic variables
Plasma concentration-time data will be analyzed using actual dosing and sampling times by 
noncompartmental methods.  Pharmacokinetic parameters will be calculated for each patient and 
summarized by dose level and study week.  As data permit, PK parameters may also be evaluated 
across dose level at each manufacturing scale or manufacturing process.  Metabolite levels will be 
summarized by dose level and time point using descriptive statistics.
11.6.5 Analyses of quality of life and cognitive variables
Scoring for the quality of life and cognitive assessments will be conducted as stated by the 
developers of the questionnaires.  Differences with respect to the changes from baseline will be 
presented descriptively.
11.7
INTERIM ANALYSIS
No formal interim analysis is planned for this study; however a formal summary of data or interim 
CSR may be produced to support regulatory approval(s) and/or other application/ submission 
requirement(s).
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12
ETHICAL AND REGULATORY STANDARDS
12.1
ETHICAL PRINCIPLES
This clinical trial will be conducted in accordance with the principles laid down by the 18th World 
Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World 
Medical Assemblies, and the ICH guidelines for Good Clinical Practice.
In compliance with Sanofi public disclosure commitments, this clinical trial will be recorded in 
the public registry website clinicaltrials.gov before the enrollment of the first patient.  The registry 
will contain basic information about the trial sufficient to inform interested patients (and their 
healthcare practitioners) how to enroll in the trial.
12.2
LAWS AND REGULATIONS
This clinical trial will be conducted in compliance with all international guidelines, and national 
laws and regulations of the countries in which the clinical trial is performed, as well as any 
applicable guidelines.  See also Section 13.1.
12.3
INFORMED CONSENT
The investigator (according to applicable regulatory requirements), or a person designated by the 
investigator, and under the investigator's responsibility, should fully inform the patient (and the 
parent[s] or guardian[s]) of all pertinent aspects of the clinical trial including the written 
information given approval/favorable opinion by the ethics committee (IRB/IEC]).  All 
participants should be informed to the fullest extent possible about the study in language and 
terms they are able to understand.
Prior to a patient’s participation in the clinical trial, the informed consent form should be signed, 
name filled in, and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion.
For patients who are less than 18 years old, the informed consent form should be signed, name 
filled in, and personally dated by the patient or the patient’s parents, or by the patient’s legally 
acceptable guardian, and by the person who conducted the informed consent discussion.  If only 
1 parent or guardian signs the consent form, the investigator must document the reason there is 
only 1 parent or guardian’s signature.  A copy of the signed and dated written informed consent 
form will be provided to the patient.
Pediatric participants who can read the assent form will do so before writing their name and 
dating or signing and dating the form.  Pediatric participants who can write but cannot read will 
have the assent form read to them before writing their name on the form.
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Pediatric participants who can understand, but who can neither write nor read, will have the assent 
form read to them in the presence of an impartial witness who will sign and date the assent form
to confirm that assent was given.
The informed consent form and the assent form used by the investigator for obtaining the patient's 
informed consent must be reviewed and approved by the sponsor prior to submission to the 
appropriate ethics committee (IRB/IEC) for approval/favorable opinion.
12.4
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
As required by local regulation, the investigator or the sponsor must submit this clinical trial 
protocol to the appropriate ethics committee (IRB/IEC) and is required to forward to the 
respective other party a copy of the written and dated approval/favorable opinion signed by the 
Chairman with ethics committee (IRB/IEC) composition.
The clinical trial (study number, clinical trial protocol title, and version number), the documents 
reviewed (clinical trial protocol, informed consent form, investigator’s brochure, investigator’s 
curriculum vitae, etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion.
Investigational medicinal product will not be released at the study site and the investigator will 
not start the study before the written and dated approval/favorable opinion is received by the 
investigator and the sponsor.
During the clinical trial, any amendment or modification to the clinical trial protocol must be 
submitted to the ethics committee (IRB/IEC) before implementation, unless the change is 
necessary to eliminate an immediate hazard to the patients, in which case the IRB/IEC should be 
informed as soon as possible.  It should also be informed of any event likely to affect the safety of 
patients or the continued conduct of the clinical trial, in particular any change in safety.  All
updates to the investigator’s brochure will be sent to the ethics committee (IRB/IEC).
A progress report is sent to the ethics committee (IRB/IEC) at least annually and a summary of 
the clinical trial’s outcome at the end of the clinical trial.
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13
STUDY MONITORING
13.1
RESPONSIBILITIES OF THE INVESTIGATOR(S)
The investigator(s) and delegated investigator staff undertake(s) to perform the clinical trial in 
accordance with this clinical trial protocol, ICH guidelines for Good Clinical Practice, and the 
applicable regulatory requirements.
The investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the sponsor (including security rules).  The 
investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, discrepancy resolution form, or other appropriate instrument) 
in an accurate and legible manner according to the instructions provided and to ensure direct 
access to source documents by sponsor representatives. In particular, the Investigator must permit 
study-related monitoring, audits, IRB/IEC review, and regulatory agency inspections and provide 
direct access to source data documents.
Particular attention should be paid to the confidentiality of the patient's data to be transferred.
The investigator may appoint such other individuals as he/she may deem appropriate as 
subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol.  All subinvestigators shall be appointed and listed in a timely manner.  The 
subinvestigators will be supervised by and work under the responsibility of the investigator.  The 
investigator will provide them with a copy of the clinical trial protocol and all necessary 
information.
13.2
RESPONSIBILITIES OF THE SPONSOR
The sponsor of this clinical trial is responsible to health authorities for taking all reasonable steps 
to ensure the proper conduct of the clinical trial protocol as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded in the CRFs.  Thus, the main duty of 
the monitoring team is to ensure the safety, well-being, and rights of all study subjects are 
observed, and to assist the investigator and the sponsor in maintaining a high level of ethical, 
scientific, technical, and regulatory quality in all aspects of the clinical trial.
At regular intervals during the clinical trial, the site will be contacted through monitoring visits, 
letters, or telephone calls by a representative of the monitoring team to ensure patient safety, 
well-being, and rights are observed, and to review study progress, investigator and patient 
compliance with clinical trial protocol requirements and any emergent problems.  These 
monitoring visits will include, but not be limited to, review of the following aspects: patient 
informed consent, patient recruitment and follow-up, SAE documentation and reporting, AESI 
documentation and reporting, AE documentation, IMP allocation, patient compliance with the 
IMP regimen, IMP accountability, concomitant therapy use, and quality of data.
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Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Study Monitoring Plan. 
13.3
SOURCE DOCUMENT REQUIREMENTS
According to the ICH guidelines for Good Clinical Practice, the monitoring team must check the 
CRF entries against the source documents, except for the pre-identified source data directly 
recorded in the CRF.  The informed consent form will include a statement by which the patient 
allows the sponsor’s duly authorized personnel, the ethics committee (IRB/IEC), and the 
regulatory authorities to have direct access to original medical records that support the data on the 
CRFs (eg, patient's medical file, appointment books, original laboratory records, etc).  These 
personnel, bound by professional secrecy, must maintain the confidentiality of all personal 
identity or personal medical information (according to confidentiality and personal data protection 
laws and rules).
13.4
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS AND 
ADDITIONAL REQUEST
It is the responsibility of the investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the sponsor to record (according to sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner.  All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data.
Should a correction be made, the corrected information will be entered in the CRF overwriting the 
initial information.  An audit trail allows identifying the modification.
Data are available within the system to the sponsor as soon as they are entered in the CRF.
The computerized handling of the data by the sponsor when available in the CRF may generate 
additional requests (discrepancy resolution form) to which the investigator is obliged to respond 
by confirming or modifying the data questioned.  The requests with their responses will be 
managed through the CRF.
13.5
USE OF COMPUTERIZED SYSTEMS
The following computerized systems may be used during the different steps of the study:
x
For data management activities, Medidata RAVE.
x
For PK activities, WinNonlin.
x
For statistical activities, SAS.
x
For pharmacovigilance activities, AWARE.
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x
For monitoring activities, IMPACT.
x
For medical writing activities, VEEVA VAULT.
x
For MRI activities, WebSend, BioPACS, and BioTrack.
x
For IMP management, NASCA.
x
For ECGs, CAMI7.
x
For ECHO, Digiview.
x
For central laboratory tests, Covance LabLink.
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14
ADMINISTRATIVE EXPECTATIONS
14.1
CURRICULUM VITAE
A current copy of the curriculum vitae describing the experience, qualifications, and training of 
each investigator and subinvestigator will be signed, dated, and provided to the sponsor prior to 
the beginning of the clinical trial.
14.2
RECORD RETENTION IN STUDY SITES
The investigator must maintain confidentiality for all study documentation, and take measures to 
prevent accidental or premature destruction of these documents.
The investigator should retain the study documents at least 25 years after the completion or 
discontinuation of the clinical trial.
However, applicable regulatory requirements should be taken into account in the event that 
a longer period is required.
The investigator must notify the sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation.
If the investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the investigator shall inform the sponsor and the relevant records shall be transferred to a mutually 
agreed upon designee.
14.3
CONFIDENTIALITY
All information disclosed or provided by the sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, the CRFs, the investigator's brochure, and the results obtained during the course of the 
clinical trial is confidential prior to the publication of results.  The investigator and any person 
under his/her authority agree to undertake to keep confidential and not to disclose the information 
to any third party without the prior written approval of the sponsor.
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committees (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality.
The subinvestigators shall be bound by the same obligation as the investigator.  The investigator 
shall inform the subinvestigators of the confidential nature of the clinical trial.
The investigator and the subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account.
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Furthermore, the investigator and the sponsor agree to adhere to the principles of personal data 
confidentiality in relation to the patients, investigators, and collaborators involved in the study.
14.4
PROPERTY RIGHTS
All information, documents, and IMP provided by the sponsor or its designee are and remain the 
sole property of the sponsor.
The investigator shall not mention any information or the product in any application for a patent 
or for any other intellectual property rights.
All the results, data, documents, and inventions that arise directly or indirectly from the clinical 
trial in any form shall be the immediate and exclusive property of the sponsor.
The sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance).  The sponsor shall be under no obligation to patent, 
develop, market, or otherwise use the results of the clinical trial.
As the case may be, the investigator and/or the subinvestigators shall provide all assistance 
required by the sponsor, at the sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents.
14.5
DATA PROTECTION
x
The patient's personal data, which are included in the sponsor database, shall be treated in 
compliance with all applicable laws and regulations.
x
When archiving or processing personal data pertaining to the investigator and/or to the 
patients, the sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party.
x
The sponsor also collects specific data regarding the investigator, as well as personal data 
from any person involved in the study, that may be included in the sponsor’s databases.  
The data shall be treated by both the sponsor and the investigator in compliance with all 
applicable laws and regulations.
Patient race will be collected in this study because these data are required by several health 
authorities, including the United States Federal Drug Administration.  The following options will 
be listed for race on the CRF: American Indian or Alaska Native; Asian; Black; Native Hawaiian 
or Other Pacific Islander; White; Japanese; and the additional options of Not Reported and 
Unknown.
14.6
INSURANCE COMPENSATION
The sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements.  
The insurance of the sponsor does not relieve the investigator and the collaborators from 
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maintaining their own liability insurance policy.  An insurance certificate will be provided to the 
ethics committees (IECs/IRBs) or health authorities in countries requiring this document.
14.7
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice, 
and applicable regulatory requirements, the investigator should permit auditing by or on the behalf 
of the sponsor and inspection by regulatory authorities.
The investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional secrecy, and 
as such, will not disclose any personal identity or personal medical information.
The investigator must make every effort to assist with the performance of the audits and 
inspections, giving access to all necessary facilities, data, and documents.
As soon as the investigator is notified of a planned inspection by the authorities, he must inform 
the sponsor and authorize the sponsor to participate in this inspection.
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections.
Any result and information arising from the inspections by the regulatory authorities must be 
immediately communicated by the investigator to the sponsor.
The investigator must take appropriate measures required by the sponsor to take corrective actions 
for all issues identified during the audit or inspections.
14.8
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE
14.8.1 Decided by the sponsor
Decided by the sponsor in the following cases:
x
If the information on the product leads to doubt as to the benefit/risk ratio.
x
If the investigator has received from the sponsor all IMP, means, and information 
necessary to perform the clinical trial and has not included any patient after a reasonable 
period of time mutually agreed upon.
x
In the event of breach by the investigator of a fundamental obligation under this 
agreement, including but not limited to, breach of the clinical trial protocol, breach of the 
applicable laws and regulations, or breach of the ICH guidelines on Good Clinical 
Practice.
x
If the total number of patients are included earlier than expected.
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The sponsor reserves the right to stop the study or patient treatment at any time for any reason.  In 
any case, the sponsor will notify the investigator of its decision by written notice.
14.8.2 Decided by the investigator
The investigator must notify (30 days prior notice) the sponsor of his/her decision and give the 
reason in writing.
In all cases (decided by the sponsor or by the investigator), the appropriate ethics committee(s) 
(IRB/IEC) and Health Authorities should be informed according to applicable regulatory 
requirements.
14.9
CLINICAL TRIAL RESULTS
The sponsor will be responsible for preparing a clinical study report and providing a summary of 
study results to the investigator.
The coordinating investigator who will sign off on the study report will be the investigator who 
first enrolled the largest number of patients in the trial.
14.10 PUBLICATIONS AND COMMUNICATIONS
The investigator agrees not to publish or release data or information pertaining to the study prior 
to the sponsor’s written consent, being understood that the sponsor will not unreasonably withhold 
its approval.
As the study is being conducted at multiple sites, the sponsor agrees that, consistent with scientific 
standards, the first presentation or publication of the results of the study shall be made only as part 
of a publication of the results obtained by all sites performing the protocol.  However, if no 
multicenter publication has occurred within 12 months of the completion of this study at all sites, 
the investigator shall have the right to publish or present independently the results of this study to 
the review procedure set forth herein.  The investigator shall provide the sponsor with a copy of 
any such presentation or publication derived from the study for review and comment at least 
30 days in advance of any presentation or submission for publication.  In addition, if requested by 
the sponsor, any presentation or submission for publication shall be delayed for a limited time, not 
to exceed 90 days, to allow for filing of a patent application or such other measures as the sponsor 
deems appropriate to establish and preserve its proprietary rights.
The investigator shall not use the name(s) of the sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the sponsor.  The sponsor 
shall not use the name(s) of the investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s).
The sponsor has the right at any time to publish the results of the study.
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15
CLINICAL TRIAL PROTOCOL AMENDMENTS
All appendices attached hereto and referred to herein are made part of this clinical trial protocol.
The investigator should not implement any deviation from or changes to the clinical trial protocol 
without agreement by the sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial.  Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the investigator and by the sponsor, and the signed amendment will be filed with this 
clinical trial protocol.
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
ethics committee (IRB/IEC) and also by regulatory authorities if substantial prior to its 
implementation, unless there are overriding safety reasons.
In some instances, an amendment may require a change to the informed consent form.  The 
investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected, 
if necessary.
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16
BIBLIOGRAPHIC 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, editors. The Metabolic and Molecular Bases of Inherited Diseases. 8th. 2001. pp. 
3589-610.
2. Horinouchi K, Erlich S, Perl DP, Ferlinz K, Bisgaier CL, Sandhoff K, et al. Acid 
sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease. Nat Genet. 
1995;10(3):288-93.
3. Miranda SR, He X, Simonaro CM, Gatt S, Dagan A, Desnick RJ, et al. Infusion of 
recombinant human acid sphingomyelinase into Neimann-Pick disease mice leads to visceral, 
but not neurological, correction of the pathophysiology. FASEB J. 2000;14(13):1988-95.
4. Dhami R, He X, Gordon RE, Schuchman EH. Analysis of the lung pathology and alveolar 
macrophage function in the acid sphingomyelinase-deficient mouse model of Niemann-Pick 
disease. Lab Inves. 2001;81(7):987-99.
5. McGovern MM, Wasserstein MP, Kirmse B, Duvall WL, Schiano T, Thurberg BL, et al. 
Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant 
human acid sphingomyelinase) in adults with Niemann-Pick disease type B (acid 
sphingomyelinase deficiency). Genet Med. 2015.
6. Wasserstein MP, Jones SA, Soran H, Diaz GA, Lippa N, Thurberg BL, et al. Successful 
within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency. Mol 
Genet Metab. 2015;116(1-2):88-97.
7. European Medicines Agency Committee for Medicinal Products for Human Use. Guideline on 
data monitoring committees. 2005.
8. Mendelson DS, Wasserstein MP, Desnick RJ, Glass R, Simpson W, Skloot G, et al. Type B 
Niemann-Pick disease: findings at chest radiography, thin-section CT, and pulmonary function 
testing. Radiology. 2006;238(1):339-45.
9. American Thoracic Society. Lung function testing: selection of reference values and 
interpretative strategies. Am Rev Respir Dis. 1991;144(5):1202-18.
10. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation 
of spirometry. Eur Respir J. 2005;26(2):319-38.
11. Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The rapid 
assessment of fatigue severity in cancer patients: Use of the Brief Fatigue Inventory. Cancer. 
1999;85(5):1186-96.
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12. Wang XS, Cleeland CS, Mendoza TR, Engstrom MC, Liu S, Xu G, et al. The effects of pain 
severity on health-related quality of life: A study of Chinese cancer patients. Cancer. 
1999;86(9):1848-55.
13. Cleeland CS, Ryan KM. Pain assessment: Global use of the Brief Pain Inventory. Ann Acad 
Med Singapore. 1994;23(2):129-38.
14. Schunemann HJ, Goldstein R, Mador MJ, McKim D, Stahl E, Puhan M, et al. A randomised 
trial to evaluate the self-administered standardised chronic respiratory questionnaire. Eur 
Respir J. 2005;25(1):31-40.
15. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey: Conceptual framework 
and item selection. Med Care. 1992:30(6):473-83.
16. Varni JW, Burwinkle TM, Seid M. The PedsQL as a pediatric patient-reported outcome: 
reliability and validity of the PedsQL Measurement Model in 25,000 children. Expert Rev 
Pharmacoecon Outcomes Res. 2005;5(6):705-19.
17. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 
Stanford University Press; 1959;p48-57.
18. Marshall WA and Tanner JM. Variations in the Pattern of Pubertal Changes in Boys. Arch Dis 
Child. 1970;45(239):13-23.
19. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969;44(235):291-303.
20. Maas M, van Kuijk C, Stoker J, Hollak CE, Akkerman EM, Aerts JF, et al. Quantification of 
bone involvement in Gaucher disease: MR imaging bone marrow burden score as an 
alternative to Dixon quantitative chemical shift MR imaging--initial experience. Radiology. 
2003;229(2):554-61.
21. Robertson PL, Maas M, Goldblatt J. Semiquantitative assessment of skeletal response to 
enzyme replacement therapy for Gaucher's disease using the bone marrow burden score. Am J 
Roentgenol. 2007;188(6):1521-8.
22. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis; Summary report for 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network Symposium. J Allergy Clin Immunol. 2006;117(2):391-7.
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17
APPENDICES
17.1
APPENDIX A: COUNTRY SPECIFIC REQUIREMENTS
This section is not applicable. 
17.2
APPENDIX B: PROTOCOL AMENDMENT HISTORY
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Clinical Trial Summary.
17.2.1 Amended Clinical Trial Protocol 06 (29-Jan-2021)
This amended protocol (06) is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
The primary reasons for this amendment are described below:
1. During a regional or national emergency declared by a governmental agency such as the 
COVID-19 pandemic, to allow more flexibility with regard to additional options for monitoring 
techniques in compliance with applicable country-specific regulations.
2. During a regional or national emergency declared by a governmental agency such as the 
COVID-19 pandemic that can lead to site closure or extenuating circumstances that prevent an in-
person site visit, for the switch from Process C(
) investigational medicinal product (IMP) to the 
updated manufacturing Process C(
) IMP, adding the possibility to perform the first infusion at 
home for eligible patients in agreement between the Sponsor and the Investigator and in 
compliance with applicable country-specific regulations. 
3. Liver function test (LFT) monitoring after infusion is already included in this protocol. 
However, review of the interim data from the clinical development program has identified 
"Transient elevation in transaminases associated with ceramide release during the dose escalation 
phase with olipudase alfa" as an important identified risk. Therefore, additional recommendations 
for the management of transaminase elevation during dose escalation have been added to the 
protocol. 
Other important changes include:
1. In the context of this long-term study, the assessments have been streamlined to reduce patient 
burden. Assessments to ensure patient safety will be preserved. This change will be implemented 
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after the cutoff date for a planned second database lock of the study for purpose of regulatory 
submissions in 2021 (the first cutoff date was on 10 December 2019). 
2. During the study, pediatric patients who reach adult age (18 years old) will receive the adult 
infusion volume.
3. Other changes, omissions and corrections have also been addressed.
Protocol amendment summary of changes table
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary- 
Study design 
Language added for clarification: During the study, pediatric 
patients who will reach adult age (18 years old) will receive 
the adult infusion volume. 
Clarification on how to manage 
the IMP in patients reaching the 
adult age  
Clinical Trial Summary-Study 
treatment 
Language added for clarification: During clinical development 
of olipudase alfa, incremental changes were made to the 
olipudase alfa manufacturing process. The different 
processes are referred to as Process B, C(
) and C(
).  
Clarification on the olipudase 
alfa manufacturing process 
changes 
Clinical Trial Summary-
Endpoint(s) 
Sphingomyelin in plasma and metabolites in dried blood spot 
will no longer be assessed after the cutoff date for a planned 
second database lock of the study for purpose of regulatory 
submissions in 2021 
Analysis of sphingomyelin, 
ceramide and other metabolites 
(sphingosine-1- phosphate) in 
plasma or DBS through 
52 weeks of treatment has been 
completed for all patients. Lyso-
sphingomyelin and ceramide 
which represent the most 
informative readouts for 
pharmacodynamic response to 
treatment will be maintained 
throughout the study to continue 
to monitor levels of substrate 
and its metabolic product. In the 
context of this long-term study, 
these assessments will be 
streamlined to reduce patient 
burden. Assessments to ensure 
patient safety have been 
preserved. 
Clinical Trial Summary-
Assessment Schedule 
Addition of:  
48 hours post-infusion assessments will no longer be 
assessed after the cutoff date for a planned second database 
lock of the study for purpose of regulatory submissions in 
2021. 
During the dose escalation period, for transaminases 
assessed after infusion, if any AST or ALT value is >2x 
baseline and >ULN, the test should be repeated prior to the 
next scheduled infusion. Depending on the test results, the 
dose can be adjusted (repeated or reduced) or treatment can 
be withheld to allow additional transaminase monitoring, 
based on the physician’s clinical judgment. 
The assessments have been 
streamlined to reduce patient 
burden in the extension phase of 
this trial. 
Assessments to ensure patient 
safety have been preserved. 
The 48 hours post-infusion 
assessments no longer 
assessed after the cutoff date 
for a planned second database 
lock of the study for purpose of 
regulatory submissions in 2021; 
however, 24 hours post-infusion 
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Section # and Name 
Description of Change 
Brief Rationale 
Baseline is defined as the following:  
· For initial dose escalation: last values prior to first dose of 
olipudase alfa 
· For dose re-escalation: last values prior to the first re-
escalation dose 
Below text is updated: 
In the first 5 years, pharmacodynamic (PD) evaluations will 
occur every 3 months then every 6 months after the cutoff 
date for a planned second database lock of the study for 
purpose of regulatory submissions in 2021. After 5 years, PD 
evaluations will occur every 12 months. PK evaluation will 
occur every 12 months only in the first 5 years and upon 
introduction of Process C(
) or Process C(
) at any time 
during the study.  
assessments remain. Therefore, 
patient safety is not being 
compromised. 
Transient elevation in 
transaminases associated with 
ceramide release during the 
dose escalation phase with 
olipudase alfa has been added 
as an important identified risk. 
Therefore, additional 
recommendations for the 
management of transaminase 
elevation during dose escalation 
have been added to the 
protocol. 
Section 1 - Study Flow 
Charts.
Updated manufacturing scale has been replaced by Process 
C(
). 
Updated manufacturing process has been replaced by 
Process C(
). 
Five new flowcharts (Tables 2, 4, 6, 8, and 10) have been 
added (resulting in table renumbering) describing 
assessments after cutoff for planned second database lock in 
2021. 
Previous flow charts with the addition of: only applicable 
before the implementation of changes that will occur after the 
cutoff date of the second database lock  
For each of the flow charts initially presented in the protocol, 
complementary flow charts have been added to be effective 
after the cutoff date for a planned second database lock of the 
study for purpose of regulatory submissions in 2021. 
The following parameters will no longer been assessed: 
-
Metabolites in plasma: ACE, sphingomyelin  
-
Metabolites in dried blood spot  
-
48 hours after infusion: vital sign measurements, 
LFTs, hematology, and safety during dose re-
escalation 
Timing changed from quarterly to every 6 months through 
Year 5 for the following parameters: 
-
Metabolites in plasma: ceramide, lyso-
sphingomyelin 
-
Efficacy biomarkers: serum chitotriosidase, CCL18 
-
Bone biomarkers (alkaline phosphatase, 
C-telopeptide) 
if site visits are not possible (eg, during the COVID-19 
pandemic) replaced by: If the site visit is not possible during a 
Clarification on olipudase alfa 
manufacturing process changes 
In the context of this long-term 
study, some assessments will 
be streamlined to reduce patient 
burden. Given current 
knowledge about the study drug, 
assays can be replaced by 
targeted testing. Assessments to 
ensure patient safety will be 
preserved. This change will be 
implemented after the cutoff 
date for a planned second 
database lock of the study for 
purpose of regulatory 
submissions in 2021 (the first 
cutoff date was on 10 December 
2019): sites will be informed of 
the effective date. 
Analysis of sphingomyelin, 
ceramide and other metabolites 
(sphingosine-1- phosphate) in 
plasma or DBS through 52 
weeks of treatment has been 
completed for all patients. Lyso-
sphingomyelin and ceramide 
which represent the most 
informative readouts for 
pharmacodynamic response to 
treatment will be maintained 
throughout the study to continue 
to monitor levels of substrate 
and its metabolic product.  
Analysis of ACE through 52 
weeks of treatment has been 
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Section # and Name 
Description of Change 
Brief Rationale 
regional or national emergency declared by a governmental 
agency such as the COVID-19 pandemic due to site closure 
or extenuating circumstances that prevent an in-person site 
visit  
completed for all patients. Initial 
objective to monitor for changes 
with treatment were achieved; 
no further longitudinal analysis is 
required. 
The other assessments have 
been streamlined to reduce 
patient burden in the extension 
phase of this trial. Assessments 
to ensure patient safety have 
been preserved. 
 
Section 1.6 Study flow chart 
Addition of: 
Switch from Process B to Process C for new manufacturing 
scale  
Switch from Process C(
) to Process C(
) for the updated 
manufacturing process 
Clarification on the olipudase 
alfa manufacturing processes 
Section 4.1 Introduction 
Addition of: During clinical development of olipudase alfa, 
incremental changes were made to the olipudase alfa 
manufacturing process. The different processes are referred 
to as Process B, C(
) and C(
).  
Clarification on the olipudase 
alfa manufacturing processes 
Section 6.1.1 Treatment 
period 
Below text is updated: 
PK evaluations will occur every 12 months only in the first 5 
years and upon introduction of a drug product from Process B 
to the new manufacturing scale Process C or from Process 
C(
) to the updated manufacturing Process C
) at any 
time during the study. 
In the first 5 years, pharmacodynamic (PD) evaluations will 
occur every 3 months then every 6 months after the cutoff 
date for a planned second database lock of the study for 
purpose of regulatory submissions in 2021. After 5 years, PD 
evaluations will occur every 12 months. PK evaluation will 
occur every 12 months only in the first 5 years and upon 
introduction of Process C(
) or Process C(
) at any time 
during the study. 
Clarification on olipudase alfa 
manufacturing process changes 
Section 8.1.1 Treatments 
administered 
Added: If the site visit is not possible during a regional or 
national emergency declared by a governmental agency such 
as the COVID-19 pandemic due to site closure or extenuating 
circumstances that prevent an in-person site visit 
Clarification when a site visit is 
not possible   
Section 8.1.2 – Route and 
method of administration 
Language updated: During the study, pediatric patients who 
reach adult age (18 years old) will receive the adult infusion 
volume. 
Clarification on how to manage 
the IMP in patients reaching the 
adult age 
Section 8.1.5 – Dosing 
delays or missed doses 
48 hours post-infusion assessments will no longer be assessed 
after the cutoff date for a planned second database lock of the 
study for purpose of regulatory submissions in 2021 
The assessments have been 
streamlined to reduce patient 
burden in the extension phase of 
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Section # and Name 
Description of Change 
Brief Rationale 
During the dose escalation period, for transaminases assessed 
after infusion, if any AST or ALT value is >2x baseline and 
>ULN, the test should be repeated prior to the next scheduled 
infusion. Depending on the test results, the dose can be 
adjusted (repeated or reduced) or treatment can be withheld to 
allow additional transaminase monitoring, based on the 
physician’s clinical judgment. 
Baseline is defined as the following:  
· For initial dose escalation: last values prior to first dose of 
olipudase alfa 
· For dose re-escalation: last values prior to the first re-
escalation dose 
this trial. 
Assessments to ensure patient 
safety have been preserved. 
The 48 hours post-infusion 
assessments no longer assessed 
after the cutoff date for a planned 
second database lock of the 
study for purpose of regulatory 
submissions in 2021; however, 
24 hours post-infusion 
assessments remain. Therefore, 
patient safety is not being 
compromised. 
Transient elevation in 
transaminases associated with 
ceramide release during the dose 
escalation phase with olipudase 
alfa has been added as an 
important identified risk. 
Therefore, additional 
recommendations for the 
management of transaminase 
elevation during dose escalation 
have been added to the protocol. 
Section 9.1.15 – Immune 
response assessments 
Added: If introduction of a drug product from Process C(
) or 
from Process C(
) occurs, testing will occur monthly for the 
first 6 months after introducing the drug product from Process 
C(
) or Process C(
) 
Clarification on olipudase alfa 
manufacturing process changes. 
Section 9.3.8 
Pharmacokinetics 
PK testing will only occur yearly for the first 5 years and upon 
the introduction of Process C(
) or Process C(
) at any time 
during the study.  For Process C(
), if treatment is not 
interrupted, PK sample collection will take place at the patient’s 
last infusion under the current manufacturing scale and at the 
first infusion Process C(
). For introduction of drug product 
from Process C(
),if treatment is not interrupted, PK sample 
collection will take place at the second infusion under Process 
C(
). 
Clarification regarding olipudase 
alfa manufacturing process 
changes 
Section 9.5 Sampled blood 
volume 
Added: If a PK or IgG sample collection for the planned 
introduction of drug product from Process C(
) was 
erroneously taken 
Clarification regarding olipudase 
alfa manufacturing process 
changes 
Section 10.2.1 – Home 
infusions. 
For the switch from Process C(
) IMP to the updated 
manufacturing Process C(
) IMP, if the site visit is possible, 
the patient should  receive the first infusion at the site. 
However, if the site visit is not possible due to site closure or 
extenuating circumstances that prevent an in-person site visit 
(eg, during COVID-19 pandemic), the first infusion of Process 
C(
) is allowed during home infusion for eligible patients in 
agreement between the Sponsor and the Investigator in 
compliance with applicable country-specific regulations. 
To facilitate treatment 
continuation via home infusion 
during the COVID-19 pandemic 
when site visit is not available 
for eligible patients. 
No safety risks are anticipated 
based on the following:  
1.
Process C(
) IMP is 
produced using an 
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Section # and Name 
Description of Change 
Brief Rationale 
updated 
manufacturing 
process; it is produced 
as per Good 
Manufacturing 
Process (GMP) 
requirements and is 
considered 
comparable to 
Process C(
) IMP.  
2.
There is clinical 
experience with the 
switch from Process 
C(
) to Process 
C(
). 
3.
There is appropriate 
selection of patients in 
home infusion setting 
with appropriate 
medical support. 
 
Section 13.1 – 
Responsibilities of the 
Investigator (s). 
Language added for clarification: In particular, the Investigator 
must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to 
source data documents. 
To further clarify the 
responsibilities of the 
Investigator(s). 
Section 13.2 – 
Responsibilities of the 
Sponsor. 
Language added: Monitoring details describing strategy (eg, 
risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues 
and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Study Monitoring Plan. 
To include the possibility to 
perform remote monitoring 
during a regional or national 
emergency such as the current 
COVID-19 pandemic. 
Section 17.2 - Appendix B 
Protocol Amendment History  
 
Due to addition of amendment history for Amended Clinical 
Trial Protocol 05 (18-Aug-2020) as sub-section 17.2.1.1, all 
further sub-sections were re-numbered accordingly.. 
To conform with the usual 
process for amendment history. 
17.2.2 Amended Clinical Trial Protocol 05 (18-Aug-2020)
This amended protocol (05) is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
This amendment is mainly made to change the reintroduction dose to a lower dose for patients 
who missed 3 or more infusions and allow dose reintroduction and quarterly visits to be  
performed via home infusion for eligible patients if the site visit is not possible due to site closure 
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or extenuating circumstances that prevent an in-person site visit (eg, during COVID-19
pandemic). This amended protocol extended cognitive and adaptive function assessments, ABAS 
and DP-3, to all pediatric patients who have performed the assessment during the previous 
DFI13803 study. The amendment also provided guidance regarding assessments related to 
updated manufacturing process and home infusion. Other changes, omissions and corrections are 
addressed. 
Protocol amendment summary of changes table
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary- 
Study design, Duration of 
Study Period (per patient); 
Sections 4.2 Study 
Rationale; 6 Study Design; 
6.1.1 Treatment Period; 6.3 
Duration of Study 
Participation  
Add the highlighted text to the sentence: Patients will receive 
olipudase alfa every 2 weeks for 9 years or marketing 
approval, whichever comes first, unless the patient decides to 
enter another olipudase alfa clinical trial within the 9-year 
period prior to marketing approval. 
To give patients in this study the 
opportunity to enroll in another 
olipudase clinical trial prior to 
marketing approval 
Clinical Trial Summary- 
Study design; Sections 6 
Study Design; 6.1.1 
Treatment Period; 6.3 
Duration of Study 
Participation 
Add the highlighted text to the sentence: “If marketing 
approval was not available, extension of follow up beyond 9 
years would be considered with sponsor’s approval in 
accordance with local regulations” 
 
For consistency  
 
 
 
Clinical Trial Summary- Dose 
regimen; Sections 1- Study 
Flow Charts; 8.1.1- 
Treatment administered,   
Add “Quarterly visits will occur at the site. If the site visit is not 
possible due to site closure or extenuating circumstances that 
prevent an in-person site visit (eg, during COVID-19 pandemic) 
and home infusion is already approved for the eligible patient, 
quarterly visits will be done at home. Quarterly visit specific 
assessments that need a site visit will not be done at that time 
and will be done as unscheduled as soon as site visits become 
available. In such a case, some of the quarterly visit 
assessments may be done by home nurse (eg, lab sampling) 
and by the site through the phone (eg, Health-related quality of 
life instruments)”. 
To facilitate treatment 
continuation via home infusion in 
circumstances like COVID-19 
pandemic when site visit is not 
available for eligible patients 
Clinical Trial Summary-- 
Dose regimen; Sections 1- 
Study Flow Charts; 8.1.1- 
Treatment administered, 
8.1.5-Dosing delays or 
missed doses,  
For patients who have missed 3 or more doses ≥0.6 mg/kg, 
reintroduction of olipudase alfa should occur at the 
hospital/study site. If the site visit is not possible due to site 
closure or extenuating circumstances that prevent an in-person 
site visit (eg, during COVID-19 pandemic), reintroduction may 
be done via home infusion. 
To facilitate treatment 
continuation via home infusion in 
circumstances like COVID-19 
pandemic when site visit is not 
available for eligible patients 
Clinical Trial Summary- 
Endpoints 
Add Weight and Height (pediatric patients only) to the list of 
primary endpoints 
For consistency with 
section 9.1.1 Primary Objectives 
Clinical Trial Summary—
Endpoints; Section 9.1.3- 
Other endpoints 
Extend cognitive and adaptive assessments for patients who 
performed the assessments in DFI13803  
 
To continue monitoring cognitive 
and adaptive functions beyond 
6 years of age  
Clinical Trial Summary—
Endpoints; Section 9.1.3- 
Other endpoints; 9.3.10 
Remove “Differential liver DNA methylation densities of 
peroxisome proliferator-activated receptor gamma (PPARγ) 
gene promoter in plasma circulating cell-free DNA (ccfDNA)” 
This exploratory analysis uses 
left over samples from the time 
patients had a liver biopsy. The 
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Section # and Name 
Description of Change 
Brief Rationale 
Differential liver DNA 
methylation densities of 
PPARγ gene promoter in 
plasma 
from the list of other assessment endpoints. 
samples have been challenging 
to obtain in this already small 
group of 5 adult patients. 
Therefore, the endpoint is being 
removed.  
Clinical Trial Summary-- 
Assessment schedule; 
Sections 1 - Study Flow 
Charts, 8.1.5, Dosing delays 
or missed doses  
Remove ECG from the list of assessments to be done in case 
of dose reintroduction 
Remove a redundant 
assessment that is done 
according to schedule 
Sections 1- Study Flow 
Charts and 1.6 
Pharmacokinetic sampling; 
9.5-Sampled blood volume 
Add “schedule of PK and IgG sample collection after 
introduction of drug product from updated manufacturing 
process. Also add “If a PK or IgG sample collection for the 
planned introduction of drug product from an updated 
manufacturing process was erroneously taken, the future 
sample collection will be adjusted to the blood volume per each 
age cohort in order to avoid excessive blood withdrawal” 
For clarity and guidance in 
case of introduction of updated 
manufacturing process and in 
case of erroneously taken 
samples in relation to blood 
volume 
Sections 1- Study Flow 
Charts: 1.1, 1.2, 1.3 ,1.4 1.5: 
footnote a 
Add “Quarterly visit specific assessments that need a site visit 
will not be done at that time and will be done as unscheduled 
as soon as site visits become available. In such a case, some 
of the quarterly visit assessments may be done by home nurse 
(eg, lab sampling) and by the site through the phone (eg, 
Health-related quality of life instruments)” 
Clarify details of assessments in 
case of site in availability and 
continuation of treatment via 
home infusion 
Sections 1- Study Flow 
Charts:  1.1, 1.2, 1.3 ,1.4 1.5: 
footnote a 
Provide option of Telehealth visit in accordance with local 
regulations 
Facilitate treatment continuity if 
site visit is not available 
Sections 1- Study Flow 
Charts 
Footnote hierarchy changed due to addition 
Formatting 
Sections 1.3- Study Flow 
Charts  
Add columns for “Study completion, patient discontinuation and 
withdrawal” visit schedule to Year 1 pediatric chart also add 
corresponding safety follow up visit schedule 
Correct previous omission 
Sections 1- Study Flow 
Charts: 1.1, 1.2, footnote d; 
1.3 ,1.4, 1.5 footnote e 
Add that weight is not required at home infusion visits unless 
quarterly visit occurs at home. 
Clarify guidance regarding 
weight taking during home 
infusion 
Section 8.1.1-treatment 
administration 
Decrease dose reintroduction for patients who have missed 3 
or more infusions to 0.3 instead of 0.6 mg/kg as follows: -“If the 
previous dose was ≥>0.6 mg/kg, the next dose must be 0.6 
0.3 mg/kg (0.3 mg/kg should be repeated at the subsequent 
infusion, similar to dose escalation schedule in the original 
study)” 
Change reintroduction dose 
after missing multiple 
consecutive infusion to a lower 
dose 
Section 9.1.10-
Electrocardiograms 
 Spell out the word electrocardiograms  
Clarity 
Section 9.6- Future use of 
samples 
Add the sentence “These samples will be stored for 15 years 
after end of the study in compliance with applicable country-
specific regulations. 
Add guidance for future sample 
use to match WSIs 
Section 10.2.1-Home 
infusions  
Modify IAR management guidance during home infusion “ For 
patients experiencing an IAR while being infused at home, the 
Clarify the guidance for IAR 
during home infusion regarding 
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Section # and Name 
Description of Change 
Brief Rationale 
investigator should assess whether or not it is safe for the 
patient to continue to be treated via home infusion or return to 
the study site for their following infusion and when the patient 
would be ready to resume home infusion. In case home 
infusion continues, the investigator will guide the home infusion 
staff on the measures to be followed for subsequent infusion to 
manage the IAR (eg, infusion interruption, premedication, 
change the infusion rate, etc). 
the need to site and home 
management  
Section 10.2.1- Home 
infusions 
Add language to detail management of severe hypersensitivity 
reaction and anaphylaxis: “If recurrent IARs or hypersensitivity 
reactions occur, the investigator should assess whether or not 
it is safe for the patient to continue to be treated via home 
infusion. If a severe hypersensitivity reaction or an anaphylaxis 
reaction occurs, during an infusion given at home, treatment 
will be discontinued immediately, and appropriate medical 
treatment will be initiated. The patient will return to the study 
site for further management until the investigator agrees with 
the sponsor that it is safe for the patient to continue to be 
treated via home infusion. 
Further safety details in case of 
home infusion 
Section 14.2 Record 
retention in study sites 
The investigator should retain the study documents at least 15 
25 years after the completion or discontinuation of the clinical 
trial. 
Modify record retention at the 
study site to match SOPs and 
WSIs 
Section 16 Bibliographic 
references 
Modify the source of the article in reference number 1 
Update reference data as the 
old URL was not valid 
Section 17.2- appendix B: 
Protocol amendment history 
insert amended protocol 4 summary of changes 
Update appendices according to 
the amended protocol 
17.2.3 Amended protocol 04 (31-Jul-2019)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
[because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study].
OVERALL RATIONALE FOR THE AMENDMENT
This amendment is made to indicate the different assessments that will be done after 
manufacturing process update as per regulatory authorities’ requirements. Previous omissions and 
errors were corrected.
Protocol amendment summary of changes table
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Title was updated to reflect Amended Clinical Trial 
Protocol 04 and removed reference to recombinant human 
Reflect the update of the amended 
clinical trial protocol. 
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Section # and Name 
Description of Change 
Brief Rationale 
acid sphingomyelinase from title. 
Title Page 
The protocol date was changed to reflect 31-Jul-2019. 
Reflect the updated date of approval 
of the document. 
Names and Addresses Of 
Sponsor information for Sanofi Genzyme was added. 
The change was made to reflect the 
update of the amended clinical trial 
protocol. 
Protocol Amendment 
Summary of Changes 
Document History, Amended Clinical Trial Protocol, and 
Overall Rationale For The Amendment were added. 
This change was made to adhere to 
Sanofi policy. 
Protocol amendment 
summary of changes table 
Summary of changes table was added to amended clinical 
trial protocol. 
This change was made to adhere to 
Sanofi policy.  
Clinical Trial Summary, 
Duration Of Study Period 
(per patient) 
Addition of the following language was made to this 
section “and health authorities”. 
Clarify that with sponsor’s and health 
authorities’ approval the study 
duration extension beyond 9 years 
would be considered.  
1.1 Flow Chart For Adults: 
Year 1 Through Year 5 
Footnote “j” was edited to describe PK testing upon the 
introduction of a drug product from a new or an updated 
manufacturing process. 
Assessment to be done after 
manufacturing process update. 
1.2 Flow Chart For Adults: 
Beyond Year 5 
Information for testing Hematology, Hemoglobin level and 
platelet count if a drug product from an updated 
manufacturing process was administered was added to 
this section.  
Assessment to be done after 
manufacturing process update. 
1.2 Flow Chart For Adults: 
Beyond Year 5 
Information for testing of anti olipudase alfa antibody (IgG) 
if introduction of a drug product from an updated 
manufacturing process or a manufacturing scale change 
occurs was added. 
Assessment to be done after 
manufacturing process update. 
1.2 Flow Chart For Adults: 
Beyond Year 5 
Footnote “g” was added to this section that describes PK 
testing that will only occur upon the introduction of a drug 
product from a new manufacturing scale or an updated 
manufacturing process. 
Assessment to be done after 
manufacturing process update. 
1.3 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Year 1 
Information for testing of anti olipudase alfa antibody (IgG) 
if introduction of a drug product from an updated 
manufacturing process or a manufacturing scale change 
occurs was added. 
Assessment to be done after 
manufacturing process update. 
1.3 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Year 1 
Footnote “e” added information about collection of 
hemoglobin and platelet count if a drug product from 
an updated manufacturing process is administered.  
Assessment to be done after 
manufacturing process update. 
1.3 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Year 1 
Footnote “j” added information to describe PK testing that 
will only occur upon the introduction of a drug product from 
a new manufacturing scale or an updated manufacturing 
process. 
Assessment to be done after 
manufacturing process update. 
1.4 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Year 2 Through Year 5 
Information for testing of anti olipudase alfa antibody (IgG) 
if introduction of a drug product from an updated 
manufacturing process or a manufacturing scale change 
occurs was added. 
Assessment to be done after 
manufacturing process update. 
1.4 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Footnote “g” added information about collection of 
hemoglobin and platelet count if a drug product from an 
Assessment to be done after 
manufacturing process update. 
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Section # and Name 
Description of Change 
Brief Rationale 
Year 2 Through Year 5 
updated manufacturing process is administered. 
1.4 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Year 2 Through Year 5 
Footnote “m” added information to describe PK testing that 
will only occur upon the introduction of a drug product from 
a new manufacturing scale or an updated manufacturing 
process.    
Assessment to be done after 
manufacturing process update. 
1.5 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Beyond Year 5 
Information for testing Hematology, Hemoglobin level and 
platelet count if a drug product from an updated 
manufacturing process was administered was added to 
this section. 
Assessment to be done after 
manufacturing process update. 
1.5 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Beyond Year 5 
Information for PK testing for visit/timing was added. 
Assessment to be done after 
manufacturing process update. 
1.5 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Beyond Year 5 
Information for testing of anti olipudase alfa antibody (IgG) 
if introduction of a drug product from an updated 
manufacturing process or a manufacturing scale change 
occurs was added. 
Assessment to be done after 
manufacturing process update. 
1.5 Flow Chart For Pediatric 
(Former DFI13803) Patients: 
Beyond Year 5 
Footnote “I” added information to describe PK testing that 
will only occur upon the introduction of a drug product from 
a new manufacturing scale or an updated manufacturing 
process. 
Assessment to be done after 
manufacturing process update. 
1.6 Study Flow Chart: 
Pharmacokinetic Sampling 
Text is modified to describe the PK testing to be done as 
a result of the introduction of drug product from an 
updated manufacturing process, or an updated 
manufacturing process. 
Assessment to be done after 
manufacturing process update. 
1.6 Study Flow Chart: 
Pharmacokinetic Sampling  
Table 6: Pharmacokinetic 
sampling in adults 
PK sampling in adults if an updated manufacturing 
process occurs was added to this table.  
Assessment to be done after 
manufacturing process update. 
1.6 Study Flow Chart: 
Pharmacokinetic Sampling  
Table 7: Pharmacokinetic 
sampling in pediatric patients 
PK sampling in pediatric patients if introduction of a drug 
product an updated manufacturing process occurs was 
added to this table. 
Assessment to be done after 
manufacturing process update. 
4.2 Study Rationale 
Addition of the following text was made to this section “and 
health authorities’ approval in accordance with local 
regulations’”. 
Clarify that with sponsor’s and health 
authorities’ approval the study 
duration extension beyond 9 years 
would be considered. 
6.1.1 Treatment period 
Beyond 5 years, PK testing will only occur upon 
introduction of a drug from a new manufacturing scale or 
an updated manufacturing process.  Description of the 
criteria to obtain PK sample collection was added.  
Assessment to be done after 
manufacturing process update. 
6.2 Interim Analysis 
Interim CSR to support regulatory approvals and/or other 
submission/application requirement(s) was added to this 
section.  
Clarify the plan for interim CSR. 
8.1.8 Treatment 
discontinuation 
Modify text for patient discontinuation due participating in 
another interventional investigational study. 
Clarify language regarding the 
approvals needed in case of protocol 
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Section # and Name 
Description of Change 
Brief Rationale 
amendment to adhere to Sanofi 
policy. 
9.1.15 Immune response 
assessments 
Sample collection of anti-olipudase alfa IgG antibodies 
was edited to describe if introduction of drug product from 
an updated manufacturing process occurs. 
Assessment to be done after 
manufacturing process update. 
9.3.8.3.1 Sampling time in 
adults 
For introduction of drug product from an updated 
manufacturing process, PK sample collection will only take 
place at the second infusion under the new manufacturing 
process update was added. 
Assessment to be done after 
manufacturing process update. 
9.3.8.3.2 Number of 
pharmacokinetic samples in 
adults, Table 9: Approximate 
number of plasma samples in 
adult patients 
Table updated to add number of PK samples to be taken 
at the second infusion on updated manufacturing process. 
Assessment to be done after 
manufacturing process update. 
9.3.8.4.2 Number of 
pharmacokinetic samples in 
pediatric patients, Table 11: 
Approximate number of 
plasma samples by pediatric 
age cohort 
Table updated to add number of PK samples to be taken 
at the second infusion on updated manufacturing process 
for adolescent, child, and infant/early child cohorts. 
Assessment to be done after 
manufacturing process update. 
9.5 Sampled Blood Volume 
Text is modified to reference additional table and to clarify 
action in case of multiple samples from the same 
assessment in the 3 pediatric cohorts. 
Explain blood samples needed and 
actions for assessments due to 
manufacturing process update. 
9.5 Sampled Blood Volume, 
Table 14: Additional 
approximate sampled blood 
volume in patients ages 12 to 
<18 years with an olipudase 
alfa updated manufacturing 
process 
Table added to show blood volume required in case of 
fracturing process update in patient aged 12 to <18. 
Clarify of blood volume calculation 
for manufacturing process update. 
9.5 Sampled Blood Volume, 
Table 18: Additional 
approximate sampled blood 
volume in the child cohort 
(6 to <12 years) and ages 
3 to <6 years with an 
olipudase alfa manufacturing 
process update 
Table added to show blood volume required in case of 
fracturing process update in the child cohort (6 to 
<12 years) and ages 3 to <6 years. 
Clarify of blood volume calculation 
for manufacturing process update. 
9.5 Sampled Blood Volume, 
Table 22: Additional 
approximate sampled blood 
volume in patients from birth 
to ≤2 years of age with 
an olipudase alfa 
manufacturing process 
update 
Table added to show blood volume required in case of 
fracturing process update in patients from birth to ≤2 years 
of age. 
Clarify of blood volume calculation 
for manufacturing process update. 
10.2.1 Home infusions 
“Updated manufacturing process” was added to criteria 
that must be met. 
Assessment to be done after 
manufacturing process update. 
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Section # and Name 
Description of Change 
Brief Rationale 
11.6.4 Analysis of 
pharmacokinetic and 
pharmacodynamic variables 
Add manufacturing process update option to PK analysis. 
Addition of manufacturing process 
update. 
11.7 Interim Analysis 
A formal summary of data or interim CSR may be 
produced to support regulatory approval(s) and/or other 
application submission requirement(s) was added to this 
section. 
Clarify the plan for interim CSR. 
15 Clinical Trial Protocol 
Amendments 
Addition of required criteria for written approval/favorable 
opinion of any amendment to the clinical trial protocol 
“also by regulatory authorities if substantial” was added to 
this section.  
This change was made to adhere to 
Sanofi policy. 
17 Appendices 
This entire section, including all subsections (17.1, 17.2, 
17.2.1, 17.2.2, and 17.2.3) were added to the amended 
clinical trial protocol.  
This change was made to adhere to 
Sanofi policy. 
17.2.4 Amended protocol 03 based on Protocol Amendment 03 (25 April 2018)
REASON FOR AMENDMENT:
1. Extend the study treatment period from 5 years to 9 years
In section(s): Clinical Trial Summary: Study Design, Duration of Study Period; 1 Study Flow 
charts (1.1 through 1.6 [former protocol amendment 2 sections 1.1 through 1.4]); 4.2 Study 
Rational; 6 Study Design; 6.1.1 Treatment Period; 6.3 Duration of Study Participation
Rationale:
LTS13632 was set to follow patients rolling over from previous adult study (Phase 1b) and 
Pediatric study (Phase 1/2). The objective is to assess long term safety and efficacy for 5 years or 
until marketing approval whichever comes first. So far, there was no marketing approval and no 
other treatment option available in the study countries.
This change aim to extend safety and efficacy follow up of the enrolled patients if they wish, for 
4 more years or until marketing approval whichever comes first. The treatment period will change 
from 5 years to 9 years to allow for better treatment options for patients at the end of treatment. 
It is also included in this change that if marketing approval was not available, extension of follow 
up beyond 9 years would be considered with sponsor’s approval.
Specific schedules of assessment for both adults and children populations in this extension period 
have been proposed.
2. Remove a redundant exclusion criterion
In section(s): Clinical Trail Summary: Study Population, Main Selection Criteria (Exclusion 
Criteria); 7.2.2 Exclusion criteria related to the current knowledge of the compound and condition
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Rationale:
The exclusion criterion number E 06 states that “The patient has an alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) >250 IU/L or total bilirubin >1.5 mg/dL”.
However, patients enter the study by rolling over from previous studies (adult Phase 1b and 
pediatric Phase 1/2) without any screening assessment before rolling over after end of treatment of 
the previous study. 
Moreover, Liver Functions are strictly followed in previous studies and this extension study via 
Dose Limiting Toxicities (DLTs) and Dose Stopping Criteria which are also reviewed by Data 
Monitoring Committee (DMC). 
Based on the above, EC 06 is redundant and this amendment proposes to remove.
3. Remove the option of another liver biopsy after 5 years treatment in adult 
patients
In section(s): 1.1 Flow Chart for Adults; 9.1.12 Liver biopsy for sphingomyelin in liver tissue 
(only patients who previously participated in the DFI13412 study)
Rationale:
In the current protocol (Protocol Amendment 2) it is indicated that an additional biopsy may take 
place at 5 years in the study, but only if necessary based on analysis of the 3 year biopsy for the 
group of adult patients.
The 3 year biopsy analysis of the adult patients did not show evidence suggestive of a progressive 
worsening of fibrosis to cirrhosis in patients treated with olipudase alfa. Hence it was decided that 
further biopsies after 5 years treatment is not needed.
4. Update the target number of patients to be approximately 25 instead of 17 
In section(s): Clinical Trial Summary: Total Expected Number of Patients; Statistical 
Considerations, sample Size Determination; 6 Study Design; 11.2 Determination of the Sample 
Size
Rationale:
All adult patients were recruited. This change serves to update the target number of patients 
according to Phase 1/2 pediatric (DFI13803) study amendment 4 (dated 21-Aug-2017), which 
plans to enroll approximately 20 patients, instead of 12.
5. Remove selected assessments from the flow chart list 
In section(s): 1.3 (former protocol amendment 2 Section 1.2) Flow Chart for Pediatric (Former 
DFI13803) Patients: Year 1; 1.4 (former protocol amendment 2 Section 1.2) Flow Chart for 
Pediatric (Former DFI13803) Patients: Year 2 Through Year 5; 9.3.3 Cycle ergometry; 
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Rationale:
Remove cycle ergometry in pediatric patients. The assessment has not provided any benefit to 
follow activities in children due to the difficult applicability and low compliance.
Remove Angiotensin Converting Enzyme measurement in both adult and pediatric populations. 
The assessment does not provide any benefit to follow efficacy or safety.
6. Add option to conduct a future additional questionnaire about home infusion 
experience to patients who received home infusion treatment 
In section(s): 9.1.2 Secondary endpoints (efficacy); 9.2.6.3 Additional questionnaires; 
10.2.1 Home infusions
Rationale:
This is a provision in the protocol of the option to conduct future additional short and one-time 
questionnaire about home infusion experience to patients who received home infusion treatment.
7. Add Differential liver DNA methylation densities of PPARɣ gene promoter in 
plasma ccfDNA
In section(s): Clinical Trial Summary (End Points), (Other endpoints); 9.1.3 Other endpoints; 
9.3.10 Differential liver DNA methylation densities of PPARɣ gene promoter in plasma
Rationale:
Differential liver DNA methylation of peroxisome proliferator-activated receptor gamma 
(PPARɣ) gene promoter has recently been shown to stratify patients in terms of fibrosis severity. 
Plasma DNA methylation signatures reflect the molecular pathology associated with fibrosis liver 
disease. Remarkably, PPARɣ hypermethylation correlated with progression to cirrhosis in 
alcoholic liver disease (ALD) and with specific stages of liver fibrosis in non-alcoholic fatty liver 
disease (NAFLD). DNA methylation markers at the human PPARɣ promoter detectable in 
circulating cell-free DNA (ccfDNA) display differential methylation densities and could 
potentially be used to non-invasively stratify liver fibrosis severity in patients with NAFLD.
(Hardy T, et al. Gut 2016;0:1-8. doi:10.1136/gutjnl-2016-311526 [downloaded Apr 11, 2016]  and 
Yi.it.B, et.al. Gut Epub ahead of print: doi:10.1136/ gutjnl-2017-315668 [downloaded Feb 26, 
2018])
In order to assess this potential biomarker in ASMD patients, it would be clinically useful to 
compare the differential methylation densities of the adult patients participating in the LTS13632 
study to base differential methylation densities while they were participating in the Phase 1b
(DFI13412) study.
Whenever possible, and if enough volume of left-over plasma is available at all time points of 
interest, plasma samples that were obtained at the same time of the liver biopsy performed at Year 
3 study visit will be used to assess ccfDNA differential methylation densities. These densities will 
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be compared with the samples taken from the same patients when they were participating in the 
Phase 1b (DFI13412) study, to detect change in fibrosis differentiation using this biomarker. In 
this way, there will be no additional blood draws or procedures added to the protocol.
8. Clarify language of collection of blood samples (beyond 5 years) and 
pharmacokinetics sample and analysis
In section(s): 1.6 (former protocol amendment 2 section 1.4) Study Flowchart: Pharmacokinetic 
sampling; 9.3.8 Pharmacokinetics; 9.3.8.3.1 Sampling time in adults; 9.3.8.4.1 Sampling time in 
pediatric patients; 9.5 Sampled Blood Volume
Rationale:
Clarify and update language to address study extension and clarify other procedures.
9. Clarify reporting guidelines of Adverse Events of Special Interest
In section(s): 10.5.2.5 Summary of adverse event reporting, table 22 (former protocol amendment 
2 table 17)
Rationale:
Adding AESI lab values to the relevant table
17.2.5
Amended protocol 02 based on Protocol Amendment 02 (25 April 2017)
REASON FOR AMENDMENT:
1. Change in assessments that will not be repeated at end of study/early discontinuation 
visit 
In section(s): 1.1, 1.3
Rationale:
Correction of error in previous section.
2. Dose calculation based on weight in site and home infusion visits
In section(s): 1.1, 1.2, 1.3
Rationale:
Weight change between visits is insignificant, therefore dose calculation using weight from 
previous site visit is allowed. In home infusion visit, the last weight taken on site will be used.
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3. Clarification of time points at which vital signs should be taken 
In section(s): 1.1, 1.2, 1.3
Rationale:
Time points added were missing from previous version.
4. Clarification of assessments needed upon manufacturing scale change
In section(s): 1.1, 1.2, 1.3, 1.4, 9.1.5, 9.2.1, 9.2.3, 9.3.8, 9.5, 10.2.1
Rationale:
Upon manufacturing scale change, certain assessments are requested by health authorities. Details 
were added in this amendment for clarification. 
5. Clarification of neurological examination
In section(s): 1.2, 1.3, 9.1.6.2
Rationale:
Clarify that same neurologist to perform neurological examination from any of previous studies 
through this study and all throughout this study if possible
6. Change in dose stopping (and AESI) criteria 
In section(s): 10.5.1.3.4
Rationale:
Correction of errors and clarify level of liver function criteria of dose stopping and AESI.
7. Addition of recommendation on usage of cationic amphiphilic antihistamines in rules 
on concomitant medications
In section(s): 8.6, 8.6.1
Rationale:
Addition of commonly used medications for clarification.
8. Clarification of IAR definition and treatment
In section(s): 8.6, 8.6.1
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Rationale:
Clarify language of IAR description and caution of IAR suggestive of hypersensitivity treatment 
about medications that may affect study medication efficacy.
9. Clarification of liver biopsy evaluation
In section(s): 9.1.12
Rationale:
Clarification of liver biopsy assessment language
10. Addition of future use of samples section
In section(s): 9.6
Rationale:
Missing from previous version
17.2.6 Amended protocol 01 based on Protocol Amendment 01 (23 March 2016)
REASON FOR AMENDMENT:
Changes listed in this section are regarded as “substantial” because they have a significant impact 
on:
x
The safety or physical or mental integrity of the patients,
x
The scientific values of the trial; or,
x
The conduct or management of the trial.
1. Change expected number of patients from “65-70 patients” to “up to 17 patients.
In sections: Clinical trial summary (Study population, Total expected number of 
patients), 6.
Rationale: This trial allows current patients to continue treatment.  Based on the number of 
patients in this trial and the DFI13803 pediatric trial, the maximum number of patients is 
already known to be 17.
2. Provide option for home infusions.
In sections: Clinical trial summary (Dose regimen), 8.1.1, 10.2.
Rationale: Patients are on stable doses that they have been tolerating well.  This provision 
eases the travel and hospitalization burden on patients without affecting patient safety.
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3. Provide specific guidelines on treatment “reintroduction” defined as management of 
patients who have missed 1 or more olipudase alfa doses.
In sections: Clinical trial summary (Dose regimen), 8.1.1, 8.1.5.
Rationale: Issue was not addressed in previous version.
4. Remove the requirement that the sponsor must be consulted to determine the 
appropriate dose of olipudase alfa for dose adjustments or if a patient misses 1 or 
more doses.
In section: Clinical trial summary (Dose regimen), 8.1.1, 8.1.4.
Rationale: Guidance on how to restart treatment when patients have missed consecutive 
doses is provided in Section 8.1.1 of the protocol.
5. Remove continuous heart rate monitoring as an endpoint.
In sections: Clinical trial summary (Endpoints, Primary endpoints, Data pertaining to the 
safety and tolerability of olipudase alfa), 1.1, 9.1.1, 9.2.
Rationale: Patients in the LTS13632 trial have all completed the dose escalation regimen. 
As such, they are outside the period where fluctuations of ceramide could lead to more 
severe adverse events. The results of continuous ECG monitoring to date from studies 
DFI13412 and LTS13412 have not revealed any clinically significant changes. Moreover, 
enzyme therapies, as a class effect, are not known to detrimentally effect cardiac function. 
As such, continuous ECG monitoring was removed.
6. Add these endpoints.
In sections: Clinical trial summary (Endpoints, Primary endpoints, Data pertaining to the 
safety and tolerability of olipudase alfa), 9.1, 9.2.2.1, 9.2.2.2, 9.2.7, 9.2.8, 9.2.9, 9.3, 9.3.7, 
9.3.8, 9.3.9, 9.4.2, 9.4.7, 9.4.9.1.
x
Primary:
-
Extended neurologic examinations in adults and pediatric patients,
-
Doppler echocardiography,
-
Liver biopsy (original adult patients),
-
Liver ultrasound with Doppler (pediatric patients).
x
Secondary:
-
Hand X-ray for bone age and bone maturation (pediatric patients),
-
Tanner staging (pediatric patients),
-
Linear patient growth by height Z--score (pediatric patients).
x
Other endpoints:
-
Cognitive and adaptive function (pediatric patients only, until age 6 years),
-
Bone biomarkers,
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Photographs (optional).
Rationale: These are relevant clinical endpoints for pediatric patients entering the trial, 
which were part of the primary pediatric study, and for continued evaluation of adult 
patients (eg, liver biopsy).
7. Specify that, “The term ‘pediatric patients only’ means patients coming from the 
original pediatric trial, DFI13803.  Some of these patients will reach adult age 
[18 years old] while in this study.  They will continue the assessments schedule they 
were on in the original trial.  These patients will be adults by age, but they will 
remain part of the “pediatric patient” cohort.” They will not follow the adult 
procedures in this study (eg, liver biopsy).
In sections: Clinical trial summary (Assessment schedule), 1.1, 9, 9.4.9.1.
Rationale: Pediatric patients will not have some baseline assessments for comparison 
(eg, liver biopsy, DXA of femurs and spine).  This statement is intended to clarify to site 
personnel which assessments pertain to adults and which to pediatric patients.
8. Add that for patients who missed 3 infusions or more infusions between trials, some 
assessments may be repeated at study entry after discussion between the sponsor and 
the investigator.
In sections: Clinical trial summary (Assessment schedule), 1.1.
Rationale: Since the rate at which sphingomyelin reaccumulates when olipudase alfa is 
interrupted, it may be necessary to repeat some efficacy assessments in case of prolonged 
investigational product suspension.
9. Add: “If a patient has missed 3 or more doses ≥0.6 mg/kg, reintroduction of 
olipudase alfa for patients receiving infusions at home should occur at the 
hospital/study site.  If a patient misses 2 or fewer doses, the investigator can decide 
whether reintroduction for patients receiving infusions at home should occur at the 
hospital/study site.”
In sections: Clinical trial summary (Dose regimen), 1.1, 8.1.1, 8.1.5.
Rationale: To ensure patient’s safety.
10. Add assessments for patients who require dose reintroduction.
x
Patients who require dose reintroduction will have these assessments at each 
infusion until reaching their usual dose of olipudase alfa:
-
Before infusion: vital signs, liver function tests, hematology, ECG, and safety 
biomarkers,
-
Immediately after infusion: vital signs and ECG,
-
24 hours: vital signs, liver function tests, and safety biomarkers,
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48 hours: vital signs, liver function tests, hematology, ECG, and safety 
biomarkers.
In sections: Clinical trial summary (Assessment schedule), 1.1, 8.1.5.
Rationale: To monitor patient safety during reintroduction.
11. Add that PK testing will only occur yearly and upon the introduction of a new 
manufacturing scale.
In sections: 1.2, 9.4.8.
Rationale: Provide appropriate and continuous monitoring, in particular for manufacturing 
scale changes.
12. Add that for a new manufacturing scale, if treatment is not interrupted, PK sample 
collection will take place at the patient’s last infusion under the current 
manufacturing scale and at the first infusion under the new manufacturing scale.
In sections: 1.1, 1.2, 9.4.8.
Rationale: To provide patients’ data on drug comparability.
13. Add that if a manufacturing scale change occurs, immune response assessments will 
be monthly for the first 6 months after starting the new scale, and quarterly after 
that.
In sections: 1.1, 1.2, 9.4.8.
Rationale: Per FDA request.
14. Add that in case reintroduction of olipudase alfa coincides with a manufacturing 
scale change, PK samples will be collected at the infusion at which patients receive 
their usual dose of olipudase alfa under the new manufacturing scale. 
In sections: 1.2, 9.3.8.
Rationale: To provide patients’ data on drug comparability.
15. Added PK sampling times, number of samples, and parameters in adults and 
pediatric patients.
In sections: 1.2, 9.3.8.3.
Rationale: Clarify the number of samples for adults and pediatric patients and when they 
will be obtained.
16. Added PK sampling time point at 96 hours for adults and pediatric patients.
In section: 1.2.
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Rationale: Allow comparison of PK in adults and pediatric patients.
17. Added PK total blood volumes for pediatric patients.
In sections: 1.2, 9.5.
Rationale: Specify maximum blood volume for blood samples per health authority 
requirement.
18. Add that the patients must be willing and able to avoid certain medications and 
herbal supplements for 10 days before and 3 days after liver biopsies.
In sections: 7.2.1, 8.6.
Rationale: Decrease the risk of bleeding from liver biopsies and to avoid liver toxicity.
19. Clarify patient stopping criteria.
In section: 8.1.7
Rationale: The role of the DMC in an emergency is to review safety data and recommend
stopping the study if necessary to ensure patient safety.  However, this does not limit the 
ability of investigators to make an immediate decision to discontinue dosing in an 
individual patient due to any AE that raises significant concern regarding the safety of 
olipudase alfa, as described in Section 8.1.6 of the protocol.
20. Remove O2 saturation from vital signs.
In section: 9.2.4.
Rationale: As part of this amendment to the protocol, dose escalation is not part of the 
trial.  Patients are on stable doses, and therefore monitoring without measuring 
O2 saturation is appropriate.
21. Change safety biomarker test from multiplex immunoassay to specific biomarkers 
including, but not limited to, hsCRP, iron, ferritin, cardiac troponin I, IL-6, IL-8,
plasma ceramide and calcitonin.
In sections: 9.2.5, 9.2.10.
Rationale: Given current knowledge about the study drug, broad immunoassay can be 
replaced by targeted testing.
22. Change the definition of overdose from “at least twice the intended dose within the 
intended therapeutic interval” to “an increase of at least 30% of the dose to be 
administered in the specified duration, or if the dose is administered in less than half 
the recommended duration of administration.”
In section: 10.5.2.3.1.
Rationale: To align with the investigator brochure and the Sanofi template
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SAP_001.pdf: 


Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................. 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objectives ............................................................................................................................ 6 
1.2.2 
Secondary objectives ....................................................................................................................... 6 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 6 
1.4 
STUDY PLAN ................................................................................................................................... 7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 7 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN........................ 7 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ....................................................................... 9 
2.1 
ANALYSIS ENDPOINTS .................................................................................................................. 9 
2.1.1 
Demographic and baseline characteristics ...................................................................................... 9 
2.1.2 
Prior or concomitant medications ..................................................................................................... 9 
2.1.3 
Safety endpoints ............................................................................................................................. 10 
2.1.3.1 
Adverse events............................................................................................................................... 10 
2.1.3.2 
Deaths ............................................................................................................................................ 12 
2.1.3.3 
Laboratory safety parameters ........................................................................................................ 12 
2.1.3.4 
Vital signs ....................................................................................................................................... 13 
2.1.3.5 
Electrocardiogram .......................................................................................................................... 13 
2.1.3.6 
Echocardiogram with Doppler ........................................................................................................ 13 
2.1.3.7 
Physical Examination ..................................................................................................................... 13 
2.1.3.8 
Extended Neurological Examination .............................................................................................. 14 
2.1.3.9 
Liver Biopsy (Patients from adult study DFI13412) ........................................................................ 14 
2.1.3.10 Liver ultrasound Doppler (Patients from pediatric study DFI13803) .............................................. 14 
2.1.4 
Efficacy endpoints .......................................................................................................................... 14 
2.1.4.1 
Abdominal magnetic resonance imaging ....................................................................................... 14 
2.1.4.2 
Pulmonary function tests ................................................................................................................ 15 
2.1.4.3 
Pulmonary imaging - high resolution computed tomography (HRCT) and Chest X-rays ............... 16 
2.1.4.4 
Pulmonary imaging - Chest X-rays ................................................................................................ 17 
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2.1.4.5 
Cycle ergometry ............................................................................................................................. 17 
2.1.4.6 
Physician’s global assessment ...................................................................................................... 17 
2.1.4.7 
Hematology .................................................................................................................................... 18 
2.1.4.8 
Fasting lipids (including Lipoproteins of Interest) ........................................................................... 18 
2.1.4.9 
Efficacy biomarkers ........................................................................................................................ 18 
2.1.4.10 Bone disease assessments (Patients from adult study DFI13412) ............................................... 18 
2.1.4.11 Bone biomarkers ............................................................................................................................ 19 
2.1.4.12 Bone age by hand X-ray (Patients from pediatric study DFI13803) ............................................... 19 
2.1.4.13 Tanner staging (Patients from pediatric study DFI13803).............................................................. 19 
2.1.4.14 Height Z-score (Patients from pediatric study DFI13803) .............................................................. 19 
2.1.5 
Pharmacodynamic endpoints ......................................................................................................... 19 
2.1.6 
Pharmacokinetic endpoints ............................................................................................................ 20 
2.1.7 
Health Outcome Measures ............................................................................................................ 20 
2.1.7.1 
For patients from adult study DFI13412 ......................................................................................... 20 
2.1.7.2 
For patients from pediatric study DFI13803 ................................................................................... 23 
2.1.8 
Cognitive and adaptive function testing (Patients from pediatric study DFI13803) ........................ 24 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 25 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 26 
2.3.1 
Safety population ............................................................................................................................ 26 
2.3.2 
Pharmacokinetic population ........................................................................................................... 26 
2.3.3 
Pharmacodynamic population ........................................................................................................ 26 
2.4 
STATISTICAL METHODS ............................................................................................................. 26 
2.4.1 
Demographics and baseline characteristics .................................................................................. 27 
2.4.2 
Baseline safety parameters ............................................................................................................ 27 
2.4.3 
Baseline efficacy parameters ......................................................................................................... 28 
2.4.4 
Baseline pharmacodynamic parameters ........................................................................................ 28 
2.4.5 
Prior or concomitant medications ................................................................................................... 28 
2.4.6 
Extent of investigational medicinal product exposure and compliance .......................................... 29 
2.4.6.1 
Extent of investigational medicinal product exposure .................................................................... 29 
2.4.6.2 
Compliance .................................................................................................................................... 29 
2.4.7 
Analyses of safety data .................................................................................................................. 30 
2.4.7.1 
Analyses of adverse events ........................................................................................................... 30 
2.4.7.2 
Clinical laboratory evaluations ........................................................................................................ 34 
2.4.7.3 
Vital signs ....................................................................................................................................... 35 
2.4.7.4 
Electrocardiogram .......................................................................................................................... 35 
2.4.7.5 
Echocardiogram with Doppler ........................................................................................................ 35 
2.4.7.6 
Physical examinations .................................................................................................................... 35 
2.4.7.7 
Extended neurological examinations ............................................................................................. 36 
2.4.7.8 
Liver biopsy (Patients from adult study DFI13412) ........................................................................ 36 
2.4.7.9 
Liver ultrasound Doppler (Patients from pediatric study DFI13803) .............................................. 36 
2.4.7.10 Safety biomarkers .......................................................................................................................... 36 
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2.4.7.11 Immune response assessments .................................................................................................... 36 
2.4.8 
Analyses of efficacy endpoints ....................................................................................................... 38 
2.4.8.1 
Spleen and liver volumes ............................................................................................................... 39 
2.4.8.2 
Pulmonary function testing ............................................................................................................. 39 
2.4.8.3 
Pulmonary imaging - high resolution computed tomography ......................................................... 40 
2.4.8.4 
Pulmonary imaging - Chest X-ray .................................................................................................. 40 
2.4.8.5 
Cycle ergometry ............................................................................................................................. 40 
2.4.8.6 
Physician’s global assessment of change ...................................................................................... 41 
2.4.8.7 
Hematology .................................................................................................................................... 41 
2.4.8.8 
Fasting lipids (including lipoproteins of interest) ............................................................................ 41 
2.4.8.9 
Efficacy biomarkers ........................................................................................................................ 42 
2.4.8.10 Bone disease assessments (Patients from adult study DFI13412) ............................................... 42 
2.4.8.11 Bone biomarkers ............................................................................................................................ 42 
2.4.8.12 Bone age by hand X-ray (Patients from pediatric study DFI13803) ............................................... 42 
2.4.8.13 Tanner staging (Patients from pediatric study DFI13803).............................................................. 42 
2.4.8.14 Height z-score (Patients from pediatric study DFI13803) .............................................................. 43 
2.4.8.15 Subgroup analyses for efficacy (Patients from pediatric study DFI13803) .................................... 43 
2.4.9 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 44 
2.4.9.1 
Pharmacodynamic analysis............................................................................................................ 44 
2.4.9.2 
Pharmacokinetic analysis ............................................................................................................... 44 
2.4.10 
Analyses of health outcome questionnaires and cognitive and adaptive function ......................... 44 
2.4.10.1 For patients from adult study DFI13412 ......................................................................................... 45 
2.4.10.2 For patients from pediatric study DFI13803 ................................................................................... 45 
2.5 
PATIENT NARRATIVES ................................................................................................................ 46 
2.6 
DATA HANDLING CONVENTIONS............................................................................................... 47 
2.6.1 
General conventions ...................................................................................................................... 47 
2.6.2 
Missing data ................................................................................................................................... 47 
2.6.3 
Windows for time points ................................................................................................................. 48 
2.6.4 
Unscheduled visits ......................................................................................................................... 48 
3 
INTERIM ANALYSIS ..................................................................................................................... 49 
4 
DATABASE LOCK ........................................................................................................................ 50 
5 
SOFTWARE DOCUMENTATION .................................................................................................. 51 
6 
REFERENCES ............................................................................................................................... 52 
7 
LIST OF APPENDICES ................................................................................................................. 53 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) CRITERIA .......... 54 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABAS-3: 
Adaptive Behavior Assessment System, Third Edition 
ADA: 
anti-drug antibody 
AESI: 
adverse events of special interest  
AP: 
alkaline phosphatase 
AUC0-inf: 
area under the concentration versus time curve from time 0 textraoplated to 
infinity 
BMI: 
body mass index 
CL: 
total body clearance 
Cmax: 
maximum plasma concentration 
CV: 
coefficient of variation 
DBP: 
diastolic blood pressure  
DBS: 
dried blood spots 
DP-3: 
Developmental Profile 3 
DXA: 
dual-energy X-ray absorption  
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
FEV1: 
forced expiratory volume in the first 1 second 
FVC: 
forced vital capacity 
HDL: 
high-density lipoprotein 
HR: 
heart rate 
LDL: 
low-density lipoprotein 
LLOQ: 
lower limit of quantification 
NE: 
not evaluable 
PCSA: 
potentially clinically significant abnormality 
PKDM: 
pharmacokinetics, dynamics and metabolism 
PT: 
preferred term 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure  
SD: 
standard deviation 
SEM: 
standard error of the mean 
SMPD1: 
acid sphingomyelinase gene 
SOC: 
system organ class 
t1/2z: 
terminal half-life 
tmax: 
time to reach Cmax 
ULN: 
upper limit of normal 
VAS: 
visual analogue scale 
VLDL: 
very low-density lipoprotein 
VSS: 
volume of distribution at steady state. 
WHO-DRUG: 
World Health Organization-Drug Dictionary  
WMW: 
Wilcoxon-Mann-Whitney 
 
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Statistical Analysis Plan  
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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical techniques to be used to analyze data from the study LTS13632 which is 
an extension study in the use of olipudase alfa in patients with acid sphingomyelinase deficiency 
(ASMD). It is based on Amended Clinical Trial Protocol 4, dated 31Jul2019. The purpose of the 
SAP is to ensure the credibility of the study findings by pre-specifying the statistical approaches to 
the analysis of study data prior to database lock. 
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a multinational, multicenter, nonrandomized, open-label, long-term treatment study of 
approximately 25 patients who have previously participated in a study of olipudase alfa. 5 adult 
patients rolled over from study DFI13412 into LT13632 study and approximately 20 pediatric 
patients are expected to roll over from study DFI13803. Patients will be enrolled directly into this 
study from their previous study. Enrolled patients will receive an IV infusion of olipudase alfa 
every 2 weeks for 9 years, or marketing approval, whichever comes first. If marketing approval 
was not available, extension of follow up beyond 9 years would be considered with sponsor’s 
approval. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to obtain data regarding the safety of olipudase alfa in 
patients with ASMD who are exposed to long-term treatment with olipudase alfa. 
1.2.2 Secondary objectives 
The secondary objectives of this study are to obtain data regarding the efficacy of olipudase alfa 
and to characterize olipudase alfa PD and PK following long-term administration. 
1.3 
DETERMINATION OF SAMPLE SIZE 
Sample size is determined by the number of patients who complete the treatment phase of 
a previous clinical study of olipudase alfa, sign the informed consent form, and meet the eligibility 
criteria. The sample size is expected to be 17 – 5 from the adult study, 12 from the pediatric study. 
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1.4 
STUDY PLAN 
After completion of treatment period in the previous study, patients or their parents/legal 
guardians (pediatric patients) will sign informed consent to continue treatment in this extension 
study, at the dose the patient completed the previous study. Patients are expected to transition to 
the long term study without treatment interruptions. Circumstances where there may be a gap 
between trials are foreseen in the protocol and treatment administration guidance is provided 
accordingly (for details, see the protocol). During the treatment period, patients will receive an 
IV infusion of olipudase alfa every 2 weeks for 9 years (or marketing approval, whichever comes 
first). If marketing approval was not available, extension of follow up beyond 9 years would be 
considered with sponsor’s approval. Safety and efficacy assessments will occur at regular 
3, 6, or 12 month intervals throughout the treatment period. Pharmacodynamic evaluations will 
occur every 3 months and PK evaluations will occur every 12 months. After treatment completion 
or premature withdrawal, an end-of treatment visit is scheduled in 2 weeks, and a safety follow-up 
phone call is scheduled in 30-37 days.  
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
In the section of statistical consideration of the Amended Clinical Trial Protocol 4 Section 11.6.3, 
treatment period is defined as time from first dose to the last dose of IMP +14 days. In this SAP, 
in order to incorporate the data from original study (ie, adult study DFI13412 or pediatric study 
DFI13803), the treatment period definition is changed to “the time from the first infusion of IMP 
(included) from original study to the end of the current study”.  
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
The SAP Version 2 was based on Amended Clinical Trial Protocol 1. This SAP is based on 
Amended Clinical Trial Protocol 4 (dated 31July 2019).  
 The post-treatment period has been removed from Section 2.1.3, since there is no 
pre-specified post-treatment period in the protocol. 
 The paired t-test was used for testing change from baseline and/or percent change from 
baseline. Because the baseline value is highly correlated with change from baseline and/or 
percent change from baseline, the paired t-test has been changed to analysis of covariance 
with baseline included as covariates as indicated in Section 2.4.8.  
 The definition of common TEAE, TEAE of infection, Hypersensitivity IARs and TEAE of 
bleeding are updated in Section 2.1.3.1. 
 Analyses of adverse events by place of infusion was added to this SAP in Section 
2.4.7.1.6. 
 Subgroup analyses for efficacy endpoints was added to this SAP for patients from 
DFI13803 in Section 2.4.8.15. 
 Patient narratives as described in Section 2.5 will be created, to replace various data listings.  
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 For Physician’s global assessment of change, the 7 categories will be converted to numeric 
values and summarized, as described in Section 2.4.8.6. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the latest available value before the first infusion in the original 
study except for hematology parameters and ECG parameters; the definition of baseline for these 
parameters could be found in Section 2.6.1.   
In addition to baseline parameters listed below, all baseline safety and efficacy parameters are 
presented along with the on-treatment summary statistics in the safety and efficacy sections 
(Section 2.4.7 and Section 2.4.8). 
Demographic characteristics 
Demographic variables are: gender (Male, Female); race (White, Black, Asian, American Indian 
or Alaska Native, Native Hawaiian or other Pacific Island, Other, Not reported, Unknown); age in 
years prior to first olipudase infusion at original study; ethnicity (Hispanic, non-Hispanic), 
Ancestry (Arab, Jewish, Turkish, Mediterranean, Eastern European, Dutch, South American 
Native Indian, Other, Not reported, Unknown), sub-ancestry for Jewish (Askhenazi, Sephardic, 
Unspecified) and for Mediterranean (Moroccan, Tunisian, Algerian, Other). This data will be 
cross-checked against the original study and should match. 
Medical history 
Medical history at the time of entry into this extension study will be collected by body system 
regarding the presence or absence of any condition, and whether the condition is current or past. In 
addition, medical history of special interest, eg, pneumonia, bronchitis, etc, to ASMD will be 
collected regarding presence of any such history. Substance abuse (smoking and alcohol) data are 
also collected. 
2.1.2 Prior or concomitant medications  
Medications are carried over from the original study when the medication is continuing at the time 
of the signing of informed consent or taken 30 days prior to the informed consent. Medications 
used before 30 days of signing of informed consent may be entered in the database at the 
discretion of the investigator. 
Concomitant medications will continue to be collected throughout the study until the final visit of 
the study. 
All medications will be coded using the World Health Organization-Drug Dictionary  
(WHO-DRUG) using the version in effect at Sanofi at the time of database lock. 
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All medications contained in the database of this study are considered concomitant medications 
since they are either continuing into or have started during this extension phase. During the study, 
certain antidepressants that may decrease olipudase alfa activity are prohibited; a detailed list is 
available in the study manual. This list is updated at least once a year with any change in 
WHO-DRUG versions. Cationic amphiphilic antihistamines, such as loratadine, desloratadine, 
astemizole, ebastine, terfenadine, and clemastine, may decrease olipudase alfa activity. Therefore, 
the need for their use in oral or IV administration should be carefully considered. For these 
medications, an exhaustive list cannot be provided, hence their use is left to the discretion of the 
investigator.  
Due to scheduled liver biopsies in adult patients, certain medications and herbal supplements can 
be hepatotoxic or can cause or prolong bleeding, and should not be taken within 10 days before 
and 3 days after the biopsy procedure. Potentially hepatotoxic medications or herbal supplements 
include, but are not limited to, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, 
erythromycin, valproic acid, antidepressants, kava, and echinacea. Medications that may cause or 
prolong bleeding include, but are not limited to, anticoagulants, ibuprofen, aspirin, garlic 
supplements, ginkgo, and ginseng. For these two classes of medications, exhaustive lists cannot be 
provided, hence their use is left to the discretion of the investigator. 
2.1.3 Safety endpoints 
The safety analysis will be based on the reported adverse events and other safety information, such 
as clinical laboratory data, vital signs, ECG, etc.  
Observation period  
The observation period in this study is the treatment epoch, which is defined as from the first 
infusion of IMP (included) from the original study to the latest available date of data in the current 
study. 
2.1.3.1 Adverse events  
Adverse events are defined in the protocol, Section 10.5.1.1. All adverse events (including serious 
adverse events will be coded to a lower-level term (LLT), preferred term (PT), high-level term 
(HLT), high-level group term (HLGT), and associated primary system organ class (SOC) using the 
version of Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at 
the time of database lock. 
Adverse events are recorded from the time of informed consent until the end of study. Any AE 
that has been ongoing in the original study at the time of informed consent in this study will be 
copied over to this study’s database and will be followed. 
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A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death, or 
 Is life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the patient 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), or 
 Requires inpatient hospitalization or prolongation of existing hospitalization, or 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect. 
 Is a medically important event. 
Adverse events of special interest (AESI) include: 
Protocol-defined IAR: Any AE that occur during the infusion or within up to 24 h after the start of 
the infusion and is considered related or possibly related to study treatment as judged by the 
investigator or the sponsor is defined as a protocol-defined IAR. An event occurring >=24 h after 
the start of an infusion may be judged an IAR at the discretion of the investigator or sponsor. 
Sponsor identification will reconcile with investigator identification of IAR before the database 
lock as much as possible. It is, however, possible that the sponsor identifies an AE as an IAR 
which the investigator did not agree to be an IAR. 
Hypersensitivity IARs: A subset of protocol-defined IARs will also be defined programmatically 
by searching for preferred terms within Hypersensitivity SMQs (ie, SMQ code 20000214 Broad 
and Narrow scope). 
Algorithm-defined IAR: All AEs that start between the start of infusion and the end of infusion 
plus 24 hours are defined as algorithm-defined IARs, irrespective of the perceived relation with 
study treatment. If an AE with missing time starts on the end of infusion date or on the following 
day, the AE will be considered an algorithm-defined IAR. 
Pregnancy: Pregnancy of a female patient enrolled in the study as well as pregnancy occurring in 
female partner of a male patient enrolled in this study are captured as an AESI.  
Symptomatic overdose: This is captured as an adverse event in this study. For details, please see 
Section 10.5.1.3.3 in the protocol.  
Quantifiable Dose Limiting Toxicities (DLT) defined based on laboratory values: The following 
laboratory values and symptoms will be considered as Quantifiable Dose Limiting Toxicities: 
 DLT1: Any increase in AST, ALT, total bilirubin, or AP >3x baseline (prior to olipudase 
alfa therapy) and > ULN. 
 DLT2: Any increase in total bilirubin or AP >1.5x baseline in the presence of AST or 
ALT > 2x ULN. 
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 DLT3: Any increase in ALT or AST >3x the ULN combined with an increase in ALT or 
AST >2x baseline (prior to olipudase alfa therapy) with symptoms of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia (> ULN). 
Adverse events of other interests include:  
 Infections: TEAEs under the system organ class of Infections and Infestations  
 Bleeding: TEAEs under the standard MedDRA queries (SMQs) of Hemorrhages 
(identified using SMQ code 20000038 broad and narrow scope). 
2.1.3.2 Deaths 
The death observation periods are defined below:  
 Death on-treatment: deaths occurring during the treatment epoch.  
 Death on-study: deaths occurring between informed consent date in this study and the end 
of the study. 
2.1.3.3 Laboratory safety parameters 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values will be converted into standard international units, and both 
US conventional units and international units will be used in all displays for continuous variables. 
The following clinical laboratory test results are assessed as part of safety profile: 
 Clinical chemistry: Sodium, potassium, calcium, chloride, blood urea nitrogen, creatinine, 
lactate dehydrogenase, total protein, albumin, glucose, phosphorus, and creatine kinase. 
These are scheduled for every 3 months. 
 Liver function tests: ALT, AST, AP, gamma-glutamyl-transferase, total bilirubin, and 
direct bilirubin. These are scheduled for every 3 months. 
 Hematology: Complete blood count with differential and platelet count, including 
hematocrit, hemoglobin, red blood cell, white blood cell, platelet, neutrophil, lymphocyte, 
monocyte, eosinophil, and basophil counts. These are scheduled for every 3 months. 
 Coagulation studies: Prothrombin time (Protime), partial thromboplastin time, 
international normalized ratio, and D-dimer. These are scheduled for every 3 months. 
 Urinalysis: Dipstick for glucose, protein, hemoglobin, leukocytes, ketones, and bilirubin. 
These are scheduled for every 3 month visit in this study. 
 Safety biomarkers: hsCRP, iron, ferritin, cardiac troponin I, IL-6, IL-8, ceramide in plasma 
and calcitonin. These are scheduled for every 3 month visit in this study. 
 Immune response assessments: anti-olipudase alfa IgG antibodies. These are scheduled for 
every 3 month visit in this study. 
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 If an IAR is anticipated to be a hypersensitivity reaction, additional laboratory parameters 
will be evaluated as soon as possible: tryptase activity and complementation activation, 
IgG and IgE. A skin testing may also be performed. 
 If an IAR is anticipated to be a cytokine release syndrome (CRS), additional laboratory 
parameters will be evaluated as soon as possible: IL-6, IL-8, calcitonin. 
2.1.3.4 Vital signs  
Vital signs are collected before and 1-hour after each infusion in this study; parameters 
include: heart rate, systolic and diastolic blood pressure, temperature and respiratory rate. Weight 
is collected before each infusion except in the case of home infusion, it is only collected in the 
previous site visit. Height is collected every six months of study treatment exposure for patients 
from DFI13803, and every 12 months into this study for patients from DFI13412. 
2.1.3.5 Electrocardiogram  
ECGs are manually read by an independent expert at the site. ECG parameters, including those 
related to QT intervals, are evaluated by a central laboratory. ECG is conducted for every 
6 months of exposure to study treatment.  
ECG parameters from the central laboratory will include interpretations related to:  
 Sinus, supraventricular and ventricular rhythm. 
 AV and intraventricular conduction. 
 Axis and voltage. 
 Chamber hypertrophy and enlargement. 
 ST-T abnormalities. 
 Ischemia and infarction. 
2.1.3.6 Echocardiogram with Doppler 
Echocardiogram with Doppler is scheduled for every 12 months (starting at 3 months in this study 
for pediatric patients). Examination will include, but not be limited to: ventricular cavity size, 
valve characterization, ejection fraction, ventricular wall thickness, regional wall motion, diastolic 
function, and pericardium characterization. Pulmonary blood pressure and blood flow will be 
determined by Doppler ultrasound. 
2.1.3.7 Physical Examination 
A complete physical examination is conducted for every 6 months (starting at 3 months in this 
study for pediatric patients), and an abbreviated physical examination (general appearance only) is 
performed pre- and post-infusion at 3-month visits that do not do complete exam. 
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2.1.3.8 Extended Neurological Examination 
An extended neurological examination is conducted every 12 months (starting at 9 months in this 
study for pediatric patients).  
2.1.3.9 Liver Biopsy (Patients from adult study DFI13412) 
Liver biopsy is done at screening, Week 26 and Year 3 for patients who previously participated in 
the DFI13412 study. Liver biopsies are evaluated by a Sanofi Genzyme pathologist for liver 
fibrosis grading and for sphingomyelin accumulation. Fibrosis staging will be performed using the 
Lathe pathology reports. Liver biopsy report will not be stored in clinical database, but be received 
by clinical personnel at the site and kept in the patient local study file. Data of fibrosis staging will 
be recorded and transferred as external data. Sphingomyelin accumulation in liver tissue that is 
assessed from liver biopsy will be discussed under pharmacodynamic endpoints (Section 2.1.5). 
2.1.3.10 Liver ultrasound Doppler (Patients from pediatric study DFI13803) 
Liver ultrasound Doppler is performed for patients transitioning from DFI13803. Ultrasound is 
performed at Screening and Week 52 in the original study, then every 6 months (starting at 
3 months in this study for pediatric patients) until 2 years, and yearly thereafter. This evaluation 
documents hepatic blood flow characteristics, principally portal vein pressure and blood flow 
direction. The structures to be examined include hepatic portal vein, the main hepatic artery and 
the main hepatic vein. Additional structures that may be examined include the network of 
intrahepatic portal veins, the main and intrahepatic arteries, the hepatic veins, the main and 
intrahepatic portal veins, the intrahepatic portion of the inferior vena cava, collateral venous 
pathways, and transjugular intrahepatic portosystemic shunts. Liver ultrasound Doppler will be 
performed using methods that are compatible with the standard institutional procedures of the 
investigational site. 
2.1.4 Efficacy endpoints 
Efficacy endpoints in this study are secondary endpoints. The schedule of data collection of these 
endpoints is described in the flow charts in Section 1.1 to 1.3 in the protocol. 
2.1.4.1 Abdominal magnetic resonance imaging 
Spleen and liver volumes will be assessed by abdominal MRI to quantify the degree of 
splenomegaly and hepatomegaly at approximately every 6 months for first 2 years in this study 
(starting at 3 months in this study for pediatric patients); for further details of timing, please refer 
to the protocol. The MRIs will be collected and read centrally by a third party blinded to patient 
number and study visit.  
The vendor will provide spleen and liver volumes in the unit of cubic millimeters. This will be 
converted to the standard unit of cubic centimeters for reporting purposes, by dividing by 1000. 
The analysis will also use the unit of Multiples of Normal (MN), and the algorithm used is as 
follows: 
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Spleen Volume (MN) = Spleen volume (cm3) / [2*weight (kg)] 
Liver Volume (MN) = Liver volume (cm3) / [25*weight (kg)] 
where weight is the available value closest to the MRI scan date. 
2.1.4.2 Pulmonary function tests 
Pulmonary function tests (PFT) will be performed in patients ≥5 years old at screening in the 
original study to measure lung volumes, air flow, and gas exchange for evidence of interstitial 
lung disease (ILD) at approximately every 6 months for first 2 years in this study (starting at 
3 months in this study for pediatric patients), and every 12 months thereafter; for further details of 
timing, please refer to the protocol. Completion of PFTs may depend on patient age or 
cooperation, or both. 
Pulmonary function testing will include, but will not be limited to, assessment of forced vital 
capacity (FVC), forced expiratory volume in the first 1 second (FEV1) of the FVC maneuver, and 
total lung capacity. Diffusing capacity of carbon monoxide (DLCO) will be used to measure gas 
exchange across the alveolocapillary membrane. Observed values of PFT parameters and DLco 
will be reported. Percent predicted values will be computed based on following algorithm (height 
and hemoglobin values are from the available ones closest to the PFT evaluation date/time, and 
age is calculated at the PFT evaluation date): 
Percent predicted values of FEV1 and FVC will use the Global Lung Initiative (GLI) 2012 
reference equations (1). 
Predicted TLC (Liters) will use the following formula for adults (2) and children (3) 
Adults (≥18 years of age):  
= 0.0795*height(cm) + 0.0032*Age(years) – 7.333 for males 
 
  
 
 
= 0.0590*height(cm) – 4.537 for females 
Children (<18 years of age): exp(24.67 - 4.91*ln(Height(cm)) – 7.16*ln(Age(months) 
+ 0.059*Sex + 1.47*ln(Height)*ln(Age)) 
Percent predicted TLC = 100*Observed TLC / Predicted TLC 
Percent predicted DLco will be computed as follows: (2, 4) and children (3, 4): 
Predicted DLco (adults), mL CO/min/mmHg: 
 
= 0.416*Height(cm) - 0.219*Age(years) - 26.34 for males 
= 0.256*Height(cm) - 0.144*Age(years) - 8.36 for females 
Predicted Dlco (children), mmol/min/kPa (Sex: 0=female, 1=male): 
= exp(34.80 - 6.89*ln(Height(cm)) – 8.66*ln(Age(months)) + 0.10*Sex 
+ 1.79*ln(Height)*ln(Age)) 
Unit conversion: mL CO/min/mmHg = mmol/min/kPa*2.987 
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Hb-adjustment factor (to be applied to DLco in unit of mL CO/min/mmHg) 
= 1.7*Hb(g/L) / [10.22 + Hb] for males, or children 15-18 yrs 
= 1.7*Hb(g/L) / [9.38 + Hb] for females, or children <15 yrs 
DLco adjusted for Hb = Observed DLco/HB-adj factor 
Percent predicted (Hb-adjusted) DLco = 100*DLco adjusted for Hb / Predicted DLco 
2.1.4.3 Pulmonary imaging - high resolution computed tomography (HRCT) and Chest X-
rays 
High-resolution computed tomography scans of the chest will be obtained at approximately every 
12 months (starting at 9 months in this study for pediatric patients); for further details of timing, 
please refer to the protocol. This evaluation is meant to quantify the degree of possible interstitial 
lung disease (ILD). 
Images will be collected centrally by a medical imaging core laboratory where they will be 
digitized and coded and read by a third party blinded to patient number and study visit. The mean 
density will be calculated at each lung level using standard HRCT software. The lung fields will 
be assessed by a central reader and scored subjectively for the degree of ILD (0=normal, 1=mild, 
2=moderate, or 3=severe). 
The bilateral lung boundaries are determined from the following 4 pre-defined levels on the 
HRCT images. 
 Level 1 includes the aortic arch. 
 Level 2 includes the carina. 
 Level 3 is midway between the carina and 1 centimeter above the hemidiaphragm. 
 Level 4 is 1 centimeter above the hemidiaphragm. 
A qualitative assessment will be made of the ILD, ground glass appearance, reticular, nodular 
density, and pleura thickening of the right and left lungs for each pre-defined levels above 
according to the following criteria: 
 0 = No disease. 
 1 = Mild (affecting 1% to 25% of the lung volume). 
 2 = Moderate (affecting 26% to 50% of the lung volume). 
 3 = Severe (affecting 51% to 100% of the lung volume). 
 NE = Not evaluable. 
The mean scores at each scheduled visit for each of the 4 qualitative assessments are calculated as 
follows: 
 Mean score across levels for left (or right) lung = Sum of scores for X levels for left 
(or right) lung / X 
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 Mean score across 4 levels and both lungs = (Mean score across X levels for left lung 
+ Mean score across X levels for right lung)/2. Pulmonary imaging – chest X-ray 
2.1.4.4 Pulmonary imaging - Chest X-rays 
A chest X-ray (posterior-anterior and lateral views) will be performed at selected sites at 
approximately every 12 months (starting at 9 months in this study for pediatric patients); for 
further details of timing, please refer to the protocol. 
Chest X-rays will be collected at the site and sent to a medical imaging core laboratory where they 
will be digitized (if not already done at the site), coded, and read by a third-party reader blinded to 
patient number and study visit. The lung fields will be scored subjectively for the degree of 
ILD - interstitial, reticular, nodular density, and pleura thickening of the right and left lungs 
separately for each pre-defined levels above according to the following criteria: 
 0 = No infiltrative lung disease. 
 1 = Mild (affecting 1% to 25% of the lung volume). 
 2 = Moderate (affecting 26% to 50% of the lung volume). 
 3 = Severe (affecting 51% to 100% of the lung volume). 
Mean score across both lungs = Sum of 2 lung scores / 2Cycle Ergometry 
Cycle ergometry is performed at every 6 months (starting at 3 months in this study for pediatric 
patients) for first 2 years in this study, and yearly thereafter; for details refer to the protocol. For 
patients transitioning from DFI13803, this assessment is not required during LTS in patients that 
are ≤6 years of age or <120 cm in height on Day 1/Week 0 in the original pediatric study, and is 
performed only in patients who have completed these assessments in DFI13803. Completion of 
the assessment may depend upon patient cooperation. 
2.1.4.5 Cycle ergometry 
Cycle ergometry assessments will include maximum workload (watts), maximum percent 
predicted workload (%), working time (min), maximum heart rate (breaths/min), maximum 
percent predicted heart rate (%), maximum O2 saturation (%), maximum respiratory rate 
(breaths/min), maximum ventilation (L/min), maximum O2 uptake (mL/min), maximum percent 
predicted O2 uptake (%), maximum CO2 output (mL/min), and maximum respiratory exchange 
ratio. maximum tidal volume (mL) and maximum percent predicted tidal volume (%) will be 
assessed for patients transitioning from study DFI13803. 
2.1.4.6 Physician’s global assessment 
The physician’s global assessment of the patient’s progress will be evaluated every 6-months 
(starting at 3 months in this study for pediatric patients) for first 2 years in this study, yearly 
thereafter; for details, refer to the protocol. The investigator evaluates the patient’s current clinical 
status compared with screening (baseline) by marking 1 of 7 categories: “marked improvement of 
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daily activities”, “moderate improvement of daily activities”, “mild improvement of daily 
activities”, “no change”, “mild worsening of daily activities”, “moderate worsening of daily 
activities” or “marked worsening of daily activities”.  
2.1.4.7 Hematology 
The clinical laboratory parameters of platelets and hemoglobin are considered as efficacy 
evaluations. Blood samples are collected for these evaluations at each scheduled clinic visit every 
6 months (in addition to hematology sample of complete blood count).  
2.1.4.8 Fasting lipids (including Lipoproteins of Interest) 
Fasting lipids evaluations are done at each scheduled clinic visit at every 3 months for first 2 years 
in this study, every 12 months thereafter. The parameters include: total cholesterol, LDL, HDL, 
VLDL, triglycerides, apolipoprotein B, apolipoprotein A1, and lipoprotein [a]. 
2.1.4.9 Efficacy biomarkers 
Serum chitotriosidase, ligand 18 (CCL-18), and ACE are evaluated every 3-months in the study.  
2.1.4.10 Bone disease assessments (Patients from adult study DFI13412) 
2.1.4.10.1 Bone marrow burden (BMB)  
This is assessed only for patients who transition from DFI13412 at every 12 months into this 
study; this assessment is not done on patients who transition from the pediatric study DFI13803. 
An MRI of lumbar spine and bilateral femur is performed, and three parameters are evaluated for 
each region: T1 weighted score, T2 weighted score, extent of involvement - femur only, 
infiltration pattern - spine only. The scale of these results is as follows: 
T1 score: 0=Slightly hyperintense or isointense, 1=Slightly hypointense, 2=Hypointense  
T2 score: 0=Isointense, 1=Slightly hypointense or slightly hyperintense, 2=Hypointense or 
hyperintense, 3=Mixed type  
Extent of Involvement: 0=No site involvement, 1=Diaphysi, 2=Proximal epiphysis/apophysis, 
3=Distal epiphysis  
Infiltration Pattern: 0=None, 1=Patchy, 2=Diffuse, 3= Fat surrounding the basivertebral vein  
Total BMB score for each region is derived by adding up the three individual score. Total BMB 
score is derived by adding the total BMB score of two regions, and ranges from 0 to 
16 [0 to 4: mild; 5 to 8: moderate; 9 to 16: marked to severe]. 
2.1.4.10.2 Dual-energy X-ray absorption (DXA) parameters) 
This is assessed only for patients who transition from DFI13412 at every 12 months into this 
study; this assessment is not done on patients who rollover from the pediatric study DFI13803. 
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DXA of lumbar spine and bilateral femur is performed, and three parameters are evaluated for 
each region (and for left and right side separately for bilateral femur): Bone mineral density 
(BMD), T-score and Z-score. The scale of these results is as follows: 
BMD: a numerical value in the unit of g/cm2 
T-score: [score >= -1] = Normal, [score > -2.5 to < -1] = Osteopenia, [score <= -2.5] = Osteoporosis 
Z-score: [score > -2] = Normal, [score <= -2] = Below normal 
A total score for bilateral femur is obtained by averaging the two side scores. 
2.1.4.11 Bone biomarkers  
Bone-specific Alkaline phosphatase and C-telopeptide levels are evaluated every 3-months in the 
study. 
2.1.4.12 Bone age by hand X-ray (Patients from pediatric study DFI13803)  
A hand X-ray is performed for patients who transition from DFI13803 study at Screening and 
Week 52 in the original study, and will continue every 6 months of exposure to olipudase alfa. 
Bone age will be provided by the central vendor - BioClinica; they will use calculations based on 
the Greulich & Pyle Atlas (5).  
2.1.4.13 Tanner staging (Patients from pediatric study DFI13803) 
Tanner stage for physical gender-related development is assessed for patients who transition from 
DFI13803 study. It is performed at Screening and every 3 months after first infusion until 
Week 52 in the original study, then continue every 6 months of exposure to olipudase alfa.  
2.1.4.14 Height Z-score (Patients from pediatric study DFI13803) 
This endpoint, reflecting failure to thrive, is specific to patients transitioning from pediatric study 
DFI13803. Patient height is collected at screening and within 24 hours prior to every infusion visit 
in the original study, then every 6 months in the extension study. Z-score is the normalized value 
when compared to mean and standard deviation of height of children considered to have normal 
growth, based on gender and age: [height – normal mean(height)]/normal SD (height). The normal 
levels are provided by World Health Organization list from 2007. Height z-score will be 
calculated and categorized using the number and percentage of patients in <= -4, > -4 to <= -3.5,  
> -3.5 to <= -3, > -3 to <= -2.5, > -2.5 to <= -2, > -2 to <= -1.5, > -1.5 to <= -1 and > -1. 
2.1.5 Pharmacodynamic endpoints  
The following parameters are evaluated every 3 months in this study:  
 Ceramide levels in dried blood spot. 
 Sphingomyelin levels in both plasma and DBS. 
 Lyso-sphingomyelin levels in both plasma and DBS. 
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 Sphingosine-1-phosphate in both plasma and DBS. 
 For patients from adult study DFI13412, Sphingomyelin accumulation is evaluated from 
liver tissue collected during liver biopsy at screening, Week 26 and Year 3.  
2.1.6 Pharmacokinetic endpoints 
Pharmacokinetic parameters will include Cmax, tmax, and AUC0-ᴛ. If applicable, t1/2z, CL, and V 
will be derived.  
2.1.7 Health Outcome Measures 
There are several health outcome questionnaires used in this study. The pediatric questionnaires 
are often age-specific, and may require response by parents (in addition to or in lieu of patient 
response). Pediatric patients transitioning to this extension study will start with the questionnaire 
appropriate for the age at entry, and will fill in questionnaire appropriate to the age at the time of 
completion of such questionnaire. 
2.1.7.1 For patients from adult study DFI13412 
These questionnaire data are collected every six months (at visits) since the original study 
DFI13412 until 2 years into this extension study, and yearly thereafter. 
 The Brief Fatigue Inventory (BFI) is a validated, self-administered questionnaire to assess 
fatigue (originally developed for cancer patients), and uses numeric rating scales from 
0 to 10 for 9 items in the scale. Patients are asked in 3 items to rate the severity of their 
fatigue at its worst, usual (these two with a recall period of 24 hours), and now; the 
response ranges from 0=“No fatigue” to 10=“Fatigue as bad as you can imagine”. The 
extent that fatigue has interfered with different aspects of the patient's life (including 
general activity, mood, walking ability, normal work – both in and outside of home, 
interpersonal relationship, and enjoyment of life) is assessed in 6 items with a recall period 
of 24 hours. 
- 
The two parts are scored separately (6). A scale score is generated for fatigue severity 
as the average of individual questions in the scale. If 2 out of 3 items are available, the 
item scores are averaged to provide fatigue severity scale score; if less than 2 item 
scores are available, the scale score is left missing. A scale score is generated for the 
fatigue interference score as the average of individual questions in the scale as long as 
at least 4 out of 6 items have non-missing response; otherwise, this scale score for the 
patient is left as missing. 
 The Brief Pain Inventory – Short Form (BPI-SF) is a validated, self-administered 
questionnaire designed to measure a patient’s perceived level of pain. The BPI-SF 
measures the patient’s intensity of pain (sensory dimension), the interference of pain in the 
patient’s life (reactive dimension), and asks the patient about pain relief, pain quality, and 
the patient’s perception of the cause of pain. The BPI-SF consists of 15 items.  
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 The scoring is based on 4 out of 8 questions in the pain severity domain, and 7 questions in 
the pain interference domain, which uses numeric scale (7). Pain severity questions ask for 
the experience of pain at its worst, at the least, on an average (all with a recall period of 
24 hours) and right at the moment; the response ranges from 0=“No pain” to 10=“Pain as 
bad as you can imagine”. Pain interference questions deal with general activity, mood, 
walking ability, normal work (both in and outside of home), interpersonal relationship, 
sleep and enjoyment of life – all with a recall period of 24 hours; the response ranges from 
0=“Does not interfere” to 10=“Completely interferes”. The two parts are scored separately. 
A scale score is generated for pain severity as the average of individual questions in the 
scale as long as 2 or more items in that scale has non-missing response; otherwise this 
scale score is left missing. A scale score is generated for pain interference as the average of 
individual questions in the scale as long as at least 50% of the questions (4 out of 7) have  
non-missing response; otherwise, this scale score for the patient is left as missing.  
 The Chronic Respiratory Disease Questionnaire Self-Administered Standardized 
(CRQ-SAS) is a validated, self-administered questionnaire designed to evaluate health 
related quality of life in adult patients with chronic airflow limitation, chronic respiratory 
disease, and cystic fibrosis (8). The CRQ-SAS has 20 items and evaluates 4 dimensions of 
respiratory impairment, including dyspnea, fatigue, emotional function, and the patient's 
feeling of control over the disease (mastery). Each item is answered in a seven-point-scale, 
with 8 reserved for “not done”. 
DYSPNEA:  
 
 
q’s 1, 2, 3, 4, 5 
FATIGUE: 
 
 
q’s 8, 11, 15, 17 
EMOTIONAL FUNCTION: 
q’s 6, 9, 12, 14, 16, 18, 20 
MASTERY: 
 
 
q’s 7, 10, 13, 19 
The scores for each question of each dimension are added and divided by the number of 
questions. Thus, using a seven-point scale for the responses, the minimum and maximum 
scores for each dimension is the same: 1 is the worst and 7 is the best. Only items that are 
answered will be scored. Therefore, items that are scored as “not done” (or left blank) will 
not be included in the summary (average) score. The average score of the completed items 
will be reported. 
 The SF-36 is a 36-item, validated, multidimensional, generic health-related quality of life 
measure that has been validated for adults in numerous healthy and ill populations 
internationally. The SF-36 consists of 36 questions, 35 of which constitute 8 scales, 
including physical functioning, role physical, bodily pain, mental health, role emotional, 
social functioning, vitality, and general health. The questionnaire will also generate 
2 summary measures known as physical health component score and mental health 
component score. 
 SF-36 scale responses are numeric in value and is transformed to a 0-100 scale with higher 
number indicating better health-related quality of life (9). Q2 is not considered a part of 8 
scales to be reported. Physical and mental health component scores are provided in a 
normalized form based on the normal population. The scoring of SF-36 will be contracted 
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out to its manufacturer Quality Metrics, which will provide the final scores of each domain 
for each patient at each time point. 
 
Scale 
Question # 
Physical functioning 
3a: vigorous activities 
 
3b: moderate activities 
 
3c: Lifting/carrying groceries 
 
3d: Climbing several flights of stairs 
 
3e: Climbing one flight of stairs 
 
3f: Bending/kneeling/ stooping 
 
3g: Walking >1 mile 
 
3h: Walking several hundred yards 
 
3i: Walking 100 yards 
 
3j: bathing/dressing 
Role physical 
4a: Cut down time on work/activity, physical 
 
4b: Accomplished less, physical 
 
4c: Limited in kind of work/activity, physical 
 
4d: Difficulty performing work/activity, physical 
Bodily Pain 
7: Pain intensity 
 
8: Pain interference 
General health 
1: health condition 
 
11a: Get sick easy 
 
11b: Heathy 
 
11c: Health get worse 
 
11d: Health excellent 
Vitality 
9a: Full of life 
 
9e: Lot of energy 
 
9g: Worn out 
 
9i: Tired 
Social functioning 
6: Extent with social interference 
 
10: Frequency with social interference 
Role emotional  
5a: Cut down time on work/activity 
 
5b: Accomplished less 
 
5c: Less careful with work/activity 
Mental health 
9b: Very nervous 
 
9c: Down in dumps 
 
9d: Calm/peaceful 
 
9f: Downhearted/depressed 
 
9h: Happy 
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 The Niemann-Pick B Health Assessment Questionnaire (NPB-HAQ), Version 2 is 
a disease-specific questionnaire that covers various aspects of fatigue, pain, respiratory, 
abdominal complaints, and quality of life, and questions specific to ASMD symptoms and 
physical activity. The questionnaire also includes items to gather information on patient 
utilization of care and caregiver support. This question has been developed internally by 
Genzyme (data on file). 
 Three domains have been identified: resource utilization, physical activity and symptoms. 
Questions 9-13 (5 questions) have been identified to be included in the resource utilization 
domain; they ask about missed work days, hospital visits, hospital stay, medical device 
use, supplemental medical service use – all with a recall period of past one year. There are 
17 different symptoms assumed common and bothersome to ASMD patients; a patient is 
to rate each symptom in a scale of 0-4 with 0=“Not a problem” and 4 is the worst 
severity/bother. Physical activity domain consists of two questions – one asking for 
frequency of participation in sports or physical exercise in past one month, the other asking 
about the specific sports/physical activity the patients regularly participates in.  
2.1.7.2 For patients from pediatric study DFI13803 
These questionnaires are collected every 6 months for first 2 years in this study, yearly thereafter. 
 The Pediatric Quality of Life (PedsQL) Generic Core scale is a brief, standardized, generic 
assessment instrument that systematically assesses patients' and parents' perceptions of 
health-related quality of life in pediatric patients with chronic health conditions (10). The 
PedsQL consists of a 23-item core measure including a self-report for children aged 5 to 
18 years and for young adults aged 18 to 25 years. A report for parents of patients from 
birth to 25 years of age is also available. This data is collected at screening, then every 
6 months until 2 years in this study, then yearly thereafter. 
In both patient and parent reports it measures four scales: Physical Functioning (8 items), 
Emotional Functioning (5 items), Social Functioning (5 items), and School Functioning 
(5 items). Psychosocial scale considers all questions in emotional, social and school 
functioning scales. The total scale considers all questions in the questionnaire, irrespective 
of individual scales. Each item in every scale uses the 4-point rating scale (0=never to 
4=almost always). The algorithm of Scale Scores is as follows:  
1. The score is first reversed in a scale of 0-100: 0=100, 1=75, 2=50, 3=25, 4=0. A higher 
score indicates better Health-Related Quality of Life. 
2. If more than 50% of the items in the scale are missing, the Scale Score is not 
computed. If 50% or more of the items in the scale are completed, Scale Score is 
computed as the arithmetic average of the items answered. 
 The PedsQL Multidimensional Fatigue Scale (10) consists of 18 questions, 6 regarding 
general fatigue, 6 regarding sleep/rest fatigue, and 6 regarding cognitive fatigue. It includes 
a self-report for children aged 5 to 18 years and for young adults aged 18 to 25 years. A 
report for parents of patients aged 2 to 25 years is also available. This data is collected at 
screening, then every 6 months until 2 years in this study, then yearly thereafter. Similar to 
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the PedsQL generic core scale, each item uses a scale of 0-4 for response, 0 indicating 
“never” and 4 indicating “almost always”. The scale scores are computed using an 
algorithm. 
 The PedsQL Pediatric Pain Questionnaire (10) consists of 3 questions that include a child 
self-report for patients aged 5 to18 years and a proxy report for parents of patients aged 
5 to 18 years. These same questionnaires will be used for patients aged 18 to 25 years 
because questionnaires are not available for young adults. This data is collected at 
screening, then every 6 months until 2 years, then yearly thereafter. 
 The first item is the degree of present pain, the second item is the degree of the worst pain, 
and the third item refers to the localization of pain and is not scored. The first two items 
will be scaled using visual analogue scales (VAS) from 0 (Not hurting/No discomfort/No 
pain) to 100 mm (Hurting a whole lot/Very uncomfortable/Severe pain). The present pain 
and worst pain are scored separately. The scores are based on line length to the nearest 
5 mm. There is no imputation process since these are single item VAS scales. 
2.1.8 Cognitive and adaptive function testing (Patients from pediatric study DFI13803) 
Developmental Profile 3 (DP-3): 
The Development profile questionnaire, Version 3 (DP-3) (11) is used for measuring cognitive 
function in patients age <6 years at entry into this study. The number of items to be answered on 
each content area of the DP-3 depends on the patient’s age and functional level. For example, 
parents of patients who are ages 4 years to 6 years answer 23 items. For each content area 
(Physical, Adaptive Behavior, Social-Emotional, Cognitive, Communication), the raw score 
indicates the number of developmental items the subject is credited for being able to complete.  
The DP-3 assessments are centrally scored to generate the General Development Score. For each 
content area and the General Development Score, standard scores, confidence intervals, 
descriptive categories, and percentile ranks are generated. For each content score, age-equivalence 
is generated.  
This data is collected at screening of the original study, then every 6 months until 2 years into this 
study, then yearly thereafter until the patient turns 6 years of age.  
Adaptive Behavior Assessment System, Third Edition (ABAS-3): 
Adaptive behavior assessment system, version 3 (ABAS-3) (12) consists of several age-specific 
rating forms; for this study, the Parent/Primary Caregiver Form (Ages 0-5) and Parent Form 
(Ages 5-21) will be used. The ABAS-3 measures adaptive behavior at three different levels. At the 
highest level is the General Adaptive Composite, which is composed of all measured skill areas. 
The next level are three adaptive domains, each comprising multiple individual skill areas; these 
domains are Conceptual, Social, and Practical. At the third level are individual adaptive skill 
areas. For each adaptive skill area, the raw score is the sum of item behavior frequency ratings for 
all items.  
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The ABAS-3 assessments are centrally scored to generate scaled scores for each adaptive skill 
area. The scaled scores are utilized to generate a standard score, percentile rank, and confidence 
interval for the General Adaptive Composite and three adaptive domains (Conceptual, Social, and 
Practical).  
This data is collected at screening of the original study, then every 6 months until 2 years into this 
study, then yearly thereafter until the patient turns 6 years of age.  
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for patient study status. 
Enrolled patients are those who signed the informed consent for this study and met all enrollment 
criteria for this study. Number and percentage (calculated based on the number of patients who 
have completed the treatment period of the original study on schedule) of enrolled patients will be 
provided. Patients who have received one infusion of olipudase alfa in this extension phase, those 
who are continuing in the study at the time of reporting, those who completed the study and those 
who prematurely discontinued the study will be summarized; percentage will be calculated based 
on the number of enrolled patients. The reason for premature discontinuation will also be 
provided.  
Protocol deviations 
During the review of the database, compliance with the protocol will be examined with regard to 
inclusion and exclusion criteria, treatment, prohibited therapies, and timing and availability of 
planned assessments. Protocol deviations will be identified by the study team before database lock 
and classified as minor, major or critical deviations, in consideration of whether this could 
potentially affect efficacy assessment endpoints. A listing of major or critical protocol deviations 
for all treated patients will be produced.  
In addition to the above, the two conditions listed below will be evaluated:  
Noncompliance: Missing 4 or more infusions for each 12 month period in this study, excluding 
for-cause missed infusions (such as when the missed infusions are required by the protocol due to 
a dose limiting toxicity), calculated over the extension phase only. Whether a missed infusion is 
for-cause or not will be reviewed and determined by the clinical team; the decision will be used in 
the determination of noncompliance. For details of calculations, please refer to Section 2.4.6.2. 
Prohibited medications intake: The prohibited medications in this study have been defined in 
Section 2.1.2. The prohibited medication use that could potentially modify the effect of olipudase 
alfa (which includes, but not limited to, certain antidepressant) or could threaten the safety of 
olipudase alfa are major protocol deviations. 
The protocol deviations identified by the review of the above two conditions will be listed for all 
treated patients as protocol deviations.  
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2.3 
ANALYSIS POPULATIONS 
2.3.1 Safety population 
All subjects who were exposed to the study treatment, olipudase alfa, ie, who received at least one 
infusion of study treatment (total or partial), will be included in the safety population. 
2.3.2 Pharmacokinetic population 
The pharmacokinetic population includes all patients who receive at least 1 infusion of olipudase 
alfa and have evaluable pharmacokinetic data available post-baseline.  
2.3.3 Pharmacodynamic population 
Pharmacodynamic population includes all patients who are treated and have at least one evaluable 
pharmacodynamic measurement available post-baseline.  
2.4 
STATISTICAL METHODS 
Data collected in this study will be presented using summary tables, figures, and data listings. 
Descriptive statistics for categorical variables will be provided using frequencies (n) and 
percentages (%). Descriptive statistics for continuous variables will be provided using number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum. All data used 
in tabular summaries or figures will be supported by listings of underlying data – raw and/or derived, 
and all figures will be supported by relevant summary information. 
All summaries will be provided for the LTS population, along with separate subgroups in the 
population according to which original study the patient belonged to: DFI13412 (adult study, 
Phase 1B, 26 weeks, 5 patients), DFI13803 (pediatric study, Phase 1/2, 64 weeks, 12 patients). In 
addition, similar summaries will be produced by age cohort of adolescent, child, infant for the 
patients who transition from pediatric study DFI13803. 
The scheduled visits in statistical displays will be labelled in months of total follow up time from the 
first infusion in the original study. For example, a 6-month visit in this study for a patient 
transitioning from the 26-week DFI13412 study will be identified as Month 12 exposure in the 
displays. The schedule of measurements for this study will be followed for display presentation with 
baseline derived from the original study. For patients in this study, the results from the original study 
visits will be included, unless specified otherwise, for the purpose of understanding the continuity of 
treatment effect during this extension phase; for details and descriptions of all results from the 
original study, please refer to the original study CSR. For parameters that are not collected in the 
extension phase will not be part of this SAP. 
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2.4.1 Demographics and baseline characteristics 
Demographic and baseline characteristics, medical history and smoking/alcohol history from 
original study will be summarized using the safety population. 
Genotype of acid sphingomyelinase gene (SMPD1), CHIT1, UGT1A1 will also be summarized 
with baseline disease characteristics, and be provided in data listings.  
The SMPD1 variant type (ie, missense, frameshift, deletion, nonsense, etc) will be derived, if 
possible, from the SMPD1 amino-acid change.  
For the classification of CHIT1 genotype, the following derivation will be applied:  
 N = Wildtype (WT)/WT = Normal / 2 functional alleles  
 H = WT/Duplication 24 (DUP24) = Heterozygous mutation / 1 functional allele  
 M = DUP24/DUP24 = homozygous mutation / 2 non-functional alleles (no chito activity)  
For the classification of UGT1A1 genotype, the following derivation will be applied:  
 UGT1A1*1 = Fully functional allele = Not Gilbert variant  
 UGT1A1*36 = Functional allele = Not Gilbert variant  
 UGT1A1*28 = Gilbert syndrome allele = Gilbert variant  
 UGT1A1*37 = Crigler-Najar syndrome type 2 allele (impaired UGT1A1) = Gilbert variant  
Patients with 0 or 1 Gilbert variant alleles will be classified as “no Gilbert Syndrome”; patients 
with 2 Gilbert variants alleles will be classified as “Gilbert Syndrome”. 
2.4.2 Baseline safety parameters 
Baseline for safety parameters (weight, height, body mass index (BMI), physical exam, vital signs, 
echocardiograms, immune response assessments, and safety biomarkers) in general is defined as 
the last available non-missing value for the parameter before the first infusion in the original 
study. Most of the baseline values will thus be from the Day 1/Week 0 pre-infusion assessments in 
the original study, with the exception of hematology parameters and possibly electrocardiogram 
(ECG). Hematology samples are collected for pediatric patients twice at screening and twice on 
first infusion visit, once before and once after the first infusion; for adult patients, they are 
collected once at screening, twice before infusion on first infusion visit and one after the first 
infusion. The average of all measurements taken before the first infusion will serve as the 
baseline. Another exception may be the ECG parameters – Day 1/Week 0 (the first infusion visit 
in the original study) is to collect ECG in triplicate before the infusion; if 2 or more than 2 of these 
triplicate collections of ECG are before the first infusion, the average of these ECG parameter 
results will be considered as the baseline value; otherwise, the baseline value of ECG parameters 
will be taken from the latest observation before the first infusion.  
Baseline safety data will be presented along with subsequent values assessed during or after 
olipudase alfa dosing using safety population. 
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2.4.3 Baseline efficacy parameters 
Baseline for efficacy parameters (spleen/liver volume, pulmonary function, pulmonary imaging, 
cycle ergometry, efficacy biomarkers, height z-score, bone disease assessments, etc) is defined as 
the last available non-missing value for the parameter before the first infusion in the original 
study, except for the hematology parameters; for complete definition of baseline derivation, please 
refer to Section 2.6.1 
2.4.4 Baseline pharmacodynamic parameters 
Baseline values for sphingomyelin and sphingomyelin metabolites, including, but not limited to, 
ceramide in dried blood spots (DBS), lyso-sphingomyelin and sphingosine-1-phosphate in both 
plasma and DBS will be the last available value before first infusion in the original study; 
typically these will be the screening values from the original study.  
Baseline pharmacodynamic data will be presented along with subsequent pharmacodynamic 
values assessed during or after olipudase alfa dosing using pharmacodynamic population. 
2.4.5 Prior or concomitant medications  
Concomitant medications have been defined in Section 2.1.2. In case the start/stop date of the 
medication is missing or incomplete preventing the unambiguous determination of the medication 
status, the medication will be categorized as concomitant. 
Medication summaries will be presented by WHO-DRUG Anatomic Class and by WHO-DRUG 
Therapeutic Class using safety population. Tables will show all medications used during the 
study, sorted by most prevalent Anatomic Class and then by descending frequency of Therapeutic 
Class within Anatomic Class based on the prevalence within the overall column.  
The prohibited medications in this study have been defined in Section 2.1.2. The list of prohibited 
antidepressant medications will be provided by the data management and will be merged with the 
concomitant medication data in the database to identify any use of it. For the cationic amphiphilic 
antihistaminics where an exhaustive list of drugs cannot be provided, clinical review performed 
before the database lock will determine whether their use constitutes a protocol deviation that 
interferes with assessment of effect of olipudase alfa. For the medications prohibited before and 
after the liver biopsies where an exhaustive list of drugs cannot be provided, clinical review 
performed before the database lock will determine whether their use constitutes a protocol 
deviation that interferes with assessment of the safety of olipudase alfa. A data listing of 
prohibited medication including antidepressant use, and any medication use identified in the 
clinical review as protocol deviation, will be provided, and will be identified with the respective 
category. 
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2.4.6 Extent of investigational medicinal product exposure and compliance  
2.4.6.1 Extent of investigational medicinal product exposure 
The extent of study treatment exposure will be assessed from the first infusion in the original 
study, and will be summarized using safety population. The duration of exposure is defined as the 
number of weeks between first infusion in the original study and disposition date in the study: 
(disposition date of the study [or the cutoff date for database lock if the patients are still ongoing] 
– first infusion date from original study + 1)/7. The number of infusions received and the duration 
of exposure will be summarized using safety population. 
The distribution of weeks on study treatment (<12 weeks, >=12 weeks to <26 weeks, >=26 weeks 
to <38 weeks, >=38 weeks to <52 weeks, >=52 weeks to <64 weeks, etc) will be provided using 
number and percentage of patients by age group cohorts and overall. The total number of  
patient-years of exposure will also be provided. 
Any overdose will be captured as an AE, and will be reported as such. 
2.4.6.2 Compliance  
Compliance to the treatment regimen will be monitored in terms of the percentage of scheduled 
infusions the patient receives during the treatment period, including exposure from the original 
study. A patient is considered noncompliant if the patient missed 4 or more infusions (excluding 
for-cause missed infusions, such as when the missed infusions are required by the protocol due to 
a dose limiting toxicity) every 12-month period in the extension study. Whether a missed infusion 
is for-cause or not will be reviewed and determined by the clinical team; the decision will be used 
in the analysis of compliance.  
Overall Compliance = 100% x Total number of infusions received / Total number of expected 
infusions 
where total number of expected infusions refers to the number of infusions expected between the 
first infusion in this study and the date of withdrawal or date of completion. It is calculated as the 
integer part of (Date of withdrawal/completion – Date of the first infusion in the extension 
study)/14. For interim calculations, date of withdrawal/completion will be substituted by the date 
of the database extraction used. 
Compliance excluding for-cause = 100% x Total number of infusions received / (Total number of 
expected infusions – total number of for-cause missed infusion) 
where the denominator is calculated as the integer part of [(Date of withdrawal/completion – Date 
of the first infusion in the extension study)/14] – number of for-cause missed infusions. For 
interim calculations, date of withdrawal/completion will be substituted by the date of the database 
extraction used. 
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Overall compliance and compliance excluding for-cause will be summarized descriptively as 
quantitative variable using safety population. The numbers and percentages of patients whose 
compliance are <80%, >=80% to <90%, >=90% to <100% and >=100% will be provided. Number 
and percentage of patients will be presented for missing 4 or more scheduled infusions, by every 
12 months of treatment exposure. 
Any interruption during infusion will be captured and provided in data listing. Any irregularities in 
dosing (such as does change or dose interruption) due to an AE will be captured with AE details, 
and will be provided with AE reports. 
2.4.7 Analyses of safety data 
The safety results will be presented using the safety population. Unless specified otherwise, the 
displays will include the original study data along with data collected in this study. Patients will be 
summarized and displayed by original study identifier, age cohort and overall. Safety data will be 
reported up to and including the time of treatment withdrawal, and follow-up for AEs, where 
applicable. The baseline value is the last available value before the first infusion of olipudase alfa 
in the original study, except for hematology parameters and possibly ECG parameters. For 
complete definition of baseline, refer to Section 2.6.1. 
For all safety data, the observation period in this study is the on-treatment period, which is 
defined as the time from the first infusion of IMP (included) from original study to the end of the 
current study  
The following definitions regarding potentially clinically significant abnormality (PCSA) will be 
applied to laboratory parameters, vital signs and ECG: 
 The PCSA values are defined as abnormal values considered medically important by the 
sponsor according to predefined criteria/thresholds based on literature review and defined 
by the sponsor for clinical laboratory tests, vital signs, and ECG. These values are provided 
in Appendix A.  
 PCSA criteria will determine which patients had at least 1 PCSA taking into account all 
evaluations performed, including unscheduled or repeated evaluations. 
 Before determining a value as PCSA, the value will be rounded to the precision that the 
PCSA criterion is defined. 
2.4.7.1 Analyses of adverse events 
2.4.7.1.1 Definitions 
Adverse events continuing from the original study into the entry into this extension study will be 
identified, and will be reported as one AE avoiding duplication of the same AE in two database. 
Adverse event summaries will include the number of events (N), number (n) and percentage (%) 
of patients experiencing an adverse event. The denominator for computation of percentages is the 
safety population. Sorting order will follow the internationally agreed MedDRA system organ 
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class (SOC) order, and further by decreasing number of events overall in preferred terms (PTs) 
within SOCs. When more than one PT has same number of events within the same SOC, the order 
of presentation will be alphabetical in PTs.  
Treatment-emergent adverse events (TEAEs) will be defined as AEs that started during the 
on-treatment period – either in this study or in the original study. 
If an AE date/time of onset is incomplete, an imputation algorithm will be used to classify the 
adverse event within the appropriate adverse event period. The algorithm for imputing date/time 
of onset will be conservative and will classify an adverse event as treatment emergent unless there 
is definitive information to determine otherwise. Details on classification of AEs with missing or 
partial onset dates are provided in Section 2.6.2. If an AE worsens in severity, only the worst 
severity is captured on the AE log page in the e-CRF. 
The AE log page in the e-CRF captures the date when the event become serious. If and when this 
date is non-missing, it indicates that the AE started as non-serious and became serious at a later 
date. To account for non-serious and serious parts of the AE collected in one AE log page, this AE 
will be split into two AEs - one non-serious, and one serious AE - with the same AE number, with 
the following modifications in data for these two AEs: 
 Non-serious AE: AE end date, AE outcome, date of death or hospitalization, autopsy 
information, criterion for serious adverse event (SAE) will be blank. 
 Serious AE: AE start date will use the date the event became serious. 
 Action taken towards study drug and action taken (toward AE) will be considered in 
relation to the date the event became serious, the last infusion date and dosing information, 
and a determination will be made, in consultation with safety monitor of the trial, as to 
whether the recorded fields belong to non-serious AE or serious AE; then the decision will 
be implemented in analysis. Any such decision will be rationalized in the CSR. 
For treatment-emergent AEs, separate listing of AEs, SAEs and IARs that started only after the 
first infusion in this extension study will be provided.  
Start day of treatment emergent AE relative to first infusion = Start date of AE – first infusion date + 1 
Start day of treatment emergent AE relative to last infusion = Start date of AE – last infusion date + 1 
Total patient year for each group will be calculated and displayed on selected AE tables. 
2.4.7.1.2 Treatment-emergent adverse events 
An overview of TEAEs will be provided to include (potentially related is defined as either 
“related” or “possibly related” as assessed by the investigator): 
 TEAEs 
 TEAEs excluding original study 
 TEAEs potentially related to study treatment 
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 TEAEs by the worst severity  
 TEAEs leading to treatment discontinuation  
 TEAEs leading to study withdrawal 
 TEAEs leading to dose reduction 
 TEAEs leading to study treatment interruption 
 Protocol-defined IARs 
 Algorithm-defined IARs 
 Treatment-emergent serious adverse events  
 Treatment-emergent serious adverse events potentially related to study treatment 
 TEAEs with fatal outcome (Deaths) 
 Treatment-emergent pregnancies 
 TEAEs which are considered symptomatic overdose 
 Dose-limiting toxicities (collected in the adverse event log page in e-CRF, see protocol 
Section 8.1.6 for details) 
The following summaries will be produced by primary SOC and PT: 
 TEAEs  
 TEAEs by the worst severity (ie, mild, moderate, or severe)  
 TEAEs potentially related to study treatment  
 TEAEs potentially related to study treatment, by the worst severity (ie, mild, moderate, or 
severe)  
The most common TEAEs will be summarized by SOC and PT for patients from pediatric study 
DFI13803 and for patients from adult study DFI13412in separate tables. The criteria of most 
common TEAEs are the following, which will be applied to the two populations separately: 
 the number of events of a preferred term is more than or equal to 2% of the number of all 
TEAEs in the population, AND 
 the number of patients who had this event is more than or equal to 2.  
For the above summary for or patients from pediatric study, it will be summarized by age cohort 
and overall.  
TEAEs by the latest infusion dose immediately preceding the start of AE will be provided by SOC 
and PT. 
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2.4.7.1.3 Adverse events of special interest 
Protocol-defined IAR: The following summaries will be produced by primary SOC and PT: 
 Protocol-defined IARs  
 Protocol-defined IARs by the worst severity 
 Protocol-defined IARs started during infusion 
 Protocol-defined IARs started between 0 hours (exclusive) and 3 hours (exclusive) post 
end of infusion 
 Protocol-defined IARs started between 3 hours (inclusive) and 24 hours (inclusive) post 
end of infusion 
 Protocol-defined IARs started between 24 hours (exclusive) and 72 hours (inclusive) post 
end of infusion 
 Protocol-defined IARs started after 72 hours post end of infusion 
Additionally, Hypersensitivity IARs will be summarized by primary SOC and PT. 
In case there are IARs identified by the sponsor (before database lock) that the investigator did not 
agree to be an IAR, sponsor-identified IARs may be added to the list of investigator-identified 
IARs to define the protocol-defined IARs, and additional summaries may be produced. 
Algorithm-defined IAR: The summary of algorithm-defined IARs by primary SOC and PT will 
be provided.  
Pregnancy: Pregnancies will be provided as part of patient narrative.  
Symptomatic overdose: The symptomatic overdose data will be provided as part of patient 
narrative. 
Quantifiable Dose Limiting Toxicities defined based on laboratory values: As defined in 
Section 2.1.3.1, the Quantifiable Dose Limiting Toxicities will be provided in a data listing. 
2.4.7.1.4 Adverse events of other interest 
Infections: TEAEs of infections are defined under the system organ class of Infections and 
Infestations. 
Bleeding: TEAEs of bleeding are defined under the standard MedDRA queries (SMQs) of 
Hemorrhages (identified using SMQ code 20000038 broad and narrow scope). Bleeding AE data 
will be summarized by SOC and PT for each age cohort. 
2.4.7.1.5 Serious adverse events 
Summary of Treatment-emergent serious adverse events will be provided by primary SOC and PT. 
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2.4.7.1.6 Analyses of adverse events by place of infusion 
To assess the comparability between site infusion and home infusion, the following adverse events 
will be analyzed, pooling patients of different age cohorts. Only adverse events that occurred after 
the date when the first patient in the study received his/her first home infusion will be included in 
these analyses.  
 Overview of treatment-emergent adverse events 
 Treatment-emergent adverse events by SOC and PT 
 Treatment-emergent adverse events by severity, and by SOC and PT 
 Treatment-emergent adverse events by the latest infusion dose, and by SOC and PT 
 Treatment-emergent serious adverse events by SOC and PT 
 Protocol defined IARs by SOC and PT 
 Protocol defined IARs by severity, and by SOC and PT 
 Protocol-defined IARs started during infusion by SOC and PT 
 Protocol-defined IARs started between 0 hours (exclusive) and 3 hours (exclusive) post 
end of infusion 
 Protocol-defined IARs started between 3 hours (inclusive) and 24 hours (inclusive) post 
end of infusion 
 Protocol-defined IARs started between 24 hours (exclusive) and 72 hours (inclusive) post 
end of infusion 
 Protocol-defined IARs started after 72 hours post end of infusion 
 Algorithm-defined IARs 
2.4.7.2 Clinical laboratory evaluations 
For parameters that are reported as BQL (below the quantification limit), the results often convey 
a clinically meaningful change. Therefore, a numerical value is necessary to be imputed for 
including these in descriptive statistics calculations as well as plotting them in by-patient graphs. 
For all these parameters the lower limit of quantification (LLOQ) is available in the database. The 
imputed value for BQL will observe the same precision as reported values, but will be lower than 
the LLOQ by the minimum of that precision. For example, if a parameter is reported to 
two decimal places, and its LLOQ is X, then the imputed value of BLQ is (X-0.01). On the other 
hand, if a parameter is reported to one decimal place, and its LLOQ is X, then the imputed value 
of BLQ is (X-0.1). Listing will provide data as BQL and <LLOQ where LLOQ will be populated. 
Observed values, change from baseline and percent change from baseline to scheduled study time 
points will be summarized in separate groups of hematology (excluding hemoglobin and platelets 
which are considered efficacy parameter, hence the analyses have been described in 
Section 2.4.8.7), liver function tests, lipids, coagulation, etc. as described in Section 2.1.3.3. By 
patient plots of WBC, ALT, AST, total bilirubin will be provided. Summary plots over time will 
also be provided as needed.  
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Laboratory values will be classified as normal, above normal, or below normal based on normal 
ranges when provided by the laboratory. Shifts from baseline to scheduled time points, any time 
during the on-treatment period and the last available value, in the abnormality of any parameters 
will be provided. 
PCSA values for hematology and liver function tests (provided in Appendix A) during the study 
(from first infusion in the original study to last available observation) will be summarized. PCSA 
values for hematology, liver function test and clinical chemistry parameters will be provided in 
separate listings. 
2.4.7.3 Vital signs 
Vital signs will include heart rate (HR, beats/minute), systolic and diastolic blood pressure 
(SBP/DBP, mmHg), respiratory rate and body temperature (°F or °C). Each vital sign parameter 
will be summarized as observed parameter value and change from baseline at each scheduled time 
point. 
PCSA values during the study (from first infusion start to last available observation) will be 
summarized. 
2.4.7.4 Electrocardiogram  
For ECG parameters, the observed data and change from baseline will be summarized at each 
scheduled time point.  
PCSA values will be summarized during the study (from first infusion start to last available 
observation).  
2.4.7.5 Echocardiogram with Doppler 
Shift tables will be created for valve characterization (including aortic regurgitation, mitral 
regurgitation, pulmonic regurgitation, tricuspid regurgitation). Summary of change from baseline 
in ejection fraction (%) and pulmonary artery systolic pressure will be provided. By-patient plots 
of left ventricular calculated ejection fraction (%) will be provided. 
2.4.7.6 Physical examinations 
Complete physical examination (except overall neurological exam - please see Section 2.4.7.7) 
will be classified as normal or abnormal. Shift tables will be provided. A listing of the abbreviated 
physical examination data will be provided.  
Observed values and change from baseline for weight, height and BMI will be summarized for all 
scheduled time points.  
For patients from the pediatric study DFI1303, the age-appropriate growth in height is a matter of 
efficacy; please see Section 2.4.8.14 for analysis of height z-scores. 
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2.4.7.7 Extended neurological examinations 
This data will be summarized and listed. The overall evaluation of neurological exam collected in 
eCRF under physical exam will be included in this section. 
2.4.7.8 Liver biopsy (Patients from adult study DFI13412) 
Liver biopsy data will be received as external data.  
The fibrosis stage will be summarized with number of patients and percentage for each stage at 
each visit. Cirrhosis and liver failure could be interpreted from this data. Change from baseline in 
Sphingomyelin from Liver biopsy will be summarized under pharmacodynamics (Section 2.4.9.1). 
Any other data from liver biopsies in the clinical database will be provided in a data listing. 
2.4.7.9 Liver ultrasound Doppler (Patients from pediatric study DFI13803) 
Liver ultrasound Doppler data will be provided in a data listing.  
2.4.7.10 Safety biomarkers 
Observed values and change from baseline will be summarized at each scheduled time point. 
Summary plots for observed values and/or by-patient plots over time will also be presented as 
appropriate. 
2.4.7.11 Immune response assessments 
Data listings will be provided to display results of anti-olipudase IgG antibody, neutralizing 
antibody, anti-olipudase alfa IgE antibody, serum tryptase activity, complement activation, and 
skin testing performed. If IgG antibody titer value is reported as <xx, the numeric value will be 
imputed as xx, the minimum required dilution (MRD), and used for summary purposes, Listing 
will provide results as reported as well as results as imputed.  
 A patient with at least one anti-drug antibody (ADA) response available in the database is 
considered evaluable. 
A patient whose ADA status is positive at baseline is considered to have pre-existing ADA. 
A patient whose ADA status is positive anytime post-baseline and is negative or missing at 
baseline is considered to have treatment-induced ADA.  
A patient whose ADA status is positive at baseline (pre-existing ADA) and the ADA titer level 
anytime post-baseline is significantly higher than that at baseline is considered to have 
treatment-boosted ADA. A difference in titer values between 2 samples representing greater than 
or equal to twice the dilution level is considered significant. In other words, the post-baseline titer 
value divided by the baseline titer value will be greater than or equal to 4 to be considered 
significant. For example, if baseline titer value is 50, the post-baseline titer value has to be >=200. 
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For patients with treatment-induced ADA, the following 3 ADA responses are defined.  
Transient ADA response is defined as: 
 Treatment-induced ADA detected only at one sampling time point post-baseline 
(excluding the last sampling time point). 
 Treatment-induced ADA detected at two or more sampling time points post-baseline, 
where the first and the last ADA-positive samples (irrespective of any negative samples in 
between) are separated by a period of less than 16 weeks, and the subject’s last sampling 
time point is ADA-negative. 
Persistent ADA response is defined as: 
 Treatment-induced ADA detected at two or more sampling time points post-baseline, 
where the first and the last ADA-positive on-treatment sample (irrespective of any 
negative samples in between) are separated by at least 16 weeks. 
 Treatment-induced ADA detected in the last two sampling time points, irrespective of the 
time period in between. 
The following subclassifications for persistent ADA response will be considered as well. 
Since this study is ongoing, the final assessment will be the final assessment at the time of 
data cutoff date for initial BLA submission. 
- 
Low response - if a patient’s peak titer ≤400 and positive at final assessment. This 
represents the first titer that is greater than a 4-fold increase from the assay minimum 
required dilution (MRD). Titers within this range would be considered as Low 
response. 
- 
Intermediate response - if a patient had persistent ADA response but peak titer is 
>400 and positive at final assessment. 
- 
Tolerized - if a patient had persistent ADA response, but negative at the final 
assessment. 
Indeterminate ADA response is defined as: 
 Only the last sampling time point is positive and all previous samples are negative. 
Pre-existing ADA = 100*(Number of patients with pre-existing ADA at baseline)/number of 
evaluable patients 
ADA Incidence = 100*(treatment-boosted + treatment-induced ADA positive patients)/number of 
evaluable patients 
The following information will be provided:  
 Number of ADA evaluable patients  
 Number (%) of patients with ADA positive/negative at baseline 
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 Number (%) of patients that never develop ADA at any time (ie, ADA is always negative 
during baseline and post-baseline visits) 
 Number (%) of patients with treatment-boosted ADA 
 Number (%) of patients with treatment-induced ADA 
 Treatment emergent ADA: Number (%) of patients with treatment-boosted/treatment-
induced ADA 
 Duration of ADA response: Number (%) of patients with transient/persistent/indeterminate 
ADA response (each category separately) 
 Number (%) of patients within persistent ADA response subclassifications: low response, 
intermediate response, tolerized (each category separately) 
 Patients with treatment-induced ADA will be further characterized 
- 
Peak ADA titer: Median and 25th/75th quantiles (min, max) of the ADA titer for peak 
ADA titer of treatment-induced ADA positive patients 
- 
Last ADA titer (final assessment): Median and 25th/75th quantiles (min, max) of the 
last ADA titer of treatment induced ADA positive patients 
 Number (%) of patients with positive neutralizing antibody (NAb)  
- 
NAb Inhibition of catalytic activity 
- 
NAb inhibition of cellular uptake 
The assessment of ADA incidence and characterization by manufacturing process B compared 
with Process C will be conducted through pooled analyses and presented in the integrated 
summary of immunogenicity. The assessment of immunogenicity and safety by Processes will be 
presented in the integrated summary of safety (ISS). 
2.4.8 Analyses of efficacy endpoints 
All efficacy analyses to assess changes in organomegaly (spleen and liver), infiltrative lung 
disease, pulmonary function, cycle ergometry endpoints, physician’s global assessment, 
hemoglobin/platelet, efficacy biomarkers, lipid profile, bone biomarkers, health outcome 
questionnaires, will be performed using the safety population. Additional endpoints for pediatric 
patients include: linear growth (height z-score), bone age, tanner staging and cognitive and 
adaptive functioning (up to the age of 6 years only).  
Baseline for efficacy parameters will be defined as the last non-missing value before the first 
infusion in the original study, except for hemoglobin and platelet; for complete definition of 
baseline values, please refer to Section 2.6.1. 
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2.4.8.1 Spleen and liver volumes 
For timing of MRI measuring spleen and liver volume, and the formula for calculating the 
volumes in multiples of normal (MN), refer to Section 2.1.4.1.  
Change from baseline and percent change from baseline for both cm^3 and MN units, in addition 
to observed values, will be calculated and summarized for all scheduled visits. The analysis of 
covariance method (including baseline as covariate) and Wilcoxon-Mann-Whitney (WMW) test 
p-values (and 95% confidence interval) for the change from baseline and percent change from 
baseline will be provided in the summary tables for spleen/liver volumes in MN unit. Box plots of 
observed values for spleen and liver volumes in MN unit will be provided. 
The correlation between spleen and liver volumes with other efficacy/safety/pharmacodynamic 
parameters may be explored graphically. 
Analysis of covariance will be used to explore difference among different age cohorts for patients 
from pediatric study DFI13803, using the following model: 
Percent change from baseline = age cohort + baseline  
2.4.8.2 Pulmonary function testing 
The parameters evaluated are DLco (mL/min/mmHg), FVC (L), FEV1(L), TLC (L). Since the 
local sites use different equations to calculate percent predicted values, the calculation is 
standardized internally by using the formula provided in Section 2.1.4.2; the percent predicted 
values calculated at site will remain in the database but will neither be listed nor summarized. The 
observed values used in analyses are provided by local sites for original study, and will be used for 
calculation of percent predicted values. The patients transitioning from the pediatric study will 
continue to use children formula used during the original study even if the age limit prescribed for 
that formula is crossed during the extension phase. 
For all 4 tests, percent (%) predicted values will be summarized for observed values, change from 
baseline and percent change from baseline using the safety population at scheduled study visit. 
The analysis of covariance method (including baseline as covariate) and WMW test p-values for 
the change from baseline and percent change from baseline will be provided in the summary tables 
for all 4 tests. Box plots of observed values, percent change from baseline for these 4 tests will be 
provided for the safety population. By-patient plots for all 4 tests over time will be provided. 
Analysis of covariance will be used to explore difference among different age cohorts for patients 
from pediatric study DFI13803, using the following model: 
Percent change in percent predicted PFT from baseline = age cohort + baseline percent predicted 
PFT 
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For patients from adult study DFI13412, a binary measure of responder (yes vs no) will be derived 
based on the change from baseline in % predicted DLco at each post-baseline visit. A patient is 
a responder at the visit, if the patient has change from baseline in % predicted DLco >=15. This 
binary measure of % predicted DLco will be included in data listing. 
2.4.8.3 Pulmonary imaging - high resolution computed tomography 
A qualitative assessment will be made for the following features: interstitial lung disease (reticular 
pattern), ground glass appearance, reticulo-nodular density (nodular densities) and pleural 
thickening of the right and left lungs based on a scale 0-3 as explained in Section 2.1.4.3. 
For all 4 features, the mean and standard deviation will be provided for observed values and 
change from baseline by each side at each level. The mean scores at each scheduled visit are 
calculated as follows: 
Mean score across 4 levels for left (or right) lung = Sum of scores for 4 levels / 4 
Mean score across 4 levels and both lungs = (Mean score across 4 levels for left lung + Mean 
score across 4 levels for right lung) / 2 
Summary of the above two types of mean scores and change from baseline for each feature will be 
provided at scheduled visits. A bar chart for the mean scores across 4 levels and both lungs of 
each feature will be provided.  
2.4.8.4 Pulmonary imaging - Chest X-ray 
The lung features (interstitial (overall ILD)), reticular, nodular, consolidation and pleura) will be 
scored subjectively for the degree of diffuse lung disease (infiltrative lung disease) in a scale of 
0-3 as explained in Section 2.1.4.4. 
For chest x-ray imaging, interstitial provides an overall assessment of interstitial lung disease with 
reticular and nodular may provide more supportive information on type of interstitial involvement. 
Consolidation provides a measure of air space disease and is assessed in addition to interstitial 
involvement. As HRCT provides a more robust characterization of the diffuse lung disease, only 
interstitial (overall ILD) of the chest X-ray will be analyzed; however data for all features will be 
provided in data listings. 
Summary of mean scores and change from baseline for interstitial will be provided by scheduled 
visits.  
2.4.8.5 Cycle ergometry 
The parameters of cycle ergometry assessments are noted in Section 2.1.4.5. Percent predicted 
values (or observed values) will be summarized by scheduled visits along with change from 
baseline. 
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2.4.8.6 Physician’s global assessment of change 
Frequency shift table for physician’s global assessment of disease severity (mild, moderate, 
severe) from the baseline will be provided at each scheduled post-baseline visit. Frequencies and 
percentages of patients at each clinical status will be provided at each scheduled post-baseline 
visit. Seven categories of Clinical Status in Physician’s global assessment of change as detailed in 
Section 2.1.4.6 will be converted to numeric values as follows: 
 “Marked improvement of daily activities” = 3. 
 “Moderate improvement of daily activities” = 2. 
  “Mild improvement of daily activities” = 1. 
  “No change” = 0. 
  “Mild worsening of daily activities” = -1.  
  “Moderate worsening of daily activities” = -2. 
 “Marked worsening of daily activities” = -3. 
Observed numeric values at each post-baseline visits will be analyzed using analysis of covariance 
(ANCOVA) model with baseline as covariate. The baseline value will be Physician’s global 
assessment of disease severity at screening with value of 1=mild, 2=moderate, 3=severe. 
2.4.8.7 Hematology 
Platelet and hemoglobin are efficacy parameters. At every six month clinic visit these two 
parameters are evaluated from two blood samples - one for complete blood count, one for 
hemogram. The average of these two values will be used for efficacy analysis. If and when 
two values are not available, the single available value will be used.   
Observed values, change from baseline and percent change from baseline will be summarized at 
each scheduled time point. Summary plots of pre-infusion values over time will be provided.  
By-patient plots over time will also be provided. 
For platelet and hemoglobin, analysis of covariance will be used to explore difference among 
different age cohorts for patients from pediatric study DFI13803, using the following model: 
Percent change from baseline in platelets = age cohort + baseline 
2.4.8.8 Fasting lipids (including lipoproteins of interest) 
Observed values and change from baseline values will be summarized at each scheduled time 
point. Summary plots of pre-infusion values over time for each lipid parameters will be provided.  
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2.4.8.9 Efficacy biomarkers 
Chitotriosidase values will be normalized prior to study analyses based on the patient's 
chitotriosidase genotype: 
Chitotriosidase genotype 
Normalization of chitotriosidase activity 
Normal 
Reported value to be used 
Heterozygous 
Value multiplied by 2 
Homozygous mutation 
Value set to “no value” 
Observed values, change from baseline and percent change from baseline for efficacy biomarkers 
will be summarized at each time point. Summary plots of observed values and change from 
baseline over time for each efficacy biomarker will be provided. 
Chitotriosidase genotype and normalized chitotriosidase activity will be listed. 
2.4.8.10 Bone disease assessments (Patients from adult study DFI13412) 
Bone marrow burden 
Observed values and change from baseline values will be summarized at each scheduled time 
point for total BMB score, total femur score and total spine score separately. Summary plots as 
well as by-patient plot of observed values over time will be provided. 
DXA parameters 
Observed values and change from baseline values will be summarized at each scheduled time 
point for BMD, T-score and Z-score by the region of femur and spine separately.  
2.4.8.11 Bone biomarkers 
Observed values and change from baseline will be summarized at each scheduled time point. 
Summary plots of observed values and change from baseline over time for each bone biomarkers 
will be provided. 
2.4.8.12 Bone age by hand X-ray (Patients from pediatric study DFI13803) 
For each patient at each scheduled baseline and post-baseline visits, the difference between the 
bone age and actual age at that visit will be calculated. Then the change from baseline in the bone 
age and actual age difference will be analyzed with analysis of covariance (ANCOVA) model with 
baseline bone age and actual age difference as covariate.  
2.4.8.13 Tanner staging (Patients from pediatric study DFI13803) 
This data will be provided in a data listing. 
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2.4.8.14 Height z-score (Patients from pediatric study DFI13803) 
The height z-score categories will be summarized for all scheduled visits. Change from baseline in 
height z-score will be analyzed with analysis of covariance (ANCOVA) model with baseline 
height z-score as covariate.  
2.4.8.15 Subgroup analyses for efficacy (Patients from pediatric study DFI13803) 
For Patients from pediatric study DFI13803, below subgroup analyses will be performed. 
To assess persistence of efficacy in patients with different baseline disease severity, the following 
subgroup analysis will be conducted: 
 Spleen volume (MN) by baseline spleen volume severity (severe vs not severe). Severe 
patients is defined as baseline spleen volume >15 multiple of normal (MN). 
 % predicted DLco by baseline % predicted DLco severity (severe vs not severe). Severe 
patients is defined by baseline % predicted DLco <40%.  
To assess the impact of immunogenicity on efficacy, descriptive summaries for spleen volume and 
platelet count will be conducted for the following two groups of patients treated with olipudase alfa: 
 Patients with treatment emergent anti-drug antibody (ADA) positive defined as either 
treatment induced or treatment boosted ADA positive at any time during olipudase alfa 
treatment. 
 Patients with ADA negative defined as neither treatment induced or treatment boosted 
ADA positive at all time during olipudase alfa treatment. 
For all the above subgroup analyses, within each subgroup, the change or percent change from 
baseline at each longitudinal time point will be summarized and analyzed with the analysis of 
covariance (ANCOVA) approach with baseline as covariate.  
The efficacy measures (spleen volume and platelet count) will also be compared between 
manufacturing Process B, Process C (
) and Process C (
) as described below.  
 To compare Process B and Process C (
), descriptive summaries for above efficacy 
measures will be created for the patients who started on Process C (
) only (patients 
never on Process B) versus patients who started on Process B and then switched to 
Process C (
) (Patients who were ever on Process B). In this analysis, the data when 
patients were exposed to Process C (
) will be excluded. 
 Descriptive summaries for above efficacy measures will be created for the patients who did 
not switch to Process C (
) yet (patients never on Process C (
)) versus patients who 
switched to Process C (
) (Patients ever on Process C (
)). 
 For patients who switched to Process C(
) and patients who switched to Process C (
) 
separately, the individual patient plot of observed values at each time point for above 
efficacy measures will be created with time point for start of each process (B, C (
) and 
C (
)) added on the plot. 
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2.4.9 Analyses of pharmacokinetic and pharmacodynamic variables 
2.4.9.1 Pharmacodynamic analysis 
Pharmacodynamic endpoints include sphingomyelin and its metabolites, including sphingomyelin 
accumulation in liver tissue, along with ceramide in DBS. These endpoints will be analyzed using 
pharmacodynamics population. Observed and change from baseline values will be summarized at 
scheduled visits. Summary plots over time for pre-infusion values will be provided. 
2.4.9.2 Pharmacokinetic analysis 
Plasma concentration-time data will be analyzed by non-compartmental methods, or nonlinear 
mixed effects modeling, based upon patient age and data suitability. Values will be reported for 
individual patient and summarized by age group cohorts, dose level, manufacturing process and 
study week as appropriate. 
For ease of presentation, mean values will be arithmetic mean unless specified. Concentration 
values below the plasma assay limit will be treated as zero in calculating mean values. Mean 
values below Lower Limit of Quantification (LLOQ) will be reported as LLOQ in the tables and 
not plotted in the figures if after Cmax. Mean calculations and their associated statistics will be 
generated from unrounded numbers and may differ slightly from those values that would be 
determined using the rounded numbers displayed in the tables. Values expressed in all tables will 
be for ease of presentation and will not be meant to imply accuracy to more than 3 significant 
figures.  
Pharmacokinetic parameters of olipudase alfa may be summarized using descriptive statistics such 
as arithmetic mean, geometric mean, SD, standard error of the mean (SEM), coefficient of 
variation (CV [%]), minimum, median, maximum, and number of observations for each study 
visit, dose level and age group cohort under the responsibility of Pharmacokinetics, Dynamics and 
Metabolism (PKDM) using Phoenix WinNonlin Professional, Version 8.1, or NONMEM (VII or 
above) running on a Linux cluster. 
Associations between ADA variables (eg, ADA status) and PK of olipudase alfa (eg, AUC) will 
be explored for olipudase alfa at selected PK visits. If applicable, plot of olipudase alfa PK 
(eg, AUC) versus the selected PK visit may be provided by ADA classifications for the olipudase 
alfa treatment group. Nab data may be explored as appropriate.  
2.4.10 Analyses of health outcome questionnaires and cognitive and adaptive function 
Patients from adult study DFI13412 fill out different questionnaires from the patients from the 
pediatric study DFI13803, hence these will be analyzed separately. 
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2.4.10.1 For patients from adult study DFI13412 
Brief Fatigue Scale (BFI) 
The severity and interference of fatigue as measured by BFI (individual questions as well as scale 
score) will be summarized separately, along with change from baseline, at each scheduled time 
point. 
Brief Pain Scale (BFI) - SF 
The severity and interference of pain as measured by BPI-SF (individual questions as well as scale 
score) will be summarized separately, along with change from baseline, at each scheduled time 
point. 
Chronic Respiratory Disease Questionnaire (CRQ-SAS) 
The 4 dimensions of CRQ-SAS - dyspnea, fatigue, emotional function, and the patient's feeling of 
control over the disease (mastery) - will be summarized separately, along with change from 
baseline, at each scheduled time point.  
SF-36 
The 8 scales measured by SF-36 - physical functioning, role physical, bodily pain, mental health, 
role emotional, social functioning, vitality, and general health - as well as the 2 summary measures 
of physical health (PCS) and mental health (MCS) will be summarized separately, along with 
change from baseline, at each scheduled time point. 
Niemann-Pick B Health Assessment Questionnaire (NPB-HAQ)  
Three domains of NPB-HAQ - resource utilization, symptoms and physical activity – will be 
summarized separately with each question at each scheduled time point.  
 For resource utilization in the past year of each scheduled time point, the following 
measures will be summarized: the total nights spent in the hospital, the number of 
emergency room or urgent care visits.  
 For symptom in the past month of each scheduled time point, frequency and level of 
bothersome of each symptom will be listed. 
 For physical activity in each scheduled time point, the number and percentage of patients 
at each frequency of physical activities will be summarized. 
2.4.10.2 For patients from pediatric study DFI13803 
The patient transitioning from the pediatric study will use the age-appropriate questionnaires at the 
entry to the extension study. As the study progresses if the patients crosses the threshold of the 
questionnaire, the new age appropriate questionnaire will be used, until the maximal age range 
(young adult). Since the baseline of the original study may use a different questionnaire than what 
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is used in the extension study, the change from baseline summaries will not be produced; 
however, when the same questionnaire is used for baseline and post-baseline visit, summary of 
change from baseline will be provided.  
PedsQL Generic Core Scales 
Individual scale scores, Psychosocial Health Summary Score, Physical Health Summary Score and 
the Total Scale Score will be calculated based on the 0-100 scale scores. Their computed values 
will be summarized at each scheduled time point. 
PedsQL Multidimensional Fatigue Scale 
Individual scale scores and the Total Scale Score will be calculated based on the 0-100 scale 
scores. Their computed values will be summarized at each scheduled time point. 
PedsQL Pediatric Pain Questionnaire 
Only the first two items out of 3 items are scored based on the 100 mm VAS. The observed values 
will be summarized at each scheduled time point. 
Developmental Profile (DP-3) and Adaptive Behavior Assessment System (ABAS-3) 
A listing of DP-3 and ABAS-3 raw and generated scores will be provided. 
For the DP-3, by-patient bar graphs will be generated to demonstrate subject’s performance over 
time using percentile rank and standard score for each content area (Physical, Adaptive Behavior, 
Social-Emotional, Cognitive, Communication) and General Development Score at all scheduled 
visits.  
For the ABAS-3, by-patient bar graphs will be generated to demonstrate subject’s performance 
over time using percentile rank and standard scores for the General Adaptive Composite and three 
adaptive domains (Conceptual, Social, and Practical) at all scheduled visits.  
In addition, to illustrate patient’s performance on the DP-3 and ABAS-3 collectively, group graphs 
by patient age will be developed showing tool standard scores of patients over time. One graph for 
the ABAS-3 General Adaptive Composite Standard Score and one graph for the DP-3 General 
Development Score Standard Score.  
2.5 
PATIENT NARRATIVES 
Patient narratives criteria for this study are as follows: 
 Deaths 
 Serious adverse event  
 Adverse Events leading to permanent treatment discontinuation 
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 Adverse events of special interest including the followings: 
- 
Protocol defined IARs (as specified in Section 2.1.3.1) 
- 
Pregnancy of female patient or partner of a male patient 
- 
Symptomatic overdose of study drug 
- 
Any increase in AST, ALT, total bilirubin, or AP >3x baseline (prior to olipudase alfa 
therapy) and > ULN 
- 
Any increase in total bilirubin or AP >1.5x baseline in the presence of AST or 
ALT >2x ULN 
- 
Any increase in ALT or AST >3x the ULN combined with an increase in ALT or 
AST >2x baseline (prior to olipudase alfa therapy) with symptoms of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness (for adults only), fever, rash, or 
eosinophilia (> ULN) 
- 
Patients from pediatric study DFI13803: asymptomatic overdose of study drug 
Patients who meet these criteria will be listed and provided to the medical writer. 
2.6 
DATA HANDLING CONVENTIONS 
2.6.1 General conventions 
In general, the baseline value is defined as latest value prior to the start of first infusion of original 
study, except for hematology parameters and possibly ECG parameters. For hematology 
parameters, the baseline value is defined as the average of all available values before the start of 
first infusion from original study. Other exception may be the ECG parameters - Day 1/Week 0 
(the first infusion visit) collects ECG in triplicate before the infusion; if 2 or more than 2 of these 
triplicate collections of ECG are before the first infusion, the average of these ECG parameter 
results from original study will be considered as the baseline value; otherwise, the baseline value 
of ECG parameters will be taken from the latest observation before the first infusion from original 
study.  
Age at ASMD diagnosis = number of years between the date of birth and the date of ASMD 
diagnosis. 
2.6.2 Missing data 
In general, no imputation is planned for missing data. The following approaches are default 
methods for missing data handling. Some exploratory analyses can be planned with different 
strategies for treating missing outcomes.  
 Categorical data at baseline will be summarized for each age group cohort using counts (n) 
and percentages (%). The number of patients with missing data may be mentioned, but will 
not be included in the denominator for the calculation of percentages unless otherwise 
specified. When relevant, the number of patients with missing data is presented. 
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 Continuous data: The analyses and summaries for variables with continuous scales will be 
based on observed data only.  
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of study treatment is 
reported on the last infusion page in e-CRF.  
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior to the 
start of first infusion or concomitantly with study, it will be considered a prior as well as 
a concomitant medication. 
Handling of adverse events with missing data 
 If the AE is missing start date and/or time, the treatment-emergent adverse event will be 
determined by the following conservative principle: An adverse event will be considered 
a treatment-emergent adverse event if it cannot be confirmed that the event is not 
a Treatment-emergent adverse event due to missing data.  
 If the timing of AE with respect to infusion start and/or end time could not be determined 
unambiguously, the AE will be assumed to be an algorithm-defined IAR. 
 If the assessment of the relationship is missing, then the relationship of possibly related is 
assumed for the summary table, but no imputation will be done at the data level. 
 If the worst severity grade is missing, a missing category will be added in the summary table. 
2.6.3 Windows for time points 
Statistical analysis will be based on the nominal visit which should follow schedule defined in 
protocol Section 1. Visits will not be windowed for analysis purposes, except for unscheduled 
visits in some cases as described in Section 2.6.4. 
2.6.4 Unscheduled visits 
In general, unscheduled visit measurements will not be included in the by-visit summaries, but 
will be used for computation of baseline and/or summaries of “any time” or “end of study” time 
points. If a scheduled post-baseline visit measurement of an efficacy parameter is missing, but 
an unscheduled visit value for the same parameter is available within 3 months (91 days) of 
scheduled 6-month or 12-month visit, the unscheduled visit value will be used to substitute the 
missing scheduled visit value. If the parameter is scheduled for evaluation every 3 months, 
a 45 day window will be used instead of 91 days. If two unscheduled visits qualify for missing 
scheduled visit value, the one closest in date to target visit date will be used. Laboratory, vital 
signs, ECG and PD parameters are collected at several times during a visit with respect to the 
infusion time, therefore a window for an unscheduled visit to substitute missing schedule values 
will not be considered.  
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3 
INTERIM ANALYSIS 
No formal interim analysis is planned for this study. A formal summary of data or interim CSR 
may be produced to support regulatory approval(s) and/or other application/submission 
requirement(s). However, due to the nature of the open label study, this analysis will have no 
impact on primary and secondary objectives of this study. 
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4 
DATABASE LOCK 
The database is planned to be locked at about 30 days after the last patient last visit. A formal 
database lock may be performed to produce summary of data or interim CSR that may be needed 
to support regulatory approval(s) and/or other submission/application requirement(s).  
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS Version 9.0 or higher. The 
exact version used will be documented in the clinical study report. 
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6 
REFERENCES 
 
1. 
Global Lung Initiative (GLI) reference [Online]. [cited 2019 Nov 05]. Available from: 
URL:http://www.ers-education.org/guidelines/global-lung-function-initiative.aspx 
2. 
Crapo RO, Morris AH. Standardized Single breath normal values for carbon Monoxide 
Diffusing Capacity. Am Rev Respir Dis. 1981;123:185-9. 
3. 
Koopman M, Zanen P, Kruitwagen CL, van der Ent CK, Arets HG. Corrigendum to 
"Reference values for paediatric pulmonary function testing: The Utrecht dataset". Respir Med. 
2011;105:1970-1. 
4. 
Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, et al. 
Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur 
Respir J. 2005;26:720-35. 
5. 
Greulich, WW, Pyle SI. Radiographic atlas of skeletal development of the hand and 
wrist. 2nd ed. Standford, Calif.: Standford University Press; 1959. 
6. 
Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The 
rapid assessment of fatigue severity in cancer patients: use of the brief fatigue inventory. Cancer. 
1999;85:1186-96. 
7. 
Cleeland, CS. The brief pain inventory. MD Anderson, TX. Copyright: 2009. 
8. 
The self-administered chronic respiratory questionnaire standardized (CRQ_SAS) and 
individualized verison (CRQ-SAI) - background information and interviewing suggestions 
(version: 07 Jul 2015).  McMaster University, Canada.  Copyright: 2001. 
9. 
Maruish ME. User’s Manual for the SF-36v2 Health Survey. 3rd ed. Lincoln, RI: 
QualityMetric, Inc; 2011. 
10. 
PedsQL Generic Core Scales scoring algorithm [Online]. [cited 2019 Nov 05]. Available 
from: URL:http://www.pedsql.org/ 
11. 
Aplern, GD. Developmental Profile 3 (DP-3). Los Angeles, CA: Western Psychological 
Services. 2007. 
12. 
Harrison P, Oakland T. Adaptive behavior assessment system, Third Edition (ABAS-3). 
Los Angeles, CA: Western Psychological Services. 2015. 
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7 
LIST OF APPENDICES 
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
 
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Appendix A 
Potentially clinically significant abnormalities (PCSA) criteria  
 
Measures 
Adult criteria 
Pediatric criteria 
Liver function tests 
 
 
ALT 
>3 * ULN 
>5 * ULN 
>10 * ULN 
>20 * ULN 
Same as adult 
AST 
>3 * ULN 
>5 * ULN 
>10 * ULN 
>20 * ULN 
Same as adult 
 
Alkaline Phosphatase 
>1.5 * ULN 
Same as adult 
Total Bilirubin 
>1.5 * ULN 
>2 * ULN 
≥1.3 ULN 
ALT and Total Bilirubin 
ALT >3 * ULN and Total Bilirubin >2 * ULN 
Same as adult 
Hematology  
 
 
WBC 
<3.0 GIGA/L (non-Black), <2.0 GIGA/L (Black), 
≥16.0 GIGA/L 
12 years or above, but less than 18 years by 
age: 
<4.5 GIGA/L 
>13.5 GIGA/L 
6 years or above, but less than 12 years by age: 
<5.0 GIGA/L 
>17.0 GIGA/L 
2 years or above, but less than 6 years by age: 
<3.0 GIGA/L 
>16.0 GIGA/L 
28 days/1 month to 23 months old 
<4.0 GIGA/L 
>20.0 GIGA/L 
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Measures 
Adult criteria 
Pediatric criteria 
Lymphocytes 
>4.0 GIGA/L 
 
12 years or above, but less than 18 years by 
age: 
<0.6 GIGA/L 
>6.0 GIGA/L 
6 years or above, but less than 12 years by age: 
<1.0 GIGA/L 
>8.0 GIGA/L 
2 years or above, but less than 6 years by age: 
<1.0 GIGA/L 
>9.5 GIGA/L 
28 days/1 month to 23 months old 
<2.0 GIGA/L 
>13.5 GIGA/L 
Neutrophils 
<1.5 GIGA/L (non-Black) 
<1.0 GIGA/L (Black) 
2 years or above, but less than 18 years by age: 
<1.2 GIGA/L 
>1.0 ULN 
28 days/1 month to 23 months old 
<1.0 GIGA/L (1-3 months) 
<1.2 GIGA/L (3-24 months) 
>1 ULN 
Monocytes 
>0.7 GIGA/L 
N/A 
Basophils 
>0.1 GIGA/L 
N/A 
Eosinophils 
>0.5 GIGA/L or 
>ULN if ULN 0.5 GIGA /L 
Same as adult 
Hemoglobin 
Males: 115 g/L (7.14 mmol/L) and 20% decrease 
from baseline; 185 g/L 
 (11.48 mmol/L) 
Females: 95 g/L (5.9 mmol/L) and 20% decrease 
from baseline; 165 g/L  
(10.24 mmol/L) 
Decrease from Baseline 20 g/L (1.24 mmol/L) 
24 months/2 years to <16/18 years old: 
<10.0 g/dL and 20% decrease from baseline, or 
decrease from baseline >=2 g/dL 
 
28 days/1 month to 23 months old (Infants):  
<9.0 g/dL and 20% decrease from baseline, or 
decrease from baseline >=2 g/dL 
Hematocrit 
Males: 0.37 v/v and 20% decrease from baseline; 
0.55 v/v 
Females: 0.32 v/v and 20% decrease from 
baseline; 0.5 v/v 
2 years or above, but less than 18 years by age:  
<0.32 l/l or 32%  
>0.47 l/l or 47% 
28 days/1 month to 23 months old 
<0.29 l/l or 29% 
>0.42 l/l or 42% 
RBC 
18 years or above by age 6 TERA/L 
N/A 
Platelets 
<100 GIGA/L and 20% decrease from baseline 
700 GIGA/L  
Same as adult 
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Measures 
Adult criteria 
Pediatric criteria 
Electrocardiogram  
 
HR 
<=50 bpm and decrease from baseline >=20 bpm 
>=120 bpm and increase from baseline >=20 bpm 
28 days/1 month to 23 months old (Infants) 
≤80 bpm and decrease from baseline ≥20 bpm 
≥175 bpm and increase from baseline ≥20 bpm 
24 months/2 years to <6 years old (Children) 
≤75 bpm and decrease from baseline ≥20 bpm 
≥140 bpm and increase from baseline ≥20 bpm 
6 to <12 years old (Children) ≤50 bpm and 
decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
12 to 16/18 years old (Adolescents) ≤50 bpm 
and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
PR 
>=200 ms and increase from baseline >=20 ms 
12 years or above, but less than 18 years by 
age: 
>=180 ms 
6 years or above, but less than 12 years by age: 
>=170 ms 
2 years or above, but less than 6 years by age: 
>=160 ms 
28 days/1 month to 23 months old (Infants) 
>=140 ms 
QRS 
>=120 ms 
 
12 years or above, but less than 18 years by age: 
>=110 ms 
6 years or above, but less than 12 years by age: 
>=100 ms 
2 years or above, but less than 6 years by age: 
>=95 ms 
28 days/1 month to 23 months old (Infants): 
>=85 ms 
QTc 
 
Absolute values (ms)                         
 
       Males              Females 
Borderline         431-450 ms     451-470 ms 
Prolonged          >450 ms         >470 ms 
Additional         ≥500 ms         ≥500 ms 
 
Increase from baseline (all ages, all gender) 
Borderline: 30-60 ms 
Prolonged: >60 ms 
12 years or above by age: 
                         Males              Females 
Borderline         431-450 ms     451-470 ms 
Prolonged          >450 ms         >470 ms 
Additional         ≥500 ms         ≥500 ms 
 
Birth/0 to <12 years old: 
Borderline         431-450 ms      
Prolonged          >450 ms          
Additional         ≥500 ms     
 
Increase from baseline (all ages) 
Borderline: 30-60 ms 
Prolonged: >60 ms      
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Measures 
Adult criteria 
Pediatric criteria 
Clinical chemistry  
 
Creatinine 
>=150 µmol/L  
>=30%  change from baseline 
>=100%  change from baseline 
 
12 years or above, but less than 18 years by 
age: 
>=132 µmol/L or 1.5 mg/dL 
6 years or above, but less than 12 years by age: 
>=90 µmol/L or 1.1 mg/dL 
Birth/0 to <6 years old (Neonates, Infants, 
Children): 
>53 μmol/L or 0.6 mg/dL 
Blood Urea Nitrogen 
(BUN) 
>=17 mmol/L 
28 days/1 month to Less than 18 years by age: 
>=6.4 mmol/L 
Chloride 
<80 mmol/L 
>115 mmol/L 
Same as adult 
Sodium 
<=129 mmol/L 
>=160 mmol/L 
<=129 mmol/L 
>=150 mmol/L 
Potassium 
<3  mmol/L 
>= 5.5 mmol/L 
 
28 days/1 month to 23 months old (Infants): 
<=3.5 mmol/L 
>=6.0 mmol/L 
24 months/2 years to 16/18 years old (Children, 
Adolescents): 
<=3.5 mmol/L 
>=5.5 mmol/L 
Glucose 
    Hypoglycaemia 
 
    Hyperglycaemia 
 
18 years or above by age: <=3.9 mmol/L and <LLN 
 
18 years or above by age: >=11.1 mmol/L (unfasted), 
>7 mmol/L (fasted) 
 
 
Less than 18 years by age: <2.7 mmol/L 
Less than 18 years by age: >=10.0 mmol/L 
(unfasted), >=7 mmol/L (fasted) 
Albumin 
18 years or above by age: <=25 g/L 
N/A 
Vital signs  
 
HR 
50 bpm and decrease from baseline 20 bpm 
120 bpm and increase from baseline20 bpm 
24 months/2 years to <6 years old (Children): 
<= 75 bpm and decrease from 
baseline>=20 bpm 
>= 140 bpm and increase from 
baseline>=20 bpm 
 
28 days/1 month to 23 months old (Infants): 
<= 80 bpm and decrease form 
baseline>=20 bpm 
>= 175 bpm and increase from 
baseline>=20 bpm 
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Measures 
Adult criteria 
Pediatric criteria 
SBP 
95 mmHg and decrease from baseline 20 mmHg 
160 mmHg and increase from baseline 20 mmHg 
 
12 years or above, but less than 18 years by 
age: 
<=90 mmHg and decrease from baseline 
>=20 mmHg 
>=119 mmHg and increase from baseline 
>=20 mmHg 
6 years or above, but less than 12 years by age: 
<=80 mmHg and decrease from baseline 
>=20 mmHg 
>=108 mmHg and increase from baseline 
>=20 mmHg 
24 months/2 years to <6 years old (Children): 
<=70 mmHg and decrease from baseline 
>=20 mmHg 
>=101 mmHg and increase from baseline 
>=20 mmHg 
28 days/1 month to 23 months old (Infants) 
<=70 mmHg and decrease from baseline 
>=20 mmHg 
>=98 mmHg and increase from baseline 
>=20 mmHg 
DBP 
<=45 mmHg and decrease from baseline>=10 mmHg 
>=110 mmHg and increase from baseline >=10 mmHg 
12 years or above, but less than 18 years by 
age: 
<=54 mmHg and decrease from baseline 
>=10 mmHg 
>=78 mmHg and increase from baseline 
>=10 mmHg 
6 years or above, but less than 12 years by age: 
<=48 mmHg and decrease from baseline 
>=10 mmHg 
>=72 mmHg and increase from baseline 
>=10 mmHg 
24 months/2 years to <6 years old (Children): 
<=34 mmHg and decrease from baseline 
>=10 mmHg 
>=59 mmHg and increase from baseline 
>=10 mmHg 
28 days/1 month to 23 months old (Infants): 
<=34 mmHg and decrease from baseline 
>=10 mmHg 
>=54 mmHg and increase from baseline 
>=10 mmHg 
Urinalysis  
 
pH 
18 years or above by age: 
N/A 
 
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