Conditions: Sphingomyelin Lipidosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: yes

Brief summary:
Primary Objective:

The primary objective of this phase 2/3 study was to evaluate the efficacy of olipudase alfa (recombinant human acid sphingomyelinase) administered intravenously once every 2 weeks for 52 weeks in adult participants with acid sphingomyelinase deficiency (ASMD) by assessing changes in: 1) spleen volume as measured by abdominal magnetic resonance imaging (MRI) (and, for the United States \[US\] only, in association with participant perception related to spleen volume as measured by splenomegaly-related score \[SRS\]); and 2) infiltrative lung disease as measured by the pulmonary function test, diffusing capacity of the lung for carbon monoxide (DLCO).

Secondary Objectives:

* To confirm the safety of olipudase alfa administered intravenously once every 2 weeks for 52 weeks.
* To characterize the effect of olipudase alfa on the participant perception related to spleen volume as measured by the SRS after 52 weeks of study drug administration. (For the US, the effect of olipudase alfa on the SRS is part of the primary objective).
* To characterize the effect of olipudase alfa after 52 weeks of study drug administration on the following outcome measures assessed sequentially:

  * The effect of olipudase alfa on liver volume;
  * The effect of olipudase alfa on platelet count;
  * The effect of olipudase alfa on fatigue;
  * The effect of olipudase alfa on pain;
  * The effect of olipudase alfa on dyspnea.

Detailed description:
The planned total duration per participant was for at least 3 years and up to 5 years and 3 months. This included up to approximately two month of screening, 52 weeks of primary analysis period, up to 4 years and 3 months of extension treatment period, an end-of- study visit within 2 weeks of the last treatment, and a safety follow-up 30 to 37 days after the last treatment.

Arms:
arm 1: Placebo (saline) administered intravenously once every 2 weeks during the 52 weeks of the primary analysis period for patients randomized to placebo. arm 2: Olipudase alfa dose (3 mg/kg body weight) in saline administered intravenously once every 2 weeks during the 52 weeks of the primary analysis period for patients randomized to olipudase alfa, and during the extension treatment period for all patients.

Interventions: intervention 1: placebo (saline) intervention 2: Olipudase alfa
Intervention descriptions: intervention 1: Pharmaceutical form: solution administered once every two weeks during the 52 weeks of the primary analysis period for participants randomized to placebo.

Route of administration: intravenous infusion intervention 2: Pharmaceutical form: Powder for concentrate for solution for infusion administered once every two weeks during the 52 weeks of the primary analysis period for participants randomized to olipudase alfa, and during the extension treatment period for all participants.

Route of administration: intravenous infusion

Protocol document:
Prot_002.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 15 
COMPOUND: olipudase alfa/GZ402665 
A Phase 2/3, multicenter, randomized, double-blinded, placebo-controlled, repeat 
dose study to evaluate the efficacy, safety, pharmacodynamics, and 
pharmacokinetics of olipudase alfa in patients with acid sphingomyelinase 
deficiency 
STUDY NUMBER: DFI12712  
NCT Number：NCT02004691
STUDY NAME: ASCEND 
VERSION DATE/STATUS: 01-Nov-2022 / APPROVED 
Version Number: 
1 
EudraCT  
2015-000371-26 
IND Number(s) 
12757 
WHO universal trial number 
Not applicable 
Date: 
01-Nov-2022
Total number of pages: 
171 
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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  
350 Water Street 
Cambridge, MA 02141 USA 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
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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 15 
All except Germany 
01 November 2022, version 1 (electronic 18.0) 
Amended Clinical Trial Protocol 14 
Germany Only 
07 June 2021, version 1 (electronic 17.0) 
Amended Clinical Trial Protocol 13 
All 
02 February 2021, version 1 (electronic 16.0) 
Amended Clinical Trial Protocol 12 
All 
15 April 2020, version 2 (electronic 15.0) 
Amended Clinical Trial Protocol 11 
All 
12 Aug 2019, version 2 (electronic 13.0) 
Amended Clinical Trial Protocol 10 
All 
05 December 2018, version 1 (electronic 11.0) 
Amended Clinical Trial Protocol 09 
All 
18 September 2018, version 2 (electronic 10.0) 
Amended Clinical Trial Protocol 08 
All 
26 January 2018, version 1 (electronic 8.0) 
Protocol Amendment 10 
All 
26 January 2018, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 07 
All 
24 August 2017, version 1 (electronic 7.0) 
Protocol Amendment 09 
All 
24 August 2017, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 06 
All 
08 February 2017, version 1 (electronic 6.0) 
Protocol Amendment 08 
All 
08 February 2017, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 05 
All 
01 February 2016, version 1 (electronic 4.0) 
Protocol Amendment 07 
All 
01 February 2016, version 2 (electronic 2.0) 
Amended Clinical Trial Protocol 05-DE 
Germany Only 
28 September 2015, version 1 (electronic 1.0) 
Protocol Amendment 06 - DE 
Germany Only 
28 September 2015, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 05-GB 
United Kingdom Only 
22 July 2015, version 1 (electronic 2.0) 
Protocol Amendment 05- GB 
United Kingdom Only 
22 July 2015, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 04 
All 
08 May 2015, version 2 (electronic 5.0) 
Protocol Amendment 04 
All 
31 March 2015, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 03 
All 
28 January 2015, version 1 (electronic 3.0) 
Protocol Amendment 03 
All 
28 January 2015, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 
All 
05 December 2014, version 1 (electronic 2.0) 
Protocol Amendment 02 
All 
05 December 2014, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 
All 
05 September 2014, version 1 (electronic 1.0) 
Protocol Amendment 01 
All 
05 September 2014, version 1 (electronic 1.0) 
Original Protocol 
 
02 April 2013, version 1 (electronic 2.0) 
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Page 4 
 
AMENDED PROTOCOL 15 (01-Nov-2022) 
This amended protocol 15 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 reason for this amendment is to allow home infusion to continue until the end of the 
extension treatment period (ETP) for patients who initiated home infusion during the COVID-19 
pandemic, and continue to be on home infusion at the time of this amendment. 
This amendment does not apply to Germany as per amended protocol 14. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
NAMES AND ADDRESSES OF 
Changed address of Sponsor to: 
Sanofi Genzyme  
350 Water Street 
Cambridge, MA 02141 USA 
To update address of Sponsor 
CLINICAL TRIAL SUMMARY - 
Study design and Dose regimen 
Following text is added: 
Patients who initiated home infusion during the 
COVID-19 pandemic, and continue to be on home 
infusion, may continue receiving home infusion by 
trained home nurses in the ETP every 2 weeks 
(± 3 days) until the end of the ETP (refer to Appendix B 
for Germany). 
 
Since there was no particular concern on safety 
identified when applying home infusion and 
considering challenges (such as burden of 
travel) to switch patients on home infusion to 
site infusion for all subsequent infusions this 
amendment will allow home infusion to 
continue until the end of the ETP for patients 
who initiated home infusion during the 
COVID-19 pandemic, and continue to be on 
home infusion at the time of this amendment. 
This amendment does not apply to Germany as 
per amended protocol 14. 
Section 1.2.2.4 Schedule of 
assessments ETP Year 3 until the 
end of study only applicable after 
the cutoff date for a planned 
second database lock of the study 
 
Following text is added in footnote a: 
Patients who initiated home infusion during the 
COVID-19 pandemic, and continue to be on home 
infusion, may continue receiving home infusion by 
trained home nurses in the ETP every 2 weeks 
(± 3 days) until the end of the ETP (refer to Appendix B 
for Germany) and, in such case, telehealth visits may 
continue until the end of the ETP (except quarterly 
visits as specified above). 
 
 
Same as above 
Section 1.2.2.4 Schedule of 
assessments ETP Year 3 until the 
end of study only applicable after 
Following text is amended in footnote t: 
Study drug infusions will occur once every 2 weeks 
(± 3 days) at the site or at home (during the COVID-19 
Same as above 
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Section # and Name 
Description of Change 
Brief Rationale 
the cutoff date for a planned 
second database lock of the study 
pandemic and in addition until the end of the ETP for 
patients who initiated home infusion during the 
COVID-19 pandemic, and continue to be on home 
infusion [refer to Appendix B for Germany]) if agreed 
between the investigator and the sponsor, for eligible 
patients, in reference to the date of the first infusion 
(Day 1) for each patient. 
Section 6.1 Description of the 
protocol 
Following text is added: 
Patients who initiated home infusion during the 
COVID-19 pandemic, and continue to be on home 
infusion, may continue receiving home infusion by 
trained home nurses in the ETP every 2 weeks 
(± 3 days) until the end of the ETP (refer to Appendix B 
for Germany). 
Same as above 
Section 8.1.1 Treatments 
administered 
Following text is added: 
Patients who initiated home infusion during the 
COVID-19 pandemic, and continue to be on home 
infusion, may continue receiving home infusion by 
trained home nurses in the ETP every 2 weeks 
(± 3 days) until the end of the ETP (refer to Appendix B 
for Germany). 
Same as above 
Section 10.1 visit schedule 
Following text is added: 
Patients who initiated home infusion during the 
COVID-19 pandemic, and continue to be on home 
infusion, may continue receiving home infusion by 
trained home nurses in the ETP every 2 weeks 
(± 3 days) until the end of ETP (refer to Appendix B for 
Germany) and, in such case, telehealth visits may 
continue until the end of the ETP (except quarterly 
visits as specified above). 
Same as above 
Section 10.1.1 Home infusions 
Following text is added: 
Patients who initiated home infusion during the 
COVID-19 pandemic, and continue to be on home 
infusion, may continue receiving home infusion by 
trained home nurses in the ETP every 2 weeks 
(± 3 days) until the end of the ETP (refer to Appendix B 
for Germany). 
Same as above 
Section 17  Appendix C Protocol 
Amendment History  
The protocol amendment history section has been 
updated. 
To conform with the usual process for 
amendment history. 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: olipudase alfa (formerly 
recombinant human acid 
sphingomyelinase) GZ402665 
STUDY No: DFI12712 
STUDY NAME: ASCEND 
TITLE 
A Phase 2/3, multicenter, randomized, double-blinded, placebo-controlled, 
repeat dose study to evaluate the efficacy, safety, pharmacodynamics, and 
pharmacokinetics of olipudase alfa in patients with acid sphingomyelinase 
deficiency 
INVESTIGATOR/TRIAL LOCATION 
Multinational – Multicenter 
PHASE OF DEVELOPMENT 
2/3 
STUDY OBJECTIVE(S) 
 
Primary objective 
The primary objective of this Phase 2/3 study is to evaluate the efficacy of 
olipudase alfa (recombinant human acid sphingomyelinase) administered 
intravenously once every 2 weeks for 52 weeks in adult patients with acid 
sphingomyelinase deficiency (ASMD) by assessing changes in: 1) spleen 
volume as measured by abdominal magnetic resonance imaging (MRI) (and, 
for the United States [US] only, in association with patient perception related to 
spleen volume as measured by splenomegaly-related score [SRS]); and 2) 
infiltrative lung disease as measured by the pulmonary function test, diffusing 
capacity of the lung for carbon monoxide (DLCO). 
Secondary objectives 
• 
To confirm the safety of olipudase alfa administered intravenously 
once every 2 weeks for 52 weeks 
• 
To characterize the effect of olipudase alfa on the patient perception 
related to spleen volume as measured by SRS after 52 weeks of 
study drug administration (For the US, the effect of olipudase alfa on 
SRS is part of the primary objective) 
• 
To characterize the effect of olipudase alfa on the following 
endpoints assessed sequentially: 
1. 
The effect of olipudase alfa on liver volume after 52 weeks of study 
drug administration 
2. 
The effect of olipudase alfa on platelet count after 52 weeks of study 
drug administration 
3. 
The effect of olipudase alfa after 52 weeks of study drug 
administration on fatigue 
4. 
The effect of olipudase alfa after 52 weeks of study drug 
administration on pain 
5. 
The effect of olipudase alfa after 52 weeks of study drug 
administration on dyspnea 
Additional objectives 
• 
To characterize the effect of olipudase alfa on liver function tests 
• 
To characterize the effect of olipudase alfa on infiltrative lung 
disease via pulmonary imaging 
• 
To characterize the effect of olipudase alfa on pulmonary functioning 
• 
To characterize the effect of olipudase alfa on the fasting lipid profile 
• 
To characterize the effect of olipudase alfa on bone disease 
• 
To characterize the effect of olipudase alfa on cardiopulmonary 
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functioning 
• 
To characterize the effect of olipudase alfa on biomarkers 
• 
To characterize the effect of olipudase alfa on hematology 
parameters 
• 
To characterize the effect of olipudase alfa on selected 
health-related quality of life questionnaires and questions therein 
• 
To characterize the pharmacodynamic effect of olipudase alfa on 
clearing sphingomyelin accumulation in liver and/or blood 
• 
To characterize the multiple-dose plasma pharmacokinetic profile of 
olipudase alfa 
• 
To explore the effect of olipudase alfa on Physician's global 
assessment of change 
• 
To explore the effect of olipudase alfa on the nuclear magnetic 
resonance (NMR) profile of high-density lipoprotein (HDL) 
• 
To explore the effect of olipudase alfa on liver function via 
echo-Doppler ultrasound 
• 
To explore the effect of olipudase alfa on inflammatory and vascular 
biomarkers 
STUDY DESIGN 
This Phase 2/3, multicenter, repeat-dose, clinical trial will be divided into 
2 consecutive major periods: 1) a randomized placebo-controlled, double-blind 
primary analysis period (PAP) from Day -60 to Week 52 to be followed by 2) 
an extension treatment period (ETP). Initially, the ETP will be double-blind as 
patients in the placebo arm cross over to active treatment. 
The PAP will include a screening/baseline period and a treatment period. 
During the screening/baseline period, from Day -60 to Day 1 preinfusion, 
approximately 36 patients will provide informed consent and undergo 
screening assessments to determine trial eligibility and undergo baseline 
measurements. If all eligibility criteria are met, then patients will be 
randomized and enter the treatment period on Day 1. Day 1 is the day the first 
infusion is administered. The visit schedule is calculated using Day 1 of the 
dose escalation period as the reference. Treatment assignment and 
randomization will be performed using an Interactive Voice Response 
System/Interactive Web Response System. Patients will be randomly and 
centrally assigned across sites and using blocks of fixed size to placebo 
(saline, 0.9% sodium chloride solution) or 3.0 mg/kg olipudase alfa in 
a 1:1 ratio. 
After completing the PAP, patients will enter the ETP and those who had been 
randomized to active arm will continue receiving the dose to which they were 
randomized during the PAP (or the highest tolerated dose [HTD], if the 
randomized dose was intolerable). Patients randomized to the placebo arm in 
the PAP will cross over to active treatment in the ETP and will undergo dose 
escalation to a target dose of 3.0 mg/kg of olipudase alfa. To maintain the 
double-blind, all patients will dose-escalate using the schedule provided (ie, 
true dose escalation for patients who were in the placebo arm during the PAP 
and mock dose escalation for patients who were in the active arm during the 
PAP). 
Study drug will be defined during the PAP as olipudase alfa or placebo and 
during the ETP as olipudase alfa and will be administered intravenously once 
every 2 weeks. Dose escalation during the PAP and ETP will occur according 
to the following schedule: (True dose-escalation for patients in the active arm 
during the PAP or the placebo arm during the ETP; mock dose-escalation for 
patients in the active arm during the ETP or placebo arm during the PAP). 
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Study week 
Scheduled dose of study drug in mg/kg 
Week 0 
0.1 
 
Week 2 
0.3 
 
Week 4 
0.3 
Week 6 
0.6 
 
Week 8 
0.6 
 
Week 10 
1.0 
 
Week 12 
2.0 
 
Week 14 
3.0 
 
Week 16 
3.0 
End of the mock dose escalation for patients 
assigned to placebo; end of true dose 
escalation for patients assigned to target dose 
3.0 mg/kg. 
Note: a Schedule does not account for rechallenge. 
Study drug includes olipudase alfa and placebo 
During the PAP, one rechallenge each will be allowed for doses administered 
at Week 0 (0.1 mg/kg or placebo) and at Week 4 (0.3 mg/kg or placebo). 
Patients who are unable to tolerate the rechallenge at those doses will be 
discontinued from the study. If a patient is discontinued due to inability to 
tolerate rechallenge (ie, a second dose of 0.3 mg/kg olipudase alfa), then an 
additional patient may be randomized. Any patient who successfully dose-
escalates through Week 4, but cannot tolerate study drug infusions at later 
weeks, will continue in the trial at the Week 4 dose (ie, 0.3 mg/kg olipudase 
alfa or placebo) until the end of treatment; likewise, any patient unable to 
tolerate a dose administered during later weeks will receive the HTD even if 
that dose is less than the target randomized dose and will continue in the ETP 
at this dose. The minimum active dose administered will be 0.3 mg/kg 
olipudase alfa. 
The same dose-escalation schedule and conditions will apply for patients who 
cross over from the placebo arm during the PAP to the active arm in the ETP, 
except that patients unable to tolerate the one rechallenge each allowed for 
doses administered at Week 54 (0.1 mg/kg olipudase alfa) and Week 58 
(0.3 mg/kg olipudase alfa) will discontinue from the study and will not be 
replaced. 
During the PAP and ETP, in-patient hospitalization will be required before and 
for at least 24 hours after the end of infusion during dose escalation 
(ie, through Week 16 and Week 70, respectively) and may be required during 
the quarterly and yearly visits up through the end of Year 2; in-patient 
hospitalization may be necessary during quarterly and yearly study visits in 
Years 3 through 5. For all other study infusions, patients will be monitored for 
at least 1 hour after the end of infusion for safety. 
Home infusion may be initiated during the COVID-19 pandemic in the ETP by 
trained home nurses if agreed between the investigator and the sponsor, in 
compliance with applicable country-specific regulations. Patients must meet 
the eligibility requirements outlined in Section 10.1.1.   
Patients who initiated home infusion during the COVID-19 pandemic, and 
continue to be on home infusion, may continue receiving home infusion by 
trained home nurses in the ETP every 2 weeks (±3 days) until the end of the 
ETP (refer to Appendix B for Germany). 
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For treatment periods during the PAP and the ETP, dose-limiting toxicity 
criteria will apply. A rescue strategy will be implemented for patients who 
experience significant clinical decline. 
STUDY POPULATION 
Main selection criteria 
Inclusion criteria 
• 
The patient is willing and able to provide signed written informed 
consent. 
• 
The patient is male or female aged 18 years or older. 
• 
The patient has documented deficiency of acid sphingomyelinase as 
measured in peripheral leukocytes, cultured fibroblasts, or 
lymphocytes; and a clinical diagnosis consistent with Niemann-Pick 
disease type B. 
• 
The patient has diffusing capacity of the lung for carbon monoxide 
(DLCO) ≤70% of the predicted normal value. 
• 
The patient has a spleen volume ≥6 multiples of normal (MN) 
measured by MRI; patients who have had partial splenectomy will be 
allowed if the procedure was performed ≥1 year before 
screening/baseline and the residual spleen volume is ≥6 MN. 
• 
The patient has an SRS ≥5. 
• 
Female patients of childbearing potential must have a negative 
serum pregnancy test for beta-human chorionic gonadotropin 
(β-HCG). 
• 
Female patients of childbearing potential and 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 for up to 15 days following their last dose of study 
drug. 
Exclusion criteria 
• 
The patient has received an investigational drug within 30 days 
before study enrollment. 
• 
The patient has a medical condition, including significant intercurrent 
illness; significant cardiac disease (eg, clinically significant 
arrhythmia, moderate or severe pulmonary hypertension or clinically 
significant valve dysfunction, or <40% left ventricular ejection 
fraction by echocardiogram [ECHO]); active hepatitis B or hepatitis 
C, or infection with human immunodeficiency virus (HIV); 
malignancy diagnosed within the past 5 years (other than non-
melanoma skin cancer), or any other serious medical condition that 
may preclude participation in the study. 
• 
The patient has a platelet count <60 x 103/μL based on the average 
of 2 samples.  
• 
The patient has an international normalized ratio (INR) >1.5. 
• 
The patient has alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >250 IU/L or total bilirubin >1.5 mg/dL 
(except for patients with Gilbert’s syndrome). 
• 
The patient has had a major organ transplant (eg, bone marrow or 
liver). 
• 
The patient is scheduled during the study for in-patient 
hospitalization including elective surgery and excluding the liver 
biopsies required per protocol. 
• 
The patient, in the opinion of the investigator, is unable to adhere to 
the requirements of the study. 
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• 
The patient is unwilling or unable to abstain from the use of alcohol 
for 1 day before and 3 days after each study drug infusion. Testing 
for blood alcohol levels will not be required. 
• 
The patient is unwilling or unable to avoid 10 days before and 3 days 
after the protocol scheduled liver biopsies, that are required at 
screening/baseline, at Week 52 and at Week 104, the use of 
medications or herbal supplements that are potentially hepatotoxic 
(eg, 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors, 
erythromycin, valproic acid, anti-depressants, kava, echinacea) 
and/or may cause or prolong bleeding (eg, anti-coagulants, 
ibuprofen, aspirin, garlic supplements, ginkgo, ginseng). 
• 
The patient requires medications that may decrease olipudase alfa 
activity (eg, fluoxetine, chlorpromazine, tricyclic antidepressants 
[eg, imipramine, or desipramine]). 
• 
The patient requires use of invasive ventilatory support. 
• 
The patient requires use of noninvasive ventilator support while 
awake for longer than 12 hours daily. 
• 
The patient is breast-feeding. 
Total expected number of patients 
Approximately 36 patients 
STUDY TREATMENT(s) 
 
Investigational medicinal product 
Formulation 
 
 
 
Olipudase alfa (GZ402665) 
Olipudase alfa will be provided as a sterile lyophilized powder and will be 
reconstituted with sterile water for injection. The prepared solution will be 
further diluted with 0.9% sodium chloride in a covered infusion bag and/or 
syringe to a specific volume based on dose to be administered. Placebo will 
be used as the reference treatment in this study and will be provided by the 
hospital pharmacy as 0.9% sodium chloride solution in an identical covered 
infusion bag and/or syringe. 
Placebo 
Saline (0.9% sodium chloride solution) 
Route of administration 
Intravenous infusion 
Dose regimen 
Once every 2 weeks (±3 days) in reference to the date of the first infusion 
(Day 1) for each patient 
Home infusion may be initiated during the COVID-19 pandemic in the ETP by 
trained home nurses if agreed between the investigator and the sponsor, in 
compliance with applicable country-specific regulations. Patients must meet 
specific eligibility requirements in (Section 10.1.1).  
Patients who initiated home infusion during the COVID-19 pandemic, and 
continue to be on home infusion, may continue receiving home infusion by 
trained home nurses in the ETP every 2 weeks (±3 days) until the end of the 
ETP (refer to Appendix B for Germany). 
ENDPOINT(S) 
 
Efficacy 
Primary efficacy endpoints 
• 
Percentage change in spleen volume (in MN) from baseline to 
Week 52 (combined with change in SRS from baseline to Week 52 
in the US only, and referred to as the “combination spleen endpoint”) 
• 
Percentage change in DLCO (in % predicted of normal) from 
baseline to Week 52 
 
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Secondary efficacy endpoints 
Secondary efficacy endpoints will include the following: 
• 
Percentage change in liver volume (in MN) from baseline to 
Week 52 
• 
Percentage change in platelet counts from baseline to Week 52 
• 
Week 52 change from baseline in fatigue severity as measured by 
Item 3 of the BFI scale 
• 
Week 52 change from baseline in pain severity as measured by Item 
3 of the BPI-SF scale 
• 
Week 52 change from baseline in dyspnea severity as measured by 
the FACIT dyspnea tool 
• 
Change in SRS from baseline to Week 52 (except US, where it is 
part of the primary “combination spleen endpoint”) 
 
Tertiary efficacy endpoints 
• 
Percentage change from baseline to Week 52 in liver function tests 
(ALT, AST, total and direct bilirubin) 
• 
Pulmonary imaging by high-resolution computed tomography 
(HRCT) and chest X-ray (in selected sites) to quantify infiltrative lung 
disease. 
• 
Other components of the pulmonary function test (ie, forced vital 
capacity [FVC], volume of air expired during the first second of FVC 
[FEV1], total lung capacity) 
• 
Fasting lipid profile (eg, high-density lipoprotein, low-density 
lipoprotein, very low-density lipoprotein, total cholesterol, 
triglycerides, apolipoprotein B, apolipoprotein A1, lipoprotein [a]) 
• 
Bone disease assessments: MRI and dual energy X-ray 
absorptiometry of lumbar spine and entire bilateral femur for bone 
marrow burden score and bone mineral density measurements 
including total density as well as T- and Z-score measurements. 
• 
Cardiopulmonary performance by treadmill ergometry 
• 
Biomarkers: angiotensin-converting enzyme (ACE), chitotriosidase, 
chemokine (C-C motif) ligand 18 (CCL18), bone-specific alkaline 
phosphatase, C-telopeptide. 
• 
Hematology parameters 
• 
Other quality of life questionnaires: 
- 
Brief Pain Inventory - Short form 
- 
Brief Fatigue Inventory 
- 
Functional Assessment of Chronic Illness Therapy 
(FACIT) - Dyspnea Short form 
- 
NPB - Health Assessment Questionnaire 
- 
Short Form-36v2 Health Survey 
- 
EuroQol - quality of life questionnaire in 5 dimensions 
- 
Health-related productivity questionnaire 
Exploratory efficacy endpoints will include the following: 
• 
Physician's global assessment of change 
• 
NMR of HDL 
• 
Echo-Doppler imaging to assess liver functioning  
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• 
Multiplex assay of inflammatory and vascular biomarkers. 
• 
Patient Global Impression of Symptom Severity (PGIS) of ASMD 
questionnaire 
• 
Patient Global Impression of Change (PGIC) scale 
• 
Treatment experience interviews 
Safety endpoints 
• 
Assessment of adverse events (AEs), including SAEs, infusion-
associated reactions (eg, cytokine release syndrome [CRS], acute 
phase reactions) and adverse events of special interest (AESIs) 
• 
Clinical laboratory tests 
• 
Vital signs 
• 
Electrocardiogram 
• 
Physical examinations 
• 
Doppler echocardiography 
• 
Biomarkers 
• 
Immune response assessments 
- 
Multiplex assay of inflammatory and vascular biomarkers (Meso 
Scale) 
Pharmacokinetics 
Plasma parameters include Cmax, tmax, AUC0-last, AUC, t1/2, CL, and Vss 
Pharmacodynamics 
• 
Clearance of sphingomyelin accumulation from baseline to Week 52 
in liver tissue 
• 
Change from baseline to Week 52 in levels of sphingomyelin, 
ceramide and other metabolites in plasma or dried blood spot 
ASSESSMENT SCHEDULE 
Screening assessments will be completed within a 60-day window before 
Day 1 and results will be available before the first study drug infusion. 
Assessments for baseline measurements will be made before randomization. 
Schedules for efficacy, safety, pharmacodynamic, and pharmacokinetic 
assessments as well as eDiary assessments are presented in Section 1.2. 
The patient schedule for completing eDiary assessments at home is presented 
in Section 1.3. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination 
The sample size calculations are based on the 2 primary efficacy endpoints of 
percentage change from baseline in spleen volume (expressed in MN) at 
Week 52 and the percentage change from baseline in DLCO (expressed as % 
predicted of normal) at Week 52. The assumptions for the spleen volume 
endpoint are the following: 
• 
An 11.8% common standard deviation based on data from previous 
ASMD and Gaucher disease type 1 studies 
• 
A 30% mean difference from baseline to Week 52 between 
3.0 mg/kg olipudase alfa and placebo in percentage change in 
spleen volume MN 
• 
An expected exclusion rate from the modified intent-to-treat (mITT) 
population of 11% 
Based on the above assumptions, a comparison between 3.0 mg/kg olipudase 
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alfa and placebo would have over 95% power using a t-test at a 2-sided 5.0% 
significance level with 36 patients randomized 1:1 to placebo or 3.0 mg/kg 
olipudase alfa. At a 2.5% significance level, the power would still be over 95%. 
The following assumptions for the DLCO endpoint are based on results 
obtained from the olipudase alfa Phase 1b study DFI13412: 
• 
A 20% common standard deviation 
• 
A 25% mean difference from baseline to Week 52 between 
3.0 mg/kg olipudase alfa and placebo in percentage change in 
DLCO (in % predicted) 
• 
An expected exclusion rate from the mITT population of 11% 
Based on these assumptions, a comparison between the 3.0 mg/kg treatment 
arm and the placebo arm will have 93% power using a t-test at a 2-sided 5.0% 
significance level and with 36 patients randomized 1:1 to placebo or 3.0 
mg/kg. 
The assumptions for the splenomegaly-related score endpoint came from the 
Sanofi-sponsored clinical trial in myelofibrosis (JAKARTA, NCT# 01437787). 
The assumptions for the power calculations are: 
• 
A common standard deviation of 9.4 
• 
A mean difference of 8.0 from baseline to Week 52 between 
3.0 mg/kg of olipudase alfa and placebo in the SRS 
• 
An expected exclusion rate from the mITT population of 11% 
Based on the above assumptions, a comparison between 3.0 mg/kg of 
olipudase alfa and placebo will have 82% power using a t-test to detect 
a statistical trend, defined as 2-sided p-value ≤0.15, with 36 patients 
randomized 1:1 to placebo and 3.0 mg/kg of olipudase alfa. 
For the US protocol, in which a combination spleen endpoint is used, using the 
simplifying assumption that the 2 components of the combination spleen 
endpoint (spleen volume and SRS) are independent, the likelihood that 
statistical significance (spleen volume significance based on Hochberg 
procedure and SRS p-value ≤0.15) will be declared for the combination spleen 
endpoint is greater than 80%. 
Analysis populations 
The randomized population will include any patient who had been allocated 
to a randomized treatment arm regardless if study drug was administered. 
The safety population is a subset of the randomized population and will 
include randomized patients who received at least 1 infusion (partial or total). 
This is the primary population for the safety analysis. 
The mITT population is the same as the safety population, and is used as the 
primary population for the efficacy analysis. 
The per protocol population will be a subset of the mITT population who 
have no major protocol deviations that are expected to interfere with 
assessments of the 2 primary efficacy endpoints. 
The extension treatment population will consist of patients who completed 
the PAP and who continue into the extension treatment period. 
The pharmacokinetic (PK) population will consist of mITT patients who have 
evaluable drug concentration data. 
The pharmacodynamic (PD) population will consist of mITT patients who 
have at least 1 evaluable PD marker data available post-baseline. 
Patients who are included in the safety population and have rescue therapy 
initiated are included in the rescue therapy population. Since in the ETP all 
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subjects get olipudase alfa, the rescue therapy is relevant only for the PAP. 
 
Analysis of efficacy 
The 2 primary efficacy endpoints (percentage change in spleen volume in MN 
from baseline to 52 weeks and percentage change in DLCO in % predicted 
from baseline to 52 weeks) will be analyzed in the mITT population using the 
mixed model for repeated measures. The secondary efficacy endpoints will 
also be analyzed using this method. In the United States, spleen volume is 
combined with change in SRS from baseline to Week 52 and is referred to as 
the “combination spleen endpoint”. 
The primary and secondary endpoints will be tested using a 2-stage 
gatekeeping strategy to maintain the 5% familywise error rate. A Hochberg 
method will be used to test the 2 primary endpoints. For the US only, if spleen 
volume is significant, change in SRS from baseline to Week 52 will be tested 
at the 0.15% level. The secondary endpoints will be tested in a closed, 
hierarchical fashion. 
 
Analysis of safety 
Safety analyses may be performed using the safety population. Additional 
summaries will be conducted using the most recent dose the patient received 
before the event of interest. 
All AEs will be coded using the most recent version of the Medical Dictionary 
for Regulatory Activities (MedDRA). Adverse event (AE) incidence tables will 
present by system organ class (SOC) (sorted by internationally agreed order) 
and preferred term (PT) 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 period. The 
denominator for computation of percentages is the safety population within 
each treatment arm. 
All treatment-emergent AEs (TEAEs), all TEAEs potentially related to study 
drug, all TEAEs leading to treatment discontinuation and/or study 
discontinuation, all TEAEs that are IARs, all treatment-emergent SAEs 
(including treatment-related SAEs), and all AEs with fatal outcome will be 
summarized. The TEAE observation period will be defined as the time from 
the first infusion of study drug through the end of study visit or 30 to 37 days 
after the last infusion of study drug whichever one occurs later. 
Detailed listings of TEAEs, SAEs, AESIs, related TEAEs, and discontinuations 
due to TEAEs will be provided and include the randomized treatment arm and 
olipudase alfa dose of the infusion or placebo before or during the occurrence 
of the TEAE, when applicable.  
The number of TEAEs and annualized rate, and the number and proportion of 
patients reporting specific TEAEs will be tabulated for the overall analyses of 
TEAEs. 
The ECG data will be analyzed using the Bazett’s and Fridericia’s QT 
correction methods. All ECG variables will be summarized for each 
randomization dose group/dose and time point. Change from baseline will also 
be calculated and summarized using descriptive statistics. 
 
Pharmacokinetics 
Plasma concentration-time data will be analyzed using actual dosing and 
sampling times by non-compartmental methods. Pharmacokinetic parameters 
will be summarized by dose level, study week as appropriate, and in relation to 
immunogenicity. If data do not lend to non-compartmental analysis, or for 
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additional analyses, model based approaches such as nonlinear mixed effects 
modeling may be used. 
Pharmacodynamics 
Concentration-time data for sphingomyelin and metabolites will be 
summarized using descriptive statistics. Individual and summary statistics will 
be presented. 
All other pharmacodynamic parameters will be summarized using descriptive 
statistics. Change from baseline will be calculated and summarized. 
Exploratory correlation analyses will be attempted to evaluate relationships 
between different pharmacodynamic markers and between sphingomyelin 
and/or lyso-sphingomyelin levels from different sources. 
Lyso-sphingomyelin and ceramide represent most informative readouts for 
pharmacodynamic response to treatment. Only these 2 parameters will be 
assessed after the cutoff date for a planned second database lock of the study 
for purpose of regulatory submissions in 2021. 
 
Pharmacokinetics-pharmacodynamics 
Exploratory PK-PD analyses may be performed to elucidate dose-response 
and concentration response relationships with biomarkers of safety and/or 
efficacy. The PK-PD relationships may be explored graphically and if 
a relationship is apparent, PK-PD modeling may be attempted and results 
reported, as appropriate. 
Interim analysis 
No interim analysis is planned during PAP. However, during ETP, a formal 
summary of data or interim CSRs may be produced to support regulatory 
approval(s) and/or other submission/application requirement(s). 
DURATION OF STUDY PERIOD (per 
patient)  
The longest study duration per patient will be for at least 3 years and up to 
5 years and 3 months dependent upon continued regulatory approval of this 
protocol: 
• 
Screening/baseline: up to 60 days 
• 
Primary analysis period: approximately 52 weeks 
• 
Extension treatment period: until study completion (up to 4 years) 
• 
End of study visit within 2 weeks after the last treatment 
• 
Follow up phone call 30-37 days after the last treatment visit 
STUDY COMMITTEES 
Independent Data Monitoring Committee 
 
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1 
FLOW CHARTS AND SCHEDULES OF ASSESSMENTS  
1.1 
 STUDY FLOW CHARTS  
1.1.1 Flow chart for primary analysis period through Week 52  
 
Dose escalation (mg/kg) 
W0/ 
Day 1 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
0.6 
1.0 
2.0 
3.0 
3.0 
0.3 
0.6 
0.3 
0.1 
3.0 
/
W2 
W4 
W6 
W8 
W10 
W12 
W14 
QV 
W16 
Treatment 
arm 
 
Randomization 
1:1 
36 patients 
Screening and 
baseline 
measurements 
(day -60 to day 1) 
Placebo 
W52 
Legend: 
QV = quarterly visit 
Note: Numerical values are in mg/kg 
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1.1.2 Flow chart for extension treatment period  
 
 
Dose escalation (mg/kg) 
 
W N 
W 60 
W 62 
W 64 
W 66 
W 68 
QV 
W 70 
W N+2 
0.1 
0.3 
0.3 
0.6 
0.6 
1.0 
2.0 
3.0 
3.0 
... 
... 
Extension treatment period 
PAP treatment period/52W 
Active (3.0) 
... 
W 52 
QV 
True treatment crossover for placebo and mock 
crossover for active arm  
Initial treatment 
arm 
 
W 54 
W 56 
W 58 
3.0 
3.0 
3.0 
3.0 
3.0 
3.0 
3.0 
3.0 
3.0 
... 
... 
Placebo 
(P)
... 
P 
3.0 
Legend: 
P = placebo 
QV = quarterly visit 
Note: Numerical values are in mg/kg 
Placebo arm in PAP          true dose escalation to 3.0 mg/kg 
Active arm in PAP             mock dose escalation to 3.0 mg/kg 
 
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1.2 
SCHEDULES OF ASSESSMENTS  
1.2.1 Primary analysis period  
1.2.1.1 Schedule of assessments: Year 1 - PAP screening to Week 16  
 
Year 1: PAP 
Screening to Week 16 
Screening 
Dose escalation perioda 
Study procedures 
Day 
-60 to -1b 
W0 
Day 1c 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
QV 
W16 
SCREENINGd/ENROLLMENT/BASELINE 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Assign patient number 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history including medications administered 
within 30 days 
X 
 
 
 
 
 
 
 
 
 
Alcohol and tobacco usage 
X 
 
 
 
 
 
 
 
 
 
Demographics and baseline characteristics 
X 
 
 
 
 
 
 
 
 
 
Screening eDiarye 
X 
 
 
 
 
 
 
 
 
 
ASM activity in peripheral leukocytes and dried blood spot 
X 
 
 
 
 
 
 
 
 
 
Genotyping:f SMPD1, CHIT1, UGT1A1 
X 
 
 
 
 
 
 
 
 
 
Lab testing for enrollment 
 
 
 
 
 
 
 
 
 
 
• 
HIV antibody testing 
X 
 
 
 
 
 
 
 
 
 
• 
Hepatitis B surface antigen test 
X 
 
 
 
 
 
 
 
 
 
• 
Hepatitis C antibody test 
X 
 
 
 
 
 
 
 
 
 
• 
β-HCG pregnancy testg 
X 
 
 
 
 
 
 
 
 
 
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Year 1: PAP 
Screening to Week 16 
Screening 
Dose escalation perioda 
Study procedures 
Day 
-60 to -1b 
W0 
Day 1c 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
QV 
W16 
Optional blood sample for pharmacogenetic assessment 
Pharmacogenetic informed consent form 
 
Any time after the pharmacogenetic ICF has been obtained 
Randomization to placebo or olipudase alfah 
 
X 
 
 
 
 
 
 
 
 
SAFETY 
AE/SAE assessmenti 
Continuous monitoring 
Concomitant medications and therapies 
Continuous monitoring 
Complete physical examinationj 
X 
X 
 
 
 
 
 
 
X 
 
Abbreviated physical examinationk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight, BMI 
X 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital sign measurements 
X 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Electrocardiogramn 
X 
X 
 
 
 
 
 
 
X 
 
Echocardiogram with Doppler 
X 
 
 
 
 
 
 
 
X 
 
Clinical laboratory sampling 
 
Liver function testing and coagulation 
X 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Hematologyp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry and urinalysis (dipstick only) 
X 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
β-HCG pregnancy testg 
X 
X 
 
X 
 
X 
 
X 
 
X 
Samplingq for hsCRP, iron, ferritin, ceramide, 
cardiac-specific troponin I, calcitonin 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune response monitoring 
 
Multiplex assayq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-olipudase alfa IgG 
 
X 
 
X 
 
X 
 
X 
 
X 
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Year 1: PAP 
Screening to Week 16 
Screening 
Dose escalation perioda 
Study procedures 
Day 
-60 to -1b 
W0 
Day 1c 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
QV 
W16 
Neutralizing antibodies 
 
Only in patients positive for IgG olipudase alfa 
If a patient develops IAR - hypersensitivity reaction(s): 
 
 
• 
Anti-olipudase alfa IgG 
• 
Anti-olipudase alfa IgE 
 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample ≥3 days after the 
event or before the next infusion. 
• 
Tryptase activity 
• 
Complement activation 
 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample 1 to 3 hours after 
the event. 
Skin testing 
 
As needed for hypersensitivity reactions - See study manual 
In case of cytokine release syndrome: 
 
Multiplex assay (Meso Scale) 
 
For suspicion of CRS, collect immediately, unless already collected within the past 30 minutes 
Calcitonin 
 
EFFICACY/PHARMACODYNAMICS 
Abdominal MRIr 
X 
 
 
 
 
 
 
 
 
 
Echo-Doppler of liver 
X 
 
 
 
 
 
 
 
 
 
Chest X-rays 
X 
 
 
 
 
 
 
 
 
 
Pulmonary HRCT scan 
X 
 
 
 
 
 
 
 
 
 
Pulmonary function tests 
X 
 
 
 
 
 
 
 
 
 
Treadmill ergometry 
X 
 
 
 
 
 
 
 
 
 
Fasting lipid profile 
X 
 
 
 
 
 
 
 
X 
 
NMR of HDL 
X 
 
 
 
 
 
 
 
 
 
MRI scans of lumbar spine and bilateral femur 
X 
 
 
 
 
 
 
 
 
 
DXA scans of lumbar spine and bilateral femur 
X 
 
 
 
 
 
 
 
 
 
Sphingomyelin, ceramide, and other metabolites in plasmaq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Metabolites in dried blood spot 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chitotriosidase, ACE, CCL18 
X 
 
 
 
 
 
 
 
X 
 
Serum bone-specific ALP and C-telopeptide 
X 
 
 
 
 
 
 
 
X 
 
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Year 1: PAP 
Screening to Week 16 
Screening 
Dose escalation perioda 
Study procedures 
Day 
-60 to -1b 
W0 
Day 1c 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
QV 
W16 
Health-related quality of life instruments 
 
• 
BFI, BPI-SF, EQ-5D, SF-36 
X 
 
 
 
 
 
 
 
 
 
• 
Health-Related Productivity Questionnaire, PGIS and 
PGIC, and NPB-HAQ 
Xt 
 
 
 
 
 
 
 
X 
 
• 
eDiaryu 
 
 
 
 
 
 
 
 
 
 
- 
Distribute eDiary device to patients 
X 
 
 
 
 
 
 
X 
 
 
- 
Collect eDiary device from patients 
 
X 
 
 
 
 
 
 
X 
 
Physician global assessment 
X 
 
 
 
 
 
 
 
 
 
Liver biopsyv 
X 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFUSION AND PHARMACOKINETICS 
Study drug infusionw 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingx 
 
 
X 
 
 
 
X 
 
X 
 
Abbreviations: ACE = angiotensin-converting enzyme; AE=adverse event; ALP = alkaline phosphatase; ASM = acid sphingomyelinase; β-HCG = beta-human chorionic gonadotropin; BFI = Brief Fatigue Inventory; 
BMI=body mass index; BPI-SF = Brief Pain Inventory - Short Form; CCL18 = chemokine (C-C motif) ligand 18; DXA = dual-energy X-ray absorptiometry; EQ-5D = EuroQOL-5 dimensions questionnaire; HIV = human 
immunodeficiency virus; HDL = high-density lipoprotein; HRCT = high-resolution computed tomography; hsCRP = heat-sensitive C-reactive protein; IAR = infusion-associated reaction; IgE=immunoglobulin E; 
IgG = immunoglobulin G; MRI = magnetic resonance imaging; NMR = nuclear magnetic resonance; NPB-HAQ = NPB - Health Assessment Questionnaire; PAP = primary analysis period; PGIC=Patient Global 
Impression of Change scale; PGIS=Patient Global Impression of Symptom Severity questionnaire; PK=pharmacokinetic; SAE=serious adverse event; SF-36 = Short Form-36; QV = quarterly visit; W = study week. 
a Study drug infusions will occur once every 2 weeks (±3 days) in reference to the date of the first infusion (Day 1). Assessments will be performed at the indicated visits ±7 days, unless otherwise specified. Unless 
specified otherwise, study procedures should preferably occur before infusion and during approximately the same time of day for each visit (in reference to the screening/baseline visit). When multiple 
assessments are required, the order will be vital signs before ECG before blood draw. 
b In exceptional circumstances, screening may be extended beyond the 60 day window after consultation with the sponsor. In this case, some assessments done at the beginning of screening may have to be 
repeated. 
c Day 1 is the day the first infusion is administered. The visit schedule is calculated using Day 1 of the PAP as the reference. 
d Rescreening may be possible for patients who screen failed, but is subject to sponsor approval. Imaging, function tests (eg, PFTs, ergometry), and questionnaires performed within 12 weeks of the expected date 
of randomization can be used for rescreening. All labs will be repeated, except genotyping and ASM activity measurements. The eDiary will not be repeated.  
e The e-Diary will be administered once at the beginning of the screening period to check the related inclusion criterion, and a second time as baseline just before the first infusion (see footnote u). 
f 
SMPD1, CHIT1, and UGT1A1 will be genotyped only if historical results are not available, or if historical results are available, but mutations were not annotated using the guidelines of the Human Genome 
Variation Society (http://www.hgvs.org/). 
g Serum β-HCG test for pregnancy at screening only; urine β-HCG up to 24 hours before the first infusion of the study; then before infusion once every 4 weeks; if positive, repeat test with serum. 
h Randomization can occur a few days before the first infusion. All baseline assessments will be done before the first infusion. 
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i 
Adverse events will be captured from the time the patient provides signed informed consent through the safety follow-up period (30 to 37 days after the patient’s last study infusion).  
j 
The complete physical examination will include a neurological examination (mental status, cranial nerves, muscle strength, sensation, deep-tendon reflexes, and coordination); examinations of lymph nodes, heart, 
lungs, abdomen, and extremities/joints; and an assessment of the general appearance, skin, and HEENT (head, eyes, ears, nose, and throat). 
k The abbreviated examination of general appearance only will be carried out before and after each study drug infusion. 
l 
The patient’s weight at the previous visit, instead of the weight at the current visit, can be used to calculate the dose of drug to be infused at the current visit if the weight at the current visit is missing. 
m Vital sign measurements will include blood pressure, heart rate, respiratory rate, and temperature. At all visits during the dose escalation period and at all quarterly visits, collection times will be prior to the infusion 
(within 30 ±10 minutes of infusion start); halfway through (ie, when half the expected time for infusion duration has elapsed); at the end of infusion (±10 minutes); 2 hours ±10 minutes, 4 hours ±10 minutes, and 
6 hours ±10 minutes after the end of the infusion; and every 8 hours ±1 hour until the patient has been discharged. At these visits, vital signs should also be measured at discharge ±10 minutes, which may or 
may not represent an additional measurement to the schedule described above. For these visits, patients should remain hospitalized at the site for at least 24 hours after the end of the infusion. The investigator 
may decide that longer monitoring is required.  
n Electrocardiograms will be performed before any blood is collected. At screening, 1 ECG will be performed. On Day 1 of Week 0, ECG will be performed in triplicate (3 ECGs in a row) within 24 hours before 
infusion and as a singlet 4 hours ±10 minutes, 12 hours ±1 hour, and 24 hours ±3 hours after the end of infusion. At all other study visits, 1 ECG will be administered each before infusion and 4 hours ±10 minutes, 
12 hours ±1 hour, and 24 hours ±3 hours after the end of infusion. 
o Samples will be taken for liver function testing and coagulation within 24 hours before infusion and at 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion. Samples will be taken for urinalysis and 
clinical chemistry within 24 hours before infusion. 
p At screening, 2 samples will be taken at least 24 hours and up to 2 weeks apart, 1 sample for complete blood count and 1 sample for hemoglobin, white blood cell count, and platelet count. From Day 1 to W16, 
1 sample for complete blood count with differential will be taken within 24 hours before infusion and one 24 hours ±3 hours after the end of infusion. 
q Sample will be taken within 24 hours before infusion and 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion for metabolites in plasma and biomarkers including but not limited to: hsCRP, iron, 
ceramide, ferritin, cardiac troponin-I, calcitonin, and multiplex assay (Meso Scale) for other biomarkers indicative of inflammation and vascular damage. 
r 
Spleen and liver volumes will be measured from the abdominal MRI. Patients will be required to fast from solid foods (liquids such as water or juice will be permitted) for ≥6 hours before an abdominal MRI to 
reduce the effect of a meal on MRI data. 
s Chest X-ray will be performed in selected sites. 
t 
Questionnaires will be completed at all indicated visits, except PGIC will not be completed at screening. 
u Patients will fill out the eDiary as part of the baseline assessments during the evening of the 7 consecutive days before the first infusion and each quarterly visit (see Section 1.3). If the patient does not fill out the 
eDiary on the day before infusion, (ie, missing the Day 7 entry), then the patient will be allowed to make the day 7 eDiary entry in the clinic before study drug infusion. 
v Liver biopsy samples will be collected at screening to determine baseline histopathology. See the study manual for guidelines on prohibited medications and therapies that are not to be taken within 10 days before 
and 3 days after the procedure. 
w Patients must be hospitalized before the start of the infusion and remain hospitalized for at least 24 hours after the end of infusion during dose escalation period. Blood will be collected and safety assessments 
(including vital signs [footnote m]) will be performed. Study drug infusions will occur once every 2 weeks (±3 days) in reference to the date of the first infusion (Day 1) for each patient. 
x See Section 1.2.3 for the PK sampling schedule. 
 
 
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1.2.1.2 Schedule of assessments: Year 1 - PAP Week 18 through Week 52  
 
Year 1: PAP 
Week 18 through 
Week 52 
Study weeka 
Study procedures 
W18 W20 W22 W24 W26 
QV 
W28 
W30 
W32 
W34 
W36 
W38 
QV 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
QV 
SAFETY 
AE/SAE assessmentb 
Continuous monitoring 
Concomitant medications and 
therapies 
Continuous monitoring 
Alcohol and tobacco use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Complete physical examinationc 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Abbreviated physical 
examinationd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital sign measurementse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramf 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Echocardiogram with doppler 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical laboratory sampling 
• 
Liver function testing 
and coagulationg 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
• 
Hematologyh 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
• 
Clinical chemistry and 
urinalysis (dipstick 
only)g 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
• 
β-HCG pregnancy testi 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Sampling for hsCRP, iron, 
ferritin, cardiac-specific 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
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Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 24 
Year 1: PAP 
Week 18 through 
Week 52 
Study weeka 
Study procedures 
W18 W20 W22 W24 W26 
QV 
W28 
W30 
W32 
W34 
W36 
W38 
QV 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
QV 
troponin I, calcitonin, ceramidej 
Immune response monitoring 
Multiplex assayj 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Anti-olipudase alfa IgG k 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
• 
Neutralizing antibodies 
Only in patients positive for IgG olipudase alfa 
If a patient develops IAR - hypersensitivity reaction(s): 
• 
Anti-olipudase alfa IgG 
• 
Anti-olipudase alfa IgE 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample ≥3 days after the event or before the next infusion. 
• 
Tryptase activity 
• 
Complement activation 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample 1 to 3 hours after the event. 
Skin testing 
As needed for hypersensitivity reactions – See study manual 
If cytokine release syndrome: 
Multiplex assay (Meso Scale) 
For suspicion of CRS, collect immediately unless already collected within the past 30 minutes 
Calcitonin 
EFFICACY/PHARMACODYNAMICS 
Abdominal MRIl 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Liver biopsym 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Echodoppler of liver 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chest X-rayn 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pulmonary HRCT scan 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pulmonary function tests 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Treadmill ergometry 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Fasting lipid profile 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
NMR of HDL 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 25 
Year 1: PAP 
Week 18 through 
Week 52 
Study weeka 
Study procedures 
W18 W20 W22 W24 W26 
QV 
W28 
W30 
W32 
W34 
W36 
W38 
QV 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
QV 
MRI scans of lumbar spine and 
bilateral femur 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
DXA scans of lumbar spine and 
bilateral femur 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Sphingomyelin, ceramide, and 
other metabolites in plasmaj 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Metabolites in dried blood spot 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Chitotriosidase, ACE, CCL18 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Serum bone-specific ALP and 
C-telopeptide 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Health-related quality of life instruments 
• 
BFI, BPI-SF, EQ-5D, 
SF-36 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
• 
Health-Related 
Productivity 
Questionnaire, PGIS 
and PGIC, and 
NPB-HAQ 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
• 
eDiaryo 
- 
Distribute eDiary 
device to patients 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
- 
Collect eDiary device 
from patients 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Physician global assessment 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
STUDY DRUG INFUSION AND PHARMACOKINETICS 
Study drug infusionp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingq 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
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Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 26 
Abbreviations: ACE = angiotensin-converting enzyme; AE=adverse event; ALP = alkaline phosphatase; β-HCG = beta-human chorionic gonadotropin; BFI = Brief Fatigue Inventory; BPI-SF = Brief Pain Inventory - Short 
Form; CCL18 = chemokine (C-C motif) ligand 18; DXA = dual-energy X-ray absorptiometry; EQ-5D = EuroQOL-5 dimensions questionnaire; HDL = high-density lipoprotein; HRCT = high-resolution computed 
tomography; hsCRP = heat-sensitive C-reactive protein; IAR = infusion-associated reaction; IgE = immunoglobulin E; IgG = immunoglobulin G; MRI = magnetic resonance imaging; NMR = nuclear magnetic resonance; 
NPB-HAQ = NPB - Health Assessment Questionnaire; PAP = primary analysis period; PGIC = Patient Global Impression of Change scale; PGIS = Patient Global Impression of Symptom Severity questionnaire; 
PK = pharmacokinetic; SAE = serious adverse event; SF-36 = Short form-36; QV = quarterly visit; W = study week. 
a Study drug infusions will occur once every 2 weeks (±3 days) in reference to the date of the first infusion (Day 1). Assessments will be performed at the indicated visits ±7 days, unless otherwise specified. Unless 
specified otherwise, study procedures should preferably occur before infusion and during approximately the same time of day for each visit (in reference to the screening/baseline visit). When multiple 
assessments are required, the order will be vital signs before ECG before blood draw. 
b Adverse events will be captured from the time the patient provides signed informed consent through the safety follow-up period (30 to 37 days after the patient’s last study infusion). 
c The complete physical examination will include a neurological examination (mental status, cranial nerves, muscle strength, sensation, deep-tendon reflexes, and coordination); examinations of lymph nodes, heart, 
lungs, abdomen, and extremities/joints; and an assessment of the general appearance, skin, and HEENT (head, eyes, ears, nose, and throat). 
d The abbreviated examination of general appearance only will be carried out before and after each study drug infusion. 
e Vital sign measurements will include blood pressure, heart rate, respiratory rate, and temperature. At quarterly visits, collection times will be prior to the infusion (within 30 ±10 minutes of infusion start); halfway 
through (ie, when half the expected time for infusion duration has elapsed); at the end of infusion (±10 minutes); 2 hours ±10 minutes, 4 hours ±10 minutes, and 6 hours ±10 minutes after the end of the infusion; 
and every 8 hours ±1 hour until the patient has been discharged. Vitals signs should also be measured at discharge ±10 minutes, which may or may not represent an additional measurement to the schedule 
described above. For these quarterly visits, patients should remain at the site for at least 24 hours after the end of infusion. The investigator may decide that longer monitoring is required. At all visits except 
quarterly visits and dose escalation visits, vital sign collection times will be prior to the infusion (within 30 minutes ±10 minutes of infusion start); halfway through (ie, when half the expected time for infusion 
duration has elapsed); at the end of infusion ±10 minutes; and at discharge ±10 minutes (1 hour post-infusion). At any visit the investigator may decide that longer monitoring is required. 
f 
A single ECG will be administered each before infusion and 4 hours ±10 minutes, 12 hours ±1 hour, and 24 hours ±3 hours after the end of infusion. Electrocardiograms will be performed before the blood draw 
scheduled at the same time point. 
g Samples will be taken for liver function testing and coagulation within 24 hours before and 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion. Samples will be taken for urinalysis and clinical 
chemistry within 24 hours before infusion. 
h For hematology at quarterly visits, except yearly visits, 1 sample for complete blood count with differential will be taken within 24 hours before infusion and one 24 ±3 hours after the end of infusion. At yearly visits, 
2 samples will be taken at least 24 hours and up to 2 weeks apart before infusion, the first for complete blood count with differential and the second for hemoglobin and white blood cell and platelet counts only. In 
addition, at yearly visits, 1 sample for complete blood count with differential will be taken 24 ±3 hours after the end of infusion. 
i 
Urine β-HCG up to 24 hours before infusion, once every 4 weeks; if positive, repeat test with serum. 
j 
Sample will be taken within 24 hours before infusion and 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion for metabolites in plasma and biomarkers including but not limited to: hsCRP, iron, 
ceramide, ferritin, cardiac troponin-I, calcitonin, and multiplex assay (Meso Scale) for other biomarkers indicative of inflammation and vascular damage. 
k For the switch from Process C
 IMP to the updated manufacturing process C
 IMP, collection will be monthly for the first 6 months after starting the new update, and quarterly after that. 
l 
Spleen and liver volumes will be measured from the abdominal MRI. Patients will be required to fast from solid foods (liquids such as water or juice will be permitted) for ≥6 hours before an abdominal MRI to 
reduce the effect of a meal on MRI data. 
m See the study manual for guidelines on prohibited medications and therapies that are not to be taken within 10 days before and 3 days after the liver biopsy. 
n Chest X-ray will be performed in selected sites. 
o Patients will fill out the eDiary during the evening of the 7 consecutive days before each quarterly visit (see Section 1.3). If the patient does not fill out the eDiary on the day before infusion, (ie, missing the Day 7 
entry), then the patient will be allowed to make the day 7 eDiary entry in the clinic before study drug infusion. 
p Patients must be hospitalized before the start of the infusion and remain hospitalized for at least 24 hours after the end of infusion during quarterly visits during PAP. Blood will be collected and safety assessments 
(including vital signs [footnote e]) will be performed. For all other visits, patients will be observed after the end of infusion for at least 3 hours. Study drug infusions will occur once every 2 weeks (±3 days) in 
reference to the date of the first infusion (Day 1) for each patient. 
q See Section 1.2.3 for the PK sampling schedule. 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 27 
1.2.2 Schedule of assessments: extension treatment period  
1.2.2.1 Schedule of assessments: ETP - Year 2 Week 54 to Week 70  
Year 2: ETP Week 54 to Week 70 
Dose escalation perioda 
Study procedures 
W54 
 
W56 
W58 
W60 
W62 
W64 
W66 
W68 
QV 
W70 
Treatment crossoverb 
X 
 
 
 
 
 
 
 
 
SAFETY 
AE/SAE assessmentc 
Continuous monitoring 
Concomitant medications and therapies 
Continuous monitoring 
Complete physical examinationd 
X 
 
 
 
 
 
 
X 
 
Abbreviated physical examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weightf 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital sign measurementsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramh 
X 
 
 
 
 
 
 
X 
 
Echocardiogram with Doppler 
 
 
 
 
 
 
 
X 
 
Clinical laboratory sampling 
 
Liver function testing and coagulationi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry and urinalysis (dipstick 
only)i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
β-HCG pregnancy testk 
 
X 
 
X 
 
X 
 
X 
 
Sampling for hsCRP, iron, ferritin, 
cardiac-specific troponin I, calcitonin, ceramidel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune response monitoring 
 
Multiplex assayl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 28 
Year 2: ETP Week 54 to Week 70 
Dose escalation perioda 
Study procedures 
W54 
 
W56 
W58 
W60 
W62 
W64 
W66 
W68 
QV 
W70 
Anti-olipudase alfa IgG 
X 
 
X 
 
X 
 
X 
 
X 
Neutralizing antibodies 
Only in patients positive for IgG olipudase alfa 
If a patient develops IAR - hypersensitivity reaction(s): 
• 
Anti-olipudase alfa IgG 
• 
Anti-olipudase alfa IgE 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample ≥3 days after the event or before the next 
infusion. 
• 
Tryptase activity 
• 
Complement activation 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample 1 to 3 hours after the event. 
Skin testing 
As needed for hypersensitivity reactions - See study manual 
In case of cytokine release syndrome: 
Multiplex assay (Meso Scale) 
For suspicion of CRS, collect immediately unless already collected within the past 30 minutes 
Calcitonin 
EFFICACY/PHARMACODYNAMICS 
Fasting lipid profile 
 
 
 
 
 
 
 
X 
 
Sphingomyelin, ceramide, and other metabolites 
in plasmal 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Metabolites in dried blood spot 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chitotriosidase, ACE, CCL18 
 
 
 
 
 
 
 
X 
 
Serum bone-specific ALP and C-telopeptide 
 
 
 
 
 
 
 
X 
 
Health-related quality of life instruments 
 
• 
Health-Related Productivity 
Questionnaire, PGIS and PGIC, and 
NPB-HAQ 
 
 
 
 
 
 
 
X 
 
• 
eDiarym 
 
 
 
 
 
 
 
 
 
- 
Distribute eDiary device to patients 
 
 
 
 
 
 
X 
 
 
- 
Collect eDiary device from patients 
 
 
 
 
 
 
 
X 
 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 29 
Year 2: ETP Week 54 to Week 70 
Dose escalation perioda 
Study procedures 
W54 
 
W56 
W58 
W60 
W62 
W64 
W66 
W68 
QV 
W70 
STUDY DRUG INFUSION AND PHARMACOKINETICS 
Study drug infusionn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingo 
X 
 
 
 
 
 
 
X 
 
Abbreviations: ACE=angiotensin-converting enzyme; AE = adverse event; ALP = alkaline phosphatase; β-HCG = beta-human chorionic gonadotropin; BFI = Brief Fatigue Inventory; BPI-SF = Brief Pain 
Inventory - Short Form; CCL18 = chemokine (C-C motif) ligand 18; EQ-5D = EuroQOL-5 dimensions questionnaire; ETP = extension treatment period; hsCRP = heat-sensitive C-reactive protein; IAR = infusion-
associated reaction; IgE = immunoglobulin E; IgG = immunoglobulin G; NPB-HAQ = NPB - Health Assessment Questionnaire; PAP = primary analysis period; PGIC = Patient Global Impression of Change scale; 
PGIS = Patient Global Impression of Symptom Severity questionnaire; PK = pharmacokinetic; SAE = serious adverse event; SF-36 = Short Form-36; QV = quarterly visit; W = study week. 
a Study drug infusions will occur once every 2 weeks (±3 days) in reference to the date of the first infusion (Day 1). Assessments will be performed at the indicated visits ±7 days, unless otherwise specified. Unless 
specified otherwise, study procedures should preferably occur before infusion and during approximately the same time of day for each visit (in reference to the screening/baseline visit). When multiple 
assessments are required, the order will be vital signs before ECG before blood draw. 
b True crossover for patients on placebo during the PAP and mock crossover for patients already on active treatment. 
c Adverse events will be captured from the time the patient provides signed informed consent through the safety follow-up period (30 to 37 days after the patient’s last study infusion).  
d The complete physical examination will include a neurological examination (mental status, cranial nerves, muscle strength, sensation, deep-tendon reflexes, and coordination); examinations of lymph nodes, heart, 
lungs, abdomen, and extremities/joints; and an assessment of the general appearance, skin, and HEENT (head, eyes, ears, nose, and throat) 
e The abbreviated examination of general appearance only will be carried out before and after each study drug infusion. 
f 
The patient’s weight at the previous visit, instead of the weight at the current visit, can be used to calculate the dose of drug to be infused at the current visit if the weight at the current visit is missing. 
g Vital sign measurements will include blood pressure, heart rate, respiratory rate, and temperature. At all visits during the dose escalation period and at quarterly visits, collection times will be prior to the infusion 
(within 30 ±10 minutes of infusion start); halfway through (ie, when half the expected time for infusion duration has elapsed); at the end of infusion (±10 minutes); 2 hours ±10 minutes, 4 hours ±10 minutes, and 
6 hours ±10 minutes after the end of the infusion; and every 8 hours ±1 hour until the patient has been discharged. Vital signs should also be measured at discharge ±10 minutes, which may or may not represent 
an additional measurement to the schedule described above. For these visits, patients should remain at the site for at least 24 hours. The investigator may decide that longer monitoring is required. 
h Electrocardiograms will be performed before any blood is collected. One ECG will be performed each before infusion and 4 hours ±10 minutes, 12 hours ±1 hour, and 24 hours ±3 hours after the infusion. 
i 
Samples will be taken for liver function testing and coagulation within 24 hours before infusion and at 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion. Samples will be taken for urinalysis and 
clinical chemistry within 24 hours before infusion. 
j 
One sample for complete blood count with differential will be taken within 24 hours before infusion and one 24 hours ±3 hours after the end of infusion. 
k Urine β-HCG test for pregnancy before infusion, once every 4 weeks; if positive, retest using serum. 
l 
Sample will be taken within 24 hours before infusion and 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion for metabolites in plasma and biomarkers including but not limited to: hsCRP, iron, 
ceramide, ferritin, cardiac troponin-I, calcitonin, and multiplex assay (Meso Scale) for other biomarkers indicative of inflammation and vascular damage. 
m Patients will fill out the eDiary during the evening of the 7 consecutive days before each quarterly visit (see Section 1.3). If the patient does not fill out the eDiary on the day before infusion, (ie, missing the Day 7 
entry), then the patient will be allowed to make the day 7 eDiary entry in the clinic before study drug infusion. 
n Patients must be hospitalized before the start of the infusion and remain hospitalized for at least 24 hours after the end of infusion during the dose escalation period and during quarterly visits. Blood will be 
collected and safety assessments (including vital signs [footnote g]) will be performed. Study drug infusions will occur once every 2 weeks (±3 days) in reference to the date of the first infusion (Day 1) for each 
patient. 
o See Section 1.2.3 for the PK sampling schedule. 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 30 
1.2.2.2 Schedule of assessments: ETP - Year 2 Week 72 to Week 104 only applicable before the implementation of changes that will 
occur after the cutoff date of the second database lock  
 
Year 2: ETP Year 2 
Week 72 to Week 104 
Study weeka 
Study procedures 
W72 W74 
W76 
W78 
W80 
QV 
W82 
W84 
W86 
W88 
W90 
W92 
QV 
W94 
W96 
W98 
W100 
W102 
W104 
QV 
SAFETY 
AE/SAE assessmentb 
Continuous monitoring 
Concomitant medications and 
therapies 
Continuous monitoring 
Alcohol and tobacco usage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Complete physical examinationc 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Abbreviated physical 
examinationd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighte, BMI 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital sign measurementsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramg 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Echocardiogram with Doppler 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical laboratory sampling 
• 
Liver function testing 
and coagulationh 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
• 
Hematologyi  
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
• 
Clinical chemistry and 
urinalysis (dipstick 
only)h  
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
• 
β-HCG pregnancy testj 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 31 
Year 2: ETP Year 2 
Week 72 to Week 104 
Study weeka 
Study procedures 
W72 W74 
W76 
W78 
W80 
QV 
W82 
W84 
W86 
W88 
W90 
W92 
QV 
W94 
W96 
W98 
W100 
W102 
W104 
QV 
Sampling for hsCRP, iron, ferritin, 
cardiac-specific troponin I, 
calcitonin, ceramidel 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Immune response monitoring 
Multiplex assayl 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Anti-olipudase alfa IgGk 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
• 
Neutralizing antibodies 
Only in patients positive for IgG olipudase alfa 
If a patient develops IAR/hypersensitivity reaction(s): 
• 
Anti-olipudase alfa IgG 
• 
Anti-olipudase alfa IgE 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample ≥3 days after the event or before the next infusion. 
• 
Tryptase activity 
• 
Complement activation 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample 1 to 3 hours after the event. 
Skin testing 
As needed for hypersensitivity reactions - See study manual 
In case of cytokine release syndrome: 
Multiplex assay (Meso Scale) 
For suspicion of CRS, collect immediately unless already collected within the past 30 minutes 
Calcitonin 
EFFICACY/PHARMACODYNAMICS 
Abdominal MRIm 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Liver biopsyn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Echodoppler of liver 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chest X-rayo 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Pulmonary HRCT scan 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Pulmonary function tests 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Treadmill ergometry 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Fasting lipid profile 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 32 
Year 2: ETP Year 2 
Week 72 to Week 104 
Study weeka 
Study procedures 
W72 W74 
W76 
W78 
W80 
QV 
W82 
W84 
W86 
W88 
W90 
W92 
QV 
W94 
W96 
W98 
W100 
W102 
W104 
QV 
NMR of HDL 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
MRI scans of lumbar spine and 
bilateral femur 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
DXA scans of lumbar spine and 
bilateral femur 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Sphingomyelin, ceramide, and 
other metabolites in plasmal 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Metabolites in dried blood spot 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Chitotriosidase, ACE, CCL18 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum bone-specific ALP and 
C-telopeptide 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Health-related quality of life instruments 
• 
BFI, BPI-SF, EQ-5D,  
SF-36 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
• 
Health-Related 
Productivity 
Questionnaire, PGIC 
and PGIS, and 
NPB-HAQ 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
• 
eDiaryp 
 
- 
Distribute eDiary device 
to patients 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
- 
Collect eDiary device 
from patients 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Physician global assessment 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
STUDY DRUG INFUSION AND PHARMACOKINETICS 
Study drug infusionq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingr 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 33 
Abbreviations: ACE = angiotensin-converting enzyme; AE=adverse event; ALP = alkaline phosphatase; β-HCG = beta-human chorionic gonadotropin; BFI = Brief Fatigue Inventory; BMI = body mass index; 
BPI-SF = Brief Pain Inventory - Short Form; CCL18 = chemokine (C-C motif) ligand 18; DXA = dual-energy X-ray absorptiometry; EQ-5D = EuroQOL-5 dimensions questionnaire; ETP = extension treatment period; 
HDL = high-density lipoprotein; HRCT = high resolution computed tomography; hsCRP = heat-sensitive C-reactive protein; IAR = infusion-associated reaction; IgE = immunoglobulin E; IgG = immunoglobulin G; 
MRI = magnetic resonance imaging; NMR = nuclear magnetic resonance; NPB-HAQ = NPB – Health Assessment Questionnaire; PGIC = Patient Global Impression of Change scale; PGIS = Patient Global Impression 
of Symptom Severity questionnaire; PK = pharmacokinetic; SAE=serious adverse event; SF-36 = Short Form-36; QV = quarterly visit; W = study week. 
 
a Study drug infusions will occur once every 2 weeks (±3 days) at the study site or at home (during the Covid-19 pandemic) if agreed between the investigator and the sponsor, for eligible patients), in reference to 
the date of the first infusion (Day 1). Assessments will be performed at the indicated visits ±7 days, unless otherwise specified. Unless specified otherwise, study procedures should preferably occur before infusion 
and during approximately the same time of day for each visit (in reference to the screening/baseline visit). Quarterly visits will occur at the site. During the COVID-19 pandemic, if site visits are not possible and 
home infusion is already approved for the eligible patient, quarterly visits will be done at home, quarterly visit assessments will not be done, and home infusion visits will continue with biweekly assessments. In 
such a case, some of the quarterly visit assessments can be done by the site through the phone (eg, Health-related quality of life instruments) and the rest of missed quarterly visit assessments will be done as 
unscheduled, as soon as site visits become available. When multiple assessments are required, the order will be vital signs before ECG before blood draw. Telehealth visits are an acceptable alternative to site 
visits during the COVID-19 pandemic, in accordance with institutional policy and with applicable country-specific regulations. 
b Adverse events will be captured from the time the patient provides signed informed consent through the safety follow-up period (30 to 37 days after the patient’s last study infusion). 
c The complete physical examination will include a neurological examination (mental status, cranial nerves, muscle strength, sensation, deep-tendon reflexes, and coordination); examinations of lymph nodes, heart, 
lungs, abdomen, and extremities/joints; and an assessment of the general appearance, skin, and HEENT (head, eyes, ears, nose, and throat). 
d The abbreviated examination of general appearance only will be carried out before and after each study drug infusion. 
e Weight at previous on-site quarterly visit or home visit (during COVID-19 pandemic, if ≥3 months passed since last on-site quarterly visit) may be used to calculate drug dosage at current visit. 
f 
Vital sign measurements will include blood pressure, heart rate, respiratory rate, and temperature. At quarterly visits, collection times will be prior to the infusion (within 30 ±10 minutes of infusion start); halfway 
through (ie, when half the expected time for infusion duration has elapsed); at the end of infusion (±10 minutes); 2 hours ±10 minutes, 4 hours ±10 minutes, and 6 hours ±10 minutes after the end of infusion; and 
every 8 hours ±1 hour until the patient has been discharged. Vital signs should also be measured at discharge ±10 minutes, which may or may not represent an additional measurement to the schedule described 
above. For these quarterly visits, patients should remain at the site for at least 24 hours. The investigator may decide that longer monitoring is required. At all visits except quarterly visits and dose escalation visits, 
vital sign collection times will be prior to the infusion (within 30 minutes ±10 minutes of infusion start); halfway through (ie, when half the expected time for infusion duration has elapsed); at the end of infusion 
±10 minutes; and at discharge ±10 minutes (1 hour post-infusion). At any visit the investigator may decide that longer monitoring is required. 
g Electrocardiograms will be performed before any blood draws. Single ECGs will be performed before infusion and 4 hours ±10 minutes, 12 hours ±1 hour, and 24 hours ±3 hours after the end of infusion. 
h Samples will be taken for liver function testing and coagulation within 24 hours before infusion and at 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion. Samples will be taken for urinalysis and 
clinical chemistry within 24 hours before infusion. 
i 
For hematology at quarterly visits, except yearly visits, 1 sample for complete blood count with differential will be taken within 24 hours before infusion and one 24 hours after the end of infusion. At yearly visits, 
2 samples will be taken at least 24 hours and up to 2 weeks apart before infusion, the first for complete blood count with differential and the second for hemoglobin and white blood cell and platelet counts only. In 
addition, at yearly visits, 1 sample for complete blood count with differential will be taken 24 hours ±3 hours after the end of infusion. For the switch from Process C(
) IMP to the updated manufacturing process 
C
 IMP, 2 samples will be taken during an infusion 3 months after the introduction of the drug from the updated manufactured process C
, at least 24 hours and up to 2 weeks apart.  
j 
Urine β-HCG up to 24 hours before infusion, once every 4 weeks; if positive, then retest with serum. 
k For the switch from Process C(
) IMP to the updated manufacturing Process C(
) IMP, collection will be monthly for the first 6 months after starting the new update, and quarterly after that. 
l 
Sample will be taken within 24 hours before infusion and 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion for metabolites in plasma and biomarkers including but not limited to: hsCRP, iron, 
ceramide, ferritin, cardiac troponin-I, calcitonin, and multiplex assay (Meso Scale) for other biomarkers indicative of inflammation and vascular damage. 
m Spleen and liver volumes will be measured from the abdominal MRI. Patients will be required to fast from solid foods (liquids such as water or juice will be permitted) for ≥6 hours before an abdominal MRI to 
reduce the effect of a meal on MRI data. 
n See the study manual for guidelines on prohibited medications and therapies that are not to be taken within 10 days before and 3 days after the liver biopsy procedure. 
o Chest X-ray will be performed in selected sites. 
p Patients will fill out the eDiary during the evening of the 7 consecutive days before each quarterly visit (see Section 1.3). If the patient does not fill out the eDiary on the day before infusion, (ie, missing the Day 7 
entry), then the patient will be allowed to make the day 7 eDiary entry in the clinic before study drug infusion. 
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q Patients may be hospitalized before the start of the infusion and remain hospitalized for at least 24 hours after the end of infusion during quarterly visits (ie, W80, W92, and W104). Blood will be collected and 
safety assessments (including vital signs [footnote f]) will be performed. Study drug infusions will occur once every 2 weeks (±3 days) at the site or at home (during the Covid-19 pandemic) if agreed between the 
investigator and the sponsor, for eligible patients, once every 2 weeks (±3 days) in reference to the date of the first infusion (Day 1) for each patient. Quarterly visits will occur at the site. During the COVID-19 
pandemic, if home infusion approved for the eligible patient, quarterly visits will be done at home. 
r 
See Section 1.2.3 for the PK sampling schedule. 
 
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1.2.2.3 Schedule of assessments: ETP - Year 3 until end of study only applicable before the implementation of changes that will occur 
after the cutoff date of the second database lock  
  
Year 3 
Year 4 
Year 5 
Study weeksa 
End of 
studyb 
(early d/c) 
Safety 
follow-up 
phone 
call 
 
 
QV 
 
QV 
 
QV 
 
QV 
Study procedures
Year 3 
W106-W116 
W118 
W120-W130 
W132 
W134-W142 
W144 
W146-W154 
W156 
Year 4 
W158-W168 
W170 
W172-W182 
W184 
W186-W194 
W196 
W198-W206 
W208 
Year 5 
W210-W220 
W222 
W224-W234 
W236 
W238-W246 
W248 
W250-W258 
W260 
SAFETY 
AE/SAE assessmentc 
Continuous monitoring 
Concomitant medications and therapies 
Continuous monitoring 
Alcohol and tobacco usage 
 
 
 
 
X 
 
Complete physical examinationd 
 
X 
 
X 
 
X 
 
X 
X 
 
Abbreviated physical examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weightf, BMI 
 
X 
 
X 
 
X 
 
X 
 
 
Height 
 
 
 
 
 
 
 
X 
 
 
Vital sign measurements 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
X 
 
Electrocardiogram 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
X 
 
Echocardiogram with Doppler 
 
 
 
 
 
 
 
 
X 
 
Clinical laboratory sampling 
 
• 
Liver function testing and 
coagulation  
 
Xi 
 
Xi 
 
Xi 
 
Xi 
X 
 
• 
Hematology 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
Xk 
 
• 
Clinical chemistry and urinalysis 
(dipstick only)  
 
Xi 
 
Xi 
 
Xi 
 
Xi 
X 
 
• 
β-HCG pregnancy testl 
Every 4 weeks 
X 
 
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Year 3 
Year 4 
Year 5 
Study weeksa 
End of 
studyb 
(early d/c) 
Safety 
follow-up 
phone 
call 
 
 
QV 
 
QV 
 
QV 
 
QV 
Study procedures
Year 3 
W106-W116 
W118 
W120-W130 
W132 
W134-W142 
W144 
W146-W154 
W156 
Year 4 
W158-W168 
W170 
W172-W182 
W184 
W186-W194 
W196 
W198-W206 
W208 
Year 5 
W210-W220 
W222 
W224-W234 
W236 
W238-W246 
W248 
W250-W258 
W260 
Sampling for hsCRP, iron, ferritin, cardiac-
specific troponin I, calcitonin, ceramide 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
X 
Immune response monitoring 
Multiplex assay 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
X 
Anti-olipudase alfa IgGm 
 
X 
 
X 
 
X 
 
X 
X 
 
• 
Neutralizing antibodies 
Only in patients positive for IgG olipudase alfa 
If a patient develops IAR - hypersensitivity reaction(s): 
• 
Anti-olipudase alfa IgG 
• 
Anti-olipudase alfa IgE 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample ≥3 days after the 
event or before the next infusion. 
 
 
• 
Tryptase activity 
• 
Complement activation 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample 1 to 3 hours after the 
event. 
 
 
Skin testing 
As needed for hypersensitivity reactions - See study manual 
 
 
In case of cytokine release syndrome: 
Multiplex assay (Meso Scale) 
For suspicion of CRS, collect immediately unless already collected within the past 30 minutes 
 
 
Calcitonin 
EFFICACY/PHARMACODYNAMICS 
Abdominal MRIo 
 
 
 
X 
 
 
 
X 
X 
 
Echodoppler of liver 
 
 
 
 
 
 
 
X 
X 
 
Chest X-rayp 
 
 
 
X 
 
 
 
X 
X 
 
Pulmonary HRCT scan 
 
 
 
X 
 
 
 
X 
X 
 
Pulmonary function tests 
 
 
 
X 
 
 
 
X 
X 
 
Treadmill ergometry 
 
 
 
X 
 
 
 
X 
X 
 
Fasting lipid profile 
 
X 
 
X 
 
X 
 
X 
X 
 
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Amended Clinical Trial Protocol 15  
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Property of the Sanofi Group - strictly confidential 
Page 37 
Year 3 
Year 4 
Year 5 
Study weeksa 
End of 
studyb 
(early d/c) 
Safety 
follow-up 
phone 
call 
 
 
QV 
 
QV 
 
QV 
 
QV 
Study procedures
Year 3 
W106-W116 
W118 
W120-W130 
W132 
W134-W142 
W144 
W146-W154 
W156 
Year 4 
W158-W168 
W170 
W172-W182 
W184 
W186-W194 
W196 
W198-W206 
W208 
Year 5 
W210-W220 
W222 
W224-W234 
W236 
W238-W246 
W248 
W250-W258 
W260 
NMR of HDL 
 
 
 
 
 
 
 
X 
 
 
MRI scans of lumbar spine and bilateral 
femur 
 
 
 
 
 
 
 
X 
X 
 
DXA scans of lumbar spine and bilateral 
femur 
 
 
 
 
 
 
 
X 
X 
 
Sphingomyelin, ceramide, and other 
metabolites in plasman 
 
X 
 
X 
 
X 
 
X 
X 
 
Metabolites in dried blood spot 
 
X 
 
X 
 
X 
 
X 
X 
 
Chitotriosidase, ACE, CCL18 
 
X 
 
X 
 
X 
 
X 
X 
 
Serum bone-specific ALP and C-telopeptide 
 
X 
 
X 
 
X 
 
X 
 
 
Health-related quality of life instruments 
• 
BFI, BPI-SF, EQ-5D, SF-36 
 
 
 
X 
 
 
 
X 
X 
 
• 
Health-Related Productivity 
Questionnaire, PGIC and PGIS,  
and NPB-HAQ 
 
X 
 
X 
 
X 
 
X 
X 
 
• 
eDiaryq 
- 
Collect eDiary device from 
patients 
 
X 
 
X 
 
X 
 
X 
 
 
Treatment experience interviewr 
X 
 
 
Physician global assessment 
 
 
 
X 
 
 
 
X 
X 
 
STUDY DRUG INFUSION AND PHARMACOKINETICS 
Study drug infusions 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PK samplingt 
 
 
 
X 
 
 
 
 
 
 
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Property of the Sanofi Group - strictly confidential 
Page 38 
Abbreviations: ACE = angiotensin-converting enzyme; AE=adverse event; ALP = alkaline phosphatase; β-HCG = beta-human chorionic gonadotropin; BFI = Brief Fatigue Inventory; BMI = body mass index; 
BPI-SF = Brief Pain Inventory - Short Form; CCL18 = chemokine (C-C motif) ligand 18; DXA = dual-energy X-ray absorptiometry; EQ-5D = EuroQOL-5 dimensions questionnaire; ETP = extension treatment period; 
HD = high-density lipoprotein; HRCT = high resolution computed tomography; hsCRP = heat-sensitive C-reactive protein; IAR = infusion-associated reaction; IgE = immunoglobulin E; IgG = immunoglobulin G; 
MRI = magnetic resonance imaging; NMR = nuclear magnetic resonance; NPB-HAQ = NPB - Health Assessment Questionnaire; q4w = once every 4 weeks; PGIC = Patient Global Impression of Change scale; 
PGIS = Patient Global Impression of Symptom Severity questionnaire; PK = pharmacokinetic; SAE = serious adverse event; SF-36 = Short Form-36; QV = quarterly visit; W = study week. 
a Study drug infusions will occur once every 2 weeks (±3 days) at the site or at home (during the COVID-19 pandemic) if agreed between the investigator and the sponsor, for eligible patients, in reference to the 
date of the first infusion (Day 1). Assessments will be performed at the indicated visits ±7 days, unless otherwise specified. Unless specified otherwise, study procedures should preferably occur before infusion 
and during approximately the same time of day for each visit (in reference to the screening/baseline visit). Quarterly visits will occur at the site. During the COVID-19 pandemic, if site visits are not possible and 
home infusion is already approved for the eligible patient, quarterly visits will be done at home, quarterly visit assessments will not be done, and home infusion visit will continue with biweekly assessments. In such 
a case, some of the quarterly visit assessments can be done by the site through the phone (eg, Health-related quality of life instruments). the rest of the missed quarterly visit assessments will be done as 
unscheduled, as soon as site visits become available. When multiple assessments are required, the order will be vital signs before ECG before blood draw. Telehealth visits are an acceptable alternative to site 
visits during the COVID-19 pandemic, in accordance with institutional policy and with applicable country-specific regulations. 
b The EOS visit will be completed within 2 weeks after the final treatment. At the EOS visit and for patients who discontinue after the dose escalation period of the PAP or the ETP, NPB Health Assessment, 
NPB-HAQ, PGIS questionnaires, abdominal MRI, liver echo Doppler, HRCT, chest X-ray, pulmonary function tests, treadmill ergometry, and echocardiogram with Doppler will not be repeated if they had been 
done within 3 months prior; DXA and bone MRI will not be repeated if they had been done within 6 months prior. Patients who discontinue during the dose escalation period of the PAP or the ETP will have more 
limited assessments (see detail in Section 10.1). 
c Adverse events will be captured from the time the patient provides signed informed consent through the safety follow-up period (30 to 37 days after the patient’s last study infusion). 
d The complete physical examination will include a neurological examination (mental status, cranial nerves, muscle strength, sensation, deep-tendon reflexes, and coordination); examinations of lymph nodes, heart, 
lungs, abdomen, and extremities/joints; and an assessment of the general appearance, skin, and HEENT (head, eyes, ears, nose, and throat). 
e The abbreviated examination of general appearance only will be carried out before and after each study drug infusion. 
f 
Weight at previous on-site or home visit (during COVID-19 pandemic, if ≥3 months passed since last on-site quarterly visit) may be used to calculate drug dosage at current visit. 
g Vital sign measurements will include blood pressure, heart rate, respiratory rate, and temperature. At quarterly visits, collection times will be prior to the infusion (within 30 ±10 minutes of infusion start); halfway 
through (ie, when half the expected time for infusion duration has elapsed); at the end of infusion (±10 minutes); 2 hours ±10 minutes, 4 hours ±10 minutes, and 6 hours ±10 minutes after the end of the infusion; 
and every 8 hours ±1 hour until the patient has been discharged. Vital signs should also be measured at discharge ±10 minutes, which may or may not represent an additional measurement to the schedule 
described above. For these visits, patients should remain at the site for at least 24 hours. The investigator may decide that longer monitoring is required. At all visits except quarterly visits and dose escalation 
visits, vital sign collection times will be prior to the infusion (within 30 minutes ±10 minutes of infusion start); halfway through (ie, when half the expected time for infusion duration has elapsed); at the end of 
infusion ±10 minutes; and at discharge ±10 minutes (1 hour post-infusion). At any visit the investigator may decide that longer monitoring is required. 
h Electrocardiograms will be performed before any blood draws. Single ECGs will be performed before infusion and 4 hours ±10 minutes, 12 hours ±1 hour, and 24 hours ±3 hours after the end of infusion. 
i 
Samples will be taken for liver function testing and coagulation within 24 hours before infusion and at 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion. Samples will be taken for urinalysis and 
clinical chemistry within 24 hours before infusion. 
j 
For hematology at quarterly visits except yearly visits, 1 sample for complete blood count with differential will be taken within 24 hours before infusion and one 24 hours ±3 hours after the end of infusion. At yearly 
visits, 2 samples will be taken at least 24 hours and up to 2 weeks apart before infusion, the first for complete blood count with differential and the second for hemoglobin and white blood cell and platelet counts 
only. In addition, at yearly visits, 1 sample for complete blood count with differential will be taken 24 hours ±3 hours after the end of infusion. For the switch from Process C(
) IMP to the updated manufacturing 
process C(
) IMP , 2 samples will be taken during an infusion 3 months after the introduction of the drug from the updated manufactured process, at least 24 hours and up to 2 weeks apart. 
k At the end of study visit, 1 sample will be taken for complete blood count with differential. 
l 
Urine β-HCG up to 24 hours before infusion, once every 4 weeks; if positive, then retest with serum. 
m For the switch from Process C(
) IMP to the updated manufacturing process C(
 IMP, collection will be monthly for the first 6 months after starting the new update, and quarterly after that. 
n Sample will be taken within 24 hours before infusion and 24 hours ±3 hours and 48 hours ±3 hours after the end of infusion for metabolites in plasma and biomarkers including but not limited to: hsCRP, iron, 
ceramide, ferritin, cardiac troponin-I, calcitonin, and multiplex assay (Meso Scale) for other biomarkers indicative of inflammation and vascular damage. 
o Spleen and liver volumes will be measured from the abdominal MRI. Patients will be required to fast from solid foods (liquids such as water or juice will be permitted) for ≥6 hours before an abdominal MRI to 
reduce the effect of a meal on MRI data. 
p Chest X-ray will be performed in selected sites. 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 39 
q Patients will fill out the eDiary during the evening of the 7 consecutive days before each quarterly visit (see Section 1.3). If the patient does not fill out the eDiary on the day before infusion, (ie, missing the Day 7 
entry), then the patient will be allowed to make the Day 7 eDiary entry in the clinic before study drug infusion. 
r 
Only for patients consenting to the qualitative structured interviews 
s In-patient hospitalization may be needed throughout the infusion and for at least 24 hours after the end of infusion during quarterly visits and yearly visits in years 3 to 5. Blood will be collected and safety 
assessments (including vital signs [footnote g]) will be performed. For all other visits, patients will be observed after the end of infusion for at least 1 hour Study drug infusions will occur once every 2 weeks (±3 
days) at the site or at home (during the COVID-19 pandemic) if agreed between the investigator and the sponsor, for eligible patients, in reference to the date of the first infusion (Day 1) for each patient. Quarterly 
visits will occur at the site. During the COVID-19 pandemic if home infusion already approved for the eligible patient, quarterly visits will be done at home. 
t 
See Section 1.2.3 for the PK sampling schedule. 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
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Property of the Sanofi Group - strictly confidential 
Page 40 
1.2.2.4 Schedule of assessments ETP Year 3 until the end of study only applicable after the cutoff date for a planned second database 
lock of the study  
 
Year 3 
Year 4 
Year 5 
Study weeksa 
End of 
studyb 
(early d/c) 
Safety 
follow-up 
phone 
call 
 
 
QV 
 
QV 
 
QV 
 
QV 
Study procedures
Year 3 
W106-W116 
W118 
W120-W130 
W132 
W134-W142 
W144 
W146-W154 
W156 
Year 4 
W158-W168 
W170 
W172-W182 
W184 
W186-W194 
W196 
W198-W206 
W208 
Year 5 
W210-W220 
W222 
W224-W234 
W236 
W238-W246 
W248 
W250-W258 
W260 
SAFETY 
AE/SAE assessmentc 
Continuous monitoring 
Concomitant medications and therapies 
Continuous monitoring 
Alcohol and tobacco usage 
 
 
 
 
X 
 
Complete physical examinationd 
 
X 
 
X 
 
X 
 
X 
X 
 
Abbreviated physical examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weightf, BMI 
 
X 
 
X 
 
X 
 
X 
 
 
Height 
 
 
 
 
 
 
 
X 
 
 
Vital sign measurements 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
X 
 
Electrocardiogram 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
X 
 
Echocardiogram with Doppler 
 
 
 
 
 
 
 
 
X 
 
Clinical laboratory sampling 
 
• 
Liver function testing and 
coagulation  
 
Xi 
 
Xi 
 
Xi 
 
Xi 
X 
 
• 
Hematology 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
Xk 
 
• 
Clinical chemistry and urinalysis 
(dipstick only)  
 
Xi 
 
Xi 
 
Xi 
 
Xi 
X 
 
• 
β-HCG pregnancy testl 
Every 4 weeks 
X 
 
Sampling for hsCRP, iron, ferritin, cardiac-
specific troponin I, calcitoninn 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
X 
VV-CLIN-0254389 18.0


Amended Clinical Trial Protocol 15  
01-Nov-2022 
GZ402665-DFI12712 - olipudase alfa 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 41 
Year 3 
Year 4 
Year 5 
Study weeksa 
End of 
studyb 
(early d/c) 
Safety 
follow-up 
phone 
call 
 
 
QV 
 
QV 
 
QV 
 
QV 
Study procedures
Year 3 
W106-W116 
W118 
W120-W130 
W132 
W134-W142 
W144 
W146-W154 
W156 
Year 4 
W158-W168 
W170 
W172-W182 
W184 
W186-W194 
W196 
W198-W206 
W208 
Year 5 
W210-W220 
W222 
W224-W234 
W236 
W238-W246 
W248 
W250-W258 
W260 
Immune response monitoring 
Multiplex pro-inflammatory panel 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
X 
Anti-olipudase alfa IgGm 
 
X 
 
X 
 
X 
 
X 
X 
 
• 
Neutralizing antibodies 
Only in patients positive for IgG olipudase alfa 
If a patient develops IAR - hypersensitivity reaction(s): 
• 
Anti-olipudase alfa IgG 
• 
Anti-olipudase alfa IgE 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample ≥3 days after the 
event or before the next infusion. 
 
 
• 
Tryptase activity 
• 
Complement activation 
For a moderate/severe or recurrent IAR that is suggestive of hypersensitivity, collect sample 1 to 3 hours after the 
event. 
 
 
Skin testing 
As needed for hypersensitivity reactions - See study manual 
 
 
In case of cytokine release syndrome: 
Multiplex pro-inflammatory panel 
(Meso Scale) 
For suspicion of CRS, collect immediately unless already collected within the past 30 minutes 
 
 
Calcitonin 
EFFICACY/PHARMACODYNAMICS 
Abdominal MRIo 
 
 
 
X 
 
 
 
X 
X 
 
Echodoppler of liver 
 
 
 
 
 
 
 
X 
X 
 
Chest X-rayp 
 
 
 
 
 
 
X 
X 
 
Pulmonary HRCT scan 
 
 
 
X 
 
 
 
X 
X 
 
Pulmonary function tests 
 
 
 
X 
 
 
 
X 
X 
 
Treadmill ergometry 
 
 
 
 
 
 
X 
X 
 
Fasting lipid profile 
 
X 
 
X 
 
X 
 
X 
X 
 
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Amended Clinical Trial Protocol 15  
01-Nov-2022 
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Property of the Sanofi Group - strictly confidential 
Page 42 
Year 3 
Year 4 
Year 5 
Study weeksa 
End of 
studyb 
(early d/c) 
Safety 
follow-up 
phone 
call 
 
 
QV 
 
QV 
 
QV 
 
QV 
Study procedures
Year 3 
W106-W116 
W118 
W120-W130 
W132 
W134-W142 
W144 
W146-W154 
W156 
Year 4 
W158-W168 
W170 
W172-W182 
W184 
W186-W194 
W196 
W198-W206 
W208 
Year 5 
W210-W220 
W222 
W224-W234 
W236 
W238-W246 
W248 
W250-W258 
W260 
MRI scans of lumbar spine and bilateral 
femur 
 
 
 
 
 
 
 
X 
X 
 
DXA scans of lumbar spine and bilateral 
femur 
 
 
 
 
 
 
 
X 
X 
 
Ceramide, lyso-sphingomyelin in plasmaq  
 
 
X 
 
 
X 
X 
 
Chitotriosidase, CCL18q 
 
 
 
X 
 
 
 
X 
X 
 
Serum bone-specific ALP and C-telopeptideq
 
 
X 
 
 
X 
 
 
Health-related quality of life instruments 
• 
BFI, BPI-SF, EQ-5D, SF-36 
 
 
 
X 
 
 
 
X 
X 
 
• 
Health-Related Productivity 
Questionnaire, PGIC and PGIS,  
and NPB-HAQ 
 
X 
 
X 
 
X 
 
X 
X 
 
• 
eDiarys 
- 
Collect eDiary device from 
patients 
 
X 
 
X 
 
X 
 
X 
 
 
Treatment experience interviewsr 
X 
 
 
Physician global assessment 
 
 
 
X 
 
 
 
X 
X 
 
STUDY DRUG INFUSION AND PHARMACOKINETICS 
Study drug infusiont 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PK samplingu 
 
 
 
X 
 
 
 
 
 
 
Abbreviations: ACE = angiotensin-converting enzyme; AE=adverse event; ALP = alkaline phosphatase; β-HCG = beta-human chorionic gonadotropin; BFI = Brief Fatigue Inventory; BMI = body mass index; 
BPI-SF = Brief Pain Inventory - Short Form; CCL18 = chemokine (C-C motif) ligand 18; DXA = dual-energy X-ray absorptiometry; EQ-5D = EuroQOL-5 dimensions questionnaire; ETP = extension treatment period; 
HD = high-density lipoprotein; HRCT = high resolution computed tomography; hsCRP = heat-sensitive C-reactive protein; IAR = infusion-associated reaction; IgE = immunoglobulin E; IgG = immunoglobulin G; 
MRI = magnetic resonance imaging; NMR = nuclear magnetic resonance; NPB-HAQ = NPB - Health Assessment Questionnaire; q4w = once every 4 weeks; PGIC = Patient Global Impression of Change scale; 
PGIS = Patient Global Impression of Symptom Severity questionnaire; PK = pharmacokinetic; SAE = serious adverse event; SF-36 = Short Form-36; QV = quarterly visit; W = study week. 
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Amended Clinical Trial Protocol 15  
01-Nov-2022 
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Property of the Sanofi Group - strictly confidential 
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a Study drug infusions will occur once every 2 weeks (±3 days) at the site or at home (during the COVID-19 pandemic) if agreed between the investigator and the sponsor, for eligible patients, in reference to the 
date of the first infusion (Day 1). For the switch from Process C(
) IMP to the updated manufacturing process C(
) IMP, if the site visit is not possible during a regional or national emergency declared by a 
governmental agency such as the COVID-19 pandemic (refer to Appendix B for Germany) due to site closure or extenuating circumstances that prevent an in-person site visit, to permit the first infusion of the 
Process C(
) IMP to be at  home for eligible patients in agreement between the Sponsor and the Investigator in compliance with applicable country-specific regulations. 
Assessments will be performed at the indicated visits ±7 days, unless otherwise specified. Unless specified otherwise, study procedures should preferably occur before infusion and during approximately the same 
time of day for each visit (in reference to the screening/baseline visit). Quarterly visits will occur at the site. During the COVID-19 pandemic, if site visits are not possible and home infusion is already approved for 
the eligible patient, quarterly visits will be done at home, quarterly visit assessments will not be done, and home infusion visit will continue with biweekly assessments. In such a case, some of the quarterly visit 
assessments can be done by the site through the phone (eg, Health-related quality of life instruments). the rest of the missed quarterly visit assessments will be done as unscheduled, as soon as site visits become 
available. When multiple assessments are required, the order will be vital signs before ECG before blood draw. Telehealth visits are an acceptable alternative to site visits during the COVID-19 pandemic, in 
accordance with institutional policy and with applicable country-specific regulations. Patients who initiated home infusion during the COVID-19 pandemic, and continue to be on home infusion, may continue 
receiving home infusion by trained home nurses in the ETP every 2 weeks (±3 days) until the end of the ETP (refer to Appendix B for Germany) and, in such case, telehealth visits may continue until the end of the 
ETP (except quarterly visits as specified above).  
b The EOS visit will be completed within 2 weeks after the final treatment. At the EOS visit and for patients who discontinue after the dose escalation period of the PAP or the ETP, NPB Health Assessment, 
NPB-HAQ, PGIS questionnaires, abdominal MRI, liver echo Doppler, HRCT, chest X-ray, pulmonary function tests, treadmill ergometry, and echocardiogram with Doppler will not be repeated if they had been 
done within 3 months prior; DXA and bone MRI will not be repeated if they had been done within 6 months prior. Patients who discontinue during the dose escalation period of the PAP or the ETP will have more 
limited assessments (see detail in Section 10.1). 
c Adverse events will be captured from the time the patient provides signed informed consent through the safety follow-up period (30 to 37 days after the patient’s last study infusion). 
d The complete physical examination will include a neurological examination (mental status, cranial nerves, muscle strength, sensation, deep-tendon reflexes, and coordination); examinations of lymph nodes, heart, 
lungs, abdomen, and extremities/joints; and an assessment of the general appearance, skin, and HEENT (head, eyes, ears, nose, and throat). 
e The abbreviated examination of general appearance only will be carried out before and after each study drug infusion. 
f 
Weight at previous on-site or home visit (during COVID-19 pandemic, if ≥3 months passed since last on-site quarterly visit) may be used to calculate drug dosage at current visit. 
g Vital sign measurements will include blood pressure, heart rate, respiratory rate, and temperature. At quarterly visits, collection times will be prior to the infusion (within 30 ±10 minutes of infusion start); halfway 
through (ie, when half the expected time for infusion duration has elapsed); at the end of infusion (±10 minutes); 2 hours ±10 minutes, 4 hours ±10 minutes, and 6 hours ±10 minutes after the end of the infusion; 
and every 8 hours ±1 hour until the patient has been discharged. Vital signs should also be measured at discharge ±10 minutes, which may or may not represent an additional measurement to the schedule 
described above. For these visits, patients should remain at the site for at least 24 hours. The investigator may decide that longer monitoring is required. At all visits except quarterly visits and dose escalation 
visits, vital sign collection times will be prior to the infusion (within 30 minutes ±10 minutes of infusion start); halfway through (ie, when half the expected time for infusion duration has elapsed); at the end of 
infusion ±10 minutes; and at discharge ±10 minutes (1 hour post-infusion). At any visit the investigator may decide that longer monitoring is required. 
h Electrocardiograms will be performed before any blood draws. Single ECGs will be performed before infusion and 4 hours ±10 minutes, 12 hours ±1 hour, and 24 hours ±3 hours after the end of infusion. 
i Samples will be taken for liver function testing and coagulation within 24 hours before infusion and 24 hours ±3 hours after the end of infusion. Samples will be taken for urinalysis and clinical chemistry within 24 
hours before infusion. 
j 
For hematology at quarterly visits except yearly visits, 1 sample for complete blood count with differential will be taken within 24 hours before infusion and one 24 hours ±3 hours after the end of infusion. At yearly 
visits, 2 samples will be taken at least 24 hours and up to 2 weeks apart before infusion, the first for complete blood count with differential and the second for hemoglobin and white blood cell and platelet counts 
only. In addition, at yearly visits, 1 sample for complete blood count with differential will be taken 24 hours ±3 hours after the end of infusion. For the switch from Process C(
) IMP to the updated manufacturing 
process C(
) IMP , 2 samples will be taken during an infusion 3 months after the introduction of the drug from the updated manufactured process, at least 24 hours and up to 2 weeks apart.   
k At the end of study visit, 1 sample will be taken for complete blood count with differential.   
l Urine β-HCG up to 24 hours before infusion, once every 4 weeks; if positive, then retest with serum. 
m For the switch from Process C(
 IMP to the updated manufacturing Process C(
) IMP, collection will be monthly for the first 6 months after starting the new update, and quarterly after that. 
n Sample will be taken within 24 hours before infusion and 24 hours ±3 hours after the end of infusion for biomarkers including but not limited to hsCRP, iron, ferritin, cardiac troponin-I, calcitonin, and multiplex pro-
inflammatory panel (Meso Scale) for other biomarkers indicative of inflammation. 
o Spleen and liver volumes will be measured from the abdominal MRI. Patients will be required to fast from solid foods (liquids such as water or juice will be permitted) for ≥6 hours before an abdominal MRI to 
reduce the effect of a meal on MRI data. 
p Chest X-ray will be performed in selected sites. 
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q Samples will be taken within 24 hours before infusion. 
r Only for patients consenting to the qualitative structured interviews 
s Patients will fill out the eDiary during the evening of the 7 consecutive days before each quarterly visit (see Section 1.3). If the patient does not fill out the eDiary on the day before infusion, (ie, missing the Day 7 
entry), then the patient will be allowed to make the Day 7 eDiary entry in the clinic before study drug infusion. 
t In-patient hospitalization may be needed throughout the infusion and for at least 24 hours after the end of infusion during quarterly visits and yearly visits in years 3 to 5. Blood will be collected and safety 
assessments (including vital signs [footnote g]) will be performed. For all other visits, patients will be observed after the end of infusion for at least 1 hour. Study drug infusions will occur once every 2 weeks 
(±3 days) at the site or at home (during the COVID-19 pandemic and in addition until the end of the ETP for patients who initiated home infusion during the COVID-19 pandemic, and continue to be on home 
infusion [refer to Appendix B for Germany]) if agreed between the investigator and the sponsor, for eligible patients, in reference to the date of the first infusion (Day 1) for each patient. Quarterly visits will occur at 
the site. During the COVID-19 pandemic if home infusion already approved for the eligible patient, quarterly visits will be done at home. 
u See Section 1.2.3 for the PK sampling schedule. 
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1.2.3 Pharmacokinetic sampling during the primary analysis and extension treatment periods  
 
 
Before 
infusiona 
Midway 
through 
End of 
infusion 
Hours after the infusionb 
1 hour 
4 hours 
8 hours 
24 hours 
48 hours 
96 hours 
168 hours 
Study week 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study week 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study week 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study week 26 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study week 38 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study week 52 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Study week 54 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Study week 68 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Study week 80 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Study week 132 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Study week 184 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Study week 236 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
In case of switch from 
Process C(
) IMP to 
the updated 
manufacturing 
Process C(
) IMP c 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
a Preinfusion 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. 
c For the switch from Process C(
) IMP to the updated manufacturing Process C(
) IMP, samples for PK will be collected at the second dose that is administered after the switch following the same PK sampling 
schedule  
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1.3 
PATIENT HOME-BASED ACTIVITIES  
 
Prepare to complete eDiary 
during these study weeks 
Complete eDiary at home during the evening: 7 consecutive days before Day 1 and quarterly visit infusions 
Bring eDiary 
device to clinic 
for these study 
week infusion 
visits  
Early during screening 
period for 
7 consecutive days 
7 days 
before next 
infusion 
6 days 
before next 
infusion 
5 days 
before next 
infusion 
4 days 
before next 
infusion 
3 days 
before next 
infusion 
2 days 
before next 
infusion 
Evening 
before next 
infusion 
Complete eDiary early during 
screening for inclusion criterion 
verificationa  
X 
 
 
 
 
 
 
 
 
Receive eDiary device before 
first infusion 
 
X 
X 
X 
X 
X 
X 
X 
Day 1 
W13-W14 
 
X 
X 
X 
X 
X 
X 
X 
W14 QV 
W25-W26 
 
X 
X 
X 
X 
X 
X 
X 
W26 QV 
W37-W38 
 
X 
X 
X 
X 
X 
X 
X 
W38 QV 
W51-W52 
 
X 
X 
X 
X 
X 
X 
X 
W52 QV 
W67-W68 
 
X 
X 
X 
X 
X 
X 
X 
W68 QV 
W79-W80 
 
X 
X 
X 
X 
X 
X 
X 
W80 QV 
W91-W92 
 
X 
X 
X 
X 
X 
X 
X 
W92 QV 
W103-W104 
 
X 
X 
X 
X 
X 
X 
X 
W104 QV 
W117-W118 
 
X 
X 
X 
X 
X 
X 
X 
W118 QV 
W131-W132 
 
X 
X 
X 
X 
X 
X 
X 
W132 QV 
W143-W144 
 
X 
X 
X 
X 
X 
X 
X 
W144 QV 
W155-W156 
 
X 
X 
X 
X 
X 
X 
X 
W156 QV 
W169-W170 
 
X 
X 
X 
X 
X 
X 
X 
W170 QV 
W183-W184 
 
X 
X 
X 
X 
X 
X 
X 
W184 QV 
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Prepare to complete eDiary 
during these study weeks 
Complete eDiary at home during the evening: 7 consecutive days before Day 1 and quarterly visit infusions 
Bring eDiary 
device to clinic 
for these study 
week infusion 
visits  
Early during screening 
period for 
7 consecutive days 
7 days 
before next 
infusion 
6 days 
before next 
infusion 
5 days 
before next 
infusion 
4 days 
before next 
infusion 
3 days 
before next 
infusion 
2 days 
before next 
infusion 
Evening 
before next 
infusion 
W195-W196 
 
X 
X 
X 
X 
X 
X 
X 
W196 QV 
W207-W208 
 
X 
X 
X 
X 
X 
X 
X 
W208 QV 
W221-W222 
 
X 
X 
X 
X 
X 
X 
X 
W222 QV 
W235-W236 
 
X 
X 
X 
X 
X 
X 
X 
W236 QV 
W247-W248 
 
X 
X 
X 
X 
X 
X 
X 
W248 QV 
W259-W260 
 
X 
X 
X 
X 
X 
X 
X 
W260 QV 
Abbreviations: QV = quarterly visit; W = study week 
a The e-Diary will be administered once at the beginning of the screening period to check the related inclusion criterion, and a second time as baseline just before the first infusion. 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 15 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
1 
FLOW CHARTS AND SCHEDULES OF ASSESSMENTS .......................................................... 16 
1.1 
STUDY FLOW CHARTS ................................................................................................................ 16 
1.1.1 
Flow chart for primary analysis period through Week 52 ............................................................... 16 
1.1.2 
Flow chart for extension treatment period ..................................................................................... 17 
1.2 
SCHEDULES OF ASSESSMENTS ............................................................................................... 18 
1.2.1 
Primary analysis period .................................................................................................................. 18 
1.2.1.1 
Schedule of assessments: Year 1 - PAP screening to Week 16 ................................................... 18 
1.2.1.2 
Schedule of assessments: Year 1 - PAP Week 18 through Week 52 ........................................... 23 
1.2.2 
Schedule of assessments: extension treatment period ................................................................. 27 
1.2.2.1 
Schedule of assessments: ETP - Year 2 Week 54 to Week 70 .................................................... 27 
1.2.2.2 
Schedule of assessments: ETP - Year 2 Week 72 to Week 104 only applicable before the 
implementation of changes that will occur after the cutoff date of the second database lock ....... 30 
1.2.2.3 
Schedule of assessments: ETP - Year 3 until end of study only applicable before the 
implementation of changes that will occur after the cutoff date of the second database lock ....... 35 
1.2.2.4 
Schedule of assessments ETP Year 3 until the end of study only applicable after the cutoff 
date for a planned second database lock of the study .................................................................. 40 
1.2.3 
Pharmacokinetic sampling during the primary analysis and extension treatment periods ............ 45 
1.3 
PATIENT HOME-BASED ACTIVITIES .......................................................................................... 46 
2 
TABLE OF CONTENTS ................................................................................................................ 48 
2.1 
LIST OF TABLES ........................................................................................................................... 54 
2.2 
LIST OF FIGURES ......................................................................................................................... 54 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 55 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 57 
5 
STUDY OBJECTIVES ................................................................................................................... 60 
5.1 
PRIMARY ....................................................................................................................................... 60 
5.2 
SECONDARY ................................................................................................................................ 60 
6 
STUDY DESIGN ............................................................................................................................ 62 
6.1 
DESCRIPTION OF THE PROTOCOL ........................................................................................... 62 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 63 
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6.2.1 
Duration of study participation for each patient ............................................................................. 63 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 64 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 64 
6.4 
STUDY COMMITTEES .................................................................................................................. 64 
7 
SELECTION OF PATIENTS .......................................................................................................... 65 
7.1 
INCLUSION CRITERIA .................................................................................................................. 65 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 65 
8 
STUDY TREATMENTS ................................................................................................................. 67 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 67 
8.1.1 
Treatments administered ............................................................................................................... 67 
8.1.2 
Route and method of administration .............................................................................................. 68 
8.1.3 
Dosing considerations .................................................................................................................... 68 
8.1.3.1 
Dose adjustments .......................................................................................................................... 68 
8.1.3.2 
Dosing delays or missed doses ..................................................................................................... 69 
8.1.3.3 
Escalation schema ......................................................................................................................... 70 
8.1.4 
Dose-limiting toxicities.................................................................................................................... 73 
8.1.5 
Study interruption criteria ............................................................................................................... 73 
8.1.6 
Rescue treatment ........................................................................................................................... 74 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 74 
8.3 
BLINDING PROCEDURES ............................................................................................................ 74 
8.3.1 
Methods of blinding ........................................................................................................................ 74 
8.3.2 
Randomization code breaking during the study ............................................................................. 75 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 75 
8.5 
PACKAGING AND LABELING ...................................................................................................... 75 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 76 
8.7 
RESPONSIBILITIES ...................................................................................................................... 76 
8.7.1 
Treatment accountability and compliance...................................................................................... 77 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 77 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 77 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 79 
9.1 
EFFICACY ENDPOINTS ............................................................................................................... 79 
9.1.1 
Primary efficacy endpoints ............................................................................................................. 79 
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9.1.2 
Secondary efficacy endpoints ........................................................................................................ 79 
9.1.3 
Tertiary and exploratory efficacy endpoints ................................................................................... 79 
9.1.4 
Assessment of efficacy endpoints .................................................................................................. 81 
9.1.4.1 
Abdominal magnetic resonance imaging ....................................................................................... 81 
9.1.4.2 
Pulmonary imaging ........................................................................................................................ 81 
9.1.4.3 
Pulmonary function tests ................................................................................................................ 82 
9.1.4.4 
eDiary assessments ....................................................................................................................... 83 
9.1.4.5 
Cardiopulmonary assessments (treadmill ergometry) ................................................................... 83 
9.1.4.6 
Fasting lipid profile ......................................................................................................................... 84 
9.1.4.7 
Biomarkers ..................................................................................................................................... 84 
9.1.4.8 
Liver function tests ......................................................................................................................... 84 
9.1.4.9 
Hematology .................................................................................................................................... 84 
9.1.4.10 Liver ultrasound with Doppler ........................................................................................................ 84 
9.1.4.11 Skeletal involvement ...................................................................................................................... 85 
9.1.4.12 Multiplex assay of inflammatory and vascular biomarkers ............................................................ 85 
9.1.4.13 Health-related quality of life questionnaires ................................................................................... 86 
9.1.4.14 Treatment experience interviews ................................................................................................... 87 
9.1.4.15 Physician’s global assessment of change from baseline ............................................................... 87 
9.2 
SAFETY ENDPOINTS ................................................................................................................... 88 
9.2.1 
Adverse events .............................................................................................................................. 88 
9.2.2 
Laboratory safety variables ............................................................................................................ 88 
9.2.3 
Vital signs ....................................................................................................................................... 89 
9.2.4 
Electrocardiogram variables .......................................................................................................... 89 
9.2.5 
Doppler echocardiography ............................................................................................................. 89 
9.2.6 
Physical examination ..................................................................................................................... 90 
9.2.7 
Biomarkers ..................................................................................................................................... 90 
9.2.8 
Multiplex assays ............................................................................................................................. 90 
9.2.9 
Immunogenicity assessments ........................................................................................................ 90 
9.2.10 
Infusion-associated reactions ........................................................................................................ 91 
9.3 
PHARMACOKINETIC AND PHARMACODYNAMIC ENDPOINTS ............................................... 92 
9.3.1 
Pharmacodynamic endpoints ......................................................................................................... 92 
9.3.1.1 
Sphingomyelin in liver tissue .......................................................................................................... 92 
9.3.1.2 
Sphingomyelin and metabolites in plasma and dried blood spot ................................................... 92 
9.3.2 
Pharmacokinetic endpoints ............................................................................................................ 93 
9.3.2.1 
Pharmacokinetic sampling time ..................................................................................................... 93 
9.3.2.2 
Pharmacokinetic handling procedures ........................................................................................... 93 
9.3.2.3 
Bioanalytical methods .................................................................................................................... 93 
9.3.2.4 
Pharmacokinetic parameters ......................................................................................................... 93 
9.4 
PHARMACOGENETIC ASSESSMENTS ...................................................................................... 94 
9.5 
FUTURE USE OF SAMPLES ........................................................................................................ 95 
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9.6 
OTHER ASSESSMENTS .............................................................................................................. 95 
9.6.1 
Demographic information and medical history ............................................................................... 95 
9.6.2 
Acid sphingomyelinase enzyme activity......................................................................................... 95 
9.6.3 
Genotyping: SMPD1, CHIT1, UGT1A1 .......................................................................................... 96 
9.7 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 96 
10 
STUDY PROCEDURES ................................................................................................................ 99 
10.1 
VISIT SCHEDULE .......................................................................................................................... 99 
10.1.1 
Home infusions ............................................................................................................................ 101 
10.2 
DEFINITION OF SOURCE DATA ................................................................................................ 103 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ..................................... 103 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ......................... 104 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ......................... 105 
10.3.3 
List of criteria for permanent treatment discontinuation ............................................................... 105 
10.3.4 
Handling of patients after permanent treatment discontinuation ................................................. 106 
10.3.5 
Procedure and consequence for patient withdrawal from study .................................................. 106 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................ 107 
10.4.1 
Definitions of adverse events ....................................................................................................... 107 
10.4.1.1 Adverse event .............................................................................................................................. 107 
10.4.1.2 Serious adverse event ................................................................................................................. 107 
10.4.1.3 Adverse event of special interest ................................................................................................. 108 
10.4.1.4 Definitions for criteria of adverse events ...................................................................................... 110 
10.4.2 
General guidelines for reporting adverse events ......................................................................... 112 
10.4.3 
Instructions for reporting serious adverse events ........................................................................ 113 
10.4.4 
Guidelines for reporting adverse events of special interest ......................................................... 114 
10.4.4.1 Reporting of adverse events of special interest with immediate notification ............................... 114 
10.5 
OBLIGATIONS OF THE SPONSOR ........................................................................................... 115 
10.6 
ADVERSE EVENTS MONITORING ............................................................................................ 115 
11 
STATISTICAL CONSIDERATIONS ............................................................................................ 116 
11.1 
GENERAL CONSIDERATIONS .................................................................................................. 116 
11.2 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 116 
11.3 
DISPOSITION OF PATIENTS ..................................................................................................... 117 
11.4 
ANALYSIS POPULATIONS ......................................................................................................... 117 
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11.5 
STATISTICAL METHODS ........................................................................................................... 118 
11.5.1 
Extent of investigational medicinal product exposure .................................................................. 118 
11.5.2 
Analyses of efficacy endpoints ..................................................................................................... 118 
11.5.2.1 Primary efficacy analysis ............................................................................................................. 118 
11.5.2.2 Secondary efficacy analyses ....................................................................................................... 119 
11.5.3 
Extension treatment period .......................................................................................................... 119 
11.5.4 
Multiplicity considerations ............................................................................................................ 119 
11.5.5 
Analyses of safety data ................................................................................................................ 120 
11.5.5.1 Adverse events ............................................................................................................................ 121 
11.5.5.2 Physical examinations, vital signs, electrocardiograms, and echocardiograms .......................... 122 
11.5.5.3 Clinical laboratory tests ................................................................................................................ 122 
11.5.5.4 Immune response assessments .................................................................................................. 122 
11.5.6 
Pharmacokinetic and pharmacodynamic analyses ...................................................................... 123 
11.5.6.1 Pharmacokinetic analyses ........................................................................................................... 123 
11.5.6.2 Pharmacodynamic analyses ........................................................................................................ 123 
11.5.6.3 Pharmacokinetics - pharmacodynamics ...................................................................................... 123 
11.5.7 
Analyses of quality of life variables .............................................................................................. 123 
12 
ETHICAL AND REGULATORY STANDARDS ........................................................................... 124 
12.1 
ETHICAL PRINCIPLES ............................................................................................................... 124 
12.2 
LAWS AND REGULATIONS ....................................................................................................... 124 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ............................. 124 
13 
STUDY MONITORING................................................................................................................. 126 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 126 
13.2 
RESPONSIBILITIES OF THE SPONSOR ................................................................................... 126 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................. 127 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS AND ADDITIONAL 
REQUEST .................................................................................................................................... 127 
13.4.1 
Use of computerized systems ...................................................................................................... 128 
14 
ADDITIONAL REQUIREMENTS ................................................................................................. 129 
14.1 
CURRICULUM VITAE.................................................................................................................. 129 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................. 129 
14.3 
CONFIDENTIALITY ..................................................................................................................... 129 
14.4 
PROPERTY RIGHTS ................................................................................................................... 130 
14.5 
DATA PROTECTION ................................................................................................................... 130 
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14.6 
INSURANCE COMPENSATION .................................................................................................. 130 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 131 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 131 
14.8.1 
Decided by the Sponsor ............................................................................................................... 131 
14.8.2 
Decided by the Investigator ......................................................................................................... 131 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 132 
14.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 132 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 133 
16 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 134 
17 
APPENDICES .............................................................................................................................. 137 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION .................................................................................................... 137 
APPENDIX B 
COUNTRY-SPECIFIC REQUIREMENTS ......................................................................... 141 
APPENDIX C 
PROTOCOL AMENDMENT HISTORY ............................................................................. 142 
 
 
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2.1 
LIST OF TABLES  
Table 1 - Dose escalation scheme during the PAP ....................................................................................... 71 
Table 2 - Pharmacokinetic parameters and definitions ................................................................................. 94 
Table 3 - Summary of adverse event reporting instructions ........................................................................ 113 
 
2.2 
LIST OF FIGURES  
Figure 1 - Dose escalation algorithm ............................................................................................................. 72 
 
 
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3 
LIST OF ABBREVIATIONS  
 
ACE: 
angiotensin-converting enzyme 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
APR: 
acute phase reaction 
ASM: 
acid sphingomyelinase 
ASMD: 
acid sphingomyelinase deficiency 
ASMKO: 
ASM 'knock-out' 
AST: 
aspartate aminotransferase 
BMB: 
bone marrow burden 
BMI: 
body mass index 
CCL18: 
chemokine (C-C motif) ligand 18 
CRS: 
cytokine release syndrome 
DBS: 
dried blood spot 
DLCO: 
diffusing capacity of the lung for carbon monoxide 
DLT: 
dose-limiting toxicity 
DMC: 
Data Monitoring Committee 
DXA: 
dual energy X-ray absorptiometry 
ECHO: 
echocardiogram 
eCRF: 
electronic case report form 
EOS: 
end of study 
EQ-5D: 
EuroQol-5 dimensions quality of life questionnaire 
EQ-5D-5L: 
EuroQol 5 dimension, 5 level health status measure 
ETP: 
extension treatment period 
FEV1: 
volume of air expired during the first second of FVC 
FVC: 
forced vital capacity 
hsCRP: 
high sensitivity C-reactive protein 
HTD: 
highest tolerated dose 
IARs: 
infusion-associated reactions 
ILD: 
infiltrative lung disease 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRB/IEC: 
Institutional Review Board/Independent Ethics Committee 
IV: 
intravenous(ly) 
IXRS: 
Interactive (Voice or Web) Response System 
LFT: 
liver function test 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
modified intent-to-treat 
MN: 
multiples of normal 
MRI: 
magnetic resonance imaging 
NMR: 
nuclear magnetic resonance 
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NPB-HAQ: 
NPB Health Assessment Questionnaire 
NPD: 
Niemann-Pick disease 
NPD B: 
NPD type B 
PAP: 
primary analysis period 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
PFT: 
pulmonary function test 
PGIC: 
Patient Global Impression of Change 
PGIS: 
Patient Global Impression of Symptom Severity  
PK: 
pharmacokinetic 
PT: 
preferred term 
QV: 
quarterly visit 
SAEs: 
serious adverse events 
SF-36: 
Short Form-36 Health Survey 
SMPD1: 
sphingomyelin phosphodiesterase 1, acid lysosomal 
SOC: 
system organ class 
SRS: 
splenomegaly-related score 
TEAEs: 
treatment-emergent adverse events 
TLC: 
total lung capacity 
ULN: 
upper limit of normal 
β-HCG: 
β-human chorionic gonadotropin 
 
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4 
INTRODUCTION AND RATIONALE  
Human acid sphingomyelinase deficiency (ASMD) is a serious, rare, and life-threatening 
lysosomal storage disorder for which only palliative treatment exists. Patients with ASMD are 
unable to metabolize sphingomyelin properly due to mutations in the gene sphingomyelin 
phosphodiesterase 1, acid lysosomal (SMPD1), whose transcription and translation results in 
a defective enzyme acid sphingomyelinase (ASM). Inactivity of ASM leads to the lysosomal 
accumulation of sphingomyelin and, secondarily, increases in cholesterol and other related lipids, 
mostly in the spleen, liver, lung, and bone marrow. 
Historically, ASMD has been diagnosed as Niemann-Pick disease (NPD) and of either Types A or 
B disease. Niemann-Pick disease type A is characterized as the early-onset and acute 
neuronopathic 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 much milder disease with no or little neurological 
involvement. Of the more common disease manifestations are hepatosplenomegaly and 
dyslipidemia; other, more variable features include liver dysfunction, pulmonary disease, skeletal 
involvement, 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. The 
majority of patients diagnosed with Type B disease live into adulthood. As an autosomal recessive 
single gene disease, ASMD generates a spectrum of phenotypes and cases have been classified 
that are intermediate to the A and B extremes. Patients with this intermediate form, Niemann-Pick 
disease type A/B, may develop neurologic symptoms during childhood and have a chronic 
neurodegenerative disease course. 
Genzyme has been developing a potential enzyme therapy, olipudase alfa, for the treatment of the 
non-neurological manifestations of ASMD. This recombinantly-derived enzyme is expressed in 
Chinese hamster ovary cells (CHO) 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 enzyme replacement therapy has been demonstrated in the acid 
sphingomyelinase knock out (ASMKO) mouse model of ASMD (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). Although chronic dosing in the ASMKO mouse model is limited because the animal 
succumbs to the neurologic disease resulting from the natural progression of complete ASMD and 
subsequent shortened lifespan of 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; 
however, ASMKO mice given single high bolus doses of olipudase alfa (≥10 mg/kg) showed 
evidence of toxicity. The same single high doses did not cause toxic effects in normal mice, 
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Sprague Dawley rats, or cynomolgus monkeys, which suggested 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 olipudase alfa 
administered over 8 days) followed by a high dose (20 mg/kg of olipudase alfa 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) did not cause toxicity. 
In a Phase 1 study (SPHINGO-00605), the safety, pharmacokinetic, and pharmacodynamic 
profiles of single, ascending doses of olipudase alfa were evaluated (5). Single doses of 0.03, 0.1, 
0.3, 0.6, and 1.0 mg/kg 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 after dosing 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 study was terminated by the sponsor after the single patient dosed at 1.0 mg/kg 
olipudase alfa presented with hyperbilirubinemia and an acute phase reaction (APR) with clinical 
symptoms. Subsequently, the patient was confirmed to have Gilbert’s syndrome. Because no other 
signs of liver toxicity or hemolysis were evident, the observed hyperbilirubinemia may have been 
secondary to specific inhibition of bilirubin uptake into hepatocytes and/or glucuronide 
conjugation of bilirubin within hepatocytes. 
In the completed Phase 1b, open-label, multicenter, ascending dose study (DFI13412) in 5 adult 
patients with ASMD, the safety and tolerability of olipudase alfa was evaluated during a 26-week 
treatment period (6). After receiving an initial intravenous dose of 0.1 mg/kg olipudase alfa, 
patients dose-escalated in a step-wise manner to a target intravenous dose of 3.0 mg/kg. All 
patients remained at the 3.0 mg/kg olipudase alfa dose for the remainder of the treatment period. 
Upon study completion, patients enrolled into an open-label, long term treatment study 
(LTS13632) (7). 
The progressive, within-patient olipudase alfa dose escalation regimen was well tolerated in adult 
patients with ASMD. No serious or severe AEs or deaths were reported in the study. Related AEs 
consisted predominantly of infusion-associated reactions (IARs), the majority of which were mild 
in severity with all patients recovering without sequelae. At the end of the 26 week treatment 
period, improvements were observed in several individual efficacy parameters and included mean 
decreases in spleen and liver volumes by 25.3% and 17.1%, respectively; decreased interstitial 
lung disease scores; increased percent predicted diffusing capacity of the lung for carbon 
monoxide (DLCO); reduction in serum chitotriosidase, chemokine (C-C motif) ligand 18 (CCL18), 
and angiotensin-converting enzyme (ACE), biomarkers indicative of disease burden; a positive 
trend towards a less pro-atherogenic lipid profile; and trends for improvement in quality of life 
assessments for fatigue and pain. 
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This Phase 2/3 study has been designed as double-blinded and placebo-controlled to demonstrate 
the efficacy of olipudase alfa in decreasing spleen volume and improving pulmonary function 
after 52 weeks of study drug administration. Secondarily, the clinical benefit of olipudase alfa for 
patients with ASMD will be assessed based on symptom-based disease scores from patient 
reported outcome instruments. The effect of study drug on the common ASMD symptom 
complaints of pain, fatigue, dyspnea, and SRS will be examined from responses to an eDiary. The 
effect of study drug on the disease-relevant clinical manifestations of liver volume and platelet 
counts will be analyzed. 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY  
The primary objective of this Phase 2/3 study is to evaluate the efficacy of olipudase alfa 
(recombinant human acid sphingomyelinase) administered intravenously once every 2 weeks for 
52 weeks in adult patients with ASMD by assessing changes in: 1) spleen volume as measured by 
abdominal magnetic resonance imaging (MRI) (and for the United States [US] only, in association 
with patient perception related to spleen volume as measured by splenomegaly-related score 
[SRS]); and, 2) infiltrative lung disease as measured by the pulmonary function test DLCO. 
5.2 
SECONDARY  
Secondary and additional objectives include the following: 
Secondary objectives 
• To confirm the safety of olipudase alfa administered intravenously once every 2 weeks for 
52 weeks 
• To characterize the effect of olipudase alfa on the patient perception related to spleen 
volume as measured by SRS after 52 weeks of study drug administration (For the United 
States, the effect of olipudase alfa on SRS is part of the primary objective) 
• To characterize the effect of olipudase alfa on the following endpoints assessed 
sequentially: 
1. The effect of olipudase alfa on liver volume after 52 weeks of study drug administration 
2. The effect of olipudase alfa on platelet count after 52 weeks of study drug 
administration 
3. The effect of olipudase alfa after 52 weeks of study drug administration on fatigue 
4. The effect of olipudase alfa after 52 weeks of study drug administration on pain 
5. The effect of olipudase alfa after 52 weeks of study drug administration on dyspnea 
Additional objectives 
• To characterize the effect of olipudase alfa on liver function tests (LFTs) 
• To characterize the effect of olipudase alfa on infiltrative lung disease via pulmonary 
imaging 
• To characterize the effect of olipudase alfa on pulmonary functioning 
• To characterize the effect of olipudase alfa on the fasting lipid profile 
• To characterize the effect of olipudase alfa on bone disease 
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• To characterize the effect of olipudase alfa on cardiopulmonary functioning 
• To characterize the effect of olipudase alfa on biomarkers 
• To characterize the effect of olipudase alfa on hematology parameters 
• To characterize the effect of olipudase alfa on selected health-related quality of life 
questionnaires and questions therein 
• To characterize the pharmacodynamic effect of olipudase alfa on clearing sphingomyelin 
accumulation in liver and/or blood 
• To characterize the multiple-dose plasma pharmacokinetic profile of olipudase alfa 
• To explore the effect of olipudase alfa on Physician's global assessment of change 
• To explore the effect of olipudase alfa on the nuclear magnetic resonance (NMR) profile 
of high-density lipoprotein (HDL) 
• To explore the effect of olipudase alfa on liver function via echo-Doppler ultrasound 
• To explore the effect of olipudase alfa on inflammatory and vascular biomarkers 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE PROTOCOL  
This Phase 2/3, multicenter, repeat-dose, clinical trial will be divided into 2 consecutive major 
periods: 1) a randomized placebo-controlled, double-blind primary analysis period (PAP) from 
Day -60 to Week 52 to be followed by 2) an extension treatment period (ETP). Initially, the ETP 
will be double-blind as patients in the placebo arm cross over to active treatment. 
The PAP will include a screening/baseline period and a treatment period. During the 
screening/baseline period, from Day -60 to Day 1 preinfusion, approximately 36 patients will 
provide informed consent and undergo screening assessments to determine trial eligibility and 
undergo baseline measurements. If all eligibility criteria are met, then patients will be randomized 
and enter the treatment period on Day 1. Day 1 is the day the first infusion is administered. The 
visit schedule is calculated using Day 1 of the dose escalation period as the reference. Treatment 
assignment and randomization will be performed using an Interactive Voice Response 
System/Interactive Web Response System (IXRS). Patients will be randomly and centrally 
assigned in a 1:1 ratio across sites using blocks of fixed size into 1 of 2 arms, placebo, saline 0.9% 
sodium chloride solution, or 3.0 mg/kg olipudase alfa target dose. Dose-escalation during the PAP 
to the randomized target doses will occur according to the schedule provided in Section 8.1.3 and 
Table 1. To maintain the double-blind, all patients will dose-escalate using the schedule provided 
(true dose escalation for patients who were in the placebo arm during the PAP and mock dose 
escalation for patients in the active arm during the PAP). 
After completing the PAP, patients will enter the ETP. Those who were randomized to the active 
arm will continue receiving the dose to which they were randomized during the PAP (or the 
highest tolerated dose [HTD], if the randomized dose was intolerable). Patients randomized to the 
placebo arm in the PAP will cross over to active treatment in the ETP and will undergo dose 
escalation to a target dose of 3.0 mg/kg olipudase alfa. 
Study drug will be defined during the PAP as olipudase alfa or placebo and during the ETP as 
olipudase alfa and will be administered intravenously once every 2 weeks. 
During the PAP, one rechallenge each will be allowed for doses administered at Week 0 
(0.1 mg/kg olipudase alfa or placebo) and at Week 4 (0.3 mg/kg olipudase alfa or placebo). 
Patients who are unable to tolerate the rechallenge at those doses will be discontinued from the 
study. If a patient is discontinued due to inability to tolerate rechallenge (ie, a second dose of 
0.3 mg/kg olipudase alfa), then an additional patient may be randomized. Any patient who 
successfully dose-escalates through Week 4, but cannot tolerate study drug infusions at later 
weeks, will continue in the trial at the Week 4 dose (ie, 0.3 mg/kg olipudase alfa or placebo) until 
end of study; likewise, any patient unable to tolerate a dose administered during later weeks will 
receive the HTD even if that dose is less than the target randomized dose and will continue in the 
ETP at this dose. The minimum active dose administered will be 0.3 mg/kg olipudase alfa. 
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During the ETP, the same dose-escalation conditions will apply for patients who cross over from 
the placebo arm during the PAP to the active treatment arm, except that patients unable to tolerate 
the rechallenge allowed each at Week 54 (0.1 mg/kg olipudase alfa) and at Week 58 (0.3 mg/kg 
olipudase alfa) will discontinue from the study and will not be replaced. 
During the PAP and ETP, in-patient hospitalization will be required preinfusion and for at least 
24 hours after the infusion during dose escalation (ie, through Week 16 and Week 70, 
respectively) and may be required at the quarterly and yearly visits up through the end of Year 2; 
in-patient hospitalization may be necessary during quarterly and yearly study visits in Years 3 
through 5. For all other infusions, patients will be monitored for safety in the clinic for at least 1 
hour. All patients will have an end of study/early discontinuation visit within 2 weeks after the 
last infusion of study treatment. In addition, all patients will receive a follow-up phone call for 
safety approximately 30 to 37 days after the last infusion of study drug. 
Home infusion may be initiated during a regional or national emergency declared by a 
governmental agency such as the COVID-19 pandemic (refer to Appendix B for Germany) in the 
ETP by trained home nurses if agreed between the investigator and the sponsor, in compliance 
with applicable country-specific regulations. Patients must meet specific eligibility requirements 
(Section 10.1.1).  Patients who initiated home infusion during the COVID-19 pandemic, and 
continue to be on home infusion, may continue receiving home infusion by trained home nurses in 
the ETP every 2 weeks (±3 days) until the end of the ETP (refer to Appendix B for Germany). 
For treatment periods during the PAP and the ETP, dose-limiting toxicity (DLT) criteria will 
apply. A rescue strategy will be implemented for patients who experience significant clinical 
decline. See Section 8.1. 
6.2 
DURATION OF STUDY PARTICIPATION  
6.2.1 Duration of study participation for each patient  
The length of a patient's participation will be defined from Day 1 until the last planned 
assessment/visit, for at least 3 years and up to 5 years and 3 months dependent upon continued 
regulatory approval of this protocol. The approximate longest study duration per patient will be as 
follows: 
• Screening period will be up to 60 days 
• PAP treatment period will be approximately 52 weeks. A patient will be considered “PAP 
completed” when the patient has been administered study drug at the target randomized or 
HTD and has completed the Week 52 assessments. 
• After 52 weeks in the PAP, patients will enter and remain in the ETP for at least 2 years 
and up to 4 years dependent upon continued regulatory approval of this protocol. A patient 
will be considered ‘ETP completed’ when the patient completes the end of study visit 
(within 2 weeks after the last treatment) or has responded to the final safety follow-up 
phone call from the study site made 30 to 37 days after the patient’s final administration of 
study drug (as applicable). 
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6.2.2 Determination of end of clinical trial (all patients)  
The study will be considered completed when the last patient has their follow-up phone call. 
6.3 
INTERIM ANALYSIS  
No interim analysis is planned during PAP. However, during ETP, a formal summary of data or 
interim CSR(s) may be produced to support regulatory approval(s) and/or other 
submission/application requirement(s). 
6.4 
STUDY COMMITTEES  
An independent Data Monitoring Committee (DMC), composed of members independent from 
the sponsor and the study investigators, is implemented 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 (8). 
Data Monitoring Committee meetings will occur at regular intervals as outlined in the DMC 
charter. The report of a potential DLT 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. Additional 
responsibilities of the DMC will be contained in the DMC charter. 
The first formal meeting of the DMC will occur approximately 3 months after the first patient has 
been treated in the study. 
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7 
SELECTION OF PATIENTS  
7.1 
INCLUSION CRITERIA  
I 01. The patient is willing and able to provide signed written informed consent. 
I 02. The patient is male or female, aged 18 years or older. 
I 03. The patient has documented deficiency of ASM as measured in peripheral leukocytes, 
cultured fibroblasts, or lymphocytes; and a clinical diagnosis consistent with NPD B. 
I 04. The patient has DLCO ≤70% of the predicted normal value. 
I 05. The patient has spleen volume ≥6 multiples of normal (MN) measured by MRI; patients 
who have had partial splenectomy will be allowed if the procedure was performed ≥1 year 
before screening/baseline and the residual spleen volume is ≥6 MN. 
I 06. The patient has an SRS ≥5. 
I 07. Female patients of childbearing potential must have a negative serum pregnancy test for 
beta-human chorionic gonadotropin (β-HCG). 
I 08. Female patients of childbearing potential and 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 for up to 15 days following their last dose of study drug. 
7.2 
EXCLUSION CRITERIA  
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria: 
E 01. The patient has received an investigational drug within 30 days before study enrollment. 
E 02. The patient has a medical condition, including significant intercurrent illness; significant 
cardiac disease (eg, clinically significant arrhythmia, moderate or severe pulmonary 
hypertension or clinically significant valve dysfunction, or <40% left ventricular ejection 
fraction by echocardiogram ECHO); active hepatitis B or hepatitis C, or infection with 
human immunodeficiency virus (HIV); malignancy diagnosed within the past 5 years 
(other than non-melanoma skin cancer), or any other serious medical condition that may 
preclude participation in the study.  
E 03. The patient has a platelet count <60 x 103/μL based on the average of 2 samples. 
E 04. The patient has an international normalized ratio (INR) >1.5. 
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E 05. The patient has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>250 IU/L or total bilirubin >1.5 mg/dL (except for patients with Gilbert’s syndrome). 
E 06. The patient has had a major organ transplant (eg, bone marrow or liver). 
E 07. The patient is scheduled during the study for in-patient hospitalization including elective 
surgery and excluding the liver biopsies required per protocol. 
E 08. The patient, in the opinion of the investigator, is unable to adhere to the requirements of 
the study. 
E 09. The patient is unwilling or unable to abstain from the use of alcohol for 1 day before and 
3 days after each study drug infusion. Testing for blood alcohol levels will not be required. 
E 10. The patient is unwilling or unable to avoid 10 days before and 3 days after the protocol 
scheduled liver biopsies, that are required at screening/baseline, at Week 52 and at 
Week 104, the use of medications or herbal supplements that are potentially hepatotoxic 
(eg, 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors, erythromycin, valproic 
acid, anti-depressants, kava, echinacea) and/or may cause or prolong bleeding 
(eg, anti-coagulants, ibuprofen, aspirin, garlic supplements, ginkgo, ginseng). 
E 11. The patient requires medications that may decrease olipudase alfa activity (eg, fluoxetine, 
chlorpromazine, tricyclic antidepressants [eg, imipramine, or desipramine]). 
E 12. The patient requires use of invasive ventilatory support. 
E 13. The patient requires the use of noninvasive ventilator support while awake for longer than 
12 hours daily. 
E 14. The patient is breast-feeding. 
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
Olipudase alfa is a sterile, non-pyrogenic white to off-white lyophilized cake supplied in 
single-use, 20 cc Type 1 glass vials. Each vial contains 20 mg of extractable olipudase alfa. 
The lyophilized powder will be reconstituted with 5.1 mL of sterile water for injection to yield 
a concentration of 4.0 mg/mL olipudase alfa, which will be further diluted in 0.9% sodium 
chloride solution to a specific volume based on the dose to be administered. 
Detailed instructions on the preparation, storage, and administration for study drug will be 
provided in the pharmacy manual. 
See Section 8.7 for product handling and complaints reporting. 
8.1.1 Treatments administered  
The term “study drug” will refer to olipudase alfa and placebo (saline [0.9% sodium chloride 
solution]), but only olipudase alfa is an IMP. 
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(
).  
Dosing with study drug will be by intravenous infusion every 2 weeks (±3 days) in reference to 
the date of the first infusion (Day 1) for each patient. The 52-week treatment period of the PAP 
will begin on Day 1 with the first infusion of study drug. 
To maintain the double-blind, all patients regardless of treatment assignment will undergo dose 
escalation under the same conditions and according to the schedule provided in Table 1. 
All infusions will take place in a monitored setting with ready access to emergency resuscitation 
equipment and medications (see Section 10.1 for information on timing for in-patient 
hospitalization). One rechallenge each will be allowed for doses administered at Week 0 
(0.1 mg/kg olipudase alfa or placebo) and at Week 4 (0.3 mg/kg olipudase alfa or placebo). 
Patients who are unable to tolerate the rechallenge at those doses will be discontinued from the 
study. If a patient is discontinued due to inability to tolerate rechallenge, (ie, a second dose of 
0.3 mg/kg olipudase alfa), then an additional patient may be randomized but only during the PAP. 
During the PAP and ETP, in-patient hospitalization will be required preinfusion and for at least 
24 hours after the infusion during dose escalation (ie, through Week 16 and Week 70, 
respectively) and may be required at the quarterly and yearly visits up through the end of Year 2; 
in-patient hospitalization may be necessary during quarterly and yearly study visits in Years 3 
through 5.  
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Home infusion may be initiated during COVID-19 (ETP) by trained home nurses every 2 weeks 
(±3 days), if agreed between the investigator and the sponsor, in compliance with applicable 
country-specific regulations. Patients must meet specific eligibility requirements (Section 10.1.1). 
Patients who initiated home infusion during the COVID-19 pandemic, and continue to be on 
home infusion, may continue receiving home infusion by trained home nurses in the ETP every 
2 weeks (±3 days) until the end of the ETP (refer to Appendix B for Germany). 
For the switch from Process C(
) IMP to the updated manufacturing Process C(
) IMP, 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. 
For treatment periods during both the PAP and ETP, DLT criteria will apply. A rescue strategy 
will be implemented for patients who experience significant clinical decline (see Section 8.1.6). 
Dose escalation will follow criteria described in Section 8.1.3.3. Patients unable to tolerate the 
target randomized dose will receive the highest dose tolerable once every 2 weeks for the 
remainder of the study. The minimum active dose administered will be 0.3 mg/kg olipudase alfa. 
8.1.2 Route and method of administration  
Duration of study drug infusions will be the same regardless of treatment assignment and each 
infusion will last for approximately 220 minutes, except at W0 when it will last approximately 
35 minutes and at W54 where it will last approximately 255 minutes. 
For each patient, intravenous infusion with study drug should occur at approximately the same 
time of day. There are no restrictions on the infusion timing with respect to meals. 
See Section 8.1.3.2 for information on dose adjustments following dosing delays or missed 
infusions. 
8.1.3 Dosing considerations  
Dosing will be based on an individual patient’s mass (ie, weight) as outlined in Section 8.1.1. For 
patients with 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. 
8.1.3.1 Dose adjustments  
Dose adjustments may also be considered at any time in consultation with the sponsor and may be 
recommended based on current safety or efficacy analysis results obtained from completed or 
ongoing clinical studies with olipudase alfa. 
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8.1.3.2 Dosing delays or missed doses  
Patients will be infused with study drug once every 2 weeks (±3 days) with all infusions 
scheduled relative to the first study infusion on Day 1 of Week 0. If a study drug infusion is 
delayed by more than 3 days, then that infusion will be considered a missed infusion and will not 
be administered. The patient will receive the last previously tolerated dose of study drug upon 
return to the clinic for the next scheduled visit. During any dose escalation period, if more than 
1 consecutive infusion is missed, then the next infusion will be reduced by 1 dose level. 
Outside a dose escalation period, or if the patient has already reached his/her maximum tolerated 
dose, for a patient who has missed 2 consecutive doses:  
• If the last dose was 0.3 mg/kg or 0.6 mg/kg, the patient should receive the same dose at the 
next scheduled infusion and for the rest of the study period.  
• If the last dose was 1, 2, or 3 mg/kg, the first reintroduction dose should be 1 level below 
the last dose.  
- 
During this dose re-escalation, the schedule of assessments (except PK) will be similar 
to dose escalation period starting from the corresponding dose.  
- 
If this dose re-escalation happened during the PAP, re-escalation of 0.6 mg/kg will 
correspond to Week 6, repetition of 0.6 mg/kg will correspond to Week 8, 1 mg/kg to 
Week 10, 2 mg/kg to Week 12 and 3 mg/kg to Week 14 assessments.  
Outside a dose escalation period, or if the patient has already reached his/her maximum tolerated 
dose, a patient who has missed 3 or more consecutive doses:  
• If the last dose was 0.3 mg/kg, the patient will receive a dose of 0.3 mg/kg at the next 
scheduled infusion and for the rest of the study period.  
• If the last dose was 0.6, 1, 2, or 3 mg/kg, the first reintroduction dose will be 0.3 mg/kg 
(0.3 mg/kg should be repeated at the subsequent infusion, similar to dose escalation 
schedule).  
- 
During this dose re-escalation, the schedule of assessments (except PK) will be similar 
to dose escalation period starting from the corresponding dose.  
- 
If this dose re-escalation happened during the PAP, re-escalation of 0.6 mg/kg will 
correspond to Week 6, repetition of 0.6 mg/kg will correspond to Week 8, 1 mg/kg to 
Week 10, 2 mg/kg to Week12 and 3 mg/kg to Week 14 assessments.  
Following this first reintroduction dose, the dose will be escalated at subsequent infusions up to 
the dose the patient had previously reached prior to the interruption (target dose or maximum 
tolerated dose) following the standard escalation process described in Table 1. 
Outside the dose escalation period during ETP, patients who require dose reintroduction will have 
the following assessments at each infusion until reaching their target or maximum tolerated dose 
of olipudase alfa: 
• Continuous monitoring of AE/SAE and concomitant medications and therapies (see study 
manual). 
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• Abbreviated examination of general appearance before and after infusion 
• Before infusion: vital sign measurements, liver function tests (LFTs), hematology tests and 
safety biomarkers and if available during home infusion from the same blood sample, 
clinical chemistry, multiplex assay and pharmacodynamic biomarkers. 
• Immediately after infusion: vital sign measurements. 
• 24 hours  after infusion: vital sign measurements, LFTs, hematology and safety 
biomarkers and if available during home infusion from the same blood sample, clinical 
chemistry, multiplex assay and pharmacodynamic biomarkers. 
• 48 hours  after infusion: vital sign measurements, LFTs, hematology and safety 
biomarkers and if available during home infusion from the same blood sample, clinical 
chemistry, multiplex assay and pharmacodynamic biomarkers.  
The 48 hours assessments after infusion 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. 
• Urine β-HCG for pregnancy every 4 weeks as described in “footnote k” in Section 1.2.2.1. 
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 
Dose reintroduction will be done at the site. During a regional or national emergency declared by 
a governmental agency such as the COVID-19 pandemic (refer to Appendix B for Germany) or 
extenuating circumstances that prevent an in-person site visit, dose reintroduction can take place 
via home visits in compliance with applicable country-specific regulations applying criteria in 
Section 10.1.1 and performing the same dose reintroduction list of assessments (see study manual 
for details). 
8.1.3.3 Escalation schema  
See Table 1 and Figure 1 for the dose escalation schedule and algorithm, respectively. During 
dose escalation (PAP and ETP), patients will be admitted to the hospital as described in  
Section 10.1. 
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Table 1 - Dose escalation scheme during the PAP  
Study week 
PAPa 
Scheduled study 
drugb dose 
 
Week 0c 
0.1 mg/kg 
 
Week 2 
0.3 mg/kg 
 
Week 4c 
0.3 mg/kg 
 
Week 6 
0.6 mg/kg 
 
Week 8 
0.6 mg/kg 
 
Week 10 
1.0 mg/kg 
 
Week 12 
2.0 mg/kg 
 
Week 14 
3.0 mg/kg 
 
Week 16 
3.0 mg/kg 
End of the mock dose escalation for patients assigned to placebo; end of true dose 
escalation for patients assigned to target dose 3.0 mg/kg. 
a Study weeks do not account for rechallenges. 
b Study drug means olipudase alfa and placebo. 
c A rechallenge will be permitted only once at Week 0 and at Week 4. 
The same dose-escalation schedule and conditions will apply for patients who cross over from the 
placebo arm during the PAP to the active treatment arm in the ETP, except that patients unable to 
tolerate the 1 rechallenge each allowed for doses administered at Week 54 (0.1 mg/kg olipudase 
alfa) and Week 58 (0.3 mg/kg olipudase alfa) will discontinue from the study and will not be 
replaced. 
The following criteria will determine the next dose of study drug to be administered, provided the 
patient does not experience an AE that meets the DLT (Section 8.1.4). Only AEs not related to the 
patient’s underlying condition will affect dose escalation. These criteria apply to AEs considered 
related to study treatment: 
1. If the patient experiences no AE or a mild AE, escalate to the next dose. 
2. If the patient experiences a moderate AE, repeat the same dose. 
3. If the patient experiences a severe AE, decrease to the prior dose. 
If a patient presents on the day of infusion either with an unresolved AE or an acute illness, 
neither of which meets the patient DLT criteria (Section 8.1.4), then study drug infusion may be 
withheld or administered at the discretion of the investigator. If it is not possible to administer 
a regularly scheduled infusion within the 3-day window allowed per protocol, see Section 8.1.3.2. 
 
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Figure 1 - Dose escalation algorithm  
 
Patient randomized to 
olipudase alfa or placebo 
Patient discontinues; 
another patient 
randomized (PAP only) 
Patient discontinues; 
another patient 
randomized (PAP only) 
0.3 or placebo 
Continue dosing once 
every 2 weeks until 
the end of the study 
 
Severe 
AE  
Patient discontinues; 
another patient 
randomized (PAP only) 
0.1 or placebo 
0.3 or placebo 
0.1 or placebo 
  
Moderate 
or severe 
AE  
  
Moderate 
AE 
  
No or  
mild AE 
  
Moderate 
AE  
  
No or  
mild AE 
0.3 or placebo 
  
Severe 
AE  
  
No or  
mild AE 
  
Moderate 
or severe 
AE  
 
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8.1.4 Dose-limiting toxicities  
For the purpose of this study, the events listed below are considered indicative of a potential DLT 
for study drug at a given dose. If a potential DLT is observed, dosing will be temporarily stopped 
in an individual patient or in the entire study, and the DMC will review the safety data. The DMC 
will then provide recommendation(s) to the sponsor regarding further patient treatment 
(Section 6.4). Screening for eligible patients may continue during DMC review of patient or study 
stopping events. 
If any of the following AEs occur, dosing will be temporarily stopped for the specific patient who 
experienced the AE, pending DMC review and recommendation (taking into consideration the 
relatedness of the AE to study treatment): 
• Any SAE, not related to the patient's underlying condition and considered related to the 
study treatment. 
• Any increase in AST, ALT, total bilirubin, or alkaline phosphatase (AP) >3x baseline 
(prior to olipudase alfa therapy) and > the upper limit of normal (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). 
• Any AE that, in the opinion of the investigator or sponsor, raises significant concern 
regarding the safety of olipudase alfa at the administered dose. 
When study drug dosing is interrupted for a particular patient, safety monitoring of the patient will 
continue. If the AE(s) is/are reversible and the clinical laboratory tests (including LFTs) have 
normalized, the patient will resume dosing and receive the previously-tolerated lower dose 
(ie, dose administered on a previous week without incident). Depending on the patient's response, 
dose escalation will either continue (as described in Section 8.1.1) or the patient will remain at the 
previously tolerated dose (ie, the patient's HTD). 
The investigator is responsible for notifying the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) in writing when a potential DLT is being evaluated at an investigative site. 
8.1.5 Study interruption criteria  
If either of these criteria are met: 
• 2 patients develop the same severe AE that is not related to their underlying condition, or 
• 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. 
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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. 
See the study manual and the IXRS manual for unblinding procedures. 
8.1.6 Rescue treatment  
If during the course of the study, a patient satisfies one or more of the following criteria indicative 
of clinical decline due to ASMD progression and after excluding other possible causes, study drug 
will be unblinded and the patient will be switched to the 3.0 mg/kg olipudase alfa group; dose 
escalating procedures and caveats provided in Table 1 and Section 8.1.3 will apply. See the study 
manual and the IXRS manual for unblinding procedures. 
• Hemoglobin level falls below 7 g/dL and remains below 7 g/dL when hematology 
laboratory testing is repeated after approximately 2 weeks. 
• Platelet count falls below 30 000/mm3 and remains below 30 000/mm3 when hematology 
laboratory testing is repeated after approximately 2 weeks. 
• A clinically significant bleeding episode assessed by the investigator as related to a low 
platelet count. 
These patients will continue to be followed in the study. Upon confirmation of the need for rescue 
treatment, patients will have organ volume MRI and PFTs performed if prior tests were performed 
more than 12 weeks before. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)  
No noninvestigational medicinal product will be required for this study. 
8.3 
BLINDING PROCEDURES  
8.3.1 Methods of blinding  
This study has a double-blind, placebo-controlled design. During both the PAP and the first part 
of the ETP, patients, investigators, and the sponsor will be blinded to the identity of study 
treatment. Also, patients and investigators will not have access to the randomization (treatment 
codes) except under circumstances described in Section 8.3.2, until after the database lock for 
PAP and dose escalation in ETP has completed (sponsor will be blinded until database lock for 
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PAP). To maintain the double-blind, all patients regardless of treatment assignment will undergo 
dose escalation (true or mock) in the same manner in both the PAP and ETP. 
The investigators and the sponsor will also be blinded to the PK data. Genzyme Clinical Supplies 
will remain unblinded throughout the study to provide the appropriate study drug to patients.  
At the facilities where the PK measurements, ADA, and selected biomarkers are determined, the 
samples will be analyzed prior to data base lock leading to unblinding of responsible bioanalysts. 
Bioanalysts are excluded from the clinical trial team and a process will be set up to prevent any 
potential unblinding.  
8.3.2 Randomization code breaking during the study  
In case of an AE, the code should only be broken in circumstances when knowledge of the 
identity of study drug is required for treating the patient and in consultation with the sponsor. 
Code breaking can be performed at any time by using the proper module of the IXRS and/or by 
calling any other phone number provided by the sponsor for that purpose. If the blind is broken, 
including for rescue treatment (Section 8.1.6), the investigator should document the date, the hour, 
and the reason for breaking the code. See the IXRS manual for the code breaking process. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
Upon confirmation by the medical monitor that the patient meets all eligibility criteria and 
completion of the screening and baseline assessments, eligible patients will be randomized as 
described below. 
Treatment assignment and randomization will be performed using an IXRS. Approximately 
36 patients will be randomly assigned across sites, using blocks of fixed size into 1 of 2 treatment 
arms, placebo or 3.0 mg/kg olipudase alfa target dose, in a 1:1 ratio. 
Olipudase alfa will be packaged with kit codes and sent to an unblinded pharmacist at the 
investigational site for preparation. The appropriate quantity of vials will be assigned via IXRS 
based on patient weight, current dose level, and randomization group. The randomization will be 
performed centrally by the IXRS, which will generate the patient randomization list. The patient 
number allocated by the IXRS is a specific 9-digit number consisting of the following: 3-digit 
country code (ISO), 3-digit site number, and 3-digit sequential number at the site with leading 
zeroes, beginning with 001. Once randomized in the PAP, the patient’s identification number will 
not change during the entire study. 
8.5 
PACKAGING AND LABELING  
Olipudase alfa will be provided as a sterile lyophilized powder to be reconstituted with sterile 
water for injection, and further diluted with a 0.9% sodium chloride solution for administration in 
a covered infusion bag and/or syringe. Placebo will be the reference treatment in this study and 
will be provided by the hospital pharmacy as 0.9% sodium chloride solution in an identical 
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covered infusion bag and/or syringe. The sponsor will supply olipudase alfa vials and coordinate 
the packaging and distribution services in accordance with the administration schedule. The 
diluent bags and placebo will be provided by the investigational sites. 
The olipudase alfa label text will meet the national legislations requirements of the participating 
countries and will comply with Good Manufacturing Practice. The label text will minimally 
include the protocol number, description of vial contents, packaging number, storage conditions, 
the sponsor’s name and address, and any required caution statement as mandated by the countries 
involved. The study drug is to be prescribed only by the investigator. Under no circumstance will 
the study drug be used other than as directed by the protocol. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE  
Olipudase alfa must be kept in a secure area with restricted access, and 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 pharmacy manual. 
It is recommended that the reconstituted product be used immediately after reconstitution. 
Additional stability data are provided in the pharmacy manual. 
8.7 
RESPONSIBILITIES  
The unblinded designee of the investigator (hospital pharmacist or other appropriate personnel) 
allowed to store and dispense the study drug will be responsible for ensuring that study drug used 
in the clinical trial is securely maintained as specified by the sponsor and in accordance with 
applicable regulatory requirements. 
Study drug will be dispensed in accordance with the investigator's prescription. It is the 
responsibility of the unblinded designee to ensure that an accurate record of study drug issued and 
returned is maintained. 
Any quality issue noticed with the receipt or use of study drug (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) will be promptly notified to 
the sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of study drug may be subject to initiation of a recall procedure by 
the sponsor. In this case, the investigator or designee will be responsible for promptly addressing 
any request made by the sponsor, in order to recall study drug and eliminate potential hazards. 
Under no circumstances will the investigator or designee supply study drug to a third party, allow 
the study drug to be used other than as directed by this clinical trial protocol, or dispose of study 
drug in any other manner. 
The investigator is responsible for notifying the IRB/IEC in writing when a potential DLT is 
being evaluated at his/her investigative site. 
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8.7.1 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 periods. Every effort should be made to 
ensure that no infusion is missed. 
Noncompliance is defined as missing 4 total infusions (not for cause, such as when the missed 
doses are required by the protocol due to a DLT) per each 12-month 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). 
8.7.2 Return and/or destruction of treatments  
Reconciliation of study drug must be performed at the site by an unblinded designee of the 
investigator and an unblinded monitor using treatment log forms and documented on center study 
drug inventory. 
If appropriate, a written authorization for destruction will be provided by the sponsor clinical trial 
team once the reconciliation is achieved. Destruction of study drug may be performed at the site 
depending on the site and local requirements; alternatively, study drug may be returned to the 
sponsor for destruction. 
8.8 
CONCOMITANT MEDICATION  
Medications and therapeutic procedures received by the patient in the 30 days before the first 
scheduled infusion with study drug until the final follow-up phone call will be recorded on the 
Prior and Concomitant Medication field of the electronic case report form (eCRF) as appropriate. 
Prior and concomitant medications will be coded according to the World Health Organization 
Drug Dictionary. 
• Prior medications will be defined as medications that are taken in the 30 days before the 
first infusion of study drug. 
• Concomitant medications will be defined as medications that are taken after the first 
infusion of study drug. 
During the entire study, prohibited medications include those that may decrease olipudase alfa 
activity (eg, fluoxetine, chlorpromazine, tricyclic antidepressants [eg, imipramine, or 
desipramine]). See the study manual for information on 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 
antihistaminics. 
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Only during the 10 days before and 3 days after the scheduled liver biopsies will patients be 
prohibited from using medications or herbal supplements that are potentially hepatotoxic 
(eg, 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors, erythromycin, valproic acid, 
anti-depressants, kava, echinacea) and/or may cause or prolong bleeding (eg, anticoagulants, 
ibuprofen, aspirin, garlic supplements, ginkgo, ginseng). See the study manual for guidance on 
concomitant medications that can affect bleeding time and/or are potentially hepatotoxic, 
including over-the-counter and prescription products containing nonsteroidal anti-inflammatory 
drugs or aspirin. 
Pretreatment for prophylactic management of IARs should not be used systematically. In patients 
who experience moderate to severe or recurrent IARs with evidence of hypersensitivity (as 
defined in Section 10.4.4), 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. 
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 discontinuations. 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 study drug infusion will be managed according to the general 
standards of care consistent with the treatment of such reactions. If anaphylaxis or other severe 
allergic reactions occur, the infusion will be discontinued immediately, and appropriate medical 
treatment will 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  
9.1 
EFFICACY ENDPOINTS  
9.1.1 Primary efficacy endpoints  
The primary efficacy endpoints are the percentage change in spleen volume (in MN) from 
baseline to Week 52 (combined with change in SRS from baseline to Week 52 in the US only, and 
referred to as the “combination spleen endpoint”) and percentage change in DLco (in % predicted 
of normal) from baseline to Week 52 (assessments described in Section 1.2 and Section 9.1.4). 
Spleen volume will be assessed by abdominal MRI to quantitate the degree of splenomegaly at the 
time points specified in Section 1.2. Magnetic resonance imaging data will be collected and read 
centrally by a medical imaging core laboratory, blinded to patient, treatment arm, and time point, 
where it will be processed and coded. 
The procedure for administering the DLco PFT to measure gas exchange across the 
alveolocapillary membrane is standardized in accordance with American Thoracic 
Society/European Respiratory Society guidelines. 
9.1.2 Secondary efficacy endpoints  
Secondary efficacy endpoints include the following: 
• Percentage change in liver volume (in MN) from baseline to Week 52 
• Percentage change in platelet counts from baseline to Week 52 
• Week 52 change from baseline in fatigue severity as measured by item 3 of the BFI scale 
• Week 52 change from baseline in pain severity as measured by item 3 of the BPI-SF scale 
• Week 52 change from baseline in dyspnea severity as measured by the FACIT dyspnea 
tool 
• Change in SRS from baseline to Week 52 (except US, where it is part of the primary 
“combination spleen endpoint”) (Section 9.1.4.4, Section 9.1.4.13) 
9.1.3 Tertiary and exploratory efficacy endpoints  
Tertiary efficacy endpoints are the following: 
• Percentage change from baseline to Week 52 in liver function tests (ALT, AST, and direct 
and total bilirubin) 
• Pulmonary imaging by HRCT and chest X-ray (in selected sites) to quantify infiltrative 
lung disease (ILD).  
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• Other components of the pulmonary function test (ie, forced vital capacity [FVC], volume 
of air expired during the first second of FVC [FEV1], total lung capacity [TLC]) 
• Fasting lipid profile (eg, high-density lipoprotein [HDL], low-density lipoprotein, very 
low-density lipoprotein, total cholesterol, triglycerides, apolipoprotein B, apolipoprotein 
A1, lipoprotein [a]) 
• Bone disease assessments: MRI and dual energy X-ray absorptiometry (DXA) of lumbar 
spine and entire bilateral femur will provide bone marrow burden (BMB) score and bone 
mineral density measurements including total density as well as T- and Z-score 
measurements 
• Cardiopulmonary performance by treadmill ergometry 
• Biomarkers: ACE, chitotriosidase, CCL18, bone-specific AP, C-telopeptide 
ACE 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. 
• Hematology parameters 
• Other quality of life questionnaires: 
- 
Brief Pain Inventory - Short form 
- 
Brief Fatigue Inventory 
- 
Functional Assessment of Chronic Illness Therapy (FACIT) - Dyspnea Short form 
- 
NPB - Health Assessment Questionnaire (NPB-HAQ) 
- 
Short Form - 36v2 Health Survey (SF-36) 
- 
EuroQol - quality of life questionnaire in 5 dimensions (EQ-5D) 
- 
Health-related productivity questionnaire 
Exploratory efficacy endpoints will include the following: 
• Physician's global assessment of change 
• NMR of HDL (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) 
• Echo-Doppler imaging to assess liver functioning and portal hypertension 
• Multiplex assay of inflammatory and vascular biomarkers (Multiplex assay of vascular 
biomarkers 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) 
• Patient Global Impression of Symptom Severity (PGIS) of ASMD questionnaire  
• Patient treatment experience interview 
• Patient Global Impression of Change (PGIC) scale 
• An additional questionnaire about home infusion experience may be added for patients 
who received home infusion treatment. 
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9.1.4 Assessment of efficacy endpoints  
The schedule for all assessments related to efficacy endpoints is provided in Section 1.2. Study 
procedures will occur before infusion and during approximately the same time for each visit (in 
reference to the screening/baseline visit), unless stated otherwise. 
9.1.4.1 Abdominal magnetic resonance imaging  
Spleen and liver volumes will be assessed by abdominal MRI to quantitate the degree of 
splenomegaly and hepatomegaly at the time points specified in the study flow charts. Patients will 
be required to fast from solid foods (liquids such as water or juice will be allowed) for at least 
6 hours before an abdominal MRI to reduce the effect of a meal on the MRI data. 
Abdominal MRI will be performed as described in the vendor manual. Magnetic resonance 
imaging data will be collected and read centrally by a medical imaging core laboratory, blinded to 
patient, treatment arm, and time point where it will be processed and coded. 
9.1.4.2 Pulmonary imaging  
High resolution computed tomography scans of the chest will be obtained to quantitate the 
degree of infiltrative lung disease, if present. Lung imaging data will be collected, processed, and 
coded centrally by a medical imaging core laboratory and evaluated by readers blinded to patient, 
treatment arm, and time point. 
The bilateral lung boundaries are determined from the following 4 predefined 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 cm above the hemidiaphragm 
• Level 4 is 1 cm above the hemidiaphragm 
A qualitative assessment 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 (9): 
• 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 
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Chest X-rays will be collected in selected sites and sent to a medical imaging core laboratory 
where they will be digitized (if not already done at the site) and coded. Frequency of chest X-ray 
will be reduced from every 6 months to yearly after the cutoff date for a planned second database 
lock of the study for purpose of regulatory submissions in 2021. The lung fields will be assessed 
by central reviewers blinded to patient, treatment arm, and time point and scored subjectively for 
the degree of infiltrative lung (9): 
• 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) 
• NE = Not evaluable 
9.1.4.3 Pulmonary function tests  
Pulmonary function tests (PFTs) will be performed to assess evidence of infiltrative lung disease 
by measuring lung volume, air flow, and gas exchange (10). Pulmonary function testing 
equipment calibration and test administration protocols will be standardized according to the 
guidelines put forth by the American Thoracic Society (11). Pulmonary function tests will be 
administered approximately at the same daily time for each assessment (ie, in reference to the 
screening assessment) and will be collected and analyzed by a central reader. 
• Diffusing capacity of carbon monoxide (DLCO): diffusing capacity measures the rate of 
diffusion of a diffusion limited gas (carbon monoxide [CO]) per minute across the 
alveolocapillary membrane. Diffusing capacity of CO will be calculated by comparing the 
amount of CO exhaled following a known amount of inhaled CO. Helium, which does not 
diffuse across the alveolocapillary membrane, will be included as a tracer with the inspired 
CO to control for air trapping 
• Forced vital capacity (FVC): The FVC is the total volume of air expired during a forced 
maneuver and will be measured using standard spirometric techniques 
• Forced expiratory volume in 1 second (FEV1): The FEV1 is the volume of air expired 
during the first second of FVC and will be measured using standard spirometric techniques 
• Total lung capacity (TLC): The TLC is the total volume of air within the lungs following 
a maximal inspiratory effort and will be measured using standard techniques 
Please refer to the vendor manual for details about PFTs. 
Patients who routinely take bronchodilators must withhold bronchodilators before PFTs as 
follows: 
• Short-acting inhaled or oral bronchodilators (eg, albuterol) - 8 hours 
• Medium-acting inhaled bronchodilators (eg, atrovent) - 12 hours 
• Long-acting inhaled or oral bronchodilators (eg, salmeterol) - 24 hours  
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9.1.4.4 eDiary assessments  
An eDiary will be distributed to patients according the schedule provided in Section 1.2. The 
eDiary will be completed by patients according to the schedule provided in Section 1.3 and will 
be composed of the following: 
• Item 3 from the BPI-SF 
• Item 3 from the BFI 
• The FACIT-dyspnea Short form (Section 9.1.4.13), except for the screening eDiary 
• The SRS (Section 9.1.4.13) 
If the patient does not fill out the eDiary on the day before infusion, (ie, missing the Day 7 entry), 
then the patient will be allowed to make the Day 7 eDiary entry in the clinic before study drug 
infusion. 
9.1.4.5 Cardiopulmonary assessments (treadmill ergometry)  
Cardiopulmonary status will be assessed using a treadmill ergometer to measure patient work 
output under controlled conditions. Frequency of treadmill ergometry will be reduced from every 
6 months to yearly after the cutoff date for a planned second database lock of the study for 
purpose of regulatory submissions in 2021. As the patient walks on treadmill, the workload will 
be incrementally increased until the patient can no longer proceed. Patients will breathe through 
a tube connected to a one-way valve to continuously measure oxygen (O2) uptake, carbon dioxide 
(CO2) output, and tidal volume throughout the test. Heart rate, respiratory rate, and digital O2 
saturation will also be monitored continuously. For each workload, steady state levels will be 
calculated for O2 uptake, CO2 output, tidal volume, ventilation, and respiratory exchange ratio. 
The following parameters will be used for analysis: 
• Maximum O2 uptake (absolute and % predicted) 
• Maximum CO2 output 
• Maximum tidal volume  
• Maximum respiratory rate (breaths/min) 
• Maximum respiratory exchange ratio 
• Maximum ventilation (L/min) 
• Maximum O2 saturation 
• Maximum heart rate (absolute and % predicted) 
• Maximum workload (absolute and % predicted) 
• Working time 
Treadmill ergometry assessments must occur approximately at the same daily time as the 
screening assessment (in reference to the screening assessment) to ensure consistency of results. 
Procedures for treadmill ergometry are detailed in the treadmill procedure manual. 
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9.1.4.6 Fasting lipid profile  
The fasting lipid profile will include but not be limited to: 
• High density lipoprotein 
• Low density lipoprotein 
• Very low density lipoprotein 
• Total cholesterol 
• Triglycerides 
• Apolipoprotein B, apolipoprotein A1, and lipoprotein [a] 
Additionally, the NMR profile of HDL will be characterized (12, 13). NMR profile of HDL will 
no longer be assessed after the cutoff date for a planned second database lock of the study for 
regulatory submissions in 2021. 
9.1.4.7 Biomarkers  
Samples for serum chitotriosidase, CCL18, and ACE will be collected as specified in Section 1.2 
and analyzed for efficacy. ACE 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. 
9.1.4.8 Liver function tests  
Although blood samples will be taken for liver function testing as part of the standard laboratory 
assessment (Section 9.2.2), AST, ALT, and total and direct bilirubin will be assayed at baseline 
and at Week 52 as part of the analysis of tertiary efficacy endpoints. 
9.1.4.9 Hematology  
Although hemoglobin level, platelet count, and white blood cell count are part of the standard 
safety laboratory assessments (Section 9.2.2), they will also be analyzed at screening, Week 52, 
and at yearly visits (at the time points in Section 1.2.1.1 and Section 1.2.1.2, respectively) as part 
of the analysis of secondary (platelet counts) and tertiary (hematology) efficacy endpoints. 
As specified in Section 1.2, at screening, Week 52, and at yearly visits, the mean of 2 preinfusion 
samples taken at least 24 hours and up to 2 weeks apart will be used for white blood cell count, 
platelet count, and hemoglobin. 
9.1.4.10 Liver ultrasound with Doppler  
Liver ultrasound with echo-Doppler imaging will be performed as specified in Section 1.2 to 
document 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 which may be examined include the network of 
intrahepatic portal veins, the main and intrahepatic arteries, the hepatic veins, the main and 
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intrahepatic portal veins, the intrahepatic portion of the inferior vena cava, collateral venous 
pathways, and transjugular intrahepatic portosystemic shunts. Liver ultrasound with echo-Doppler 
imaging will be performed using methods that are compatible with the standard institutional 
procedures of the investigational site. 
Some of the above mentioned parameters will be used to detect the likelihood of portal 
hypertension, and if detected whether it was severe, as described in the vendor’s manual. 
Liver ultrasound will be performed as described in the vendor’s manual.  
9.1.4.11 Skeletal involvement  
Bone imaging 
Bone scan images of the femurs and lumbar spine will be obtained at the time points provided in 
Section 1.2 using DXA and MRI to evaluate bone mineral density and BMB. All bone images will 
be sent to a central reviewer, blinded to patient, treatment assignment, and time point, for analysis 
of bone disease. 
Bone mineral densities will be calculated for each patient and from which T- and Z-scores will be 
derived. The T-score ranks a patient’s bone density to that of a healthy person of the same gender. 
Z-scores rank a patient’s bone density to that of a healthy person of the same age, sex, weight, and 
ethnicity. 
From serial MRI scans, BMB will be evaluated using the BMB scoring system. The bone marrow 
signal intensity scoring system is described in previous publications (14, 15, 16) as a categorical 
score out of a possible 8 points for the lumbar spine and a categorical score out of a possible 
8 points for the femurs (score averaged from the left and right femurs) to give a total BMB score 
out of 16 points. 
Serum bone-specific alkaline phosphatase and C-telopeptide 
Samples will be collected to quantify bone-specific ALP, a marker for active bone formation, and 
C-telopeptide, an indicator of bone resorption, according to the time points specified in  
Section 1.2. 
9.1.4.12 Multiplex assay of inflammatory and vascular biomarkers  
Analysis of multiple cytokines and chemokines using inflammatory and vascular multiplex panels 
(Meso Scale) will be analyzed as both  exploratory efficacy and safety endpoints for all patients 
with available data during PAP and ETP. Only the inflammatory panel (multiplex assay of 
proinflammatory panel) will be maintained after the cutoff date for a planned second database 
lock of the study for purpose of regulatory submissions in 2021 and the vascular multiplex panels 
will no longer be assessed. See also Section 9.2.8. 
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9.1.4.13 Health-related quality of life questionnaires  
The following health-related quality of life instruments will be completed by patients according to 
the time points specified in Section 1.2. 
• The BFI is a validated, self-administered questionnaire that was originally developed to 
assess fatigue severity in cancer patients (17). The BFI has 9 items, using numeric 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. Item 3 of the BFI is also separately administered via eDiary 
(Section 9.1.4.4). 
• 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 
(18, 19). 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 and the past week. Item 3 of the BPI-SF 
is also separately administered via eDiary (Section 9.1.4.4). 
• The SRS rates 5 items: abdominal pain, abdominal discomfort, early satiety, abdominal 
body image, and ability to bend down. The 5 items were selected from the Myelofibrosis 
Symptom Assessment Form (MF-SAF) (JAKARTA, NCT# 01437787). Using a numerical 
rating scale of 0 (absent) to 10 (worst imaginable), these questions assess within the last 
24 hours the impact of splenomegaly-related items that are common in patients with 
ASMD. The scores are collected via an eDiary over 7 days (Section 9.1.4.4). Then, the 
7-day mean of the daily sum of the scores is calculated.  
• The FACIT-dyspnea Short form is a 2-part questionnaire: 10 questions in each part. In 
Part 1, patients are asked to rate how short of breath they felt during the past 7 days doing 
activities, such as dressing, walking, and common household chores; in Part 2, patients 
rate how functionally limiting the dyspnea experienced was while doing the activities 
presented in Part 1. This instrument is administered via eDiary (Section 9.1.4.4). 
• The NPB-HAQ is a disease-specific questionnaire that covers various aspects of fatigue, 
pain, respiratory, abdominal complaints, and quality of life as well as questions specific to 
ASMD symptoms and physical activity. The questionnaire administered at baseline will 
consist of items to gather information on patient background, diagnostic history, family 
history, medical/surgical history, resource utilization, current symptomatology and 
functional status. The questionnaire administered during subsequent visits will assess 
interval history and resource utilization, as well as current symptomatology and functional 
status. 
• Health-related productivity questionnaire is a validated, self-administered questionnaire 
that was developed to measure how treatment of disease impacts an individual’s ability to 
participate in the workforce and complete daily household duties. 
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• 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 (20). The SF-36 consists of 8 scales, including physical functioning, role 
physical, bodily pain, mental health, role emotional, social functioning, vitality, and 
general health and includes two summary measures of physical health and mental health 
derived from scale aggregates. 
• The EQ-5D is a standardized measure of health status developed by the EuroQol Group to 
provide a simple, generic measure of health for clinical and economic appraisal. The 
EuroQol 5 dimension, 5 level (EQ-5D-5L) health status measure consists of 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension has 5 levels: no problems, slight problems, moderate problems, severe 
problems, and extreme problems. The respondent is asked to indicate his/her health state 
by ticking (or placing a cross) in the box against the most appropriate statement in each of 
the 5 dimensions. This decision results in a 1-digit number expressing the level selected 
for that dimension. The digits for 5 dimensions can be combined in a 5-digit number 
describing the respondent’s health state. Index-based values (ie, utilities) are a major 
feature of the EQ-5D-5L instrument, facilitating the calculation of quality-adjusted life 
years that are used to inform economic evaluations of health care interventions. 
• The PGIS asks patients to rate abdominal problems, bodily pain, fatigue, and shortness of 
breath “over the past week.” The PGIS will be used to assess the validity of some of the 
PRO measures used in patients with ASMD in this study.  
• The PGIC asks patients to rate change in abdominal problems, bodily pain, fatigue, and 
shortness of breath “since beginning the study medication”. The PGIC will be used to 
assess the validity of some of the PRO measures used in patients with ASMD in this study. 
• Home infusion experience questionnaire may be added for patients who received home 
infusion treatment to ask patients about their experience of home treatment. 
9.1.4.14 Treatment experience interviews  
Qualitative semi-structured interviews will be conducted to understand patient experience living 
with ASMD and participating in this study. The interviews will be conducted over the 
telephone in patients receiving the study drug for at least last 2 years. 
9.1.4.15 Physician’s global assessment of change from baseline  
The investigator will evaluate the patient’s current clinical status according to the schedule 
provided in Section 1.2 as being mild, moderate, or severe and compare individual patient status 
made during different time points by indicating 1 of the following 7 categories: marked 
improvement, moderate improvement, mild improvement, no change, mild worsening, moderate 
worsening, or marked worsening. 
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9.2 
SAFETY ENDPOINTS  
Safety endpoints will include the following: 
• Assessment of AEs, including SAEs, IARs (eg, cytokine release syndrome [CRS], APRs), 
and adverse events of special interest (AESIs) 
• Clinical laboratory tests 
• Vital signs 
• Electrocardiogram 
• Physical examinations 
• Doppler echocardiography 
• Biomarkers 
• Immune response assessments 
• Multiplex assay of inflammatory and vascular biomarkers (Meso Scale). 
Multiplex assay for vascular biomarkers 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. 
9.2.1 Adverse events  
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 10.4 through Section 10.6. All AEs will be coded using the version of Medical 
Dictionary for Regulatory Activities (MedDRA) effective at the time of the planned database 
lock. 
9.2.2 Laboratory safety variables  
The clinical laboratory data consist of blood analyses, including hematology, clinical chemistry, 
and urinalysis. Values will be converted into standard international units and then analyzed. 
International units will be used in all listings and tables. 
The following clinical laboratory tests will be assessed by the site as specified in Section 1.2. 
IARs, APRs, and CRS’ are associated with changes in specific clinical laboratory parameters (see 
Section 9.2.1). 
• Clinical Chemistry: sodium, potassium, calcium, chloride, blood urea nitrogen, creatinine, 
lactate dehydrogenase, total protein, albumin, glucose, cholesterol, phosphorus, and 
creatine kinase 
• Liver Function Tests: ALT, AST, ALP, gamma glutamyl-transferase, total bilirubin, and 
direct bilirubin 
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• 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 
• Coagulation Studies: prothrombin time (Protime), partial thromboplastin time, INR, and 
D-dimer 
• Urinalysis: dipstick for glucose, protein, hemoglobin, leukocytes, ketones, and bilirubin 
• Additional Tests: hepatitis B surface antigen, hepatitis C antibody, human 
immunodeficiency virus antibody, serum/urine β HCG pregnancy test (women of 
childbearing potential only) 
Note: If a urine pregnancy test is positive, dosing of study drug will 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. 
9.2.3 Vital signs  
Vital signs will include systolic and diastolic blood pressure (mmHg), heart rate (beats/minute), 
respiratory rate (breaths/minute), and temperature (°F or °C). 
9.2.4 Electrocardiogram variables  
Standard 12-lead ECGs will be conducted as described in Section 1.2. 
Electrocardiograms will be performed while the patient remains in a supine position for 
approximately 5 to 10 minutes before and while conducting the ECG. The following parameters 
will be assessed: heart rate; cardiac rhythm; intervals for PR, QRS, QT and QTc; QRS axis; 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. If possible, the same examiner should perform all 
such reviews. Details for ECG procedures are provided in the vendor manual. 
9.2.5 Doppler echocardiography  
A standard 2-dimensional and M-mode Doppler echocardiogram will be conducted at time points 
specified in the schedule of assessments in Section 1.2. 
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 assessed using 
Doppler ultrasound. 
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A specialist trained in the interpretation of this test at each study site will review the 
echocardiograms according to site-specific procedures for safety. If possible, the same examiner 
will perform all such reviews. 
Details for ECHO procedures are provided in the vendor manual. 
9.2.6 Physical examination  
A complete physical examination will be performed before infusion at the time points specified in 
Section 1.2 and will include a neurological examination (mental status, cranial nerves, muscle 
strength, sensation, deep-tendon reflexes, and coordination) and an assessment of the patient’s 
general appearance; skin; head, eyes, ears, nose, and throat; and examinations of lymph nodes, 
heart, lungs, abdomen, and extremities/joints. 
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 1.2. 
Patients will be assessed for body mass and height at the time points specified in Section 1.2. 
9.2.7 Biomarkers  
Biomarkers collected for monitoring the safety of olipudase alfa will include, but not be limited to 
hsCRP, plasma ceramide, iron, ferritin, cardiac-specific troponin I, and calcitonin. 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. 
Samples will be collected as specified in Section 1.2. 
9.2.8 Multiplex assays  
Testing for inflammatory and vascular biomarkers using multiplex assay (Meso Scale) will be 
performed on blood samples taken before and after infusion during dose escalation as specified in 
Section 1.2 and in case of suspicion of cytokine release syndrome.  
IL-6, IL-8, TNF alpha, and IFN gamma were identified as key safety biomarkers during the PAP; 
as the multiplex assay of proinflammatory panel captures all these biomarkers, this panel will only 
be maintained for exploratory safety endpoint after the cutoff date for a planned second database 
lock of the study for purpose of regulatory submissions in 2021.  
Procedures for the collection, handling and shipment of all biomarker samples to be sent to the 
sponsor or central laboratory are in the vendor manual. 
9.2.9 Immunogenicity assessments  
Samples will be collected as specified in Section 1.2 for the evaluation of anti-olipudase alfa IgG 
antibodies. Patients found to be IgG seropositive will be subsequently assessed for neutralizing 
IgG antibodies to olipudase alfa. During the study period, for the switch from Process C(
) IMP 
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to the updated manufacturing process C(
) IMP, collection will be monthly for the first 6 months 
after starting the new update, and quarterly after that. 
9.2.10 Infusion-associated reactions  
In the event that a patient reports an IAR of moderate/severe intensity or recurrent that is 
suggestive of a hypersensitivity reaction (as defined in Section 10.4.1.3), 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. 
• For IgE anti-olipudase alfa antibody testing the same pre-dose 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 
• 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 
• Refer to the study-specific IAR Sample Collection Process manual for guidelines on the 
collection and shipping of samples (IgG and IgE, antidrug antibody, tryptase, and 
complement activation testing). The sponsor's Biomarkers and Clinical 
Bioanalyses-Boston laboratory will be informed of sample shipments 
• If necessary, skin testing may be performed in patients who experience an IAR that meets 
the following criteria following consultation between the investigator and the sponsor: 
- 
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 10.4.1.3 
See also study manual for skin testing procedures. 
Cytokine release syndrome: If a patient experiences an AE of moderate or severe intensity that is 
suggestive of CRS (as described in Section 10.4.1.3), an additional blood sample for the multiplex 
assay (Meso Scale) and calcitonin will be drawn immediately (if a sample had not been obtained 
already within the past 30 minutes). 
See the laboratory manual for a comprehensive list of tests and guidelines on the collection and 
shipment of samples. 
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9.3 
PHARMACOKINETIC AND PHARMACODYNAMIC ENDPOINTS  
9.3.1 Pharmacodynamic endpoints  
The pharmacodynamic endpoints will be the following: 
• Clearance of sphingomyelin accumulation from baseline to Week 52 in liver tissue 
• Change from baseline to Week 52 in levels of sphingomyelin, ceramide, and other 
metabolites in plasma or dried blood spot 
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. No further analysis of sphingomyelin or other metabolites will be 
conducted after the cutoff date for a planned second database lock of the study for purpose of 
regulatory submissions in 2021. 
9.3.1.1 Sphingomyelin in liver tissue  
Liver biopsy samples will be evaluated for sphingomyelin accumulation at baseline, Week 52 and 
Week 104 according to the schedule provided in Section 1.2. 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 for safety purposes. 
Some medications and/or herbal supplements can be hepatotoxic or cause/prolong bleeding and 
should not be taken within 10 days before and 3 days after the biopsy procedure (see the study 
manual for details). 
Sample processing, storage, and shipment guidelines are provided in the laboratory manual. 
9.3.1.2 Sphingomyelin and metabolites in plasma and dried blood spot  
Blood samples for quantifying sphingomyelin, ceramide, and other metabolites in plasma or in 
dried blood spot (DBS) will be collected according to the schedule provided in Section 1.2. No 
further analysis of sphingomyelin or other metabolites in DBS will be conducted after the cutoff 
date for a planned second database lock of the study for purpose of regulatory submissions in 
2021. Lyso-sphingomyelin and ceramide in plasma will be maintained to continue to monitor 
levels of substrate and its metabolic product. 
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9.3.2 Pharmacokinetic endpoints  
Pharmacokinetic endpoints will include evaluation in plasma of the following parameters: Cmax, 
tmax, AUC, AUC(0-last), t1/2, CL, and Vss. 
9.3.2.1 Pharmacokinetic sampling time  
Pharmacokinetic sampling will occur during the PAP and ETP according to the time points 
provided in Section 1.2. During the study period, for the switch from Process C(
) IMP to the 
updated manufacturing process C(
) IMP , samples for PK will be collected at the second dose 
that is administered after the switch following the same schedule in Section 1.2.3. If a patient 
receives only a partial infusion (eg, due to a safety concern), then sampling will be repeated at the 
next infusion of study drug. 
Time windows for PK sampling are ±10 minutes for collection times <8 hours after the end of 
infusion and ±3 hours for collection times ≥8 hours after the end of infusion. Blood will be drawn 
using an indwelling catheter from an arm that was not used for study drug administration. The 
exact time/date of PK sampling, study drug administration (including infusion start and stop 
times), and infusion rate will be recorded. 
9.3.2.2 Pharmacokinetic handling procedures  
Procedures for collection, storage, and shipment of PK samples are provided in the laboratory 
manual. 
9.3.2.3 Bioanalytical methods  
Concentrations of olipudase alfa in plasma will be determined using a validated enzyme-linked 
immunosorbent assay method. 
9.3.2.4 Pharmacokinetic parameters  
The pharmacokinetic parameters listed in Table 2 will be calculated from single- and 
multiple-dose data, as appropriate, and analyzed by non-compartmental methods. 
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Table 2 - Pharmacokinetic parameters and definitions  
Parameter 
Parameter definition 
Cmax 
Maximum plasma concentration observed 
tmax 
Time to reach Cmax 
AUC0-last 
Area under the plasma concentration versus time curve calculated using the trapezoidal method 
from time zero to the real time 
AUC 
Area under the plasma concentration versus time curve extrapolated to infinity according to the 
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 
Terminal half-life associated with the terminal slope (λz) determined according to the following 
equation: 
z
1/2Z
0.693
 
t

=
,  
where λz is the slope of the regression line of the terminal phase of the plasma concentration 
versus time curve, in semi-logarithmic scale. Half-life is calculated by taking the regression of at 
least 3 points. 
CL 
Total body clearance of a drug from the plasma calculated using the equation 
 
AUC
D
 
CL
ose
=
 
Vss 
Volume of distribution at steady state using the equation  
AUC
AUMC
 x 
CL
 
Vss =
 
The analyte and matrix for all PK parameters are olipudase alfa and plasma, respectively. 
9.4 
PHARMACOGENETIC ASSESSMENTS  
In addition to patients who have blood drawn for the baseline assessment of condition-related 
genotypes (See Section 9.6.3), for those patients who signed the optional pharmacogenetic 
informed consent form, a blood sample will be collected and stored for other pharmacogenetic 
analyses. 
This blood sample will be transferred to a site that will, on behalf of the sponsor, extract DNA 
from the sample. This sample may be used to determine a possible relationship between genes and 
response to treatment with olipudase alfa, how the body processes olipudase alfa and possible side 
effects to olipudase alfa. 
This blood sample, and the DNA that is extracted from it, will be assigned a second number, 
a Genetic ID (deidentification code) that is different from the patient identification (ID). This 
“double coding” is performed to separate a patient’s medical information and DNA data. 
The clinical study data (coded by patient ID) will be stored in the clinical data management 
system, which is a distinct database in a separate environment from the database containing the 
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pharmacogenetic data (coded by Genetic ID). The key linking patient ID and Genetic ID will be 
maintained by a third party, under appropriate access control. The matching of clinical data and 
pharmacogenetic data, for the purpose of data analysis, will be possible only by using this key, 
which will be under strict access control. All data will be reported only in coded form in order to 
maintain confidentiality. 
The DNA will be stored for up to 15 years from the completion of the clinical study report, in 
compliance with applicable country-specific regulations. 
Special procedures for storage and shipping of pharmacogenetic samples are described in detail in 
the laboratory manual. 
9.5 
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 ones used during the study 
(ie, subject/patient ID) and will be transferred to a Sanofi site (or a subcontractor site), which may 
be located outside of the country where the study is conducted. Safeguards for protecting patient 
confidentiality and personal data have been included (see Section 14.3 and Section 14.5). 
9.6 
OTHER ASSESSMENTS  
9.6.1 Demographic information and medical history  
During patient screening, demographic information including gender, date of birth, and ethnicity 
will be collected from each patient. Additionally, patients will provide a complete medical history. 
Specific information relating to any relevant prior or existing medical conditions/surgical 
procedures will be recorded on the patient’s e-CRF. The patient’s diagnosis of ASMD and first 
symptom date will also be collected and recorded, if available. 
9.6.2 Acid sphingomyelinase enzyme activity  
Acid sphingomyelinase activity will be measured as specified in Section 1.2 in peripheral 
leukocytes and dried blood spot. A central laboratory may conduct the analysis of the samples and 
provide reports. 
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9.6.3 Genotyping: SMPD1, CHIT1, UGT1A1  
Genotyping of SMPD1 and uridine diphosphoglucuronosyltransferase 1 family, polypeptide A1 
(UGT1A1) mutations will be performed by central laboratories if historical results are not 
available, or if historical results are available, but mutations were not annotated using the 
guidelines of the Human Genome Variation Society (http://www.hgvs.org/). Genotyping of 
CHIT1 will be performed by the sponsor if historical results are not available. Mutations will be 
annotated according to the guidelines of the Human Genome Variation Society 
(http://www.hgvs.org). 
Sample processing, storage, and shipment guidelines are provided in the laboratory manual. 
9.7 
APPROPRIATENESS OF MEASUREMENTS  
Dose escalation is necessary to progressively reduce stores of accumulated sphingomyelin and to 
avoid a large release of ceramide. Clinical AEs and safety biomarkers identified in the Phase 1 
single-dose and repeat-dose studies study will also be used to monitor treated patients for potential 
DLTs (as described in Section 8.1.4). 
If a patient experiences an IAR suggestive of a hypersensitivity reaction (as defined in 
Section 10.4.1.3), blood samples for anti-olipudase alfa antibody (IgG and IgE), tryptase activity, 
and complement activation testing will be collected. For patients in whom IgG antibodies 
develop, neutralizing antibody testing will also be performed. 
Efficacy parameters include improvements in spleen and liver volume (as measured by abdominal 
MRI), pulmonary imaging and function (HRCT, X-ray, PFTs), cardiopulmonary function by 
treadmill ergometry, bone disease infiltration, hematology parameters, and patient-reported 
health-related quality of life instruments. 
The DLCO was chosen as a primary efficacy endpoint because this PFT reflects the underlying 
pathophysiological infiltration manifested by disease foam cells and changes in DLco can 
objectively show the effect of olipudase alfa treatment on lung function and reducing local 
inflammation. Pulmonary involvement is common and progressive, although the extent and 
severity of involvement varies widely among patients (21). Foam cell infiltrates of the pulmonary 
alveoli block oxygen uptake through the alveolar wall into the blood vessels. This abnormal 
diffusing capacity is consistent with ILD (9) which may manifest with coughing, shortness of 
breath, and recurrent respiratory infections. With low partial pressure of oxygen (PO2) values, 
patients are affected by dyspnea upon exertion. In most patients with ASMD, decreased 
pulmonary diffusion secondary to alveolar infiltration becomes evident in childhood and 
progresses with age (22). Life-threatening bronchopneumonia may occur and cor pulmonale has 
been described; progressive pulmonary involvement is associated with higher morbidity and 
mortality (21). Severely affected patients may experience significant pulmonary compromise by 
age 15 to 20 years. The excess sphingomyelin and other lipids resulting from ineffective ASM 
clearance from macrophages result in secretion of inflammatory cytokines that lead to fibrosis and 
diminished lung capacity (23). Some patients develop chronic oxygen dependence with 
progressive pulmonary failure (21). 
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Changes in health-related quality of life after 52 weeks administration of study drug will be 
assessed with the instruments listed in Section 9.1.4.13. 
Changes from baseline in spleen volume and DLCO, separately, at Week 52 were selected as the 
primary efficacy endpoints in this Phase 2/3 study. Splenomegaly is a significant, consistently 
present manifestation of ASMD, and the degree of splenomegaly has been recognized as clinically 
relevant by disease experts and shown to be positively correlated with liver volume and 
triglyceride levels, and negatively correlated with white blood cell count, hemoglobin, high 
density lipoprotein, percent predicted FVC, and height Z score (24). In both ASMD and a similar 
lysosomal storage disorder, Gaucher disease, splenomegaly is central to the underlying 
pathophysiology and is usually the first presenting clinical sign. Furthermore, reduction in spleen 
volume is recognized as a clinically meaningful endpoint in Gaucher disease (25, 26). 
Clinical manifestations common to both ASMD and Gaucher disease include 
hepatosplenomegaly, thrombocytopenia, and anemia. Both diseases primarily affect the 
monocyte/macrophage lineage of cells and thus are diseases that affect the reticuloendothelial 
system. The main sphingolipids that accumulate in Gaucher disease (glucosylceramide) and 
ASMD (sphingomyelin) are major components of the plasma membranes of red blood cells, white 
blood cells, and platelets, which cannot be broken down by macrophages. Accordingly, 
assessments have been planned to monitor changes in hematology. 
Due to the known association of sphingomyelin with cholesterol, patients with ASMD often 
accumulate cholesterol, and subsequently are affected by dyslipidemia, characterized by a high 
atherogenic cardiovascular risk profile. Typically, the dyslipidemia is characterized by low 
concentrations of HDL and high concentrations of total cholesterol (27, 28) and recent case 
reports have described the occurrence of premature coronary artery disease (27). Accordingly, the 
fasting lipid profile will be assessed as an efficacy parameter and the NMR spectrum of HDL will 
be characterized (12, 13, 29). NMR lipid profiles analyzed for all patients through 52 weeks of 
treatment were not identified as an informative efficacy biomarker thus will be removed from the 
protocol after the cutoff date for a planned second database lock of the study for purpose of 
regulatory submissions in 2021. 
Because skeletal involvement can lead to osteopenia or osteoporosis, common manifestations of 
ASMD and splenomegaly have been shown to be inversely correlated with lumbar spine bone 
mineral density Z-scores (30), the severity of bone disease will be measured at baseline and once 
every year. A biomarker for bone resorption, C-telopeptide concentrations in serum have been 
shown to be decreased in patients with Gaucher disease. 
Although hemoglobin level, platelet count, and white blood cell count will comprise part of the 
standard safety laboratory assessments, these parameters are often abnormal in patients with 
ASMD because many cells of the reticuloendothelial system originate in the bone marrow and it 
is one of the most extensively involved organs in ASMD (31, 32). Bone marrow involvement, 
combined with hypersplenism, contributes to the thrombocytopenia, anemia, and to the 
neutropenia sometimes observed in patients with ASMD. 
Biomarkers will be measured that are known to be associated with macrophage proliferation 
(ACE), secreted by activated (NP cells) macrophages (chitotriosidase and CCL18), and 
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inflammatory background triggered in sphingolipidoses (bone-specific alkaline phosphatase, 
C-telopeptide). Changes in these biomarkers have supported the clinical responses observed with 
enzyme-replacement and substrate-reduction therapies in other sphingolipidoses such as Gaucher 
disease Type 1 and Fabry disease (33, 34, 35). The initial objective to monitor ACE changes 
through 52 weeks of treatment for all patients has been achieved; no further longitudinal analysis 
is required after the cutoff date for a planned second database lock of the study for purpose of 
regulatory submissions in 2021. CCL18 and chitotriosidase will continue to be monitored to 
assess overall disease burden.  
 
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10 
STUDY PROCEDURES  
10.1 
VISIT SCHEDULE  
The schedules of study assessments for all patients enrolled in this study are provided in 
Section 1.2. The individual evaluations are described in Section 9 and will occur before infusion 
with study drug, unless otherwise noted, and during approximately the same time for each visit (in 
reference to the screening/baseline visit). When multiple assessments are required, the order will 
be vital signs before ECG before blood draw. 
Day 1 is the day the first infusion is administered. The study visit schedule will be calculated 
using the date of Day 1 of the dose escalation period as the reference. 
Infusions will take place in a hospital. All infusions will take place in a monitored setting with 
ready access to emergency resuscitation equipment and medications. 
Patients will complete the eDiary at these time points: 
• Early in the screening period to verify inclusion criterion I06 
• Before the first infusion to collect baseline data (see Section 9.1.4.4). 
• At least 7 days before each quarterly visit of the PAP and ETP. 
• At end of study (EOS)/early discontinuation 
To collect patient responses to the composite endpoint, patients will enter responses in the eDiary 
device during the evening of the 7 consecutive days before Day 1 and each quarterly visit, 
separately, of the PAP and the ETP. Sites will distribute and collect the eDiary device according 
to the schedule presented in Section 1.2. Patients will make entries into the eDiary device at home 
according to the scheduled provided in Section 1.3. 
Rescreening may be possible for patients who screen failed, but is subject to sponsor approval. 
Imaging, function tests (eg, PFTs, ergometry), and questionnaires performed within 12 weeks of 
the expected date of randomization can be used for rescreening. All labs will be repeated, except 
genotyping and ASM activity measurements. The eDiary will not be repeated.  
In-patient hospitalization will be required before the start of the infusion and until at least 
24 hours after the end of infusion during dose escalation (ie, through Week 16 [PAP]/Week 70 
[ETP] if no dosing adjustments are necessary) and may be required during quarterly visits up 
through the end of Year 2; in-patient hospitalization may be necessary during quarterly and yearly 
study visits in Years 3 through 5. Blood will be collected and safety assessments performed 24 
and 48 hours after the end of infusion. After the cut-off date for a planned second database lock of 
the study for purpose of regulatory submissions in 2021, the 48 hours post-infusion blood 
samplings will no longer be collected. For all other visits, patients will be observed after the end 
of infusion for at least 1 hour. Study drug infusions will occur once every 2 weeks (±3 days) in 
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reference to the date of the first infusion (Day 1) for each patient, at the site or at home during a 
regional or national emergency declared by a governmental agency such as the COVID-19 
pandemic (refer to Appendix B for Germany) if agreed between the investigator and the sponsor 
for eligible patients, in compliance with applicable country-specific regulations. Quarterly visits 
will occur at the site. If site visits are not possible and home infusion is already approved for the 
eligible patient, quarterly visits will be done at home. In such a case, some of the quarterly visit 
assessments can be done by the site through the phone (eg, Health-related quality of life 
instruments). The rest of the missed quarterly visit assessments will be done as unscheduled, as 
soon as site visits become available. 
Telehealth visits are an acceptable alternative to site visits during the COVID-19 pandemic, in 
accordance with institutional policy and with applicable country-specific regulations. Patients 
who initiated home infusion during the COVID-19 pandemic, and continue to be on home 
infusion, may continue receiving home infusion by trained home nurses in the ETP every 2 weeks 
(±3 days) until the end of the ETP (refer to Appendix B for Germany) and, in such case, telehealth 
visits may continue until the end of the ETP (except quarterly visits as specified above). 
For the end of study/early discontinuation visit, assessments may vary depending on when 
discontinuation occurs.  
• Patients who discontinue during the dose escalation period of the PAP or the ETP due to 
intolerability of 0.1 and/or 0.3 mg/kg olipudase alfa or placebo (ie, during study Weeks 0 
through 6 [preinfusion]/Weeks 54 through 60 [preinfusion]) will only have: 
- 
Complete physical examination  
- 
Vital signs  
- 
Samples collected for the following assessments: 
- 
Clinical chemistry,  
- 
Coagulation 
- 
LFTs 
- 
Hematology 
- 
Urinalysis 
- 
hsCRP, iron, ferritin, plasma ceramide, cardiac specific troponin I, calcitonin 
- 
Multiplex assay  
- 
Anti-olipudase alfa IgG  
- 
β-HCG pregnancy test (if female of childbearing potential) 
- 
No other assessments will be performed, unless deemed necessary for safety reasons. 
• Patients who discontinue during the dose escalation period of the PAP or the ETP after the 
Week 6/Week 60 infusion will only have: 
- 
Complete physical examination  
- 
Vital signs 
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- 
ECG  
- 
Samples collected for the following assessments:  
- 
LFTs 
- 
Hematology 
- 
Urinalysis 
- 
hsCRP, iron, ferritin, plasma ceramide, cardiac specific troponin I, calcitonin 
- 
Multiplex assay 
- 
Anti-olipudase alfa IgG  
- 
β-HCG pregnancy test (if female of childbearing potential) 
- 
Sphingomyelin, ceramide, and other metabolites in plasma 
- 
Metabolites in dried blood spot 
- 
Chitotriosidase, ACE, and CCL18 
- 
Fasting lipid profile 
- 
No other assessments will be performed, unless deemed necessary for safety reasons.  
• For the EOS visit and for patients who discontinue after the dose escalation period of the 
PAP or the ETP, NPB Health Assessment, NPB-HAQ, PGIS questionnaires, abdominal 
MRI, liver echo Doppler, HRCT, chest X-ray, pulmonary function tests, treadmill 
ergometry, and echocardiogram with Doppler will not be repeated if they had been done 
within 3 months prior; DXA and bone MRI will not be repeated if they had been done 
within 6 months prior. All other assessments specified in Section 1.2.2.3 will be 
performed. 
10.1.1 Home infusions  
Home infusion may be given by trained home nurses during a regional or national emergency 
declared by a governmental agency such as the COVID-19 pandemic (refer to Appendix B for 
Germany) in the ETP every 2 weeks (±3 days), in compliance with applicable country-specific 
regulations. Patients must meet specific eligibility requirements outlined below.  In addition, the 
investigator and the sponsor must agree that home infusion is appropriate for each patient.  
Patients who initiated home infusion during the COVID-19 pandemic, and continue to be on 
home infusion, may continue receiving home infusion by trained home nurses in the ETP every 
2 weeks (±3 days) until the end of the ETP (refer to Appendix B for Germany). 
For a patient to receive home infusions, the following criteria must be met.   
• The investigator must agree in writing that home infusion is appropriate for the patient. 
• The patient must be willing and able to comply with home infusion procedures. 
• 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, that, in the opinion of the 
investigator, may affect the patient’s ability to tolerate the infusion.  
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• No infusion rate increases will be allowed while a patient is receiving home infusions. 
• 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. 
• Home infusion infrastructure, resources, and procedures must be established and available 
according to applicable country-specific regulations. 
• In 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 site for the subsequent visit 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 8.8). 
• 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. See Section 8.8 for details on severe hypersensitivity and 
anaphylaxis management. 
• 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. 
• 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. 
• Home infusion staff must keep source documentation of the infusion, including 
documentation of any AEs, IARs, examinations/ assessments, sample collections and 
concomitant medication.  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. 
• An additional questionnaire about home infusion experience may be added any time 
before end of the study for patients who received home infusion treatment. 
• If the site visit is not possible during a regional or national emergency declared by a 
governmental agency such as the COVID-19 pandemic (refer to Appendix B for Germany) 
due to site closure or extenuating circumstances that prevent an in-person site visit, and 
home infusion already approved for the eligible patient, the investigator can decide 
whether reintroduction should occur at the hospital/study site or home visit.   
• For the switch from Process C (
) IMP to the updated manufacturing Process C(
) IMP, 
if the site visit is not possible during a regional or national emergency declared by a 
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governmental agency such as the COVID-19 pandemic (refer to Appendix B for Germany) 
due to site closure or extenuating circumstances that prevent an in-person site visit, the 
first infusion of 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. 
10.2 
DEFINITION OF SOURCE DATA  
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the study. Source 
data are contained in source documents. Examples of these original documents and data records 
include hospital records, clinical and office charts, laboratory notes, memoranda, patients’ diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions 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, the laboratories, and other departments involved in the clinical study. 
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 eCRF. No data should therefore be 
directly entered into the eCRF. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
Study drug will be continued whenever possible; however, if study drug is stopped, it will be 
determined if the stop can be made temporarily as permanent discontinuation will be a last resort. 
Any discontinuation will be fully documented in the source and eCRF. In any case, the patient 
should remain in the study as long as possible. 
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 serum β-HCG pregnancy test at screening and before 
undergoing any further assessments and procedures. Urine β-HCG will be tested up to 24 hours 
before the first infusion of the study; then once every 4 weeks before infusion. In addition, these 
patients are required to have a negative serum or urine β-HCG pregnancy test during the PAP and 
ETP every 4 weeks after randomization before undergoing visit specific assessments and being 
infused with study drug. Patients must be willing to practice true abstinence or use 2 acceptable, 
effective methods of contraception while they are participating in the study. If a patient is no 
longer participating in the study, they must practice true abstinence or use 2 acceptable, effective 
methods of contraception for 15 days following their last dose of study drug. Every effort will be 
made to prevent pregnancy during this study. 
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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 eCRF 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 eCRF. 
Alcohol consumption 
Although blood alcohol testing will not be required, patients must be willing to abstain from the 
use of alcohol for 1 day before and 3 days after each study drug infusion (Section 7.2). 
Patients will be counseled to limit alcohol consumption during the study: 
• Male patients to a maximum of 30 g alcohol per day (2 drinks/day) 
• Female patients to a maximum of 15 g alcohol per day (1 drink/day) 
Patients who do not limit alcohol can be discontinued from the study, according to investigator’s 
discretion. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s)  
Temporary treatment discontinuation corresponds to more than 1 dose not administered to the 
patient as decided by the investigator after consultation with the sponsor. 
Temporary treatment discontinuation (also referred to as treatment interruption) may be 
considered by the investigator because of suspected AEs. 
Re-initiation of study drug administration will be done under close and appropriate clinical/and or 
laboratory monitoring after the investigator has considered to his/her best medical judgment that 
the responsibility of study drug in the occurrence of the concerned event was unlikely and if the 
study selection criteria are still met (Section 7.1 and Section 7.2). Before re-initiation of treatment, 
the sponsor must be consulted to determine the starting dose and if dose escalation will be 
required (see Section 8.1.3). 
For all patients who have missed two or more doses that require reintroduction of olipudase alfa, 
the dose reintroduction will take place at the site. During the COVID-19 pandemic, if site visits 
are not possible and home infusion is already approved for the eligible patient, the investigator 
can decide whether reintroduction should occur at the hospital/study site or home visit.   
Upon reintroduction of treatment, certain assessments will be repeated at infusions 
(Section 8.1.3.2). The investigator will decide if additional specific assessments may be required 
before the patient can begin the reintroduction regimen.  
For all temporary treatment discontinuations, the duration will be recorded by the investigator in 
the appropriate screens of the eCRF. 
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10.3.2 Permanent treatment discontinuation with investigational medicinal product(s)  
Permanent discontinuation of study drug is any discontinuation associated with the definitive 
decision from the investigator, sponsor, or the patient not to re-expose the patient to the study 
drug at any time. 
10.3.3 List of criteria for permanent treatment discontinuation  
The patient may withdraw from treatment if he/she decides to do so, at any time and irrespective 
of the reason; withdrawal may be the decision of the investigator or sponsor. All efforts will be 
made to document the reasons for discontinuation in the eCRF. 
Patients should discontinue from treatment for the following reasons: 
• The patient reported unacceptable toxicity (see Section 8.1.4) 
• The patient required intervention or therapy precluded by the protocol that was deemed by 
the investigator to be medically necessary 
• The patient was unable to comply with the requirements of the protocol 
• The patient was noncompliant with study activities or wished to be withdrawn from 
treatment 
• The patient was erroneously included in the study (failed to satisfy all study criteria in 
Section 7) 
• The patient participated in another interventional investigational study while in ASCEND 
study 
• Pregnancy 
In addition, the sponsor may decide to discontinue the study early 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 EOS/discontinuation assessments before withdrawal (as detailed in 
Section 1.2) and will receive a safety follow-up telephone call from the study site 30 to 37 days 
after the final administration of study drug. 
The investigator will document the reason(s) for treatment discontinuation/study withdrawal on 
the eCRF. 
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 eCRF 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 eCRF. 
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10.3.4 Handling of patients after permanent treatment discontinuation  
Any patient who discontinues participating in the study will be contacted by the study investigator 
to obtain information about the reason(s) for discontinuation and collection of any potential AEs. 
If possible, all tests and evaluations listed for the end of study/early discontinuation visit in 
Section 1.2 are to be carried out within 2 weeks of the last study drug infusion. If a patient fails to 
return for the necessary visits, then every effort must be made to contact the patient, determine the 
reason(s) for discontinuation, and record the reason(s) on the e-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 e-CRF and in the 
patient’s medical record. 
In addition, since the primary study comparison is based on intent to treat principle using all 
randomized patients with any study treatment, missing data, especially the key study assessments 
during the PAP (12 months) may potentially lead to biased results and challenges in assessing the 
treatment effect of the study drug. Therefore, all efforts should be made to continue to follow the 
patients for primary and key secondary endpoints, after the temporary or permanent 
discontinuation of treatment, in addition to the standard post study safety follow up. If possible, at 
the minimum, patients should be assessed at their regularly scheduled Week 52 visit (or as close 
as possible to Week 52) if treatment discontinuation occurred prior to that visit. 
10.3.5 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. Patients requesting withdrawal should be informed that withdrawal 
of consent for follow-up may jeopardize the public health value of the study. 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. 
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. 
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
The investigator is the primary person responsible for making all clinically relevant decisions on 
safety issues. 
When necessary, a specialist will be consulted in a timely manner (eg, acute renal failure, 
convulsions, skin rashes, angioedema, cardiac arrest, electrocardiographic modifications, etc). 
10.4.1 Definitions of adverse events  
10.4.1.1 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. 
10.4.1.2 Serious adverse event  
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
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 
• 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 
• Medical and scientific judgment will 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 when a condition is to be considered a medically important event. The list 
is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc) 
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- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc) 
- 
Development of drug dependency or drug abuse 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study 
- 
Chronic neurodegenerative diseases (newly diagnosed) and not part of the ASMD 
spectrum 
10.4.1.3 Adverse event of special interest  
An AESI is an AE (serious or non-serious) 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 the following: 
• Pregnancy of a female patient entered in the study as well as pregnancy occurring in 
a female partner of a male patient entered in this study 
• Symptomatic overdose (serious or non-serious) of study drug 
- 
An overdose (accidental or intentional) of study drug 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 
- 
An asymptomatic overdose will be reported as a standard AE 
• Laboratory values: The following laboratory values and symptoms will be considered 
AESIs (see also Dose-limiting toxicities in Section 8.1.4, Reporting of adverse events of 
special interest with immediate notification in Section 10.4.4.1 and Summary of adverse 
event reporting instructions in Table 3), as follows: 
- 
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, fever, rash, or eosinophilia (> ULN) 
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• Infusion-associated reactions: Some AEs may be manifestations of IARs, including 
hypersensitivity reaction, APR, and CRS; however, the original signs and symptoms may 
be reported as AEs. In the eCRF, investigators will be asked to identify if a specific AE 
represents a clinical manifestation of the IAR. 
Infusion-associated reactions are defined as AEs that occur during the infusion or within 
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 by the investigator or the sponsor as an IAR. For this 
study, IARs may present as hypersensitivity reactions, APRs, and CRS. 
- 
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. 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. 
Common symptoms of hypersensitivity reactions seen with other enzyme replacement 
therapy include urticaria, rash, dyspnea, and less frequently, angioedema. Other 
symptoms of hypersensitivity IARs include fever, hypotension, tachycardia, nausea, 
vomiting, pain, and headache. 
- 
Acute phase reactions 
Considered a type of IAR and specific to infusion with olipudase alfa, APRs were 
observed in the Phase 1 single-dose study and the Phase 1b repeat-dose study (6). 
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 in acute phase reactants including, but not limited to, neutrophils, 
iron, ferritin, fibrinogen, D-dimer, transferrin, albumin, Protime, 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. 
- 
Cytokine release syndrome 
Cytokine release syndrome is another type of IAR, attributed to the release of 
excessive amounts of cytokines shortly after the intravenous administration of certain 
therapeutic agents. The severe form of CRS is a cytokine storm, which may be life 
threatening. Nonclinical studies of high-dose olipudase alfa have suggested the 
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possibility of CRS. Increases were observed after a single dose of ≥0.3 mg/kg 
olipudase alfa in the Phase 1, single-dose study 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). 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), typical symptoms include pyrexia, nausea, vomiting, fatigue, pain, 
myalgia, and in severe cases, multi-organ system dysfunction or failure, severe 
headache, and pulmonary edema. Cytokine release syndrome will be determined based 
on combined significant laboratory findings and clinical symptoms. 
10.4.1.4 Definitions for criteria of adverse events  
Relationship to study treatment 
Assessment of the association between the AE and study exposure is important for regulatory 
reporting and will be made in blinded studies and also for known comparators. For each AE/SAE 
the investigator will determine if there is a reasonable possibility and demonstrated by evidence 
which suggests a causal relationship between the study treatment and the AE according to the 
categories below: 
• Not Related: There is no suspicion of a causal relationship between exposure and the AE. 
• Unlikely Related: No evidence exists for a causal relationship between exposure and the 
AE; however, such a relationship cannot be excluded. 
• Possibly Related: Some evidence exists that there is a possibility of a causal relationship 
between exposure and the AE. 
• Related: Strong evidence exists that there is a causal relationship between exposure and 
the AE. 
A relationship to the study drug 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 and amend the AE/SAE report accordingly. 
Severity of adverse event scoring 
Note that “severity” is not the same as “seriousness,” which is defined in Section 10.4.1.2. 
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Intensity: 
• Mild = no modification of daily activities and does not require mandatory 
corrective/symptomatic treatment. 
• Moderate = hinders normal daily activities and/or requires mandatory 
corrective/symptomatic treatment. 
• Severe = prevents daily activities and requires mandatory corrective/symptomatic 
treatment. 
Outcome 
The “outcome” describes the status of the AE, which will be provided by the investigator for each 
AE reported for each patient. Definitions for possible results of an AE include: 
• Fatal: The termination of life as a result of an AE. 
• Not recovered/not resolved: The patient has not recuperated or the AE has not improved. 
• Recovering/resolving: The patient is recuperating or the AE is improving. 
• Recovered/Resolved: The patient has recuperated or the AE has resolved. 
• Recovered with sequelae/resolved with sequelae: The AE has resolved, but the patient has 
been left with symptoms or pathology. 
• Unknown: Not known, not observed, not recorded, or refused. 
Action taken regarding the study drug 
The investigator will be required to provide the action taken on the study drug (eg, active, 
comparator) in response to the AE. Options include: 
• Dose increased: increased the frequency, strength, or amount of study drug. 
• Dose not changed: no change in administration of the study drug. 
• Dose reduced: reduced the frequency, strength, or amount of study drug. 
• Study drug is interrupted: temporary interruption in administration of the study drug. 
• Study drug is withdrawn: administration of the study drug is terminated (no further 
dosing). 
• Not applicable: applies when an event has occurred prior to initial dosing, after the last 
dose, or if the patient dies due to the event. 
• Unknown: not known, not observed, not recorded, or refused. 
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10.4.2 General guidelines for reporting adverse events  
See Table 3 for an overview of AE reporting instructions. 
• 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 will be recorded on the 
corresponding eCRF. 
• Except for IARs, whenever possible, diagnosis or single syndrome will be reported instead 
of symptoms. For IARs, all symptoms must be recorded separately. 
• The investigator will specify the date of onset, intensity, action taken with respect to study 
drug, corrective treatment/therapy given, additional investigations performed, outcome, 
and opinion as to whether a reasonable possibility exists that the AE was caused by the 
study drug. 
• The investigator should take appropriate measures to follow all AEs until clinical recovery 
has completed and laboratory results have returned to normal, or until progression has 
been stabilized, or until death, to ensure the safety of the patients. 
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol. 
• Laboratory, vital signs, or ECG abnormalities are to be recorded as AEs only if: 
- 
Symptomatic and/or 
- 
Requiring either corrective treatment or consultation, and/or 
- 
Leading to study drug discontinuation or modification of dosing, and/or 
- 
Fulfilling a seriousness criterion, and/or 
- 
Defined as an AESI (see Section 10.4.1.3) 
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Table 3 - 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 
criterion per Section 10.4.1.2 
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 10.4.1.3 and 
Section 10.4.4.1 
Yes 
 
Yes 
Yes 
 
Yes 
No 
 
No 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; SAE = serious adverse event; ULN = upper limit of normal 
10.4.3 Instructions for reporting serious adverse events  
In the case of occurrence of an SAE, the investigator must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF. 
• SEND (by email) a photocopy of all examinations carried out and the dates on which these 
examinations were performed, to the representative of the monitoring team. 
• Care will 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. 
• All further data updates will be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) will be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge. In addition, every effort will be made to further document 
any SAE that is fatal or life threatening within a week (7 days) of the initial notification. 
• A back-up plan (using a paper case report form process) will be available and used when 
the eCRF 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 study drug with a reasonable possibility, will 
be reported to the monitoring team. 
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10.4.4 Guidelines for reporting adverse events of special interest  
10.4.4.1 Reporting 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 10.4.3, even if the event does not fulfill a seriousness criterion, using the 
corresponding screens in the eCRF. 
• Pregnancy 
- 
Pregnancy occurring in a female patient or the partner of a male 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 will be discontinued 
- 
Follow-up of the pregnancy is mandatory until the outcome has been determined 
• Infusion-associated reaction (see Section 10.4.1.3), which include: 
- 
Hypersensitivity reaction 
- 
Acute-phase reaction 
- 
Cytokine release syndrome 
• Symptomatic overdose of study drug 
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. See Section 10.4.1.3. 
• The following laboratory values and symptoms (see also Dose-limiting toxicities in 
Section 8.1.4), as follows: 
- 
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, fever, rash, or eosinophilia (> ULN) 
• Any AE that, in the opinion of the investigator or sponsor, raises significant concern 
regarding the safety of olipudase alfa at the administered dose  
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10.5 
OBLIGATIONS OF THE SPONSOR  
During the study, the sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to study drug (suspected 
unexpected serious adverse reaction), to the health authorities, IECs/IRBs as appropriate 
and to the investigators 
• All SAEs that are expected and at least reasonably related to study drug 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. 
10.6 
ADVERSE EVENTS MONITORING  
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS  
11.1 
GENERAL CONSIDERATIONS  
The PAP analysis will be performed after all patients have completed the Week 52 assessments 
(ie, at the completion of the 52-week PAP treatment period) and will include a formal database 
lock, unblinding of the study treatment arms, and analyses of efficacy, safety, pharmacodynamic, 
and pharmacokinetic data. 
11.2 
DETERMINATION OF SAMPLE SIZE  
The sample size calculations are based on the 2 primary efficacy endpoints of percentage change 
from baseline in spleen volume (expressed in MN) at Week 52 and the percentage change from 
baseline in DLCO (expressed as % predicted of normal) at Week 52. The assumptions for the 
spleen volume endpoint are the following: 
• An 11.8% common standard deviation based on data from previous ASMD and Gaucher 
disease type 1 studies 
• A 30% mean difference from baseline to Week 52 between 3.0 mg/kg olipudase alfa and 
placebo in percentage change in spleen volume MN 
• An expected exclusion rate from the modified intent-to-treat (mITT) population of 11% 
Based on the above assumptions, a comparison between 3.0 mg/kg olipudase alfa and placebo 
would have over 95% power using a t-test at a 2-sided 5.0% significance level with 36 patients 
randomized 1:1 to placebo or 3.0 mg/kg olipudase alfa. At a 2.5% significance level, the power 
would still be over 95%. 
The following assumptions for the DLCO endpoint are based on results obtained from the 
olipudase alfa Phase 1b Study DFI13412: 
• A 20% common standard deviation 
• A 25% mean difference from baseline to Week 52 between 3.0 mg/kg olipudase alfa and 
placebo in percentage change in DLCO (in % predicted) 
• An expected exclusion rate from the mITT population of 11% 
Based on these assumptions, a comparison between the 3.0 mg/kg treatment arm and the placebo 
arm will have 93% power using a t-test at a 2-sided 5.0% significance level and with 36 patients 
randomized 1:1 to placebo or 3.0 mg/kg. 
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The assumptions for the splenomegaly-related score endpoint came from the Sanofi-sponsored 
clinical trial in myelofibrosis (JAKARTA, NCT# 01437787). The assumptions for the power 
calculations are: 
• A common standard deviation of 9.4 
• A mean difference of 8.0 from baseline to Week 52 between 3.0 mg/kg of olipudase alfa 
and placebo in the splenomegaly-related score 
• An expected exclusion rate from the mITT population of 11% 
Based on the above assumptions, a comparison between 3.0 mg/kg of olipudase alfa and placebo 
will have 82% power using a t-test to detect a statistical trend, defined as 2-sided p-value ≤0.15, 
with 36 patients randomized 1:1 to placebo and 3.0 mg/kg of olipudase alfa. 
For the US protocol, in which a combination spleen endpoint is used, using the simplifying 
assumption that the 2 components of the combination spleen endpoint (spleen volume and SRS) 
are independent, the likelihood that statistical significance (spleen volume significance based on 
Hochberg procedure and SRS p-value ≤0.15) will be declared for the combination spleen endpoint 
is greater than 80%. 
11.3 
DISPOSITION OF PATIENTS  
Screened patients will be defined as any patient who has signed the informed consent form. 
Screened patients who completed screening and met all eligibility criteria will be eligible for 
randomization. Patients treated without being randomized will not be considered as randomized 
and will not be included in any efficacy population. 
Randomized patients include any patient who had been allocated to a randomized treatment arm 
by IXRS regardless of whether the study drug has been administered. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.4 
ANALYSIS POPULATIONS  
The randomized population will include any patient who had been allocated to a randomized 
treatment arm regardless if study drug was administered. 
The safety population is a subset of the randomized population and will include randomized 
patients who received at least 1 infusion (partial or total). This is the primary population for the 
safety analysis. 
The mITT population is the same as the safety population, and is used as the primary population 
for the efficacy analysis. 
The per protocol population will be a subset of the mITT population who have no major protocol 
deviations that are expected to interfere with assessments of the 2 primary efficacy endpoints. 
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The extension treatment population will consist of patients who completed the PAP and who 
continue into the extension treatment period. 
The PK population will consist of mITT patients who have evaluable drug concentration data. 
The PD population will consist of mITT patients who have at least 1 evaluable PD marker data 
available post-baseline. 
Patients who are included in the safety population and have rescue therapy initiated are included 
in the rescue therapy population. Since in the ETP all subjects get olipudase alfa, the rescue 
therapy is relevant only for the PAP. 
11.5 
STATISTICAL METHODS  
11.5.1 Extent of investigational medicinal product exposure  
The extent of study treatment exposure will be assessed and summary statistics will be presented 
for the safety population. 
11.5.2 Analyses of efficacy endpoints  
Efficacy endpoints and assessments are provided in Section 9.1. 
11.5.2.1 Primary efficacy analysis  
The 2 primary efficacy endpoints (percentage change in spleen volume in MN from baseline to 
Week 52 [combined with change in SRS from baseline to Week 52 in the US only, and is referred 
to as the “combination spleen endpoint”]) and percentage change in DLCO in percent predicted 
from baseline to 52 weeks) will be analyzed in the mITT population using the mixed model for 
repeated measures. 
For percent change in DLco (% predicted) from baseline, the mixed model for repeated measures 
(MMRM) will include baseline DLco (% predicted), baseline age, treatment arm, study visit 
(Week 26, Week 52), and study visit by treatment arm interaction as covariates; have 
an unstructured variance-covariance matrix; and be fit using restricted maximum likelihood 
estimation. Comparisons between treatment arms will be made using least-square mean contrasts 
at the 52 week visit.  
The analysis will include all DLco observations after baseline in the first 12 months of the study 
regardless of the treatment discontinuation status, with the exception that measurements made 
after the switch of treatment (eg, placebo patients switch to olipudase alfa after meeting the rescue 
criteria) will not be considered. For the primary analysis, missing data will not be imputed and 
will be assumed as Missing at Random (MAR). 
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Similar analyses will be performed for the spleen volume (MN) and the splenomegaly-related 
symptom score (SRS), when baseline value of the spleen volume (or SRS) will be used as 
covariate.  
Descriptive assessment of MAR assumption and sensitivity analyses to assess the impact of 
missing data are described in the SAP. 
Hypothesis tests will be 2-sided and adjusted for multiple comparisons to maintain a family-wise 
Type 1 error rate of 5%. The details of multiplicity adjustments are provided in Section 11.5.4. 
11.5.2.2 Secondary efficacy analyses  
The secondary efficacy endpoints include the following: 
• Percentage change in liver volume (in MN) from baseline to Week 52 
• Percentage change in platelet counts from baseline to Week 52 
• Week 52 change from baseline in fatigue severity as measured by Item 3 of the BFI scale 
• Week 52 change from baseline in pain severity as measured by Item 3 of the BPI-SF scale 
• Week 52 change from baseline in dyspnea severity as measured by the FACIT dyspnea 
tool 
• Change in SRS from baseline to Week 52 (except US, where it is part of the primary 
"combination spleen endpoint") (Section 9.1.4.4) 
The secondary efficacy endpoints will be analyzed in the mITT population using the mixed model 
for repeated measures and 2 sided hypothesis tests. The multiplicity adjustment for the secondary 
endpoints using a hierarchical, closed testing principle is described in Section 11.5.4. Handling of 
the missing data for secondary efficacy endpoints will be described in the SAP. 
11.5.3 Extension treatment period  
Long-term efficacy will be summarized for all efficacy endpoints using data collected during the 
ETP. 
11.5.4 Multiplicity considerations  
The hypothesis testing for the primary efficacy endpoints and secondary efficacy endpoints will 
be adjusted for multiplicity using a 2-stage gatekeeping strategy to maintain the 5% familywise 
error rate. A Hochberg method will be used to test the 2 primary endpoints followed by 
sequential, closed hypothesis testing for the secondary efficacy endpoints. The primary efficacy 
endpoint testing will proceed as follows:  
Compare olipudase alfa to placebo on DLco and spleen volume: The overall 5% significance level 
for the two hypothesis tests will be maintained using the Hochberg method (MTP2 is maintained 
for 2-sided, 2-endpoint testing): 
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• The p-values associated with the 2 primary endpoint comparisons will be ranked and the 
higher of the 2 p-values will be compared to 0.05. If the higher p-value is ≤0.05, the 
primary efficacy testing stops, and both primary endpoints are considered statistically 
significant. 
• If the higher p-values is ≥0.05, the primary endpoint associated with the higher p-value is 
not significant and the lower p-value is compared to 0.025. If the lower p-value is ≤0.025, 
the primary endpoint associated with this p-value is considered statistically significant. 
• In the US, the combined spleen endpoint will be considered statistically significant if, 
from Steps 1 and 2, the spleen volume endpoint is significant and the SRS p-value ≤0.15. 
The hypothesis testing for the secondary efficacy endpoints will proceed in a hierarchical fashion 
using the closed testing principle, and will stop if there is a nonsignificant comparison. From 
sponsor perspective, the study is declared positive if either DLco or combination spleen endpoint 
is significant. 
For Europe and the rest of world, from sponsor perspective, the study is declared positive if at 
least one of the primary endpoints is statistically significant by the above method. 
If statistical significance is reached on both the DLco and spleen volume using the Hochberg 
method (and the trend in splenomegaly-related score is established in case of USA), then 
hypothesis testing of the secondary efficacy endpoints will proceed using sequential testing at 
5% level with the order as specified below. At any step when the endpoint is not significant at 
5% level, the formal testing in subsequent steps will stop; the p-values for the subsequent 
endpoints in the sequence will be considered exploratory and hence interpreted at the nominal 
level. This controls the overall type I error level at 5%, using the closed testing principle. If either 
of the primary endpoints is not significant, then hypothesis testing for the secondary endpoints 
will be considered exploratory, and p-values will be interpreted at the nominal level. Testing will 
proceed according to the following sequence: 
1. Percentage change in liver volume (in MN) from baseline to Week 52 
2. Percentage change in platelet counts from baseline to Week 52 
3. Week 52 change from baseline in fatigue severity as measured by Item 3 of the BFI scale 
4. Week 52 change from baseline in pain severity as measured by Item 3 of the BPI-SF scale 
5. Week 52 change from baseline in dyspnea severity as measured by the FACIT dyspnea 
tool 
6. Change in SRS from baseline to Week 52 (except US, where it is part of the primary 
"combination spleen endpoint") (Section 9.1.4.4) 
11.5.5 Analyses of safety data  
Safety analyses will be performed using the safety population by the actual treatment received, 
irrespective of the treatment to which the patient has been randomized. The actual treatment 
received is defined as:  
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• PAP analysis: olipudase alfa if any infusion in the PAP contains olipudase alfa (including 
any rescued placebo patient); placebo if all infusions in the PAP contain only placebo 
• ETP analysis: olipudase alfa  
Additional summaries may be conducted using the most recent dose the patient received before 
the event of interest. 
The summary of safety results will be presented by treatment arm. All safety analyses will be 
performed using the following common rules: 
• The baseline value is defined generally as the last available value before randomization, 
except hematology and ECG parameters. Baseline for hematology parameters is derived as 
the mean of all available results before the start of first infusion. Baseline for ECG 
parameters is derived as the mean of all available results on the Day 1/Week 0 visit before 
the start of first infusion. 
• The following definitions will be applied to laboratory parameters, ECGs and vital signs. 
- 
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. 
- 
The PCSA criteria will determine which patients had at least 1 PCSA during the on-
treatment period, taking into account all evaluations performed during the on-treatment 
period, including unscheduled or repeated evaluations. The number of all such patients 
will be the numerator for the on-treatment PCSA percentage. 
11.5.5.1 Adverse events  
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), 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 period. The denominator for computation of percentages is the safety population 
within each treatment arm. 
All treatment-emergent adverse events (TEAEs), all TEAEs potentially related to study drug, all 
TEAEs leading to treatment discontinuation and/or study discontinuation, all TEAEs that are 
IARs, all TEAEs that are SAEs (including those potentially related to treatment), and all AEs with 
fatal outcome (including fatal TEAEs) will be summarized. The TEAE observation period will be 
defined as the time from the first infusion of study drug through the end of study visit or 30 to 
37 days after the last infusion of study drug, whichever one occurs later. 
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Detailed listings of TEAEs, SAEs, AESIs, related AEs, and discontinuations due to AEs will be 
provided and include the randomized treatment arm and olipudase alfa dose of the infusion or 
placebo before or during the occurrence of the AE, when applicable. 
The number of TEAEs and annualized rate, and the number and proportion of patients reporting 
specific AEs will be tabulated for the overall analyses of AEs. 
Separate analyses of AEs may also be conducted by demographic characteristics (eg, age and 
sex). Adverse events of special interest, such as IARs, and SAEs will be analyzed similarly. 
Adverse events of special interest 
Detailed listings for AESIs will be provided. 
Deaths 
The following deaths summaries will be generated: 
• Death in nonrandomized patients or randomized and not treated patients 
• 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  
11.5.5.2 Physical examinations, vital signs, electrocardiograms, and echocardiograms  
Observed values and changes from baseline (as applicable) will be summarized. Outlier 
summaries for the ECG parameters (eg, QTc) and vital signs will be created for the safety 
population. 
The ECG data will be analyzed using the Bazett’s and Fridericia’s QT correction methods (36). 
All ECG variables will be summarized for each randomization dose group/dose and time point. 
Change from baseline will also be calculated and summarized using descriptive statistics. 
11.5.5.3 Clinical laboratory tests  
Observed values and changes from baseline to study time points will be summarized. All 
laboratory values will be classified as normal, above normal, or below normal based on normal 
ranges provided by the laboratory. Frequencies of clinically significant abnormal values and shifts 
from baseline to study time points will be summarized. Patient listings of biomarkers will be 
provided. 
11.5.5.4 Immune response assessments  
Immune response assessments will be analyzed in the safety population. The presence, absence, 
and titers of serum anti-olipudase alfa IgG antibodies and routine levels of acute phase reactants 
will be summarized over time overall and by the dose level of the infusion before or during the 
evaluation. Levels of acute phase reactants, serum tryptase, complement activation, neutralizing 
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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. 
11.5.6 Pharmacokinetic and pharmacodynamic analyses  
11.5.6.1 Pharmacokinetic analyses  
Plasma concentration-time data will be analyzed using actual dosing and sampling times by non-
compartmental methods. 
As data permit, the following PK parameters as specified in Section 9.3.2.4 will be calculated for 
each patient and each dose of olipudase alfa. 
Pharmacokinetic parameters will be assessed as a function of time (upon repeat dosing) and in 
relation to immunogenicity. If data do not lend to non-compartmental analysis, or for additional 
analyses, model based approaches such as nonlinear mixed effects modeling may be used. 
11.5.6.2 Pharmacodynamic analyses  
Pharmacodynamic endpoints are defined in Section 9.3.1. The analysis of these endpoints will use 
the PD population. 
Concentration-time data for sphingomyelin and metabolite levels will be summarized. 
All other PD parameters will be summarized using descriptive statistics. Change from baseline 
will be calculated and summarized. Exploratory correlation analyses will be attempted to evaluate 
relationships between different PD markers and between sphingomyelin and/or lyso-
sphingomyelin levels from different sources. 
11.5.6.3 Pharmacokinetics - pharmacodynamics  
Exploratory PK-PD analyses may be performed to elucidate dose-response and concentration 
response relationships with biomarkers of safety and/or efficacy. The PK-PD relationships may be 
explored graphically and if a relationship is apparent, PK-PD modeling may be attempted and 
results reported, as appropriate.  
11.5.7 Analyses of quality of life variables  
Scoring for the quality of life assessments (eg, BPI, BPI-SF, etc) will be conducted as stated by 
the developers of the questionnaires, if available. 
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12 
ETHICAL AND REGULATORY STANDARDS  
12.1 
ETHICAL PRINCIPLES  
This clinical trial will be conducted by the sponsor, the investigator, delegated investigator staff 
and subinvestigator, 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 (GCP), all applicable laws, rules 
and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments. 
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 13.3. 
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 of all 
pertinent aspects of the clinical trial including the written information given approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants will be informed to the fullest extent 
possible about the study in language and terms they are able to understand. 
Before a patient’s participation in the clinical trial, the informed consent form will be signed, 
name entered, and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient. 
The informed consent form and optional pharmacogenetic informed consent form used by the 
investigator for obtaining the patient's informed consent must be reviewed and approved by the 
sponsor before submission to the appropriate ethics committee (IRB/IEC) for approval/favorable 
opinion. 
12.3 
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. 
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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 will be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
Study drug 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 will 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 (E6), 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).  
All participant data relating to the study will be recorded on electronic CRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
CRF. Guidance on completion of CRFs will be provided in the eCRF completion guide.  
Particular attention will 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. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 25 years after the signature of the final study report unless local 
regulations or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor 
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 eCRFs. Thus, the main duty of 
the monitoring team is to ensure that the safety, well-being, and rights of all study patients 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. 
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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.  
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
The sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations).  
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 that 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, study drug allocation, patient compliance with 
the study drug regimen, study drug accountability, concomitant therapy use and quality of data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH guidelines for Good Clinical Practice, the monitoring team must check the 
eCRF 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 which support the data on 
the eCRFs (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. 
Should a correction be made, the corrected information will be entered in the eCRF 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 eCRF. 
The computerized handling of the data by the sponsor when available in the eCRF may generate 
additional requests (Discrepancy Resolution Form) to which the investigator is obliged to respond 
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by confirming or modifying the data questioned. The requests with their responses will be 
managed through the eCRF. 
13.4.1 Use of computerized systems  
The following computerized systems may be used during the different steps of the study: 
• For data management activities, Medidata Rave 
• For PK activities, PKDMS Version 2.0 incorporating WinNonlin Enterprise, 
Version 5.2.1, Pharsight 
• For statistical activities, SAS 
• For pharmacovigilance activities, AWARE 
• For monitoring activities, IMPACT 
• For medical writing activities, VEEVA VAULT 
• For MRI activities, WebSend and BioPACS 
• For the eDiary, Exco Engage Portal 
• For ECGs, Cami 7 
• For echocardiograms, Digiview 
• For pulmonary function tests, EasyDataCentral 
• For central laboratory tests, Covance Lablink 
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14 
ADDITIONAL REQUIREMENTS  
14.1 
CURRICULUM VITAE  
A current copy of the curriculum vitae describing the experience, qualification and training of 
each investigator and subinvestigator will be signed, dated and provided to the sponsor before the 
beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES  
The investigator must maintain confidentiality of 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 will be taken into account in the event that a longer 
period is required. 
The investigator must notify the sponsor before 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 eCRFs, the investigator's brochure and the results obtained during the course of the 
clinical trial, is confidential, before 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, investigator and its collaborators involved in the study. 
14.4 
PROPERTY RIGHTS  
All information, documents and study drug 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, which 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  
• The patient's personal data, which are included in the sponsor database shall be treated in 
compliance with all applicable laws and regulations 
• 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. 
• The sponsor also collects specific data regarding investigator as well as personal data from 
any person involved in the study which may be included in the sponsor’s databases, and 
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 US Food and Drug Administration. The following options will be listed 
for race on the eCRF: American Indian or Alaska Native; Asian; Black; Native Hawaiian or Other 
Pacific Islander; White; Japanese; plus 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 
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. 
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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/she 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 will 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  
The sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio. 
• Patient enrollment is unsatisfactory. 
• Noncompliance of the investigator or subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• The total number of patients are included earlier than expected. 
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. 
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In all cases (decided by the sponsor or by the investigator), the appropriate ethics committee(s) 
(IRB/IEC) and Health Authorities will be informed according to applicable regulatory 
requirements. 
14.9 
CLINICAL TRIAL RESULTS  
The sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the investigator. A full clinical study report (CSR) will be prepared when the PAP 
data becomes available. At study completion (ie, at the end of ETP), the CSR for the entire study, 
including the ETP, will be prepared. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
The investigator agrees not to publish or release data or information pertaining to the study before 
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 before 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 before implementation of the change and patient signature will be re-collected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES  
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the treatment of Gaucher disease. Semin Hematol. 2004;41(4 Suppl 5):4-14. 
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 Niemann-Pick disease mice leads to visceral, 
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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 
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5. McGovern MM, Wasserstein MP, Kirmse B, Duvall WL, Schiano T, Thurberg BL, et al. 
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6. Genzyme Corporation. An open-label, multicenter, ascending dose study of the tolerability 
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635.pdf 
9. 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 
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10. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. ATS/ERS Task 
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11. American Thoracic Society. Lung function testing: selection of reference values and 
interpretative strategies. Am Rev Respir Dis. 1991;144(5):1202-18. 
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12. Rizzo M, Otvos J, Nikolic D, Montalto G, Toth PP, Banach M. Subfractions and 
Subpopulations of HDL: An Update. Curr Med Chem. 2014;21(25):2881-91. 
13. Freedman DS, Otvos JD, Jeyarajah EJ, Shalaurova I, Cupples LA, Parise H, et al. Sex and age 
differences in lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy: 
the Framingham Study. Clin Chem. 2004;50(7):1189-200. 
14. Maas M, Hangartner T, Mariani G, McHugh K, Moore S, Grabowski GA, et al. 
Recommendations for the assessment and monitoring of skeletal manifestations in children 
with Gaucher’s disease. Skeletal Radiol. 2008;37(3):185-8. 
15. 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. 
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16. 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. 
17. 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. 
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severity on health-related quality of life: A study of Chinese cancer patients. Cancer. 
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19. Cleeland CS, Ryan KM. Pain assessment: Global use of the brief pain inventory. Ann Acad 
Med Singapore. 1994;23(2):129-38. 
20. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
framework and item selection. Med Care. 1992:30(6):473-83. 
21. McGovern MM, Lippa N, Bagiella E, Schuchman EH, Desnick RJ, Wasserstein MP. 
Morbidity and mortality in type B Niemann-Pick disease. Genet Med. 2013;15(8):618-23. 
22. Wasserstein MP, Desnick RJ, Schuchman EH, Hossain S, Wallenstein S, Lamm C, et al. The 
natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study. 
Pediatrics. 2004;114(6):e672-7. 
23. Truman JP, Al Ghadban MM, Smith KJ, Hammad SM. Acid sphingomyelinase in macrophage 
biology. Cell Mol Life Sci. 2011;68(20):3293-305. 
24. McGovern MM, Wasserstein MP, Giugliani R, Bembi B, Vanier MT, Mengel E, et al. A 
prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type 
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25. Zimran A, Brill-Almon E, Chertkoff R, Petakov M, Blanco-Favela F, Muñoz ET, et al. Pivotal 
trial with plant cell-expressed recombinant glucocerebrosidase taliglucerase alfa, a novel 
enzyme replacement therapy for Gaucher disease. Blood. 2011;118(22):5767-73. 
26. Shankar S, Lukina E, Amato DJ, Dasouki M, Packman S, Pastores GM, et al. Engage: A 
Phase 3, randomized, double-blind, placebo-controlled, multicenter study to investigate the 
efficacy and safety of eliglustat in adults with Gaucher disease type 1: 9 month results. Blood. 
2013;122(21)2275. 
27. McGovern MM, Pohl-Worgall T, Deckelbaum RJ, Simpson W, Mendelson D, Desnick RJ, et 
al. Lipid abnormalities in children with types A and B Niemann Pick disease. J Pediatr. 
2004;145(1):77-81. 
28. Lee CY, Krimbou L, Vincent J, Bernard C, Larramée P, Genest J Jr, et al. Compound 
heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with 
low HDL cholesterol. Hum Genet. 2003;112(5-6):552-62. 
29. Cromwell WC, Otvos JD. Utilization of lipoprotein subfractions. In: Davidson MH, Toth PP, 
Maki KC, editors. Contemporary Cardiology: Therapeutic Lipidology. Totowa, NJ: Humana 
Press Inc. 2007:321-47. 
30. Wasserstein M, Godbold J, McGovern MM. Skeletal manifestations in pediatric and adult 
patients with Niemann Pick disease type B. J Inherit Metab Dis. 2013;36(1):123-7. 
31. 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, Gibson K, Mitchell G eds. OMMBID - The Online Metabolic and Molecular Bases of 
Inherited Diseases. New York: McGraw-Hill; 2013. Available from: 
URL:http://ommbid.mhmedical.com/content.aspx?bookid=474&Sectionid=45374145 
32. Crocker AC, Farber S. Niemann-Pick disease: a review of eighteen patients. Medicine 
(Baltimore). 1958;37(1)1-95. 
33. van Breemen MJ, de Fost M, Maas M, Wiersma MG, Hollak CE, Poll LW, et al. Different 
dose-dependent correction of MIP-1beta and chitotriosidase during initial enzyme replacement 
therapy. J Inherit Metab Dis. 2009;32(2):274-79. 
34. Hollak CE, van Weely S, van Oers MH, Aerts JM. Marked elevation of plasma chitotriosidase 
activity. A novel hallmark of Gaucher disease. J Clin Invest. 1994;93(3):1288-92. 
35. Boot RG, Verhoek M, de Fost M, Hollak CE, Maas M, Bleijlevens B, et al. Marked elevation 
of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing 
therapeutic intervention. Blood. 2004;103(1):33-9. 
36. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline E14: The 
clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-
antiarrhythmic drugs. Version 2005.  
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17 
APPENDICES  
Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information  
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
2. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
- 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use 1 of the highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Male subjects 
• Male subjects with heterosexual partners of reproductive potential (WOCBP) are eligible 
to participate if they agree to use the following during the protocol defined timeline: 
- 
Refrain from donating sperm  
and 
- 
At least 1 of the following conditions applies: 
- 
Are and agree to remain abstinent from penile-vaginal intercourse on a long term 
and persistent basis, when this is their preferred and usual lifestyle.  
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or 
- 
Agree to use a male condom plus an additional contraceptive method with a failure 
rate of  1% per year (see table for female subjects) 
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom for the time defined in the protocol 
 
Highly effective contraceptive methods that are user dependent 
Failure rate of <1% per year when used consistently and correctlya 
• 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationb 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationb 
- 
oral 
- 
injectable 
Highly effective methods that are user independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman of 
childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method(s) of contraception 
should be used. Spermatogenesis cycle is approximately 90 days.) 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the subject.) 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. In 
this case TWO highly effective methods of contraception should be used during the treatment period and for at least [XX, corresponding to 
time needed to eliminate study treatment plus 30 days for study treatments with genotoxic potential] after the last dose of study treatment. 
 
Female subjects: 
Highly effective contraceptive methods that are user dependent 
Failure rate of <1% per year when used consistently and correctlya 
• 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationb 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationb 
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- 
oral 
- 
injectable 
Highly effective methods that are user independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb  
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman of 
childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method(s) of contraception 
should be used. Spermatogenesis cycle is approximately 90 days.) 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the study and the preferred and usual lifestyle of the subject.) 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. In 
this case TWO highly effective methods of contraception should be used during the treatment period and for at least 15 days after the last 
dose of study treatment. 
 
COLLECTION OF PREGNANCY INFORMATION 
Male subjects with partners of reproductive potential who become pregnant  
• The Investigator will attempt to collect pregnancy information on any female partner of 
a male study subject who becomes pregnant while participating in this study. This applies 
only to subjects who receive study treatment. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy.  
• Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor.  
• Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure  
Female subjects who become pregnant  
• The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study  
• Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy.  
• Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
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the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date.  
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the Sponsor. While 
the Investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of an SAE through spontaneous reporting.  
 
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Appendix B 
Country-specific requirements  
 In Germany: 
The simplification measures proposed will only apply for the duration of the current public 
health crisis due to COVID-19 in Germany, until the GUIDANCE ON THE MANAGEMENT 
OF CLINICAL TRIALS DURING THE COVID-19 (CORONAVIRUS) PANDEMIC, 
Version 4, dated February 4, 2021, is rescinded, when there is consensus that the period of the 
COVID-19 outbreak in the EU/EEA has passed. 
 
 
 
 
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Appendix C 
Protocol amendment history  
The Protocol Amendment Summary of Changes Table for the current amendment is located after 
the "Names and Addresses of Coordinating Investigator, etc…. and directly before the Clinical 
Trial Summary. 
The primary reasons for each protocol amendment are summarized below. 
AMENDED PROTOCOL 14 – Germany Only (07-Jun-2021)  
This amended protocol 14 is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
To specify that the simplification measures proposed in this protocol will only apply for the 
duration of the current public health crisis due to COVID-19 in Germany, until the GUIDANCE 
ON THE MANAGEMENT OF CLINICAL TRIALS DURING THE COVID-19 
(CORONAVIRUS) PANDEMIC, Version 4, dated February 4, 2021 is rescinded, when there is 
consensus that the period of the COVID-19 outbreak in the EU/EEA has passed. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2.2  
Schedule of assessments: 
extension treatment period 
 
In the footnote a of the Table 1.2.2.4, the text: 
“…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…” 
was modified as following: 
“…if the site visit is not possible during a regional or 
national emergency declared by a governmental 
agency such as the COVID-19 pandemic (refer to 
Appendix B for Germany) due to site closure or 
extenuating circumstances that prevent an in-
person site visit…” 
Clarification requested by German health 
authority 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1  
DESCRIPTION OF THE 
PROTOCOL 
The text: 
“Home infusion may be initiated during a regional 
or national emergency declared by a governmental 
agency such as the COVID-19 pandemic in the 
ETP by trained home nurses if agreed between the 
investigator and the sponsor, in compliance with 
applicable country-specific regulations.” 
was modified as following: 
“Home infusion may be initiated during a regional 
or national emergency declared by a governmental 
agency such as the COVID-19 pandemic (refer to 
Appendix B for Germany) in the ETP by trained 
home nurses if agreed between the investigator 
and the sponsor, in compliance with applicable 
country-specific regulations.” 
Clarification requested by German health 
authority 
Section 8.1.3.2 
Dosing delays or missed doses 
 
The text: 
“Dose reintroduction will be done at the site. During 
a regional or national emergency declared by a 
governmental agency such as the COVID-19 
pandemic or extenuating circumstances that 
prevent an in-person site visit…” 
was modified as following: 
“Dose reintroduction will be done at the site. During 
a regional or national emergency declared by a 
governmental agency such as the COVID-19 
pandemic (refer to Appendix B for Germany) or 
extenuating circumstances that prevent an in-
person site visit…” 
Clarification requested by German health 
authority 
Section 10.1 
VISIT SCHEDULE 
The text: 
“… at the site or at home during a regional or 
national emergency declared by a governmental 
agency such as the COVID-19 pandemic if agreed 
between the investigator and the sponsor for 
eligible patients…” 
was modified as following: 
“…at the site or at home during a regional or 
national emergency declared by a governmental 
agency such as the COVID-19 pandemic (refer to 
Appendix B for Germany) if agreed between the 
investigator and the sponsor for eligible patients…” 
Clarification requested by German health 
authority 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.1.1 
Home infusions 
The text: 
“Home infusion may be given by trained home 
nurses during a regional or national emergency 
declared by a governmental agency such as the 
COVID-19 pandemic in the ETP every 2 weeks 
(±3 days)” 
was modified as following: 
“Home infusion may be given by trained home 
nurses during a regional or national emergency 
declared by a governmental agency such as the 
COVID-19 pandemic (refer to Appendix B for 
Germany) in the ETP every 2 weeks (±3 days)…” 
 
The text: 
“For the switch from Process C (
) IMP to the 
updated manufacturing Process C(
) IMP, 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…” 
was modified as following: 
“For the switch from Process C (
) IMP to the 
updated manufacturing Process C(
) IMP, if the 
site visit is not possible during a regional or national 
emergency declared by a governmental agency 
such as the COVID-19 pandemic (refer to 
Appendix B for Germany) due to site closure or 
extenuating circumstances…” 
Clarification requested by German health 
authority 
Appendix B 
Country-specific requirements were added with the 
information from amended protocol 14 
Clarification according to amended 
protocol 14 
Appendix C 
Protocol amendment history was updated 
To incorporate the changes from 
amended protocol 13 to amended 
protocol 14 
 
AMENDED PROTOCOL 13 (02-Feb-2021) 
This amended protocol 13 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 as follows:  
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. 
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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 post 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. The conduct of treatment experience interviews to understand patient’s experience living 
with acid sphingomyelinase deficiency (ASMD) and participating in this study has been 
added. 
2. The assessments have been streamlined to reduce patient burden in the extension phase of 
this trial. Assessments to ensure patient safety have been 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 on 17 October 2019 was at the 
end of the PAP [primary analysis period]). 
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 - 
endpoint(s) 
Exploratory efficacy endpoints: addition of treatment 
experience interviews 
Semi-structured patient interviews have been 
added to understand the patient experience of living 
with ASMD and participating in this study 
Clinical trial summary - 
Statistical 
considerations 
Pharmacodynamics 
Only lyso-sphingomyelin and ceramide will 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 (PAP) 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. 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 1.2 - Schedule 
of assessments 
 
Schedule of assessments: previous flow charts will be only 
applicable before the implementation of changes that will occur 
after the cutoff date of the second database lock. 
Updated manufacturing scale has been replaced by Process 
C(
) 
Clarification to avoid confusion with the 
complementary flow chart 
 
 
Clarification on olipudase alfa manufacturing 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Updated manufacturing process has been replaced by Process 
C(
) 
process changes 
 
Section 1.2 - Schedule 
of assessments  
 
A complementary flow chart (Section 1.2.2.4) has 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.  
Assessment added:  
• 
Treatment experience interview 
Assessments removed:  
• 
Sphingomyelin in plasma 
• 
ACE 
• 
Metabolites in dried blood spot (DBS) 
• 
48 hours after infusion: vital sign measurements, 
LFTs, hematology, and safety during dose re-
escalation  
• 
NMR of HDL 
• 
Multiplex assay of vascular biomarkers 
Timing changed from quarterly to every 6 months, pre-infusion 
only:  
• 
Ceramide 
• 
 Lyso-sphingomyelin 
• 
Serum chitotriosidase 
• 
CCL18 
Bone biomarkers (serum bone specific ALP, Ctelopeptide) 
Timing Changed from every 6 months to yearly: 
• 
Chest X-ray 
• 
Treadmill ergometry 
48 hours post-infusion sampling removed for: 
• 
 hsCRP, iron, ferritin, cardiac-specific troponin I, 
• 
calcitonin 
LFTs and coagulation 
• 
Multiplex assay of pro-inflammatory 
biomarkers  (telopeptide)  
The assessments have been streamlined to reduce 
patient burden in the extension phase of this trial. 
Assessments to ensure patient safety have been 
preserved. 
Section 6.1 
Description of the 
protocol 
Text about home infusion during a regional or national 
emergency such as COVID-19 clarified. 
 
Section 8.1.1 
Treatments 
administered 
Following two paragraphs are added: 
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(
).  
For the switch from Process C(
) IMP to the updated 
manufacturing Process C
) IMP, 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 
Clarification on the olipudase alfa manufacturing 
process. Adding the possibility to perform the first 
infusion at home in the context of site closure or 
extenuating circumstances that prevent an in-
person site visit in compliance with applicable 
country-specific regulations.  
No safety risks are anticipated based on the 
following:  
1. Process C(
) IMP is produced using an 
updated manufacturing process; it is produced 
as per Good Manufacturing Process (GMP) 
requirements and is considered comparable to 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Sponsor and the Investigator in compliance with applicable 
country-specific regulations 
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 8.1.3.2 – 
Dosing delays or 
missed doses 
After the cutoff date for a planned second database lock of the 
study for purpose of regulatory submissions in 2021, removal 
of: 
For the fifth paragraph related to the “outside the dose 
escalation” the following change has been done: 
• 
48 hours post-infusion: vital sign measurements, 
LFTs and hematology tests and safety biomarkers 
and if available during home infusion from the same 
blood sample, clinical chemistry, multiplex assay 
and pharmacodynamic biomarkers  
Addition of: 
Assessment of the transaminases obtained after infusion 
during the dose escalation period; 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 
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; 
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 9.1.3 Tertiary 
and exploratory 
efficacy endpoints 
ACE, NMR of HDL, Multiplex assay of vascular biomarkers 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. 
Addition of patient treatment experience interview  
The assessments have been streamlined to reduce 
patient burden in the extension phase of this trial. 
Given current knowledge about the study drug, 
assays can be replaced by targeted testing. 
Analysis of ACE through 52 weeks (PAP) of 
treatment has been completed for all patients. Initial 
objective to monitor for changes with treatment 
were achieved; no further longitudinal analysis is 
required. 
Since the lipid profiles are informative efficacy 
biomarkers, the exploratory NMR of HDL will be 
removed from the protocol. This change is 
harmonized with the ongoing LTS13632 protocol 
also part of the olipudase clinical development 
program.  
Semi-structured patient interview has been added 
to understand the patient experience of living with 
ASMD and participating in this clinical trial. 
Section 9.1.4 
Assessment of 
efficacy endpoints 
Assessments reduced from every 6 months to yearly after the 
cutoff date for a planned second database lock of the study for 
purpose of regulatory submissions in 2021. 
• 
Chest X-ray 
• 
Treadmill ergometry 
The assessments have been streamlined to reduce 
patient burden in the extension phase of this trial. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 9.1.4.7 
Biomarkers 
ACE 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. 
See rationale for Section 9.1.3 above for further 
details. 
Section 9.1.4.12 
Multiplex assay of 
inflammatory and 
vascular biomarkers 
Only the multiplex assay of proinflammatory panel will be 
maintained after the cutoff date for a planned second database 
lock of the study for purpose of regulatory submissions in 2021 
and the vascular multiplex panels will no longer be assessed. 
Given current knowledge about the study drug, 
assays can be replaced by targeted testing. 
The assessments have been streamlined to reduce 
patient burden in the extension phase of this trial: 
IL-6, IL-8, TNF alpha and IFN gamma will be 
assessed. 
Section 9.1.4.14 
Treatment experience 
interviews 
To allow the conduct of treatment experience interviews 
Semi-structured patient interviews were added to 
understand the patient experience of living with 
ASMD and participating in this study. 
Section 9.2 Safety 
endpoints 
Multiplex assay for vascular biomarkers 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 this trial. 
Section 9.2.8 Multiplex 
assays 
IL-6, IL-8, TNF alpha, and IFN gamma were identified as key 
safety biomarkers during the PAP; as the multiplex assay of 
proinflammatory panel captures all these biomarkers, this 
panel only will be maintained for exploratory safety endpoint 
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 this trial. 
 
Section 9.2.9 
Immunogenicity 
assessments 
During the study period, for the switch from Process C(
) IMP 
to the updated manufacturing process C(
) IMP, collection will 
be monthly for the first 6 months after starting the new update, 
and quarterly after that 
Clarification on the updated manufacturing process 
Section 9.3.1 
Pharmacodynamic 
endpoints 
No further analysis of sphingomyelin or other metabolites will 
be conducted 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 (PAP) 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. The other 
assessments have been streamlined to reduce 
patient burden in the extension phase of this trial. 
Section 9.3.1.2 
Sphingomyelin and 
metabolites in plasma 
and dried blood spot 
No further analysis of sphingomyelin or other metabolites will 
be conducted after the cutoff date for a planned second 
database lock of the study for purpose of regulatory 
submissions in 2021. Lyso-sphingomyelin and ceramide will be 
maintained to continue to monitor levels of substrate and its 
metabolic product. 
See rationale for section 9.3.1 above for further 
details.  
Section 9.3.2.1 
Pharmacokinetic 
sampling time 
During the study period, for the switch from Process C(
 IMP 
to the updated manufacturing process C(
) IMP, samples for 
PK will be collected at the second dose that is administered 
after the switch. 
Clarification on the updated manufacturing process 
Section 9.7 
Appropriateness of 
measurements 
NMR of HDL and ACE will be removed from the protocol after 
the cutoff date for a planned second database lock of the study 
for purpose of regulatory submissions in 2021. 
CCL18 and chitotriosidase will continue to be monitored to 
assess overall disease burden.  
The assessments have been streamlined to reduce 
patient burden in the extension phase of this trial. 
See rationale for Section 9.1.3 above for further 
details. 
Section 10.1 Visits 
After the cutoff date for a planned second database lock of the 
The assessments have been streamlined to reduce 
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Section # and 
Name 
Description of Change 
Brief Rationale 
schedule 
study for purpose of regulatory submissions in 2021, the 48 
hours post-infusion blood samplings will no longer be collected. 
Text about home infusion during a regional or national 
emergency such as COVID-19 clarified. 
patient burden in the extension phase of this trial. 
Section 10.1.1 Home 
infusion 
Addition of: 
If the site visit is not possible during 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 already approved for the eligible patient, the 
investigator can decide whether reintroduction should occur at 
the hospital/study site or home visit.   
For the switch from Process C (
) IMP to the updated 
manufacturing Process C(
) IMP, 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 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. 
To facilitate treatment continuation via home 
infusion when site visit is not available for eligible 
patients during a regional or national emergency 
declared by a governmental agency such as the 
COVID-19 pandemic. 
 
Section 13.1 
Responsibilities of the 
Investigator (s) 
Language added for clarification: The Investigator must permit 
study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to 
source data documents. 
During a regional or national emergency declared 
by a governmental agency such as the COVID-19 
pandemic, to allow more flexibility with regards to 
additional options for monitoring techniques in 
compliance with applicable country-specific 
regulations. 
To further clarify the responsibilities of the 
Investigator(s). 
Section 13.2 
Responsibilities of the 
Sponsor. 
The following language has been 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 
declared by a governmental agency such as the 
COVID-19 pandemic. 
Section 17  Protocol 
amendment history – 
Appendix C  
The protocol amendment history section has been updated. 
To conform with the usual process for amendment 
history. 
AMENDED CLINICAL TRIAL PROTOCOL 12 (15-Apr-2020) 
This amended protocol (12) 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 made to provide option of home infusion during the COVID-19 pandemic for 
eligible patients during the extension treatment period (ETP) in compliance with applicable 
country-specific regulations and in case of multiple missing infusions, to clarify the process of 
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dose reintroduction, and change the  reintroduction starting dose. Previous omissions and errors 
were corrected.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary-Study design, 
Sections 1.2.2.2, 1.2.2.3 Schedule of 
Assessments, 6.1 Description of the 
protocol, 8.1.1 Treatments 
administered, 8.1.3.2 Dosing delays 
or missed doses, 10.1 Visit schedule 
Provide option for home infusion during COVID-19 
pandemic 
Home infusion is necessary 
for patients to continue 
treatment in case of 
procedure taken during 
COVID-19 pandemic 
Clinical Trial Summary-Study design, 
Sections 1.2.2.2, 1.2.2.3 Schedule of 
Assessments, 6.1 Description of the 
protocol, 10.1 Visit schedule 
Change hospitalization requirements in quarterly and 
yearly visits during ETP to be at investigator discretion 
 
Update hospitalization 
requirements to be more 
flexible at PI discretion 
regarding quarterly and 
yearly visits in ETP 
Clinical Trial Summary- Study 
design, Section10.1 Visit schedule 
Update observation period after infusion to 1 hour instead 
of 3 hours 
Match observation period in 
other studies 
Section 1.2 Schedule of 
Assessments 
Weight at previous on-site quarterly visit or home visit 
(during COVID-19 pandemic, if ≥3 months passed since 
last on-site quarterly visit) may be used to calculate drug 
dosage at current visit.  
In tables where new footnotes were added, the footnote 
numbers were updated. 
To allow dose calculation to 
be done based on quarterly 
visit weight during ETP 
Section 8.1.3.2 Dosing delays or 
missed doses 
Reduce the dose when reintroduction from 0.6 mg/kg to 
0.3 mg/kg in case patient was on a dose of ≥ 0.6 mg/kg 
and missed ≥3 infusions  
To allow safer reintroduction 
at a lower level in case of 
missing ≥3 infusions 
Section 8.1.3.2 Dosing delays or 
missed doses 
List of assessments needed during dose reintroduction. 
Reformatting of language and remove redundant 
language 
Clarify rules of dose 
reintroduction and needed 
assessments 
Section 8.8 Concomitant medication- 
treatment of infusion associated 
reaction 
In case of anaphylaxis, language updated to reflect 
immediate discontinuation of the infusion  
Clarification of anaphylaxis 
management 
Sections 9.1.3 Tertiary and 
exploratory efficacy endpoints, 
9.1.4.13 Health-related quality of life 
questionnaires,  
An additional questionnaire about home infusion 
experience may be added for patients who received 
home infusion treatment 
Record patient experience 
Section 10.1.1 Home infusions 
List of eligibility requirements for home infusion 
Provide details of who are 
eligible for home infusion 
and guidance on safety 
measures 
Section 10.3.1 Temporary treatment 
discontinuation with investigational 
medicinal product(s) 
Addition of home infusion during COVID-19 pandemic 
and guidance for reintroduction assessment 
Provide details guidance in 
case of COVID-19 
Pandemic and assessment 
during reintroduction 
Sections 9.5 Future use of samples, 
14.2 Record retention in study site 
Change document retention to 25 years and clarify that 
left over samples will be stored for future use for 15 
To comply with the standard 
procedures and match the 
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Section # and Name 
Description of Change 
Brief Rationale 
years, in compliance with country specific regulations.  
approved informed consent  
 
Amended Clinical Trial Protocol 11 (12-Aug-2019)  
This amended protocol (11) 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 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.  
 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary, 
Main selection criteria 
Exclusion Criteria 
Corrected an error in platelet count number superscript 
Correct a previous error 
Clinical Trial Summary, 
6.2.1 Duration of study 
participation for each patient 
Corrected the duration of ETP to 4 years 
 
Correct an error. The total 
duration of the study is 
correct but the ETP duration 
was to be corrected.  
Clinical Trial Summary,  
6.3 Interim Analysis 
Updated to specify that a formal summary of data or interim 
CSR may be produced to support regulatory approval(s) 
and/or other submission/application requirement(s) 
Clarify the plans for interim 
CSR (s) 
Clinical Trial Summary,  
7.2 Exclusion Criteria 
Modified E 10: The patient is unwilling or unable to avoid 
10 days before and 3 days after the protocol scheduled liver 
biopsies, that are required at screening/baseline, at Week 52 
and at Week 104, the use of medications or herbal 
supplements that are potentially hepatotoxic (eg, 3-hydroxy-3-
methyl glutaryl coenzyme A reductase inhibitors, erythromycin, 
valproic acid, anti-depressants, kava, echinacea) and/or may 
cause or prolong bleeding (eg, anti-coagulants, ibuprofen, 
aspirin, garlic supplements, ginkgo, ginseng). 
Assessment to be done after 
manufacturing process 
update 
1.2.1.2 Schedule of 
Assessments: Year 1 - PAP 
Week 18 through Week 52 
Correction of footnote reference for anti-olipudase alfa IgG 
(footnote ‘k’ instead of footnote ‘j’) 
Correct a previous error 
1.2.2.1 Schedule of 
assessments: ETP - Year 2 
Week 54 to Week 70 
Correction of footnote reference for eDiary (footnote ‘m’ 
instead of ‘l’) and study drug infusion (footnote ‘n’ instead of 
‘m’) 
Correct a previous error 
1.2.2.2 Schedule of 
assessments: ETP - Year 2 
Week 72 to Week 104 
Footnote ‘h’ has been updated to include language for 
hematology assessments in cases where drug product from an 
updated manufacturing process will be administered. 
Correction of footnote reference for study drug infusion 
(footnote ‘p’ instead of ‘o’) 
Clarification and correction of 
a previous error 
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Section # and Name 
Description of Change 
Brief Rationale 
1.2.2.3 Schedule of 
assessments: ETP - Year 3 
until end of study 
Footnote ‘i’ has been updated to include language for 
hematology assessments in cases where drug product from an 
updated manufacturing process will be administered. 
Correction of footnote reference for β-HCG pregnancy test 
(footnote ‘k’ instead of ‘j’) 
Clarification 
1.2.3 Pharmacokinetic 
sampling during the primary 
analysis and extension 
treatment periods 
Updated to include details of sampling in cases where drug 
product from an updated manufacturing process will be 
introduced. Added footnote ‘c’ to specify that during the study 
period, if drug product from an updated manufacturing process 
is administered, samples for PK will be collected at the second 
dose that is administered after the switch following the same 
schedule in other PK sampling weeks 
Assessment to be done after 
manufacturing process 
update 
9.1.2 
Added a reference to Section 9.1.4.13 for change in SRS from 
baseline to Week 52 
Clarification 
9.3.2.1 Pharmacokinetic 
sampling time 
Updated to include details of sampling in cases where drug 
product from an updated manufacturing process will be 
introduced 
Assessment to be done after 
manufacturing process 
update 
10.3.3 List of criteria for 
permanent treatment 
discontinuation 
Updated the reason for patient discontinuation from treatment: 
The patient participated in another investigational study 
Clarify that patient will be 
discontinued if participated in 
another interventional 
investigational study 
11.5.4 Multiplicity consideration 
Update language to match multiplicity rules planned 
Clarify statistical 
consideration of multiplicity of 
primary and secondary end 
points 
15 Clinical Trial Protocol 
Amendments 
Updated to state that any amendment to the clinical trial 
protocol requires written approval/favorable opinion by the 
ethics committee (IRB/IEC) and also by regulatory health 
authorities if substantial before its implementation, unless 
there are overriding safety reasons 
Clarify language regarding 
the approvals needed in case 
of protocol amendment to 
adhere to Sanofi policy 
17 Appendices 
Appendix C - Protocol 
Amendment History 
Updated to include the summary of changes from Amended 
protocol 10 
This change was made to 
adhere to Sanofi policy. 
Amended Clinical Trial Protocol 10 (05 Dec 2018)  
This amended protocol (10) 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 include the immunogenicity schedule of analysis to be followed in 
case of drug product from an updated manufacturing process is administered. Also, it is made to 
clarify language regarding the assessments done during dose reescalation.  
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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.2 Schedule of 
assessments.  
Flow chart # 
1.2.1.2 foot note k, 
1.2.2.2 footnote j, 
1.2.2.3 footnote l 
All footnotes to the 
assessment of 
Anti-olipudase alfa 
IgG  
During the study period, if drug product from an updated manufacturing process 
is administered, collection will be monthly for the first 6 months after starting the 
new update, and quarterly after that. 
 
Describe the schedule 
of immunogenicity (anti 
olipudase alfa IgG) 
assessment in case of 
manufacturing update 
to the process 
8.1.3.2 Dosing 
delays or missed 
doses 
Outside a dose escalation period, or if the patient has already reached his/her 
maximum tolerated dose, a patient who has missed 2 consecutive doses and 
whose last dose was 0.3 mg/kg or 0.6 mg/kg should receive the same dose at 
the next scheduled infusion and for the rest of the study period. If the last dose 
was 1, 2, or 3 mg/kg, the first reintroduction dose should be 1 level below the last 
dose. During this dose re-escalation, the schedule of assessments (except PK) 
will be similar to dose escalation period starting from the corresponding dose. If 
this dose re-escalation happened during the PAP, re-escalation of 0.6 mg/kg will 
correspond to week 6, repetition of 0.6 mg/kg will correspond to week 8, 1 mg/kg 
to week 10, 2 mg/kg to week12 and 3 mg/kg to week 14 assessments. If the 
dose re-escalation happened during the ETP, re-escalation of 0.6 mg/kg will 
correspond to week 60, repetition of 0.6 mg/kg will correspond to week 62, 
1 mg/kg to week 64, 2 mg/kg to week 66 and 3 mg/kg to week 68 assessments. 
For the following infusions, the dose will be escalated up to the dose the patient 
had reached prior to the infusion interruption (target dose or maximum tolerated 
dose) following the standard escalation process described in Table 1.  
Outside a dose escalation period, or if the patient has already reached his/her 
maximum tolerated dose, a patient who has missed 3 or more consecutive doses 
and whose last dose was 0.3 mg/kg will receive a dose of 0.3 mg/kg at the next 
scheduled infusion and for the rest of the study period. If the last dose was 0.6, 1, 
2, or 3 mg/kg), the first reintroduction dose will be 0.6 mg/kg. During this dose re-
escalation, the schedule of assessments (except PK) will be similar to dose 
escalation period starting from the corresponding dose. If this dose re-escalation 
happened during the PAP, re-escalation of 0.6 mg/kg will correspond to week 6, 
repetition of 0.6 mg/kg will correspond to week 8, 1 mg/kg to week 10, 2 mg/kg to 
week12 and 3 mg/kg to week 14 assessments. If the dose re-escalation 
happened during the ETP, re-escalation of 0.6 mg/kg will correspond to week 60, 
repetition of 0.6 mg/kg will correspond to week 62, 1 mg/kg to week 64, 2 mg/kg 
to week 66 and 3 mg/kg to week 68 assessments. 
Clarify language of 
dose re-escalation 
9.2.9 
Immunogenicity 
assessments 
During the study period, if drug product from an updated manufacturing process 
is administered, collection will be monthly for the first 6 months after starting the 
new update, and quarterly after that. 
Describe the schedule 
of immunogenicity (anti 
olipudase alfa IgG) 
assessment in case of 
manufacturing update 
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Section # and 
Name 
Description of Change 
Brief Rationale 
to the process. 
 
Amended Clinical Trial Protocol 09: 18-Sep-2018 
Reason for Amendment: 
This amendment was made to clarify that portal hypertension would be detected for all patients 
using already existing liver ultrasound echo parameters and also to clarify language in statistical 
analysis and pharmacokinetic assessments. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Clinical Trial 
Summary- Study 
design 
The PAP will include a screening/baseline period and a treatment period. During 
the screening/baseline period, from day -60 to day 1 preinfusion, approximately 
36 patients will provide informed consent and undergo screening assessments to 
determine trial eligibility and undergo baseline measurements. 
Clarification and 
correction 
Clinical Trial 
Summary- Study 
design 
Note: a Schedule does not account for rechallenge. 
          a Study drug includes olipudase alfa and placebo 
Correction 
Clinical Trial 
Summary- Study 
design 
If a patient is discontinued due to inability to tolerate rechallenge (ie, a second 
dose of 0.3 mg/kg olipudase alfa), then an additional patient will may be 
randomized. 
Clarification and 
correction 
Clinical Trial 
Summary- Study 
design 
For treatment periods during the PAP and the ETP, dose-limiting toxicity criteria 
and study stopping rules will apply. 
Clarification 
Clinical Trial 
Summary- Statistical 
considerations 
Patients who are included in the safety population and have rescue therapy 
initiated are included in the rescue therapy population. 
Clarification and 
correction 
Clinical Trial 
Summary- Statistical 
considerations 
Adverse event (AE) incidence tables will present by system organ class (SOC) 
(sorted by internationally agreed order) and preferred term (PT) sorted 
alphabetically for each treatment arm, and the number and percentage of patients 
experiencing an AE. 
Correction 
Clinical Trial 
Summary- Statistical 
considerations 
Exploratory correlation analyses will be attempted to evaluate relationships 
between different pharmacodynamic markers and between sphingomyelin and/or 
lysosphingomyelin levels from different sources. 
Clarification and 
correction 
Clinical Trial 
Summary- Statistical 
considerations 
The PK-PD relationships will may be explored graphically and if a relationship is 
apparent, PK-PD modeling will may l be attempted and results reported, as 
appropriate. 
Clarification and 
correction 
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Section # and 
Name 
Description of Change 
Brief Rationale 
6.1 DESCRIPTION 
OF THE 
PROTOCOL 
Patients will be randomly and centrally assigned in a 1:1 ratio across sites using 
blocks of fixed size into 1of 2 arms, placebo, saline 0.9% sodium chloride solution, 
or 3.0 mg/kg olipudase alfa target dose. Dose-escalation during the PAP to the 
randomized target doses will occur according to the schedule provided in Section 
8.1.3 and Table 1. To maintain the double-blind, all patients will dose-escalate in 
the same manner. using the schedule provided (true dose escalation for patients 
who were in the placebo arm during the PAP and mock dose escalation for 
patients in the active arm during the PAP). 
Clarification and 
correction 
 
If a patient is discontinued due to inability to tolerate rechallenge (ie, a second 
dose of 0.3 mg/kg olipudase alfa), then an additional patient will may be 
randomized. 
 
Clarification  
 
For treatment periods during the PAP and the ETP, dose-limiting toxicity (DLT) 
criteria and study stopping rules will apply. 
Correction 
8.1.1. Treatments 
administered 
If a patient is discontinued due to inability to tolerate rechallenge (ie, a second 
dose of 0.3 mg/kg olipudase alfa), then an additional patient will may be 
randomized. 
Clarification  
 
For treatment periods during the PAP and the ETP, DLT criteria and study 
stopping rules will apply. 
Clarification and 
remove repetition 
8.1.3.3 Escalation 
schema 
The following criteria will determine the next dose of study drug to be 
administered, provided the patient does not experience an AE that meets the 
patient stopping criteria DLT (Section 8.1.4).  
Correction 
 
If a patient presents on the day of infusion either with an unresolved AE or an 
acute illness, neither of which meets the patient stopping DLT criteria (Section 
8.1.4), then study drug infusion may be withheld or administered at the discretion 
of the investigator.  
Correction  
8.3 Blinding Process 
Patients, investigators, and the sponsor will be blinded to the identity of placebo 
and olipudase alfa for all study drug infusions during the entire PAP and the first 
part of the ETP. 
Clarification 
8.3.1 Methods of 
blinding 
This study has a double-blind, placebo-controlled design. During both the PAP 
and the first part of the ETP, patients, investigators, and the sponsor will be 
blinded to the identity of study treatment. for all study infusions Also, patients and 
investigators will not have access to the randomization (treatment codes) except 
under circumstances described in Section 8.3.2, until after the database lock after 
the last patient in the for PAP and dose escalation in ETP has completed the 
52-week assessments and results have been analyzed (sponsor will be blinded 
until last patient in the database lock for PAP). To maintain the double-blind, all 
patients regardless of treatment assignment will undergo dose escalation (true or 
mock) in the same manner in both the PAP and ETP. 
Clarification that liver 
ultrasound with 
Doppler parameters 
will be used to 
detect the likelihood 
of portal 
hypertension and 
severe portal 
hypertension 
8.3.1 Methods of 
blinding 
The investigators and the sponsor will also be blinded to the PK data. Genzyme 
Clinical Supplies will remain unblinded throughout the study to provide the 
appropriate study drug to patients. A pharmacokineticist will receive reports of 
olipudase alfa plasma concentrations. 
Clarification and 
correction 
 
At the facilities where the PK measurements, ADA, and selected biomarkers are 
determined, the samples will be analyzed prior to data base lock leading to 
unblinding of responsible bioanalysts. Bioanalysts are excluded from the clinical 
trial team and a process will be set up to prevent any potential unblinding.  
Clarification and 
correction 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.1.4.10 Liver 
ultrasound with 
Doppler 
Some of the above mentioned parameters will be used to detect the likelihood of 
portal hypertension, and if detected whether it was severe, as described in the 
vendor’s manual. 
Liver ultrasound will be performed as described in the vendor’s manual. 
Clarification 
Table 2 
Apparent total Total body clearance of a drug from the plasma calculated using 
the 
Clarification 
 
Apparent volume Volume of distribution at steady state using the equation 
Clarification 
10.3.4 Handling of 
patients after 
permanent 
treatment 
discontinuation 
 
 
In addition, since the primary study comparison is based on intent to treat principle 
using all randomized patients with any study treatment, missing data, especially 
the key study assessments during the PAP (12 months) may potentially lead to 
biased results and challenges in assessing the treatment effect of the study drug. 
Therefore, all efforts should be made to continue to follow the patients for primary 
and key secondary endpoints, after the temporary or permanent discontinuation of 
treatment, in addition to the standard post study safety follow up. If possible, at the 
minimum, patients should be assessed at their regularly scheduled Week 52 visit 
(or as close as possible to week 52) if treatment discontinuation occurred prior to 
that visit. 
Clarification and 
correction 
11.4 ANALYSIS 
POPULATIONS 
Patients who are included in the safety population and have rescue therapy 
initiated are included in the rescue therapy population. Since in the ETP all 
subjects get olipudase alfa, the rescue therapy is relevant only for the PAP. 
 
11.5.2.1 Primary 
efficacy analysis 
For percent change in DLco (% predicted) from baseline, the mixed model for 
repeated measures (MMRM) will include baseline DLco (% predicted), baseline 
age, treatment arm, study visit (week 26, week 52), and study visit by treatment 
arm interaction as covariates; have an unstructured variance-covariance matrix; 
and be fit using restricted maximum likelihood estimation. Comparisons between 
treatment arms will be made using least-square mean contrasts at the 52 week 
visit.  
The analysis will include all DLco observations after baseline in the first 12 months 
of the study regardless of the treatment discontinuation status, with the exception 
that measurements made after the switch of treatment (eg, placebo patients 
switch to olipudase alfa after meeting the rescue criteria) will not be considered. 
For the primary analysis, missing data will not be imputed and will be assumed as 
Missing at Random (MAR).  
Similar analyses will be performed for the spleen volume (MN) and the 
splenomegaly-related symptom score (SRS), when baseline value of the spleen 
volume (or SRS) will be used as covariate.  
Descriptive assessment of MAR assumption and sensitivity analyses to assess the 
impact of missing data are described in the SAP. 
Clarification and 
correction 
11.5.2.2 Secondary 
efficacy analyses 
Handling of the missing data for secondary efficacy endpoints will be described in 
the SAP. 
Clarification 
11.5.5.1 Adverse 
events 
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 arm, and the number and percentage of patients 
experiencing an AE. 
The number of AEsTEAEs and annualized rate, and the number and proportion of 
patients reporting specific AEs will be tabulated for the overall analyses of AEs. 
Clarification and 
correction 
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Section # and 
Name 
Description of Change 
Brief Rationale 
11.5.6.1 
Pharmacokinetic 
analyses 
As data permit, the following PK parameters as specified in Section 9.3.2.4 will be 
calculated for each patient and each dose of olipudase alfa ≥0.3 mg/kg. 
 
11.5.6.2 
Pharmacodynamic 
analyses 
Exploratory correlation analyses will be attempted to evaluate relationships 
between different PD markers and between sphingomyelin and /or lyso-
sphingomyelin levels from different sources. 
 
11.5.6.3 
Pharmacokinetics - 
pharmacodynamics 
The PK-PD relationships may be explored graphically. If and if a relationship is 
apparent, PK-PD modeling may be attempted and results reported, as 
appropriate. If appropriate, the following parameters will also be assessed: Cmax 
and area under the effect-time curve. 
Clarification and 
correction 
 
Protocol Amendment 10 Version number: 1 (electronic 1.0) Date: 
26-Jan-2018 
This amendment is associated with Amended Clinical Trial Protocol 08. 
Reason for Amendment: 
1. 
Change in patient selection criteria to remove cirrhosis from Exclusion Criteria 
In section(s): Clinical Trial summary- Study Population- Main selection Criteria- (Exclusion 
criteria); 1.2.1.1 Schedule of assessments: year 1 - PAP screening to Week 16, Selection of 
Patients; 7.2 Exclusion Criteria 
Rationale: Cirrhosis was initially included as an exclusion criterion in olipudase alfa trials based 
on the spectrum of natural history of cirrhosis in ASMD patients.  
Liver biopsies were included in these trials to monitor the potential acceleration of inflammatory 
disease from fibrosis to cirrhosis upon exposure to olipudase alfa, since known biologically active 
intermediates, the direct catabolites of acid sphingomyelin are released upon treatment. This is 
also the key for the dose escalation process applied to all trials with olipudase alfa. However, 
unpublished data (on file) available from Year 3 biopsy of the long-term, open-label, treatment 
(extension study LTS13632, of phase 1b DFI13412 study) did not show evidence suggestive of 
a progressive worsening of fibrosis to cirrhosis in patients treated with olipudase alfa (see details 
in the table below).  
 
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Patient 
Phase 1b Base  
Q2 2013 
Phase 1b EOS  
Q4 2013 –Jan14 
LTS (Year 3) 
Q1-Q3 2017 
 
 
Changes are most consistent with stage 3 
fibrosis  
Specimen <1.5 cm minimum length in SOM 
recommended to minimize sampling error 
Changes are most consistent 
with stage 4 fibrosis (cirrhosis)     
Specimen <1.5 cm minimum 
length in SOM recommended to 
minimize sampling error 
Changes compatible with 
stage 4 fibrosis (cirrhosis)         
NOTE: specimen length this 
time compliant with SOM          
Q3 2017 
 
Changes are most consistent with stage 1 
fibrosis 
Liver pathology very similar to observed 
Phase I trial (
).   
Little to no interval change is appreciated 
Changes are most consistent 
with stage 1 fibrosis 
Changes are most 
consistent with stage 2 
fibrosis (Q2 17) 
 
No cirrhosis present.   
Liver pathology very similar to observed 
Phase I trial (
) 
Changes are most consistent 
with stage 1 fibrosis  
Current liver pathology very 
similar to baseline 
Changes are most 
consistent with stage 1 
fibrosis (Q2 17) 
 
Changes are most consistent with stage 2 
fibrosis  
Specimen <1.5 cm minimum length  
Liver pathology very similar to observed 
Phase I trial 
Changes are most consistent 
with stage 3 fibrosis 
Changes are most 
consistent with stage 3 
fibrosis (Q1 17) 
 
Changes are most consistent with stage 2 
fibrosis 
Liver pathology very similar to observed 
Phase I trial 
Changes are most consistent 
with stage 2 fibrosis 
Changes are most 
consistent with stage 3 
fibrosis (Q2 17) 
The DMC is regularly consulted and presented the updates results of the 5 adult patients in 
Trial LTS13632 and these results were presented in the listing. 
Therefore, Sanofi Genzyme does not plan to conduct a liver biopsy at Year 5 in the Trial 
LTS13632 as it corroborated with the recommendation of the Liver Ad Board in April 2015. 
Currently there is one patient treated in the extension study LTS13632 whose liver biopsy fibrosis 
stage is 4 (cirrhosis) with no reported issues. 
As such, Sanofi Genzyme is proposing to remove the cirrhosis exclusion criterion from 
study DFI12712. 
Removal of the cirrhosis exclusion criterion from this study will not impact the current schedule 
of safety assessments and liver biopsies will continue to be performed at baseline, Week 52, and 
Week 104 for documentation of entry status and disease progression.  
Additionally, liver function tests criteria at entry and DLTs and stopping rules will remain 
unchanged. Patients with cirrhosis will still need to be in a compensated state, and must have liver 
functions, platelets, coagulation tests and other safety parameters values within the protocol 
acceptable ranges in order to enroll into study DFI12712.  
While keeping all provisions in place to monitor patients’ safety, it is important to evaluate the 
benefit of olipudase alfa in the population of ASMD patients with grade 4 fibrosis (cirrhosis) as 
part of the disease natural history in absence of safety risk. 
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Patient with liver biopsy diagnosed cirrhosis have not shown to have increased risk of adverse 
events from liver biopsy procedures versus patients without cirrhosis (Seeff et al, Clin 
Gastroenterol Hepatol. Author manuscript; available in PMC 2013 September 12). Therefore, 
patients diagnosed with cirrhosis during screening liver biopsy will go through the subsequent 
protocol scheduled liver biopsy assessments at Week 52 and Week 104, unless there is other 
safety concern that can be discussed with the sponsor.  
DMC recommendation on this proposed change: 
This proposed change and rational was presented to DFI12712 DMC as it is presented in this 
document. 
DMC chairman and members unanimously approved removing of cirrhosis for exclusion criteria 
for the reasons mentioned above.  
2. 
Remove liver biopsy from assessments beyond Week 104 
In section(s): 1.2.2.3 Schedule of assessments: ETP - year 3 until end of study; 
9.3.1.1 Sphingomyelin in liver tissue 
Rationale: Liver biopsy assessment is scheduled at the main study time points; baseline, Week 52, 
and Week 104. Liver biopsy assessment in these time points is set to follow the changes at 
histopathological and histochemical levels comparing olipudase alfa and placebo in PAP and one 
year thereafter in ETP. Beyond Year 2 assessments, there would be no need for further biopsy 
assessments every year based on the recent long term study results (LTS13632).  
DMC recommendation on this proposed change: 
This proposed change and rationale was presented to DFI12712 DMC as it is presented in this 
document. 
DMC chairman and members unanimously approved removing of liver biopsy assessments 
beyond Week 104 of study participation for the rational mentioned above.  
3. 
Change the secondary endpoints hierarchical order 
In section(s): Clinical Trial summary- (Endpoints); 9.1.2 Efficacy Endpoints; 11.5.2.2 Secondary 
Efficacy Analysis; 11.5.4 Multiplicity Considerations 
Rationale: SRS is included as a co-primary endpoint for US. For the rest of the world, it is among 
the secondary endpoints. The hypothesis testing for the secondary efficacy endpoints will proceed 
in a hierarchical fashion using the closed testing principle, and will stop if there is a nonsignificant 
comparison.  
The study design was based on clinically important and meaningful change in most of the ASMD 
manifestations. While spleen size is standing as a primary endpoint as an important clinical 
assessment, liver size could follow as the next important organ change. Listed thereafter, are the 
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clinical assessment of changes in platelet count, fatigue, pain and dyspnea. Then at the end, SRS 
would be sought as an expression of impact in organ size change.  
It is not expected that SRS change would be significant, but only rather expected to show (as per 
protocol) a “trend” (p ≤0.15). While a significant change would be expected for liver size change, 
followed by the other clinical changes. These important significant changes should not be missed 
in case SRS is not significant. Therefore, hierarchy is accordingly rearranged. 
4. 
Clarify language of exclusion criteria 
In section(s): Clinical Trial summary- Study Population- Main selection Criteria- (Exclusion 
criteria); 7.2, Exclusion Criteria 
Rationale: correct previous omission of mentioning that cardiac valve dysfunction should be 
clinically significant to have the patient excluded.  
In addition, other minor changes are listed in the description of changes (next section). 
 
 
Protocol Amendment 09 Version number: 1 (electronic 1.0) Date: 
24-Aug-2017 
This amendment is associated with Amended Clinical Trial Protocol 07. 
Reason for Amendment: 
1. Change in 7.2 Exclusion Criteria to include patients with non-melanoma skin cancer and 
simplify language  
In section(s): Clinical Trial summary; 7, Selection of Patients 
Rationale: The original intention was to exempt patients with superficial skin cancer from 
exclusion due to malignancy diagnose in the past 5 years. This change is to correct having this 
exemption only limited to basal cell carcinoma and to include all types of non-melanoma skin 
cancer. In addition, language of exclusion criterion due to other medical conditions was 
simplified. 
2. Add Lab Values that already are part of Adverse Events of Special Interest (AESIs) to 
the relevant sections and table 
In section(s): 10.4.1.3 Adverse event of special interest; 10.4.2, General guidelines for reporting 
adverse events; Table 3, Summary of adverse event reporting instructions 
Rationale: correct previous omission to include these lab values in corresponding sections 
describing AESIs. 
3. Correct discrepancy of PK Collection 
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In section(s): 9.3.2.1, Pharmacokinetic sampling time 
Rationale: correct previous omission as the sampling time was changed in the previous 
amendment to be ±3 hours for those samples taken ≥ 8 hours after infusion ends in the PK 
samples table, however this was omitted from change in the corresponding PK section and stayed 
as ±1 hour for those samples taken ≥ 8 hours after infusion ends. 
4. Replace all instances of “after infusion” text with “after the end of infusion” where 
applicable.  
In section(s): Clinical Trial summary; 1.2, Schedules of Assessments in multiple footnotes of 
multiple assessment flow chart tables; 9.3.2.1, Pharmacokinetic sampling time; 10.1, Visit 
Schedule 
Rationale: Clarify that “after infusion” is intended to mean “after the end of infusion.”  
5. Delete an instructional text from an appendix.   
In section(s): Appendix A, Guidance on contraceptive methods and collection of pregnancy 
information  
Rationale: Correct previous omission 
In addition, other minor changes are listed in the description of changes (next section). 
 
Protocol Amendment 08 Version number: 1 (electronic 2.0) Date:  
08-Feb-2017 
This amendment is associated with Amended Clinical Trial Protocol 06. 
1. Changes in objectives and endpoints 
In section(s): Synopsis; 5, Study objectives; 9, Study endpoints,11, Statistical considerations 
Rationale: Food and Drug Administration (FDA) request 
2. Addition of Patient Global Impression of Symptom Severity (PGIS) of ASMD and 
Patient Global Impression of Change (PGIC) 
In section(s): Synopsis; 1.2, Schedules of assessments; 9.1.3, Tertiary and exploratory efficacy 
endpoints; 9.1.4.13, Health-related quality of life questionnaires; 10.1, Visit schedule 
Rationale: FDA request 
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3. Changes in statistical analysis 
In section(s): Synopsis: 11, Statistical considerations 
Rationale: Based on discussions with FDA to include the splenomegaly-related score (SRS) in the 
combination spleen endpoint and to show the results as a “trend” when relevant. Therefore, the 
analysis was changed from truncated Hochberg to Hochberg. 
4. Clarification of time points at which vital signs should be taken 
In section(s): 1.2, Schedules of assessments 
Rationale: Correction of error in the previous version. 
5. Addition of rules on how to resume study drug administration in patients who have 
missed infusion 
In section(s): 8.1.3.2, Dosing delays or missed doses 
Rationale: Rules were omitted in the previous protocol version (but were provided in the 
Interactive [Voice or Web] Response System [IXRS] documents). 
6. Change in some of the dose limiting toxicity (DLT) conditions 
In section(s): 8.1.4, Dose-limiting toxicities; 10.4.4.1, Reporting of adverse events of special 
interest with immediate notification 
Rationale: The new rules take into account that patients may enter the study with abnormal liver 
function tests (LFTs) due to their ASMD. As a result, these patients could meet a DLT condition 
due to normal fluctuation in LFTs that would not otherwise be indicative of DLT. The new rules 
have been approved by the Data Monitoring Committee. 
7. Change in assessments to be done before rescue treatment is applied 
In section(s): 8.1.6, Rescue treatment 
Rationale: Correction of error in the previous version. 
8. Addition of recommendation on usage of cationic amphiphilic antihistamines in rules on 
concomitant medications 
In section(s): 8.8, Concomitant medication 
Rationale: These medications are commonly used. 
9. Addition of tobacco use monitoring 
In section(s): 1.2, Schedules of assessments 
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Rationale: To assess the possible effect on ASMD-related lung disease 
 
 
Protocol Amendment 07 Version number: 02 (electronic 2.0) Date: 
01-Feb-2016 
This amendment is associated with Amended Clinical Trial Protocol 05. 
Reasons for the Amendment: 
1. Remove 1.0 mg arm from the primary analysis period (PAP) 
In section(s): Clinical trial summary (Study design, Statistical considerations), 6.1, 8.1.3.3, 8.4, 
11.2, 11.5.4 
Rationale: The planned number of patients randomized to the 3mg/kg olipudase alfa and placebo 
arms was increased from 14 per arm to 18 per arm. To accommodate this increase while not 
substantially enlarging the planned sample size, the 1mg/kg olipudase alfa arm was removed from 
the study design. The rationale for this change is to increase the likelihood that a clear 
demonstration of efficacy or lack of efficacy is achieved with respect to the primary and 
secondary efficacy endpoints and to avoid ambiguous results related to underpowered endpoints. 
The assumptions used to determine the sample size for the spleen volume endpoint were informed 
by the results from several clinical trials conducted in patients with lysosomal storage disorders 
(ie, Gaucher disease). This is in contrast to the assumptions used to determine the power of the 
other primary endpoint, DLco, and important secondary efficacy endpoints such as splenomegaly-
related symptoms where minimal information was available. In situations where insufficient 
information exists for robust sample size determination, an increase in sample size is warranted.  
While efficacy and safety information from the 1 mg/kg olipudase alfa arm is of interest, it does 
not outweigh the importance of enabling the study to achieve the primary efficacy objective 
should olipudase alfa be as effective as the results from the Phase 1b study suggest. In addition, 
the increase in the number of patients treated with 3 mg/kg olipudase alfa in the primary analysis 
period and in the extension study will improve the understanding of the safety profile of the dose 
that is intended for use assuming regulatory approval. 
2. Remove 1.0 mg arm from the extended treatment period (ETP) 
In section(s): Clinical trial summary (Study design, Statistical considerations), 6.1, 8.1.3.3, 8.4, 
11.2, 11.5.4 
Rationale: To maintain consistency with the PAP 
3. Remove “dose comparison.”  
In section(s): Title page, Clinical trial summary (Title, Study design) 
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Rationale: The 1.0 mg arm is no longer part of the study and hence the study is no longer designed 
to compare doses. 
4. Remove “of different doses.”  
In section(s): Clinical trial summary (Study objectives, Primary objective), 5.1 
Rationale: The 1.0 mg arm is no longer part of the study 
5. Change randomization ratio from 2:1:2 to 1:1 during the PAP. 
In section(s): Clinical trial summary (Statistical considerations [sample size determination]), 6.1, 
8.4, 11.2 
Rationale: Removing the 1 mg/kg arm in the PAP resulted in a necessary change in the 
randomization to 1:1. During the 4 year ETP, all patients will receive olipudase alfa. 
6. Add inclusion criterion for mean splenomegaly-related symptoms score  
In section(s): Clinical trial summary (Study population [Inclusion criteria]), 7.1 
Rationale: To increase the statistical power of the evaluation of the secondary endpoint, “Change 
in splenomegaly-related symptom score from baseline to week 52”. 
7. Add contraception requirements following the last olipudase alfa infusion. 
In section(s): Clinical trial summary (Study population, Main selection criteria, Inclusion criteria), 
7.1, 10.3 
Rationale: Conventionally, true abstinence or contraception is required during the treatment 
period and following the last administration for at least 5 multiples of the investigational product’s 
half-life. Based upon the 24-hour half-life of olipudase alfa, the minimum duration for requiring 
contraception use is 5 days following the last infusion. To be conservative, the period of time that 
each patient will be required to either practice true abstinence or use 2 acceptable, effective 
methods of contraception was expanded to include 15 days after the patient’s last olipudase alfa 
infusion. 
8. Clarify that the longest study duration per patient will be for at least 3 years and up to 
5 years and 3 months dependent upon continued regulatory approval of the protocol. 
In section(s): Clinical trial summary (Duration of study period [per patient]), 6.2.1 
Rationale: Previous text can be interpreted as allowing patients to be in the study for only 3 years, 
so clarification was added. 
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9. Changed interim analysis wording from “interim analysis may be conducted” to “no 
interim analysis is planned.” 
In section(s): Clinical trial summary (Statistical considerations, Interim analysis), 6.3 
Rationale: An interim analysis was initially planned for when 20 patients completed the primary 
analysis period. The purpose of such an interim analysis was to potentially accelerate regulatory 
approval of olipudase alfa. Given the numerous operational and statistical challenges associated 
with such a strategy, and given the need for a robust benefit risk determination, it was decided that 
an interim analysis strategy was not justified. 
10. Clarify patient stopping criteria 
In section(s): 8.1.5 
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 
an any AE that raises significant concern regarding the safety of olipudase alfa, as described in 
Section 8.1.4 of the protocol.  
 
Protocol Amendment 06 - DE Version number: 01 (electronic 1.0) Date: 
28-Sep-2015 
This amendment applies to Germany and is related to Amended Clinical Trial Protocol 05-DE. 
 
Reasons for the Amendment: 
The change to the procedures reflects the removal of the conventional chest X-ray performed 
simultaneously with the Pulmonary HRCT Scan as requested by the Radiation Board of Germany 
(BfS). 
 
Protocol Amendment 05 - GB Version number: 1 (electronic 1.0) Date: 
22-Jul-2015 
This amendment applies to the United Kingdom and is related to Amended Clinical Trial Protocol 
05-GB. 
Reason for the Amendment: 
• Clarification to the length of the trial 
In section(s): Summary [Study Design section], Sections 6.1 and 6.2.1 of the protocol 
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Rationale: According to Medicines & Healthcare products Regulatory Agency (MHRA), patients 
may only be included for 3 years so clarification was added to the protocol 
• Patient stopping criteria updated to include timing of reporting to regulatory authority 
In section(s): Section 8.1.5 
Rationale: According to Medicines & Healthcare products Regulatory Agency (MHRA), timing 
of reporting needed to be clarified. 
• Addition of contraception requirements following the last olipudase alfa infusion 
In section(s): Synopsis, Section 7.1 Inclusion criteria, and Section 10.3 of the protocol 
Rationale: Conventionally, true abstinence or contraception is required during the treatment 
period and following the last administration for at least 5 multiples of the investigational product’s 
half-life. Based upon the 24 hour half-life of olipudase alfa, the minimum duration for requiring 
contraception use is 5 days following the last infusion. To be conservative, the period of time that 
each patient will be required to either practice true abstinence or use 2 acceptable, effective 
methods of contraception was expanded to include 15 days after the patient’s last olipudase alfa 
infusion.  
Actual changes to text are shown in the description of changes. 
Protocol Amendment 04 Version number: 1 (electronic 1.0) Date: 
31-Mar-2015 
This amendment is associated with Amended Clinical Trial Protocol 04. 
Reason for Amendment: 
• Addition of a splenomegaly-related symptom efficacy endpoint 
In section(s): Clinical trial summary, study flow charts, Section 5.2, Section 9.1.2, Section 9.6 
Rationale: Per the FDA’s guidance, for reduction in spleen volume to be considered clinically 
meaningful and considered a primary endpoint, it would need to be combined with improvements 
in splenomegaly-related symptoms (eg, abdominal pain, early satiety, etc) in the subset of patients 
with these symptoms 
• Change in the tools used to collect information for the composite secondary efficacy 
endpoint and include use of an eDiary 
In section(s): Clinical trial summary, study flow charts, Section 4, Section 5.2, Section 9.1.2, 
Section 9.1.4 
Rationale: According to the FDA, for reduction in spleen volume to be considered clinically 
meaningful and considered a primary endpoint, it would need to be combined with improvements 
in splenomegaly-related symptoms (eg, abdominal pain, early satiety, etc) in the subset of patients 
with these symptoms; The FDA also considers the CRQ-SAS to be too broad and suggests using 
the FACIT-dyspnea short form. Per the FDA’s guidance, select questions from the myelofibrosis 
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symptom assessment form, the FACIT-dyspnea Short form, and additional questions on 
abdominal body image and ability to bend down will be asked in an eDiary. 
- 
In the composite endpoint, replace the dyspnea questions from CRQ-SAS with the FACIT-
dyspnea Short form 
- 
In the composite endpoint, replace the Niemann-Pick Health Assessment questionnaire 
with splenomegaly-related symptoms from a modified myelofibrosis symptom assessment 
form 
- 
Include only items 3 of the Brief Pain Inventory – Short form and the Brief Fatigue 
Inventory in the composite endpoints 
• Clarify that abdominal MRIs and pulmonary imaging by HRCT will be evaluated by 
readers blinded to patient, treatment arm, and timepoint. 
In section(s): Section 9.1.4 Assessment of efficacy endpoints 
Rationale: Ensure efficacy endpoint assessment will be nonbiased 
• Demote to tertiary the secondary efficacy endpoint percentage change in liver function 
tests ALT and total bilirubin 
In section(s): Clinical trial summary, Section 5.2, Section 9.1.2, Section 9.1.3 
Rationale: To restrict the number of secondary efficacy endpoints 
• Remove requirement that inpatient hospitalization is necessary during quarterly visits of 
years 3 through 5 
In section(s): Clinical trial summary, study flow charts, Section 6.1, Section 8.1.1, Section 10.1 
Rationale: Reduce patient burden 
• Added a provision for future use of samples 
In section(s): Section 9.5 
Rationale: To allow for other research analyses to be used on left over samples from consenting 
patients. 
• Correct reporting requirements for pregnancy 
In section(s): Section 10.4.2 
Rationale: To instruct clinical sites to complete the AE form and safety complementary form as 
well as other specific forms in the event of pregnancy. 
• Clarify the “Not applicable” taken regarding action to study drug for an adverse event 
In section(s): Section 10.4.1.4 
Rationale: Sites were misusing the “not applicable” field of the eCRF when reporting action taken 
regarding the study drug. 
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• Change from the Wilcoxon Mann Whitney test to the ANCOVA method for primary 
and secondary efficacy endpoint analyses 
In section(s): Section 11.5.2 and clinical trial summary 
Rationale: Based on feedback from FDA and the CHMP advice letter, the protocol has been 
modified so that the mITT population includes patients who were randomized and treated. 
 
Protocol Amendment 03 Version number: 1 (electronic 1.0) Date: 
28-Jan-2015 
This amendment is associated with Amended Clinical Trial Protocol 03. 
Reason for Amendment: 
• New EudraCT number 
In section(s): Cover page 
Rationale: Upon feedback from countries that use the EudraCT system, a new CTA based on 
protocol amendment 3 is being submitted with a new EudraCT number. 
 
 
Protocol Amendment 2 Version number: 1 (electronic 1.0) Date: 
05-Dec-2014 
This amendment is related to Amended Clinical Trial Protocol 02. 
Reason for Amendment: 
• Change in rhASM nomenclature 
In section(s): All sections 
Rationale: The WHO recommends the INN name olipudase alfa for recombinant human acid 
sphingomyelinase deficiency. 
• The primary endpoint was modified to include change from baseline to week 52 in 
infiltrative lung disease as measured by the diffusing capacity of carbon monoxide 
(DLCO) 
In section(s): Clinical trial summary, Section 4, Section 5.1, Section 9.1.1, Section 9.6, 
Section 11.2, Section 11.5.2.1 
Rationale: The clinically relevant pulmonary function test, DLCO, was added to the 
pharmacodynamic marker change in spleen volume. The primary analyses of the 2 primary 
endpoints were adjusted accordingly. 
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- 
Inclusion criterion #04 has been adjusted to allow patients with more severe infiltrative 
lung disease to be enrolled in the study. 
- 
Added Exclusion criteria #12 and #13 around ventilatory support to ensure patients can 
participate in the DLCO assessment 
• Removal of the key secondary endpoint and reorganize the secondary endpoints 
In section(s): Clinical trial summary, Section 5.2, Section 9.1.2, Section 9.6, Section 11.5.2.2 
Rationale: With the promotion of change in DLCO to primary endpoint, the secondary endpoints, 
including the key secondary endpoint, were reorganized. The analyses of secondary endpoints 
were adjusted accordingly. 
• Added a PK sampling timepoint 
In section(s): Section 1.2.3 
Rationale: A PK sampling at 168 hours postinfusion has been added to more fully characterize 
AUC. 
• Increase the number of enrolled patients from approximately 24 to approximately 35 
In section(s): Clinical trial summary, Section 1.1.1, Section 6.1, Section 8.4, Section 11.2 
Rationale: The sample size was increased to provide the power necessary to see a treatment effect 
for the DLCO primary endpoint 
- 
Remove the 0.3 mg/kg treatment arm. 
- 
Randomization ratio in the PAP changed from 1:1:1:1 (placebo, 0.3, 1.0, 3.0 mg/kg 
olipudase alfa) to 2:1:2 (placebo, 1.0 mg/kg, 3.0 mg/kg olipudase alfa) 
- 
Remove patient stratification by baseline spleen volume 
• Remove requirement to stratify patients based on baseline spleen volume 
In section(s): Clinical trial summary, Section 6.1, Section 6.3, Section 8.4, Section 11.5.2.1, 
Section 11.5.2.2 
Rationale: Simplify statistical calculations. 
• Patients assigned to the placebo arm in the PAP will be rerandomized 1:1 in the ETP to 
1.0 mg/kg or 3.0 mg/kg olipudase alfa. 
In section(s): Clinical trial summary, Section 1.1.2, Section 6.1 
Rationale: To more fully characterize the safety and efficacy of the 1.0 mg/kg olipudase alfa dose. 
- 
Remove the olipudase alfa target dose selection in the ETP 
• Add an interim analysis of the primary endpoint after approximately 20 patients 
complete 52 weeks of treatment with study drug 
In section(s): Clinical trial summary, Section 6.3 
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Protocol Version number: 1 (electronic 1.0) Date: 05-Sep-2014 
This amendment is related to Amended Clinical Trial Protocol 01. 
• Modification of study title 
In section(s): Title page; Synopsis; page headers. 
Rationale: The protocol title has been changed to reflect the new study design and objectives. 
• Modification of study organization 
In section(s): All sections 
Rationale:  
- 
The 1 treatment period of 52 weeks in the original protocol has been increased to 
2 treatment periods in the amended protocol: a primary analysis period (PAP) of 52 weeks, 
which will be followed by an extended treatment period (ETP) lasting for total study 
duration of up to 5 years. 
- 
The dose escalation scheme has been updated to include a second 0.6 mg/kg dose to 
mitigate possible toxicity from sphingomyelin degradation that occurs too quickly. In the 
phase 1b study, DFI13412, infusion-associated reactions were more frequent when starting 
this dose and required dose-repetition or dose-reduction at next scheduled study infusions 
of higher doses. Accordingly, patients randomized to the 3.0 mg/kg treatment arm will not 
be fully dose escalated until study week 16. Consequently, study procedures scheduled for 
the week 12 quarterly visit have been shifted to week 14. 
- 
In the original protocol, patients were to be randomized to a target dose 0.3, 1.0, or 
3.0 mg/kg rhASM after the second 0.3 mg/kg infusion. In the amended protocol, patients 
will be randomized before the patient’s first infusion with study drug. 
• Modification of study design 
In section(s): All sections 
Rationale: All sections have been updated to the new study design.  
- 
The original protocol was open-label. The amended protocol is double-blinded during the 
entire primary analysis period and initially during the extended treatment period. 
- 
The original protocol did not include a placebo arm and was to enroll at least 15 patients 
1:1:1 into 1 of 3 treatment arms: 0.3, 1.0, or 3.0 mg/kg rhASM. The number of patients in 
the amended protocol has increased to approximately 24 patients who will be equally 
randomized to placebo, 0.3, 1.0, or 3.0 mg/kg rhASM. 
- 
The original protocol did not have a crossover feature. In the amended protocol, patients 
randomized to the placebo arm during the PAP will crossover to the 3.0 mg/kg treatment 
arm during the ETP. 
- 
Patients will be stratified based on baseline spleen volume into 1 of 2 groups before 
randomization in the amended protocol. 
- 
Rescue criteria have been included for patients who experience clinical decline. 
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• Modification of study objectives 
In section(s): tabulated clinical trial summary, Section 5 of the protocol 
Rationale: The primary objective has been changed to an efficacy objective. A key secondary 
objective has been added. 
• Changes to the assessments 
In section(s): Section 1.2, Section 5, Section 9 
Rationale: Because no serious adverse events or adverse events with severe intensity were 
observed in a prior clinical trial (DFI13412), the intensive monitoring for safety has been reduced. 
Other assessments have been added and those not relevant to characterizing the effect of study 
drug treatment based on past experience have been eliminated: 
- 
The time spent hospitalized during quarterly visits as an in-patient was reduced from 48- to 
24 hours after study drug infusion. 
- 
24-hour Holter monitoring and heart rate monitoring by telemetry have been eliminated. 
- 
Electrocardiograms were reduced from triplet to singlet measurements 4, 12, and 24 hours 
after study drug infusion during quarterly visits.  
- 
CRIM testing and X-rays of lumbar spine have been deleted. 
- 
The following health-related quality of life questionnaires have been added: Chronic 
Respiratory Questionnaire - Self Administered - Standard Activities, Health-related 
productivity questionnaire, Short Form-36 Health Survey, Brief Fatigue Inventory, and 
Brief Pain Inventory - Short Form. 
- 
Cycle ergometry has been changed to treadmill ergometry to accommodate sites that do not 
have a cycle ergometer. 
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SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
A Phase 2/3, multicenter, randomized, double-blinded, placebo-controlled, 
repeat-dose study to evaluate the efficacy, safety, pharmacodynamics, and 
pharmacokinetics of olipudase alfa in patients with acid sphingomyelinase 
deficiency 
GZ402665-DFI12712 
STATISTICIAN: 
 
DATE OF ISSUE: 4-Nov-2019 
Total number of pages: 
76 
NCT02004691


Statistical Analysis Plan  
4-Nov-2019 
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Version number: 3 
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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 ................................................................................ 8 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 8 
1.2 
OBJECTIVES ................................................................................................................................... 8 
1.2.1 
Primary objectives ............................................................................................................................ 8 
1.2.2 
Secondary objectives ....................................................................................................................... 9 
1.2.3 
Additional objectives ........................................................................................................................ 9 
1.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 10 
1.4 
STUDY PLAN ................................................................................................................................. 11 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................ 12 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 13 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 14 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 14 
2.1.1 
Demographic and baseline characteristics .................................................................................... 14 
2.1.2 
Prior or concomitant medications ................................................................................................... 15 
2.1.3 
Smoking and alcohol drinking ........................................................................................................ 16 
2.1.4 
Efficacy endpoints .......................................................................................................................... 16 
2.1.4.1 
Primary efficacy endpoint(s) .......................................................................................................... 16 
2.1.4.2 
Secondary efficacy endpoint(s) ...................................................................................................... 18 
2.1.4.3 
Additional efficacy endpoints ......................................................................................................... 21 
2.1.5 
Safety endpoints ............................................................................................................................ 25 
2.1.5.1 
Adverse events variables ............................................................................................................... 26 
2.1.5.2 
Deaths ............................................................................................................................................ 27 
2.1.5.3 
Laboratory safety variables ............................................................................................................ 27 
2.1.5.4 
Vital signs variables ....................................................................................................................... 29 
2.1.5.5 
Electrocardiogram variables .......................................................................................................... 29 
2.1.5.6 
Other safety endpoints ................................................................................................................... 29 
2.1.6 
Pharmacokinetic variables ............................................................................................................. 31 


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2.1.7 
Pharmacodynamic/genomics endpoints ........................................................................................ 31 
2.1.8 
Quality-of-life endpoints (patient-reported outcome) ..................................................................... 32 
2.1.9 
Health economic endpoints ............................................................................................................ 33 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 34 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 35 
2.2.2 
Protocol deviations ......................................................................................................................... 36 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 36 
2.3.1 
Efficacy populations ....................................................................................................................... 36 
2.3.1.1 
Modified intent-to-treat population ................................................................................................. 36 
2.3.1.2 
Per-protocol population .................................................................................................................. 37 
2.3.1.3 
Other efficacy population ............................................................................................................... 37 
2.3.2 
Safety population ........................................................................................................................... 37 
2.3.3 
Other analysis populations ............................................................................................................. 37 
2.4 
STATISTICAL METHODS ............................................................................................................. 37 
2.4.1 
Demographics and baseline characteristics .................................................................................. 38 
2.4.2 
Prior or concomitant medications ................................................................................................... 38 
2.4.3 
Smoking and alcohol drinking ........................................................................................................ 38 
2.4.4 
Extent of investigational medicinal product exposure and compliance ......................................... 39 
2.4.4.1 
Extent of investigational medicinal product exposure .................................................................... 39 
2.4.4.2 
Compliance .................................................................................................................................... 40 
2.4.5 
Analyses of efficacy endpoints ....................................................................................................... 41 
2.4.5.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 41 
2.4.5.2 
Analyses of secondary efficacy endpoints ..................................................................................... 44 
2.4.5.3 
Multiplicity issues ........................................................................................................................... 45 
2.4.5.4 
Subgroup analyses for the primary endpoints in PAP ................................................................... 46 
2.4.5.5 
Responder analyses for the primary endpoints in PAP ................................................................. 47 
2.4.5.6 
Compliance of eDiary data during PAP ......................................................................................... 48 
2.4.5.7 
Additional efficacy analyses in PAP ............................................................................................... 48 
2.4.5.8 
PAP+ETP efficacy analyses .......................................................................................................... 51 
2.4.6 
Analyses of safety data .................................................................................................................. 52 
2.4.6.1 
Adverse events .............................................................................................................................. 52 
2.4.6.2 
Laboratory data .............................................................................................................................. 56 
2.4.6.3 
Vital signs ....................................................................................................................................... 57 
2.4.6.4 
Electrocardiogram variables .......................................................................................................... 57 
2.4.6.5 
Echocardiogram with Doppler ........................................................................................................ 57 
2.4.6.6 
Physical examinations.................................................................................................................... 57 
2.4.6.7 
Extended neurological examinations ............................................................................................. 57 
2.4.6.8 
Liver biopsy .................................................................................................................................... 58 
2.4.6.9 
Liver function via echo-Doppler ultrasound ................................................................................... 58 
2.4.6.10 Inflammatory and vascular biomarkers .......................................................................................... 58 
2.4.6.11 Safety biomarkers .......................................................................................................................... 58 


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2.4.6.12 Immune response assessments .................................................................................................... 58 
2.4.6.13 Subgroup analyses for key safety measures in PAP ..................................................................... 60 
2.4.6.14 PAP+ETP safety analyses ............................................................................................................. 61 
2.4.7 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 61 
2.4.7.1 
Pharmacodynamic analysis ........................................................................................................... 61 
2.4.7.2 
Pharmacokinetic analysis .............................................................................................................. 62 
2.4.8 
Analyses of quality of life (patient reported outcome)/health economics variables ....................... 62 
2.4.8.1 
PAP+ETP quality of life analyses .................................................................................................. 64 
2.5 
PATIENT NARRATIVES ................................................................................................................ 64 
2.6 
DATA HANDLING CONVENTIONS .............................................................................................. 65 
2.6.1 
General conventions ...................................................................................................................... 65 
2.6.2 
Missing data ................................................................................................................................... 65 
2.6.3 
Windows for time points ................................................................................................................. 66 
2.6.4 
Unscheduled visits ......................................................................................................................... 66 
2.6.5 
Pooling of centers for statistical analyses ...................................................................................... 67 
2.6.6 
Statistical technical issues ............................................................................................................. 67 
3 
INTERIM ANALYSIS ..................................................................................................................... 69 
4 
DATABASE LOCK ........................................................................................................................ 70 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 71 
6 
REFERENCES ............................................................................................................................... 72 
7 
LIST OF APPENDICES ................................................................................................................. 74 
7.1 
FACIT-DYSPNEA SHORT FORM - CONVERSION FROM RAW TO SCALE SCORES ............. 74 
7.2 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ................................. 75 


Statistical Analysis Plan  
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACE: 
angiotensin-converting enzyme 
ADA: 
anti-drug antibody 
AE: 
adverse event 
ALT: 
alanine aminotransferase 
AP: 
alkaline phosphatase 
APR: 
acute phase reactions 
ASMD: 
acid sphingomyelinase deficiency 
AST: 
aspartate aminotransferase 
ATC: 
anatomic category 
AUC0-last: 
area under the curve extrapolate from time 0 to the time corresponding to the 
last quantifiable concentration 
AUC0-τ: 
area under the plasma concentration curve during a dosing interval τ 
BMB: 
bone marrow burden 
BMD: 
bone marrow density 
BMI: 
body mass index 
BQL: 
below the quantification limit 
CL: 
clearance 
Cmax: 
maximum plasma concentration observed 
CRS: 
cytokine release syndrome 
CSR: 
clinical study report 
CV: 
coefficient of variation 
DBP: 
diastolic blood pressure  
DBS: 
dry blood spot 
DLco: 
diffusing capacity of lungs for carbon monoxide 
DLT: 
dose-limiting toxicity 
DUP24: 
Duplication 24 
DXA: 
dual-energy X-ray absorption 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EQ-5D: 
EuroQol –5 dimensions quality of life questionnaire 
ETP: 
extension treatment period 
FACIT: 
Functional Assessment of Chronic Illness Therapy 
FEV1: 
forced expiratory volume in the first 1 second 
FVC: 
forced vital capacity 
GGT: 
gamma glutamyl-transferase 
Hb: 
hemoglobin 
HDL: 
high-density lipoprotein 
HLGT: 
high-level group term 
HLT: 
high-level term 
HR: 
heart rate 
HRCT: 
high-resolution computed tomography 


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IAR: 
infusion associated reactions 
ICF: 
informed consent form 
ILD: 
infiltrative lung disease 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
ISS: 
integrated summary of safety 
IXRS: 
interactive voice/web response system 
LDL: 
low-density lipoprotein 
LFT: 
liver function test 
LLOQ: 
lower limit of quantification 
LLT: 
lower-level term 
MAR: 
missing-at-random 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
modified intent to treat 
MMRM: 
mixed model for repeated measures 
MN: 
multiples of normal 
MRI: 
magnetic resonance imaging 
NMR: 
nuclear magnetic resonance 
NPB-HAQ: 
Niemann-Pick B Health Assessment Questionnaire 
PAP: 
primary analysis period 
PCSA: 
potentially clinically significant abnormality 
PFT: 
pulmonary function test 
PGIC: 
Patient Global Impression of Change 
PGIS: 
Patient Global Impression of Symptom Severity 
PKDM: 
pharmacokinetics, dynamics and metabolism 
PRO: 
Patient reported outcome 
PT: 
preferred term 
ROW: 
rest of world 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure  
SD: 
standard deviation 
SEM: 
standard error of the mean 
SF-36: 
Short Form-36 Health Survey 
SMQs: 
standard MeDRA queries 
SOC: 
system organ class 
SRS: 
splenomegaly-related score 
TEAE: 
treatment-emergent adverse event 
TLC: 
total lung capacity 
ULN: 
upper limit of normal 
US: 
United States 
VLDL: 
very low-density lipoprotein 
Vss: 
volume of distribution at steady state 
WBC: 
white blood cells 
WHO-DD: 
World Health Organization-Drug Dictionary 
WMW: 
Wilcoxon-Mann-Whitney 


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WT: 
Wildtype 
β-HCG: 
β-human chorionic gonadotropin 
 


Statistical Analysis Plan  
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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
This statistical analysis plan (SAP) focuses on descriptions of strategy and statistical methodology 
for the analysis of clinical data from DFI12712 trial. It has been developed based on DFI12712 
Amended Clinical Trial Protocol 11 dated 05 August 2019. This version replaces the previous 
versions of the SAP.  
A clinical study report (CSR) will be prepared when the 52-week primary analysis period (PAP) 
data become available. At study completion, ie, at the end of the extension treatment period 
(ETP), a CSR for the entire study including ETP will be prepared.  
1.1 
STUDY DESIGN AND RANDOMIZATION 
This Phase 2/3, multicenter, repeat-dose, clinical trial will be divided into 2 consecutive major 
periods: 1) a randomized placebo-controlled, double-blind PAP from Day -60 to Week 52 to be 
followed by 2) an ETP. Initially, the ETP will be double-blind as patients in the placebo arm cross 
over to active treatment. Study drug will be defined during the PAP as olipudase alfa or placebo, 
and during the ETP as olipudase alfa, and will be administered intravenously once every 2 weeks 
for 52 weeks in PAP, then for ETP. Day -60 to -1 is part of screening period with no study drug; 
some of the screening assessments which are not repeated right before the first infusion of study 
drug on Day 1 serve as baseline value for the study. 
After completing the PAP, patients will enter the ETP of the study. Those who were randomized 
to the active arm will continue receiving the dose they were receiving at the completion of the 
PAP. Patients randomized to the placebo arm in the PAP will cross over to active treatment in the 
first infusion in ETP and will undergo dose escalation to a target dose of 3.0 mg/kg olipudase alfa. 
For treatment periods during the PAP and the ETP, dose-limiting toxicity (DLT) criteria 
(protocol Section 8.1.4) and study stopping rules (protocol Section 8.1.5) will apply. If a patient 
satisfies protocol-specified criteria of rescue therapy (protocol Section 8.1.6), the individual 
treatment blind will be broken and the patient if on placebo will be switched to olipudase alfa; for 
patients already on olipudase alfa, the treatment will continue unless the patient drops out of study. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this Phase 2/3 study is to evaluate the efficacy of olipudase alfa 
(recombinant human acid sphingomyelinase) administered intravenously once every 2 weeks for 
52 weeks in adult patients with acid sphingomyelinase deficiency (ASMD)  by assessing changes 
in: 1) spleen volume as measured by abdominal magnetic resonance imaging (MRI) (and for the 
United States [US] only, in association with patient perception related to spleen volume as 
measured by splenomegaly-related score [SRS]); and, 2) infiltrative lung disease as measured by 
the pulmonary function test DLco. 


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1.2.2 Secondary objectives 
 To confirm the safety of olipudase alfa administered intravenously once every 2 weeks for 
52 weeks 
 To characterize the effect of olipudase alfa on the patient perception related to spleen 
volume as measured by SRS after 52 weeks of study drug administration (For the United 
States, the effect of olipudase alfa on SRS is part of the primary objective) 
 To characterize the effect of olipudase alfa on the following endpoints assessed 
sequentially: 
1. The effect of olipudase alfa on liver volume after 52 weeks of study drug 
administration 
2. The effect of olipudase alfa on platelet count after 52 weeks of study drug 
administration 
3. The effect of olipudase alfa after 52 weeks of study drug administration on fatigue 
4. The effect of olipudase alfa after 52 weeks of study drug administration on pain 
5. The effect of olipudase alfa after 52 weeks of study drug administration on dyspnea 
1.2.3 Additional objectives 
 To characterize the effect of olipudase alfa on liver function tests (LFT) 
 To characterize the effect of olipudase alfa on infiltrative lung disease via pulmonary 
imaging 
 To characterize the effect of olipudase alfa on pulmonary functioning 
 To characterize the effect of olipudase alfa on the fasting lipid profile 
 To characterize the effect of olipudase alfa on bone disease 
 To characterize the effect of olipudase alfa on cardiopulmonary functioning 
 To characterize the effect of olipudase alfa on biomarkers 
 To characterize the effect of olipudase alfa on hematology parameters 
 To characterize the effect of olipudase alfa on selected health-related quality of life 
questionnaires and questions therein 
 To characterize the pharmacodynamic effect of olipudase alfa on clearing sphingomyelin 
accumulation in liver and/or blood 
 To characterize the multiple-dose plasma pharmacokinetic profile of olipudase alfa 
 To explore the effect of olipudase alfa on Physician's global assessment of change 
 To explore the effect of olipudase alfa on the nuclear magnetic resonance (NMR) profile 
of high-density lipoprotein (HDL) 
 To explore the effect of olipudase alfa on liver function via echo-Doppler ultrasound 
 To explore the effect of olipudase alfa on inflammatory and vascular biomarkers 


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1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size calculations are based on the 2 primary efficacy endpoints: 
1. Percentage change in DLco (expressed as % predicted of normal) from baseline to 
Week 52 
2. a) For Europe and the rest of the world (ROW) outside of USA: the percentage change in 
spleen volume (expressed in multiples of normal [MN] ) from baseline to Week 52 
b) For US: the combination spleen endpoint which consists of two components: the 
percentage change in spleen volume (expressed in MN) from baseline to Week 52 and 
change in splenomegaly-related score from baseline to Week 52.  
Although the multiplicity adjustments in statistical testing of hypotheses ensures the study to be 
positive if only one of the two primary endpoints is significant (Section 2.4.5.3), each endpoint 
has been powered adequately in order to choose the sample size for the study as 36 randomized 
patients in 1:1 ratio in placebo and olipudase alfa treatment arms. 
 
Endpoint 
Null hypothesis 
Assumptions 
Signif. 
level 
Sample 
Size N 
Power 
Trt Diff 
SD 
Non-evaluable 
DLco 
There is no difference between 
olipudase alfa group and placebo 
group in percentage change from 
baseline in percent predicted DLco 
from baseline to Week 52. 
25% 
20% 
11% 
0.05 
36 
0.93 
Spleen 
Volume 
There is no difference between 
olipudase alfa group and placebo 
group in percentage change from 
baseline in spleen volume in multiples 
of normal from baseline to Week 52. 
30% 
11.8% 
11% 
0.05 
36 
0.99 
SRS 
There is no difference between 
olipudase alfa group and placebo 
group in change from baseline in SRS 
from baseline to Week 52. 
8 
9.4 
11% 
0.15 
36 
0.82 
The following assumptions for the DLco endpoint are based on results obtained from the 
olipudase alfa Phase 1b study DFI13412: 
 A 20% common standard deviation 
 A 25% mean difference from baseline to Week 52 between olipudase alfa and placebo in 
percentage change in DLco (in % predicted) 
 An expected exclusion rate from the primary analysis due to non-availability of results at 
Week 52 is 11% 
Based on these assumptions, a comparison between the olipudase alfa arm and the placebo arm 
will have 93% power using a t-test at a 2-sided 5% significance level and with 36 patients 
randomized 1:1 to placebo and olipudase alfa. 


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The assumptions for the spleen volume endpoint are the following: 
 An 11.8% common standard deviation based on data from previous ASMD and Gaucher 
disease Type 1 studies 
 A 30% mean difference from baseline to Week 52 between olipudase alfa and placebo in 
percentage change in spleen volume (MN) 
 An expected exclusion rate from the primary analysis due to non-availability of results at 
Week 52 is 11% 
Based on the above assumptions, a comparison between olipudase alfa and placebo will have over 
99% power using a t-test at a 2-sided 5% significance level with 36 patients randomized 1:1 to 
placebo and olipudase alfa. At 2.5% significance level, the power will still be over 99%. 
The assumptions for the splenomegaly-related score endpoint came from the Sanofi-sponsored 
clinical trial in myelofibrosis (JAKARTA, NCT# 01437787). The assumptions for the power 
calculations are the following: 
 A common standard deviation of 9.4  
 A mean difference of 8.0 from baseline to Week 52 between olipudase alfa and placebo in 
the SRS score 
 An expected exclusion rate from the primary analysis due to non-availability of results at 
Week 52 is 11% 
Based on the above assumptions, a comparison between olipudase alfa and placebo will have 
82% power using a t-test to detect a statistical trend, defined as 2-sided p-value ≤0.15, with 
36 patients randomized 1:1 to placebo and olipudase alfa. 
Using the simplifying assumption that the 2 components of the combination spleen endpoint are 
independent, the likelihood that statistical significance will be declared for the combination spleen 
endpoint is greater than 80%. 
1.4 
STUDY PLAN 
This Phase 2/3, multicenter, repeat-dose, clinical trial will be divided into 2 consecutive major 
periods: 1) a randomized placebo-controlled, double-blind PAP from Day -60 to Week 52, to be 
followed by 2) ETP for up to 4 years. Initially, the ETP will be double-blind as patients in the 
placebo arm cross over to active treatment, and the last patient completes PAP and when this 
patient is going through dose escalation the study is unblinded for analysis of PAP; ETP after 
unblinding for PAP analysis is open-label where all patients receive olipudase alfa.  
The PAP will include a screening/baseline period and a treatment period. Approximately 
36 patients who meet the eligibility criteria will be randomized in a 1:1 ratio across sites into 1of 
2 arms, placebo or 3.0 mg/kg olipudase alfa target dose. Patients will undergo a dose-escalation 
period to achieve the target dose level.  


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After completing the PAP, patients will enter the ETP. Patients randomized to the placebo arm in 
the PAP will cross over to active treatment in the ETP and will undergo dose escalation to a target 
dose of 3.0 mg/kg olipudase alfa. The patients who were randomized to the active arm will 
continue receiving olipudase alfa at the dose they complete PAP (with a mock dose escalation 
period to maintain blinding).  
Study drug will be administered intravenously once every 2 weeks. In-patient hospitalization is 
required during dose escalation period and specific visits. Other infusions are administered at the 
clinic. 
All patients will have an end of study/early discontinuation visit within 2 weeks after the last 
infusion of study treatment. In addition, all patients will receive a follow-up phone call for safety 
approximately 30 to 37 days after the last infusion of study drug. 
A rescue strategy for patients who experience significant clinical decline (specific guidelines in 
the protocol, Section 8.1.6) will be in place: these individual patients may be unblinded and if 
receiving placebo, will be switched to olipudase alfa with proper dose escalation to a target dose 
of 3.0 mg/kg. These patients will continue to be followed to the end of study. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes discrepancies between the statistical analysis described in the amended 
DFI12712 protocol 11, dated 12 August 2019, and this SAP.  
 The following language about the summary of immune response assessments in the 
protocol Section 11.5.5.4 will not be provided by the dose level of the infusion before or 
during the evaluation, since the infusion information will be included in the data listing.  
The presence, absence, and titers of serum anti-olipudase alfa IgG antibodies and routine 
levels of acute phase reactants will be summarized over time overall and by the dose level 
of the infusion before or during the evaluation. 
 The following language about the exploratory pharmacodynamic analyses in the protocol 
Section 11.5.6.2 is not planned in this SAP but may be done ad hoc if deemed necessary. 
Exploratory correlation analyses will be attempted to evaluate relationships between 
different PD markers and between sphingomyelin and /or lysosphingomyelin levels from 
different sources.  
 Multiplex assay of inflammatory and vascular biomarkers are analyzed as both exploratory 
efficacy and safety endpoints in the protocol but will be treated only as safety endpoints in 
this SAP.  
 The ETP population mentioned in the protocol Section 11.4 was removed from the SAP, 
since data for PAP+ETP will be analyzed in a cumulative way. 
 The annualized rate of TEAEs and separate analyses of AEs by demographic 
characteristics (eg, age and sex) mentioned in the protocol Section 11.5.5.1 will be 
presented in the integrated summary of safety and will not be done in the study SAP. 


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 Protocol Section 11.5.6.3 for pharmacokinetic-pharmacodynamic analyses will not be 
done at the study level, but may be conducted using pooled data from different clinical 
studies and the results may be included in a separate report. 
 For the summary of exposure, the protocol mentioned using the safety population. 
However, the population was changed to mITT population in the SAP in order to 
accurately summarize the duration of exposure prior to rescue therapy for patients who 
were randomized to placebo at the beginning. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
An updated full statistical analysis plan dated 29 August 2019 was submitted to FDA for their 
review and agreement. This document builds on that analysis plan. The main modifications made 
in this statistical analysis plan are listed as follows.  
 A subset of protocol-defined IARs was further defined programmatically by searching for 
preferred terms within Hypersensitivity reaction SMQs in Section 2.4.6.1.2. 
 The responder analyses for BFI scale - Item 3, BPI scale - Item 3, and FACIT-Dyspnea 
symptom score were added in Section 2.4.5.5 based on the interactions with health 
authorities.  
 Numerical thresholds for meaningful within-patient improvement on the SRS, 
BFI scale - Item 3, BPI scale - Item 3, and FACIT-Dyspnea symptom score were added in 
Section 2.4.5.5 based on the interactions with health authorities. 
 Cumulative distribution functions (CDFs) for the SRS, BFI scale - Item 3, 
BPI scale - Item 3 and FACIT-Dyspnea symptom score by treatment group were added in 
Section 2.4.5.5 based on the interactions with health authorities. 
 The definitions in Section 2.4.6.12 in the Immune assessment section were expanded and 
refined. 
 The compliance of eDiary data was added in Section 2.4.5.6 based on the interactions with 
health authorities.  
This SAP supersedes any previous SAPs. 


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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
The PAP analysis will be performed after all patients have had the chance to complete the 
Week 52 assessments (ie, at the completion of the 52-week PAP treatment period) and will 
include a formal database lock, unblinding of the study treatment arms, and analyses of efficacy, 
safety, pharmacodynamic, and pharmacokinetic data. The study treatments will remain blinded to 
the Sponsor until completion of the PAP; the investigator and patients will remain blinded until 
the last patient completes the dose escalation period in the ETP period. A CSR will be prepared 
for the PAP analysis. The database will contain all visits, events or procedures that occurred up to 
a cutoff date - to be pre-defined as few days after the last patient finishes PAP, and the data will 
be cleaned to a pre-specified extent. This will include PAP evaluations for all patients 
randomized, but will also include evaluations in ETP for most patients. 
A formal summary of data as a CSR during the ETP may be produced to support regulatory 
approval(s) and/or other submission/application requirement(s).  
The final CSR will be prepared after all patients have completed all the study assessments at the 
completion of the ETP and will include a final database lock. Any difference in data from PAP 
CSR will be highlighted within the final CSR.  
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value in general is defined as the last available value before first infusion. It is 
understood that these evaluations may be before or after the randomization of the patient in the 
interactive voice/web response system (IXRS). One exception to this baseline definition is the 
hematology parameters – these samples are collected twice at screening, and twice on 
first infusion visit (once before and once after the first infusion); the average of all measurements 
taken before the first infusion will serve as the baseline for hematology parameters. Another 
exception may be the ECG parameters – Day 1 (the first infusion visit) is to collect ECG in 
triplicate before the infusion; if these data qualify for the latest ECG before first infusion, the 
average of ECG parameter results from the triplicate ECG will be considered as the baseline 
value. Since all other time points including screening will collect a single ECG, if the Day 1 
pre-infusion triplicate ECG does not qualify for baseline, the baseline value of ECG parameters 
will be taken from the single ECG at the qualifying time point.  
All baseline safety and efficacy parameters (apart from those listed below) will be presented along 
with the respective safety and efficacy displays. 
Demographic characteristics 
Demographic variables are gender (Male, Female), race (American Indian or Alaska Native; 
Asian; Black; Native Hawaiian or Other Pacific Islander; White; other), age in years at screening, 


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ethnicity (Hispanic, non-Hispanic), ancestry (with special details of Jewish ancestry), country, 
human immunodeficiency virus (HIV) antibody testing, and Hepatitis tests (B surface antigen and 
C antibody tests). 
Medical history 
Complete medical history includes prior or existing condition(s) in different body systems as well 
as prior or existing medical conditions/surgical procedures of specific interest.  
Disease characteristics at baseline  
Baseline disease characteristics include age at ASMD diagnosis, number of years since ASMD 
diagnosis, acid sphingomyelinase (ASM) activity in peripheral leukocytes and dried blood spot, 
spleen status, genotyping of SMPD1, CHIT1, UGT1A1, severe splenomegaly and severe % 
predicted DLco adjusted for hemoglobin and ambient barometric pressure. 
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”. 
2.1.2 Prior or concomitant medications  
All medications and therapeutic procedures received by the patient in the 30 days before the first 
scheduled infusion with study drug until the final safety follow-up phone call 30-37 days after the 
last infusion will be recorded on the Prior and Concomitant Medication eCRF. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD). 
 Prior medications are those the patient used prior to first intake of study drug, either 
placebo or olipudase alfa. Prior medications can be discontinued before first 
administration or can be ongoing during treatment phase.  


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 Concomitant medications are any treatments received by the patient concomitantly to the 
study drug (either placebo or olipudase alfa), as medications that are taken on and after the 
first infusion of study drug. A given medication can be classified both as a prior 
medication and as a concomitant medication.  
Technical details related to computation, dates, imputation for missing dates are described in 
Section 2.6.6. 
2.1.3 Smoking and alcohol drinking  
Alcohol and tobacco usage data will be collected at screening and yearly visits.  
2.1.4 Efficacy endpoints 
2.1.4.1 Primary efficacy endpoint(s) 
The primary efficacy endpoints for Europe and the ROW are: 
 Percentage change in spleen volume (in MN) from baseline to Week 52 
 Percentage change in DLco (in % predicted of normal) from baseline to Week 52 
The primary efficacy endpoints for US are: 
 Combination spleen endpoint which has two components: 
- 
Percentage change in spleen volume (in MN) from baseline to Week 52 
- 
Change in splenomegaly-related score from baseline to Week 52 
 Percentage change in DLco (in % predicted of normal) from baseline to Week 52 
DLco measurements 
DLco is part of the pulmonary function tests (PFT), which will be performed at screening to 
measure, among other parameters, the diffusing capacity of carbon monoxide (DLco) as evidence 
of gas exchange across the alveolocapillary membrane for infiltrative lung disease (ILD). This 
parameter is measured at screening and approximately every 6 months after the first infusion in 
the study; for further details of timing, please refer to the protocol.  
Observed values of DLco will be reported by the central vendor using the readings from the 
machine that the vendor has provided to each site. 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 DLco will be computed as follows (1, 2): 
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 


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Unit conversion: mL CO/min/mmHg = mmol/min/kPa *2.987 
Hb-adjustment factor (to be applied to DLco in unit of mL CO/min/mmHg, Hb in g/dL) 
= 1 / [(1.7*Hb) / (10.22 + Hb)] for males 
= 1 / [(1.7*Hb) / (9.38 + Hb)] for females 
Ambient barometric pressure (Pamb) in unit of hPa is recorded in the vendor machine, which is 
multiplied by 0.75 to covert to the unit of mmHg. Water vapor partial pressure in lungs is 
assumed to be 47mmHg. The partial pressure of (inspired) oxygen (PiO2) in the lungs is 
calculated as: 
PiO2 = (Pamb – 47)*0.20942 
where 0.20942 is assumed to be the oxygen concentration in room air. 
Altitude-adjustment factor = 1 + 0.0031*(PiO2-150) 
DLco-adjustment factor = Hb-adjustment factor * Altitude-adjustment factor 
DLco adjusted = Observed DLco*DLco-adjustment factor 
Percent predicted adjusted DLco = 100*DLco adjusted/Predicted DLco 
Note that percent predicted DLco adjusted for hemoglobin and ambient barometric pressure is 
a part of inclusion criteria in the study. For ease of operation, the vendor-provided machine 
calculation of percent predicted DLco adjusted for Hb and ambient barometric pressure is used for 
determination of eligibility, and remain as part of the source documents; these data are not 
included in the database. Every effort has been made to match the formula the vendor uses in the 
machine, however, the screening DLco for analyses purposes is calculated separately using the 
data available in the database. In the rest of this SAP, DLco (% predicted) always refers to the 
percent predicted DLco adjusted for hemoglobin and ambient barometric pressure. 
Spleen volume – Abdominal magnetic resonance imaging 
Spleen volume will be assessed by abdominal MRI (to quantify the degree of splenomegaly and 
hepatomegaly) at screening and approximately every 6 months since the first infusion in the 
study; 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 volume 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 (weight 
coming from the respective visit; if not available, the closest one available): 
Spleen Volume (MN) = Spleen volume (cm3) / [2*weight (kg)] 


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At screening one of the inclusion criteria requires spleen volume in multiples of normal. For 
operational purposes, the vendor provides these data (in MN) to the site at screening, using the 
same formula above, taking the spleen volume (cubic millimeters) and the weight (kg) from the 
screening visit. These data from vendor are used for determination of eligibility, and remain as 
part of the source documents; these data are not included in the database. For purposes of this 
analysis, the screening spleen volume is calculated separately using available spleen volume 
(cubic millimeters) and weight (kg) from the screening visit. 
Splenomegaly-related score (primary for US) 
The splenomegaly-related score is defined as the 7-day mean of the daily sum of scores of the 
following 5 symptom assessments: abdominal pain, abdominal discomfort, early satiety, 
abdominal body image, and ability to bend down. The 5 symptoms were selected from the 
Myelofibrosis-Symptom Assessment Form. Using a numerical rating scale of 0 (absent) to 
10 (worst imaginable), these questions assess the effect of splenomegaly-related symptoms within 
the last 24 hours of assessment. 
An eDiary will be used for collecting these responses. This is collected over 7 evenings before the 
clinic visit - at screening, at randomization visit, then at every quarterly visit during the study. At 
screening the patient must fill out at least six of the seven days of the eDiary; if not, the patient 
gets to repeat the eDiary for 7 days. If the patient did not fill out the 7th day in the eDiary, the 
patient will fill in last day (Day 7) responses while at the clinic. 
The sum of the individual responses will be used in the evaluation of total daily score. A missing 
response is not allowed in the eDiary, but in case of an incomplete questionnaire (eg, eDiary 
switched off before finishing the questionnaire), the score for that day will be missing. The mean 
of the 7 consecutive daily scores from the eDiary will be used as the splenomegaly-related score. 
If there are days with missing scores, then the mean of the available daily scores from the same 
patient and same time point will be used if at least 4 out of 7 days (>50%) of data are not missing, 
otherwise, the mean of the 7 consecutive daily score will be set to missing.  
2.1.4.2 Secondary efficacy endpoint(s) 
 Percentage change in liver volume (in MN) from baseline to Week 52 
 Percentage change in platelet counts from baseline to Week 52 
 Week 52 change from baseline in fatigue severity as measured by item 3 of the BFI scale 
 Week 52 change from baseline in pain severity as measured by item 3 of the BPI scale 
 Week 52 change from baseline in dyspnea severity as measured by the Functional 
Assessment of Chronic Illness Therapy (FACIT)-Dyspnea tool 
 Change in splenomegaly-related score from baseline to Week 52 (except in US where this 
endpoint is part of the primary “combination spleen endpoint”) 


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Liver volume - abdominal magnetic resonance imaging 
Liver volumes will be assessed by abdominal MRI (to quantify the degree of splenomegaly and 
hepatomegaly) at screening and approximately every 6 months since the first infusion in the 
study; 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 liver volume 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 MN, and the algorithm used is as follows (weight coming for respective 
visit; if not available, the closest one available): 
Liver Volume (MN) = Liver volume (cm3) / [25*weight (kg)] 
Platelet count - hematology 
Platelet count is part of hematology and hemogram panel with laboratory testing of blood 
samples. Hemogram panel evaluates hemoglobin, hematocrit, platelet and white blood cells (total 
and deferential) only. Platelet count is evaluated at screening, randomization visit, at every visit 
during dose escalation (both in PAP and ETP) period, and at every quarterly visit. At quarterly 
visits except for yearly visits, and during dose-escalation visits, one sample of hematology is 
collected pre-infusion. At yearly visits, two samples - one for hematology, one for hemogram - at 
least 24 hours and up to 2 weeks apart, before infusion, are evaluated. During screening period, 
two samples - one for hematology, one for hemogram - at least 24 hours and up to 2 weeks apart 
are evaluated. In addition, about 24 hours post- infusion one sample is collected at all visits except 
for screening. In all the visits where 2 samples are collected, platelet count and hemoglobin will 
be reported as average between the 2 samples. For details of sample collection schedule, please 
refer to the protocol. 
BFI scale - Item 3 
The BFI is a validated, self-administered questionnaire that was originally developed to assess 
fatigue severity in cancer patients (3). The BFI Item 3 is about the worst fatigue severity in past 
24 hours, using numeric rating scales from 0 to 10, 0 being no fatigue, 10 being the worst fatigue. 
This particular item is collected in the eDiary prior to baseline and quarterly visits. The mean of 
the 7 consecutive daily measurements recorded in the eDiary will be used as the BFI Item 3 score. 
If the patient did not fill out the eDiary on the day before the clinic visit (Day 7), the patient will 
fill in Day 7 responses while at the clinic. If there are missing daily measurements, then the mean 
of the available measurements within the same patient and the same time point will be used if at 
least 4 out of 7 days (>50%) of data are not missing, otherwise, the mean of the 7 consecutive 
daily score will be set to missing.  
BPI-SF scale - Item 3 
The BPI-SF is a validated, self-administered questionnaire designed to measure a patient’s 
perceived level of pain (4, 5, 6, 7). The BPI-SF Item 3 is about the worst pain severity in past 
24 hours, using numeric rating scales from 0 to 10, 0 being no pain, 10 being the worst pain. This 


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particular item is collected in the eDiary prior to baseline and quarterly visits. The mean of the 
7 consecutive daily measurements recorded in the eDiary will be used as the BPI-SF Item 3 score. 
If the patient did not fill out the eDiary on the day before the clinic visit (Day 7), the patient will 
fill in Day 7 responses while at the clinic. If there are missing daily measurements, then the mean 
of the available measurements within the same patient and the same time point will be used if at 
least 4 out of 7 days (>50%) of data are not missing, otherwise, the mean of the 7 consecutive 
daily score will be set to missing. 
FACIT-Dyspnea score 
The complete FACIT-Dyspnea short form consists of 10 symptom-specific questions, and each of 
these questions has a related question asking about functional limitations (8). For the secondary 
endpoint, only the symptom-specific questions of the FACIT-Dyspnea will be used, and the 
functional limitation questions will not be used. The answer to each question can take the 
following values: 
A) Numeric values representing severity ranging from 0 (no shortness of breath) to 
3 (severely short of breath). These responses will be entered into the scoring algorithm as 
described below: 
- 
A response that the activity was not attempted specifically because of the severity of 
shortness of breath associated with it will be entered into the scoring algorithm as 
a 3 (severe shortness of breath). 
- 
A response that the activity was not attempted for any other reason than shortness of 
breath will not be assigned a numeric value and will be excluded from the scoring 
algorithm. 
- 
The raw score for the FACIT-Dyspnea will be determined by the following rules: 
i. 
If all 10 questions have numeric values then the raw score is the sum of the 
10 values. 
ii. 
If 50% or fewer of the questions have numeric results then the raw score will 
not be determined, ie, assigned a missing value. 
iii. 
Otherwise the available values will be added, the sum will be multiplied by 10, 
and then divided by the number of questions answered. 
B) The raw score as calculated above is then converted to a scale score using a conversion 
table provided by the developers of the questionnaire (8). The scale scores for 
FACIT-Dyspnea have a range of 27.7 to 75.9; conversion table is provided in Section 7.1.  
FACIT-Dyspnea questionnaire is part of Day 7 in eDiary and is administered prior to baseline and 
at every quarterly visit since the first infusion. If the patient misses Day 7 eDiary, he is allowed to 
complete Day 7, including FACIT, at the clinic visit. 
Splenomegaly-related score  
This is a primary endpoint in US; for details please refer to Section 2.1.4.1. 


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2.1.4.3 Additional efficacy endpoints 
Liver function tests 
Percentage change from baseline to Week 52 in Liver function tests (pre-infusion): alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and direct bilirubin. 
Pulmonary function tests 
Pulmonary function tests (PFT) will be performed at screening and at approximately every 
6 months since the first infusion to measure lung volumes and air flow; for further details of 
timing, please refer to the protocol.  
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 (TLC). Observed values of PFT parameters will be reported by the central 
vendor from machine reading. Percent predicted values will be computed based on following 
algorithm (height values are from the available one 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 2012 reference 
equations (9). 
Predicted TLC (liters) will use the following formula for adults (1): 
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 
Percent predicted TLC = 100*Observed TLC / Predicted TLC 
Pulmonary function imaging – high-resolution computed tomography 
High-resolution computed tomography (HRCT) scans of the chest will be obtained at screening 
and approximately every 6 months since the first infusion; for further details of timing, please 
refer to the protocol. This evaluation is meant to quantify the degree of possible diffuse lung 
disease, classically referred to as an 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 in Hounsfield units will be reported 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 diffuse 
lung disease (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. 


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 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 components of diffuse lung disease, classically 
referred to as interstitial lung disease (ILD): ILD (read specifically as reticular appearance), 
ground glass appearance, reticulo-nodular density (read specifically as nodular appearance), 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). 
 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 
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.  
No overall assessment of diffuse lung disease caused by ASMD is obtained. Rather, the key 
HRCT radiological findings are each scored individually. In the case of ILD (read specifically as 
reticular appearance), ground glass appearance, and reticulo-nodular (read specifically as nodular 
appearance), an improvement in any one of these findings may be indicative of a radiologic 
improvement in the diffuse lung disease. 
Pulmonary function imaging – chest X-ray 
A chest X-ray (posterior-anterior and lateral views) will be performed at screening and 
approximately every 6 months since the first infusion at sites, except for the patients in Germany 
(since Germany radiation board did not allow this); 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, consolidation and pleura thickening of the right and 
left lungs separately according to the following criteria: 
 0 = No infiltrative lung disease. 
 1 = Mild (affecting 1% to 25% of the lung volume). 


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 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 / 2 
Treadmill ergometry 
Treadmill ergometry is performed at screening and approximately every 6 months since the 
first infusion; for further details of timing, please refer to the protocol. Completion of the 
assessment may depend upon patient cooperation. 
Treadmill ergometry assessments will include maximum workload (watts), percent predicted 
maximum workload (%), working time (min), maximum heart rate (breaths/min), percent 
predicted maximum heart rate (%), maximum O2 saturation (%), maximum respiratory rate 
(breaths/min), maximum ventilation (L/min), maximum tidal volume (mL), percent predicted 
maximum O2 uptake (mL/min), maximum O2 uptake (%), maximum CO2 output (mL/min), and 
maximum respiratory exchange ratio. 
Fasting lipids (including lipoproteins of interest) 
Fasting lipids evaluations are done at screening and approximately every 3 months since the first 
infusion. The parameters include: total cholesterol, LDL, HDL, VLDL, triglycerides, 
apolipoprotein B, apolipoprotein A1, and lipoprotein [a]. A derived parameter of non-HDL will be 
evaluated as follows: total cholesterol minus HDL (10). 
Hematology 
Platelet counts and hemoglobin are considered efficacy parameters. The hematology and 
hemogram sample collection schedule has been described under platelet count which is 
a secondary endpoint (Section 2.1.4.2). The rest of the hematology parameters, such as 
hematocrit, white blood cell counts (WBC), and red blood cell count are part of safety endpoints. 
Hematology samples evaluate all hematology parameters, while hemogram samples evaluate only 
platelet, hemoglobin and total and deferential WBC. 
Bone disease assessments  
Bone marrow burden  
An MRI of lumbar spine and bilateral femur is performed at screening and at yearly visits. 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: 
Spine T1 score: 0=slightly hyperintense, 1=isotense, 2=slightly hypointense, 3=hypointense 
Spine T2 score: 0=isointense, 1=slightly hyperintense or slightly hypointense, 2= hyperintense or 
hypointense 
Infiltration pattern - infiltration: 0=None, 1=Patchy, 2=Diffuse 
Infiltration pattern - fat in basivertebral vein region: 0=Preservation of fat, 1=Absence of fat 


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Femur T1 score: 0=Slightly hyperintense or isointense, 1=Slightly hypointense, 2=Hypointense  
Femur 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=Diaphysis, 2=Proximal epiphysis / apophysis, 
3=Distal epiphysis  
Total bone marrow burden (BMB) score for each region is derived by adding up the individual 
scores. 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]. 
Dual-energy X-ray absorption parameters 
Dual-energy X-ray absorption (DXA) of lumbar spine and bilateral femur is performed at 
screening and at yearly visits. Three parameters are evaluated for each region, and for left and 
right side separately: 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 is obtained by averaging the two side scores within each region. 
Bone biomarkers  
Bone-specific Alkaline phosphatase and C-telopeptide levels are evaluated at screening and 
approximately every 3 months since the first infusion. 
Efficacy biomarkers 
Serum chitotriosidase, ligand 18 (CCL-18), and ACE are evaluated at screening and 
approximately every 3 months after the first infusion of the study drug. 
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” 
Physician’s global assessment 
The physician will assess the disease severity of the patient at screening, as mild, moderate, 
severe. At approximately every six months exposure of the study treatment, the disease severity 


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will be assessed. At these clinic visits, the investigator will also evaluate the patient’s current 
clinical status compared to screening (baseline) by marking 1 of 7 categories: “marked 
improvement of 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”.  
NMR of HDL 
Evaluation of HDL by NMR will be performed at Screening, then every six months since 
first infusion for 2 years, yearly thereafter. 
Liver function via echo-Doppler ultrasound 
Detected signs of portal vein hyperpressure is considered an efficacy measure and will be assessed 
through liver function via echo-Doppler ultrasound at Screening, Week 52 and Week 104. 
2.1.5 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 will be divided into epochs: 
 The screening epoch (or pretreatment epoch) is defined as the time from the signed 
informed consent date up to the start of the first infusion of investigational medicinal 
product (IMP) in the study (excluded). 
 The treatment epoch is defined as the time from the first infusion of IMP (included) to the 
end of the study. 
- 
The treatment epoch for PAP is defined as the time from the first infusion of IMP 
(included) to: 
1. the time just prior to first infusion in ETP if the patient has an infusion in ETP; 
2. the last date the data are available if the patient has no infusion in ETP. 
- 
The treatment epoch for ETP is defined as the time from the first infusion in ETP to 
the end of the study. 
Based on these epochs the safety data collected in this study will be classified as pre-treatment 
and treatment emergent. 
The on-study observation period is defined as the time within treatment epoch. 


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2.1.5.1 Adverse events variables 
Adverse event observation period  
 Pretreatment adverse events are adverse events (AEs) that started before the 
first administration of IMP. 
 Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment epoch. These will be defined separately for PAP and 
ETP. 
If due to incomplete information on AE start date/time, the period designation cannot be made 
unambiguously (for imputation of missing or incomplete dates, please refer to Section 2.6.2), the 
AE is assumed to be treatment-emergent (and treatment-emergent in PAP, if so required for 
assumption). 
All adverse events (including serious adverse events and adverse events of special interest) 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 Medical Dictionary for 
Regulatory Activities (MedDRA). 
Adverse events are collected from the time of signed informed consent until the end of the study.  
Adverse events of special interest include: 
Infusion associated reactions  
Protocol-defined infusion associated reactions (IAR): Any AE that occurs 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; in that case, the 
sponsor decision is deemed final.  
For this study, IARs may present as hypersensitivity reactions, acute phase reactions (APR), and 
cytokine release syndrome (CRS).  
IARs, specifically APRs and some hypersensitive reactions may be associated with changes in 
specific clinical laboratory parameters (see Section 10.4.1.3 of the study protocol), and will be 
reconciled with investigator identification of those events as marked in the AE log as appropriate, 
facilitated by periodic clinical/safety review of AEs. 
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. Any TEAEs with missing time but which happened on the same day or the day 
after the infusion will be considered as algorithm-defined IARs. 


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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 is captured as an adverse event of special 
interest. The eCRF provides urine pregnancy test results as positive or negative. Labs provide 
serum pregnancy test results. Pregnancy is entered in the database as an AE, and will be counted 
from the AE page. 
Symptomatic overdose: This is captured as an adverse event in this study, and will be reconciled 
with the clinical review of dosing data. For details, please see Section 10.4.1.3 in the protocol. 
This will be counted from the AE page. 
Laboratory values: The following laboratory values and symptoms will be considered AESIs: 
 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, 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). 
2.1.5.2 Deaths 
The deaths observation period are per the observation periods defined above (Section 2.1.5).  
 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 
Death is reported as a fatal outcome in AE log page in eCRF. 
2.1.5.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values will be converted into standard international units. The US 
conventional units as well as international units will be used in all listings and tables for 
continuous variables. 
Blood samples for clinical laboratories are scheduled to be taken at screening, all visits 
(every two weeks) during the dose escalation period (Week 0-16 – both in PAP and ETP), every 


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3 months thereafter, and in early termination visit if applicable, unless otherwise specified. The 
following clinical laboratory tests will be assessed by the site as specified in Section 9.2.2 of the 
study protocol. For more detailed schedule of assessment and window of time points, please refer 
to the protocol Section 1.2. The laboratory parameters will be classified as follows:  
 Clinical Chemistry (before infusion): sodium, potassium, calcium, chloride, blood urea 
nitrogen, creatinine, lactate dehydrogenase, total protein, albumin, glucose, cholesterol, 
phosphorus, and creatine kinase 
 Liver Function Tests (before infusion, 24 h and 48 h after the end of infusion): alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma 
glutamyl-transferase (GGT), total bilirubin, and direct bilirubin. The pre-infusion 
assessments on ALT, AST, total bilirubin and direct bilirubin are considered as additional 
efficacy endpoints in this study, while, the 24 h and 48 h post-infusion assessments on 
these tests are considered as safety endpoints. 
 Hematology (before infusion, 24 hours after end of infusion; in yearly visits additional 
sample of hemogram before infusion):  
- 
Hematology sample: complete blood count with differential, including hematocrit, 
hemoglobin, red blood cell, platelet, white blood cell, neutrophil, lymphocyte, 
monocyte, eosinophil, and basophil counts (as well as neutrophil, lymphocyte, 
monocyte, eosinophil, and basophil as percentages of the WBC) 
- 
Hemogram sample: platelet, hemoglobin, WBC 
 Coagulation Studies (before infusion, 24h and 48h after the end of infusion): prothrombin 
time (Protime; PT) including PT-INR, partial thromboplastin time (aPTT), and D-dimer 
 Urinalysis (before infusion): dipstick for glucose, protein, hemoglobin, leukocytes, 
ketones, and bilirubin 
 Additional Tests (screening only): hepatitis B surface antigen, hepatitis C antibody, human 
immunodeficiency virus antibody,  
 Additional Tests (every 4 weeks): serum and urine β-human chorionic gonadotropin 
(β-HCG) pregnancy test (women of childbearing potential only) 
Note: If a urine pregnancy test is positive, dosing of study drug will be withheld until results are 
confirmed with a serum β-HCG test. 
 Safety biomarkers (before infusion, 24h and 48h after the end of infusion; no testing at 
screening): hsCRP, iron, ferritin, cardiac troponin I, IL-6, IL-8, ceramide in plasma and 
calcitonin.  
 Immune response assessments (every 4 weeks during dose-escalation phase - both PAP 
and ETP, then at quarterly visits): anti-olipudase alfa IgG antibodies.  
If an IAR is suggestive of a hypersensitivity reaction, additional laboratory parameters will be 
evaluated as soon as possible: tryptase activity, complementation activation, IgG and IgE. A skin 
testing may also be performed. 


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If an IAR is suspected to be a CRS, additional laboratory parameters will be evaluated as soon as 
possible: additional multiplex assay, calcitonin (see Section 2.1.5.6 inflammatory and vascular 
biomarkers). 
2.1.5.4 Vital signs variables 
Vital signs include: systolic and diastolic blood pressure (mmHg), heart rate (beats/minute), 
respiratory rate (breaths/minute), and temperature (°F or °C). At dose-escalation visits and at 
quarterly visits, vital signs will be measured before infusion, half-way through infusion, at the end 
of infusion and at specific intervals after the end of infusion until the patient is discharged from 
the hospital; for details of time points and associated window of time, please refer to the protocol 
Section 1.2. 
2.1.5.5 Electrocardiogram variables 
ECGs are reviewed by an expert at each site then centrally read by an independent expert for 
measurement of parameters and overall interpretation. Pre-infusion ECG on the day of 
first infusion will be done in triplicate; all other ECGs - screening, Day 1 (post-infusion only) and 
at quarterly visits - are done as singlet before the infusion start, 4 h, 12 h and 24 h after the end of 
infusion. 
ECG parameters include, but not limited to, heart rate, intervals of PR, QRS, QT and QTc 
(according to Bazett/Fridericia), QRS axis. 
2.1.5.6 Other safety endpoints 
Doppler echocardiogram 
A standard 2-dimensional and M-mode Doppler echocardiogram will be conducted during the 
Screening period, at Weeks 14, 52, 68 and 104, and at early termination if applicable; for details 
please refer to Sections 1.2 and 9.2.5 of the study protocol. Examination will include ventricular 
cavity size, valve characterization, ejection fraction, ventricular wall thickness, regional wall 
motion, diastolic function, pericardium characterization, pulmonary blood pressure and blood 
flow.  
Physical examination 
A complete physical examination will be performed during the screening period, before infusion 
at Day 1 and at every quarterly visit, and will include a neurological examination (mental status, 
cranial nerves, muscle strength, sensation, deep-tendon reflexes, and coordination) and an 
assessment of the patient’s general appearance; skin; head, eyes, ears, nose, and throat; and 
examinations of lymph nodes, heart, lungs, abdomen, and extremities/joints. 
An abbreviated physical examination of the patient’s general appearance only will be performed 
before and after infusion at every infusion visit. 


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Patients will be assessed for weight at screening, every infusion visit during dose escalation 
(both PAP and ETP) and at quarterly visits. Height will be assessed at Screening and every yearly 
visit. Body mass index (BMI) will be calculated at the every visit that weight is measured, using 
the latest height and current weight available.  
Liver biopsy 
Liver biopsy is done at screening, Week 52 and Week 104. Liver biopsies are evaluated by 
a single blinded Sanofi Genzyme pathologist for liver fibrosis grading and for sphingomyelin 
accumulation. Fibrosis staging will be performed using the Laennec scoring system (11). Most of 
the pathology reports may not be included in the database, but will be received by the clinical 
personnel. Sphingomyelin accumulation from liver tissue will be provided with the liver biopsy 
results, and is discussed under pharmacodynamic endpoints (Section 2.1.7). 
Liver function via echo-Doppler ultrasound 
The liver ultrasound imaging with Doppler is performed at Screening, Week 52 and Week 104. 
The assessments include, but not limited to: 
 Portal vein: diameter, direction of flow, velocity  
 Presence of: liver surface irregularities, nodules, ascites, dysmorphia  
 Presence and location of portosystemic venous collaterals 
 Congestion index (CI) 
 Hepatic artery: diameter, resistance, pulsatility index (PI) 
 Hepatic vein waveform and profile 
 Arterio-portal velocity ratio 
 Detected signs of portal vein hyperpressure (this assessment is considered an efficacy 
assessment and will be analyzed under additional efficacy part) 
Inflammatory and vascular biomarker 
The inflammatory and vascular biomarkers are measured as part of Meso Scale Discovery panel 
within 24 hours before the start of infusion, then 24 h and 48 h (+/- 3 hours) after end of infusion 
at every visit during the dose escalation period (both in PAP and ETP) and at quarterly visits. 
Further, if a patient is suspected to have a cytokine release syndrome, a multiplex assay panel will 
be evaluated, which includes the following:  
A) Inflammatory biomarkers:  
- 
Chemokine panel: Thymus activation-regulated chemokine (TARC), Eotaxin-3, 
Eotaxin-1, Macrophage inflammatory protein 1 alpha (MIP-alpha), Macrophage 
inflammatory protein 1 beta (MIP-beta), Macrophage-Derived chemokine (MDC), 
Interferon gamma-induced protein 10 (IP-10), Monocyte chemotactic protein-1 
(MCP-1), Monocyte chemotactic protein 4 (MCP-4), Interleukin 8 (IL-8) 


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- 
Cytokine panel: Granulocyte macrophage colony stm factor (GM-CSF), Tumor 
necrosis factor beta (TNF-beta), Vascular endothelial growth factor (VEGF), 
Interleukin 1 alpha (IL-1 alpha), Interleukin 12/23 subunit P40 ((IL12/IL23p40), 
Interleukin 15 (IL-15), Interleukin 16 (IL-16), Interleukin 17 alpha (IL-17A), 
Interleukin 5 (IL-5), Interleukin 7 (IL-7) 
- 
Pro-inflammatory panel: Tumor necrosis factor alpha (TNF-alpha), Interleukin 1 beta 
(IL-1 beta), Interleukin 10 (IL-10), Interleukin 12 subunit P70 (IL12p70), 
Interleukin 13 (IL-13), Interleukin 2 (IL-2), Interleukin 4 (IL-4), Interleukin 6 (IL-6), 
Interleukin 8 (IL-8), Interferon gamma (IFN-gamma). [Please note IL-6 and IL-8 are 
considered safety biomarkers in this study.] 
B) Vascular biomarkers include:  
- 
Vascular injury panel: C Reactive Protein (CRP), Serum amyloid A protein (SAA), 
Intercellular adhesion molecule 1 (ICAM-1), Vascular cell adhesion molecule 1 
(VCAM-1) 
- 
Angiogenesis panel: Basic fibroblast growth factor (bFGF), 
Phosphatidylinositol-glycan biosynth. F (PIGF), Soluble fms-like tyrosine kinase-1 
(FIT-1), TEK (TIE2) recombinant human protein, Vascular endothelial growth factor 
(VEGF), Vascular endothelial growth factor C (VEGF-C), Vascular endothelial 
growth factor D (VEGF-D) 
2.1.6 Pharmacokinetic variables  
Pharmacokinetic endpoints will include evaluation in plasma of the following parameters: Cmax, 
AUC0-τ, AUC0-last, t1/2, CL, and Vβ. Definition of each parameter is provided in Section 9.3.2.4 of 
the study protocol. The process of sample collection has been outlined in Section 9.3.2.1. 
Concentrations of olipudase alfa in plasma will be determined using a validated enzyme-linked 
immunosorbent assay method. 
2.1.7 Pharmacodynamic/genomics endpoints  
The pharmacodynamic endpoints include: 
 Change from baseline to Week 52 in sphingomyelin in liver tissue 
 Percent change from baseline to Week 52 in: 
- 
Sphingomyelin in plasma 
- 
Lyso-sphingomyelin in plasma 
 Percent change from baseline to Week 52 in Sphingosine-1 phosphate in dried blood spot 
(DBS) 
The plasma and/or DBS samples are collected at every visit during dose-escalation (both PAP and 
ETP) and at quarterly visits thereafter.  


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Sphingomyelin accumulation is evaluated from liver tissue collected during liver biopsy at 
screening, Week 52 and Week 104. Sphingomyelin accumulation will be quantified by computer 
morphometry of high-resolution light microscopy images (11). Up to 10 blocks will be produced 
from each patient’s liver biopsy at each time point with values representing % of tissue staining 
for sphingomyelin for each block (stored as source data), and a mean +/- SD for each biopsy will 
be provided by the blinded pathologist.  
2.1.8 Quality-of-life endpoints (patient-reported outcome) 
Quality of life questionnaires include BFI, BPI-SF, Niemann-Pick B Health Assessment 
Questionnaire (NPB-HAQ) v2.0, Short Form-36 Health Survey (SF-36); FACIT-Dyspnea SF; for 
details please refer to Sections 9.1.4.13 and 9.1.4.14 in the protocol.  
 The BFI is a validated, self-administered questionnaire that was originally developed to 
assess fatigue severity in cancer patients. The BFI has 9 items, using numeric rating scale 
from 0 to 10. This questionnaire data is collected at screening and every 6 months since 
the first infusion. 
- 
Three items assess the severity of the fatigue now and at its worst and usual during 
past 24 hours. 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. 
- 
Six items assess the fatigue interference with activities of life during the preceding 
24 hours. If 4 out of 6 items are available, the item scores are averaged to provide 
fatigue interference scale; if less than 4 item scores are available, the scale score is left 
miss 
- 
Question 3 in BFI is part of eDiary and is collected over 7 days at baseline and at 
quarterly visits; this is part of secondary endpoints and has been discussed in 
Section 2.1.4.2. 
 The BPI-SF is a validated, self-administered questionnaire designed to measure a patient’s 
perceived level of pain. The BPI-SF consists of 15 items that use a numeric rating scale 
from 0-10, 0 being no pain and 10 being the worst, to assess pain severity and pain 
interference in the past 24 hours and the past week. This questionnaire data is collected at 
screening and every 6 months since the first infusion. 
- 
There are 4 questions that are used for the scale of pain severity - Q3, 4, 5, 6 in 
Ecrf - which ask for “worst” and “least” pain within past 24 hours, an average pain 
score and the pain severity “right now” respectively. If 2 or more responses are 
available (12, 13), the individual question scores are averaged to provide the scale 
score for pain severity; if only one response to the 4 questions is available (or no 
response is available at all), the scale score is left missing. 
- 
Item #9 in eCRF has seven questions asking about how the pain interfered with general 
activity, mood, sleep, etc. If 4 or more responses are available, the individual question 
scores are averaged to provide scale score for pain interference; if less than 4 responses 
are available, the scale score is left missing. 


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- 
Question 3 in BPI-SF is part of eDiary and is collected over 7 days at baseline and at 
quarterly visits; this is part of secondary endpoints and has been discussed in 
Section 2.1.4.2. 
 The NPB-HAQ v2.0 is a disease-specific questionnaire that covers various aspects of 
fatigue, pain, respiratory, and quality of life as well as questions specific to ASMD 
symptoms and physical activity. The 3 domains of this questionnaire include: resource 
utilization, symptoms and physical activity, with several questions in each, with qualitative 
or quantitative response. This questionnaire data is collected at screening and every 
3 months following the first infusion. 
 The SF-36 v2.0 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 (14, 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 and includes two summary measures of physical health and mental health 
derived from scale aggregates. These data including 8 individual scales and 2 summary 
measures are scored externally by QualityMetrics who had the proprietary rights to do so. 
This questionnaire data is collected at screening and every 6 months since the first infusion. 
 FACIT-Dyspnea Short form consists of 10 symptom-specific questions, and each of these 
questions has a related question asking about functional limitations (8). In Part 1, the 
patient rates how short of breath the patients felt in 7 days in doing different activities such 
as dressing, walking, household chores; this is already part of secondary endpoints and the 
scoring has been described in Section 2.1.4.2. Part 2 asks to rate how limiting the activities 
have been due to dyspnea, and is scored similar to part 1 (conversion scale provided in 
Section 7.1); this functional limitation section is part of additional efficacy endpoints. This 
questionnaire data is collected at screening and every 6 months since the first infusion. 
 Patient Global Impression of Symptom Severity (PGIS) is a patient-rated 5-question 
instrument on a 5-point scale, higher score indicating worse. PGIS asks patients to rate 
abdominal problems, bodily pain, fatigue, and shortness of breath “over the past week”. 
This questionnaire data is collected at screening and every 3 months since the 
first infusion. 
 Patient Global Impression of Change (PGIC) is a patient-rated 4-question instrument on 
a 7-point scale, higher score indicating worse, to rate the change in the symptoms since the 
start of study infusion. This questionnaire data is collected at screening and every 
3 months since the first infusion. 
2.1.9 Health economic endpoints  
 Health-related productivity questionnaire is a validated, self-administered questionnaire 
that was developed to measure how treatment of disease impacts an individual’s ability to 
participate in the workforce and complete daily household duties. This questionnaire data 
is collected at screening and every 3 months since the first infusion. A part of this 
questionnaire is about the workforce participation before the start of this study; this is 
collected only at screening. 


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 EQ-5D is a standardized measure of health status developed by the EuroQoL Group to 
provide a simple, generic measure of health for clinical and economic appraisal (16). The 
EQ-5D-5L consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. The respondent is asked to 
indicate his/her health state by ticking (or placing a cross) in the box against the most 
appropriate statement in each of the 5 dimensions. This decision results in a 1-digit 
number expressing the level selected for that dimension. The digits for 5 dimensions can 
be combined in a 5-digit number describing the respondent’s health state. In addition, there 
is visual analogue scale 0-100, 0 indicating the worst and 100 indicating the best that is 
scored for the patient’s health perception on the day of the visit; eCRF collects a numeric 
value between 0 and 100. This questionnaire data is collected at screening and every 
6 months since the first infusion. 
For further details, please refer to Section 9.1.4.13 in the protocol. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as patients who have signed the informed consent form (ICF). 
Eligible patients are defined as screened patients who have met all eligibility criteria. 
Randomized patients consist of all patients with a signed ICF who have had a treatment kit 
number allocated and recorded in the IXRS database, regardless of whether the treatment kit was 
used. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report by treatment group, using a summary table, and percentages 
will be provided using the number of randomized patients as the denominator (except for 
screened, eligible and non-randomized patients where a percentage will not be provided). For 
PAP CSR, the summary of the following categories will be provided up to the data cutoff date for 
the database lock of PAP. For final CSR, the summary of the following categories will also be 
provided: 
 Screened patients 
 Eligible patients 
 Nonrandomized but treated patients 
 Randomized patients 
 Randomized but not treated patients 
 Randomized and treated patients 
 Patients who received rescue therapy during PAP 


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 Patients who did not complete the study treatment period as per protocol 
 Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation 
 Status at last study contact  
- 
Completed PAP and enrolled in ETP 
- Enrolled in ETP but did not complete ETP 
- Completed ETP 
- 
Completed PAP but did not enroll in ETP 
- 
Did not complete PAP 
A patient is considered lost to follow-up if he/she is not assessed at the last protocol planned visit 
and if the time from the last successful contact to the last protocol planned visit is greater than 
30 days.  
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized twice.  
OR 
2. A patient is given a study drug not allocated by the protocol-defined randomization, such 
as a) a patient at any time in the study is given a different treatment than as randomized 
(eg, patients randomized to placebo treatment group received olipudase alfa), or 
b) a nonrandomized patient is treated with study drug. 
OR 
3. A patient receives an incorrect dose of olipudase alfa (not matching what the investigator 
requested, or not matching what IXRS instructed pharmacist to prepare, or infusion 
prepared for 1 patient given to another patient). 
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report. Whether any of these constitute a major or critical protocol deviation, and whether any of 
these adversely impact efficacy, is deferred to the decision by the sponsor’s clinical team before 
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Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
Randomization and drug allocation irregularities 
Study drug given without IRT transaction 
Erroneous study drug administration 
Randomization by error 
Patient randomized twice 
2.2.2 Protocol deviations 
Protocol deviations are qualitative and quantitative in nature. Qualitative deviations are evaluated 
and reported in a list by study monitoring team and reviewed by the study team. Quantitative 
deviations are programmed in SAS from the data, and reviewed by the study team. In both cases, 
the study team determines whether a deviation is minor, major or critical before the unblinding in 
PAP (and any that occurs in ETP at the end of study before the database lock). A summary table 
and a data listing of major or critical deviations will be provided, including, but not limited to, 
prohibited medication use as well as non-compliance. 
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy analysis. Patients who are dispensed study drug without calling the IRT 
or before calling the IRT are considered nonrandomized patients. They are excluded from any 
population for analysis, including safety. However, if these patients experienced any significant 
safety event, they will be documented separately in the clinical study report. 
For any patient screened more than once, only the data associated with the second screening will 
be used in any analysis population. The safety experience associated with any later randomization 
will be assessed separately. 
The randomized population includes any patient who had been allocated to a randomized 
treatment arm by IRT regardless of whether study drug was administered. 
2.3.1 Efficacy populations 
2.3.1.1 Modified intent-to-treat population  
The modified intent-to-treat (mITT) population is a subset of the randomized population and 
will include randomized patients who received at least 1 infusion (partial or total). [Note that the 
design of the study requires patients to be hospitalized for infusion, and the randomization 
happens when the patient is hospitalized; therefore, it is unlikely that mITT population will differ 
from the traditional ITT population which constitutes of all randomized patients irrespective of 
whether one receives a dose of study drug.] Patients will be analyzed in the treatment group to 
which they are randomized. 


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2.3.1.2 Per-protocol population 
The per-protocol population is a subset of the mITT population that has no critical or major 
protocol deviations that are expected to interfere (the list to be finalized before the database lock 
and unblinding in PAP) with assessments of the primary efficacy endpoints. 
2.3.1.3 Other efficacy population  
The mITT-C population is the subset of mITT population which excludes patients who had 
exposure to 
 of olipudase alfa in the active treatment arm. 
2.3.2 Safety population 
The safety population is defined as a subset of the randomized population who received at least 
1 infusion (partial or total), analyzed according to the treatment actually received during the PAP, 
irrespective of the treatment to which the patient has been randomized. For example, if a placebo 
patient was rescued to receive olipudase alfa in PAP, this patient will be counted as olipudase alfa 
treated patient. The safety population will not be changed after patients enter the ETP. Olipudase 
alfa infusions require special vials to be mixed with the vehicle while placebo infusions do not 
require these vials, and these vial numbers are called off by IXRS, it is unlikely that there will be 
any error in treatment received.  
The rescue population is defined as patients who have used rescue strategy in PAP (ie, unblinded 
for treatment and continued on olipudase alfa irrespective of the randomized treatment 
assignment). Data after rescue in PAP will be provided separately for the rescue population.  
In addition, nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately. 
2.3.3 Other analysis populations  
The pharmacokinetic population consists of mITT patients who have evaluable drug 
concentration data. 
The pharmacodynamic population consists of mITT patients who have at least one evaluable 
pharmacodynamic marker data available post-baseline. 
2.4 
STATISTICAL METHODS 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group. Categorical and 
ordinal data will be summarized using the number and percentage of patients. Summaries and 
summary plots are presented by randomized treatment group; by-patient plots and data listings 
will identify the randomized treatment group for each patient. 


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2.4.1 Demographics and baseline characteristics 
Parameters described in Section 2.1.1 will be summarized by randomized treatment group and 
pooled treatment groups using descriptive statistics in mITT population.  
Medical history will be summarized using body system and/or medical/surgical condition of 
specific interest, by randomized treatment group and pooled treatment groups in mITT population. 
No specific description of the safety parameters will be provided within the baseline 
characteristics displays. The baseline values will be described along with each safety analysis. 
No specific description of the efficacy parameters will be provided within the baseline 
characteristics displays. The baseline values will be described along with each efficacy analysis. 
P-values on demographic and baseline characteristic data will not be provided.  
2.4.2 Prior or concomitant medications  
The prior and concomitant medications have been defined in Section 2.1.2. 
Medications will be summarized by randomized treatment group using mITT population 
according to the WHO-DD, considering the first digit of the anatomic and therapeutic category 
(ATC) class (anatomic category) and the first 3 digits of the ATC class (therapeutic category). All 
ATC codes corresponding to a medication will be summarized, and patients will be counted once 
in each ATC category (anatomic or therapeutic) linked to the medication. Therefore patients may 
be counted more than once for the same medication, but for different ATC category. Prior and 
concomitant mediations will be summarized separately. 
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by all other therapeutic classes based on the incidence in olipudase alfa treatment group. In case 
of equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will 
be used.  
Prohibited medications during the study, if used, will be provided as part of a data listing for 
major and critical protocol deviations.  
2.4.3 Smoking and alcohol drinking  
Alcohol and tobacco usage data will be provided in listings.  


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2.4.4 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by randomized 
treatment group in mITT population (Section 2.3.1.1). 
2.4.4.1 Extent of investigational medicinal product exposure 
The extent of study drug exposure will be assessed by the duration of study drug exposure, and 
amount of dose received. 
Study drug exposure for PAP is defined below: 
For patients who did not initiate rescue therapy: 
 Duration of study drug exposure for PAP = the first dose date in ETP (or 13 days after the 
last dose date in PAP if the patient is not continuing in ETP) – first dose date in PAP, 
regardless of unplanned intermittent discontinuations 
For patients who had initiated rescue therapy during PAP: 
 Duration of rescue therapy exposure in PAP = the first dose date in ETP (or the last dose 
date in PAP + 13 days if the patient is not continuing in ETP) – first rescue therapy dose 
date in PAP, regardless of unplanned intermittent discontinuations. 
 Duration of study drug exposure for PAP before initiation of rescue therapy = the 
first rescue therapy dose date in PAP – first dose date in PAP, regardless of unplanned 
intermittent discontinuations. 
Study drug exposure for PAP (before initiation of rescue therapy if any) will be summarized 
descriptively. In addition, duration of treatment exposure in PAP may be summarized 
categorically, eg, <14 weeks, <26 weeks, etc. Duration of olipudase alfa exposure after rescue 
initiation will also be summarized. 
Cumulative study drug exposure of olipudase alfa is defined as follows: 
 Duration of cumulative study drug exposure = disposition date of the study (or the cutoff 
date for database lock if the patients are still ongoing) – first dose date of olipudase alfa 
infusion in the study + 1, regardless of unplanned intermittent discontinuations. 
Duration of cumulative study drug exposure will be summarized descriptively as well as 
categorically. 
Dose information for PAP will be assessed by the following variables for patients who received 
any dose of olipudase alfa: 
The cumulative dose for PAP is the sum of total amount of olipudase alfa in mg received in all 
infusions in PAP. Total amount of olipudase alfa in each infusion is obtained from the patient 
dose level in mg/kg multiplied by weight, adjusted for partial infusion. When the question on the 
eCRF “Was the total volume infused?” indicates “No” (ie, infusion was partial), eCRF does not 
collect the volume actually infused (to maintain blinding, the color of the liquid is covered from 


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view); this needs to be imputed from the infusion rate and infusion time as follows: if the infusion 
rate is xx ml/hour and the duration of that infusion was zz hour, then the volume infused is 
imputed as (xx times zz) ml. The sum of such individual infusion volume over different infusions 
within a visit will constitute the partial volume infused. If the resulting volume is greater than 
total volume prepared, it will be imputed as equal to total volume. In case of partial infusion, the 
total amount of olipudase alfa in the infusion is considered as proportional to the volume infused.  
Total amount of olipudase alfa in each infusion is obtained from the patient dose level in mg/kg 
multiplied by weight, adjusted for partial infusion: 
= Dose level (mg/kg) * weight (kg) if no partial infusion 
= Dose level (mg/kg) * weight (kg) * partial volume infused (mL) / Total volume prepared 
(ml) if partial infusion 
Cumulative dose in PAP for each patient will be summarized. In addition, the number and 
percentage of patients for whom the target dose of 3 mg/kg was not achieved, and separately for 
those who reach target dose but have to reduce dose later for safety reasons will be provided. 
Any incorrect dosing will be part of protocol deviations.  
The cumulative dose of olipudase alfa over the entire study will be summarized. 
2.4.4.2 Compliance 
Compliance to the treatment regimen will be monitored in terms of the percentage of scheduled 
infusions the patient receives during the treatment periods, irrespective of whether the infusion 
was total or partial. This is calculated as: 
100 x (number of infusions received) / (number of infusions intended to be received) 
For PAP, the number of infusions intended to be received is 27 over 52 weeks for a patient who 
complete PAP. 
Noncompliance in PAP is defined as missing 2 or more consecutive infusions in PAP (excluding 
for cause misses, such as when the missed doses are required by the protocol due to a DLT) or 
4 or more infusions in total in the 52-week PAP treatment period.  
Noncompliance in PAP+ETP is defined as missing 4 or more infusions in every 52-week period 
following PAP treatment period until the end of study. 
Treatment compliance for overall PAP will be summarized descriptively as quantitative variable 
using mITT population and randomized treatment group.  
The percentage of patients whose compliance is ≤85% (missing 4 or more infusions out of 
scheduled 27 infusions in PAP) will be provided. In addition, number and percentage of patients 
with noncompliance, and by reasons (missed 2 or more consecutive infusions not for cause (“not 
for cause” means there is no justifiable reasons for a missed dose, eg., DLT), or missed 4 or more 
infusions in total in the 52-week PAP) will be provided.  


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Similar summaries will be provided for PAP+ETP.  
A case of overdose will be reported as an AE and will be summarized with AE. An overdose is 
defined in Section 10.4.1.3 of the protocol. 
2.4.5 Analyses of efficacy endpoints 
Efficacy data will be analyzed by randomized treatment group in mITT population at scheduled 
time point. The statistical analyses will compare olipudase alfa versus placebo within PAP; the 
difference between two treatment groups is calculated as olipudase alfa minus placebo.  
Primary analyses period is 52 weeks.  
Efficacy analyses will use mITT population unless specified otherwise. This will include patients 
who used rescue therapy, but their data after rescue will NOT be included in the analysis. 
Sensitivity analyses including data beyond rescue therapy may be undertaken if appropriate. 
Baseline values are generally the latest value before the first infusion of the study drug, except for 
platelets and hemoglobin which are part of hematology parameters; for hematology parameter 
baseline definition, please refer to Section 2.6.1. 
2.4.5.1 Analysis of primary efficacy endpoint(s) 
The percentage change in DLco (% predicted) from baseline to 52 weeks will be analyzed in the 
mITT population using a mixed model for repeated measures (MMRM) (17, 18). The MMRM 
will include baseline DLco, baseline age, treatment arm, study visit, and study visit by treatment 
arm interaction as covariates; have an unstructured variance-covariance matrix; and be fit using 
restricted maximum likelihood estimation. If this model fails to converge, the following 
variance-covariance structures will be tested in this order: Toeplitz (equal variances and a separate 
correlation for each level of separation between the time points), AR(1) (first-order 
autoregressive, equal variances and exponentially decreasing correlations), CS (compound 
symmetry, equal variances and equal pairwise correlations across fixed time points). The 
first (co)variance structure yielding convergence will be used as the primary analysis. 
Comparisons between treatment arms will be made using least-square mean contrasts at the 
52 week visit with denominator degrees of freedom estimated using the Kenward-Roger 
approximation (19). When a variance-covariance structure other than unstructured is used, then 
the denominator degrees of freedom will be estimated using the between within method 
(DDFM=BW in SAS PROC Mixed). 


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Example SAS code for the MMRM is: 
ods output Diffs = out1 
           LSMeans = out2; 
proc mixed data = DATAIN method = reml; 
  class TRTPN WEEK USUBJID; 
  model PCHG_DLCO = BL_DLCO BL_AGE TRTPN|WEEK / s ddfm=kr; 
  repeated WEEK / type = un subject = USUBJID  r; 
  lsmeans TRTPN TRTPN*WEEK / cl diff; 
run; 
where TRTPN = treatment group, WEEK = (Week 26, Week 52), USUBJID = unique patient ID, 
PCHG_DLCO is the percent change from baseline in DLco (%predicted), BL_DLCO is the 
baseline DLco (% predicted) value, BL_AGE is the baseline age, 
type =  
UN = unstructured covariance 
TOEP = Toeplitz covariance 
AR(1) = first-order autoregressive covariance 
CS = compound symmetry covariance   
The MMRM assumes data missing-at-random (MAR) and will include all DLco observations 
except for measurements made after the initiation of rescue therapy. In addition, for patients who 
do not have Week 52 value available but have a PFT value measured after Week 38 infusion 
(eg, patients discontinuing the study or initiating rescue therapy after Week 38 but before 
Week 52 may have the PFT measurements available from early discontinuation visit or right 
before rescue therapy starts), these values will be used as Week 52 value for analysis purposes; 
Week 52 DLco will not be considered missing in such situations.  This idea is based on the 
clinical concept that PFT measurements are similar within a 12-week period. 
The percentage change in spleen volume (MN) and the change in the splenomegaly-related score 
(for US, SRS is part of primary endpoints) will be analyzed using an analogous MMRM model.   
The summary plots of the LS means from the MMRM of the percentage change in DLco 
(% predicted), the percentage change in spleen volume (MN) and the change in the 
splenomegaly-related score from baseline up to Week 52 with 95% CIs will be provided.  
Sensitivity analyses for the primary efficacy endpoints to support robustness of results will 
include the following: 
1. The MMRM described above will be run using the per-protocol population. This analysis 
will demonstrate whether the results vary depending on the population analyzed.   
2. The MMRM described above will exclude observations made after the initiation of rescue 
therapy.  As a sensitivity analysis, the observations collected after the initiation of rescue 
therapy will be included in the MMRM; the treatment arm for rescued patients will remain 


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as randomized treatment.  
The MMRM planned for the primary efficacy analysis assumes MAR. To assess the 
robustness of the primary results to that assumption a pattern mixture model will be used 
(see Section 2.6.6 for details).   
3. The MMRM planned for the primary efficacy analysis assumes multivariate normality.  
To assess the robustness of conclusions under this assumption, nonparametric testing 
method will be used: A Wilcoxon-Mann-Whitney (WMW) will be used to compare the 
primary efficacy endpoints; missing Week 52 data will be imputed using LOCF, excluding 
patients who initiate rescue therapy.   
Additional supportive analysis for splenomegaly-related scores domains 
The symptom domain score will be calculated based on the first three questions in the 
splenomegaly-related score questionnaire (abdominal discomfort, satiety and pain under the rib). 
The 7-day mean of the daily sum of scores of these three questions will be defined as the 
symptom domain score. The impact domain score will be calculated based on the last two 
questions (bending down, body image). The 7-day mean of the daily sum of scores of these 
two questions will be defined as the impact domain score. The 7-day mean of the daily scores of 
each question in the splenomegaly-related score questionnaire will be defined as the score for 
each question. The change from baseline to Week 52 in these two domain scores and each 
question in the splenomegaly-related score questionnaire will be analyzed using the MMRM, 
similarly to the primary analysis of SRS. 
Additional supportive analysis for DLco and spleen volume (MN) 
To evaluate the treatment effect on the absolute change on DLco (% predicted) and spleen volume 
(MN), the change from baseline on these two endpoints up to Week 52 will be analyzed using an 
analogous MMRM model.   


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2.4.5.2 Analyses of secondary efficacy endpoints 
Liver volume 
The MMRM model as used in the primary analysis of spleen volume under primary efficacy 
endpoints will be used to compare treatment groups for percentage change in liver volume from 
baseline to Week 52, using mITT population.  Supportive summary in mITT-C population will be 
provided.  Sensitivity analyses are not planned, but may be undertaken if necessary.  
Platelet counts 
The MMRM model as used in the primary analysis of spleen volume under primary efficacy 
endpoints will be used to compare treatment groups for percentage change in platelet count from 
baseline to Week 52, using mITT population. Data collected at the quarterly visits will be 
included in the MMRM model. Supportive summary in mITT-C population will be provided.    
BFI scale - Item 3 
The MMRM model as used in the primary analysis of spleen volume under primary efficacy 
endpoints will be used to compare treatment groups for BFI - Item 3 – for change from baseline to 
Week 52, using mITT population.  Supportive summary in mITT-C population will be provided.  
Sensitivity analyses are not planned, but may be undertaken if necessary.  
BPI scale - Item 3 
The MMRM model as used in the primary analysis of spleen volume under primary efficacy 
endpoints will be used to compare treatment groups for BPI - Item 3 – for change from baseline to 
Week 52, using mITT population. Supportive summary in mITT-C population will be provided.  
Sensitivity analyses are not planned, but may be undertaken if necessary.  
FACIT-Dyspnea symptom score 
The MMRM model as used in the primary analysis of spleen volume under primary efficacy 
endpoints will be used to compare treatment groups for FACIT-Dyspnea symptom score, change 
from baseline to Week 52, using mITT population.  Supportive summary in mITT-C population 
will be provided.  Sensitivity analyses are not planned, but may be undertaken if necessary.  
Splenomegaly-related score  
This is part of primary endpoints in US; all analyses for this endpoint are described in 
Section 2.4.5.1.  
The summary plots of the LS means from the MMRM for all the secondary efficacy endpoints in 
change or percentage change from baseline up to Week 52 with 95% CIs will be provided.  


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2.4.5.3 Multiplicity issues 
Primary endpoints  
The hypothesis testing of the primary endpoints will proceed as follows: 
 Compare olipudase alfa to placebo on DLco and spleen volume. The overall 
5% significance level for the two hypothesis tests will be maintained using the Hochberg 
method [MTP2 is maintained for 2-sided, 2-endpoint testing(20)]: 
- 
Higher of the two p-values will be compared to 0.05; if this p <0.05, both DLco and 
spleen volume are significant. 
- 
If higher p-value >=0.05, and lower p-value <0.025, then the endpoint associated with 
lower p value is significant but one associated with higher p value is not significant. 
For Europe and ROW: from the sponsor perspective, the study will be declared positive if at least 
one of the primary endpoints is statistically significant by the above method. 
For US only: If spleen volume is statistically significant based on the above testing, comparison of 
olipudase alfa versus placebo on SRS will be considered; if the two-sided p-value is <0.15, then 
the combination spleen endpoint is considered significant. Otherwise, the combination spleen 
endpoint is not significant. From the sponsor perspective, the study will be declared positive if 
either DLco or combination spleen endpoint is significant. 
Secondary endpoints (sequential testing) 
If statistical significance is reached on both the DLco and spleen volume using the Hochberg 
method (and the trend in splenomegaly-related score is established in case of USA), then 
hypothesis testing of the secondary efficacy endpoints will proceed using sequential testing at 
5% level with the order as specified below. At any step when the endpoint is not significant at 
5% level, the formal testing in subsequent steps will stop; the p-values for the subsequent 
endpoints in the sequence will be considered exploratory, and hence interpreted at the nominal 
level. This controls the overall type I error level at 5%, using the closed testing principle. If either 
of the primary endpoints is not significant, then hypothesis testing for the secondary endpoints 
will be considered exploratory, and p-values will be interpreted at the nominal level. 
For Europe and ROW, the order of testing for secondary endpoints is as follows: 
1. Percentage change in liver volume from baseline to Week 52 
2. Percentage change in platelet count from baseline to Week 52 
3. Change in BFI scale, Item 3 - from baseline to Week 52 
4. Change in BPI scale, Item 3 - from baseline to Week 52 
5. Change in FACIT-Dyspnea symptom score from baseline to Week 52 
6. Change in SRS from baseline to Week 52 


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In the US, the order of testing for secondary endpoints is as follows: 
1. Percentage change in liver volume from baseline to Week 52 
2. Percentage change in platelet count from baseline to Week 52 
3. Change in BFI scale, Item 3 - from baseline to Week 52 
4. Change in BPI scale, Item 3 - from baseline to Week 52 
5. Change in FACIT-Dyspnea symptom score from baseline to Week 52 
2.4.5.4 Subgroup analyses for the primary endpoints in PAP 
The consistency of the treatment effect in PAP will be evaluated as follows for percentage change 
from baseline to Week 52 of spleen volume (MN) and percentage change from baseline to 
Week 52 of % predicted DLco separately:  
 Spleen volume by baseline spleen volume severity (severe vs not severe). Severity is 
defined as baseline spleen volume >15 multiple of normal (MN).  
 % predicted DLco by baseline % predicted DLco severity (severe vs not severe). Severity 
is defined as baseline % predicted DLco <40%.  
In addition, for the endpoints of percentage change from baseline to Week 52 of spleen volume 
(MN), SRS, and % predicted DLco, the consistency of treatment effect in PAP will be assessed by 
the following subgroups: 
 Baseline ALT or AST abnormality (ALT or AST ≥1 ULN vs ALT and AST <1 ULN) 
 Baseline total bilirubin abnormality (total bilirubin ≥1.5 ULN vs total bilirubin <1.5 ULN) 
For the percentage change from baseline to Week 52 of spleen volume (MN), whether or not the 
presence of portal hypertension has an effect on olipudase alfa treatment will be assessed by the 
following subgroup: 
 Presence vs absence of portal hypertension at baseline (detected signs of portal vein 
hyperpressure is “likely severe portal hypertension” or “likely portal hypertension” for 
presence of portal hypertension vs detected signs of portal vein hyperpressure is “unlikely 
portal hypertension” for absence of portal hypertension) 
Descriptive summaries on the observed values, change from baseline and percent change from 
baseline to Week 52 of spleen volume (MN) for patients with severe portal hypertension at 
baseline will be provided as well if there are at least 3 patients identified with severe portal 
hypertension at baseline. If the number of patients with severe portal hypertension at baseline is 
low (<3), only individual patient data will be provided in listings. 
Due to the small sample size in these subpopulations, treatment difference within the subgroup 
will be difficult to interpret. Therefore, the focus of these analyses will be on assessment of 
interaction between subgroups and the treatment.  
For each subgroup, same MMRM models for the primary efficacy endpoints using data from the 
specific subgroup only will be conducted to provide estimate of treatment effect within each 


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subgroup. The summary plots of the LS means from the MMRM of the percentage change in 
DLco (% predicted) and spleen volume (MN) from baseline up to Week 52 with 95% CIs by 
subgroups will be provided. 
To assess the interactions between subgroup and treatment, the same MMRM models for the 
primary efficacy endpoints described in Section 2.4.5.1 will be applied with the addition of 
subgroup, subgroup-by-visit interaction, subgroup-by-treatment interaction, 
subgroup-by-treatment-by-visit interaction. The p-value for overall subgroup-by-treatment 
interaction, subgroup-by-treatment-by-visit interaction, subgroup-by-visit interaction as well as 
the p-value for subgroup-by-treatment interaction at week 52 will be provided.  
2.4.5.5 Responder analyses for the primary endpoints in PAP 
For the responder analyses specified below, binary measure of responder (yes vs no) at Week 52 
will be analyzed with logistic regression including treatment and baseline as covariates. Patients 
who had missing data at Week 52 will be counted as non-responder. Number and % of responder, 
as well as odds ratio, 95% CI and p-value from the logistic regression model will be provided. 
Responder analyses for spleen volume  
In addition to evaluating the percent change from baseline, a responder analysis will be performed 
to assist in the interpretation of a clinically meaningful result. In Gaucher disease, therapeutic 
goals for splenomegaly include reduction in spleen volume of 30-50% within year 1 of enzyme 
replacement therapy (21). Therefore a responder analysis will be performed, setting the threshold 
for response at <= -30% change from baseline in spleen volume at 52 weeks.  
Responder analyses for % predicted DLco 
International guidelines for clinically meaningful changes in DLco have been published for 
idiopathic pulmonary fibrosis (IPF) including 2017 Spanish IPF guidelines and the 2017 French 
IPF guidelines indicate a decrease of >15% DLCO in absolute values is associated with increased 
risk of mortality (22, 23). At the same time, the Connective Tissue Disease- associated interstitial 
lung disease (CTD-ILD) -OMERACT CTD-ILD working group has consensus guideline indicates 
that a relative 15% change constitutes a clinically meaningful change (24).  
In addition, Pelligrino et al (25), set a clinically meaningful threshold at 10% and similar values in the 
range of approximately 10-14% has been reported reviewing datasets from larger studies (26, 27).  
Therefore, a responder analysis will be performed using a threshold of 15% improvement in DLco 
from baseline. This means if a patient has a change from baseline on DLco (% predicted) >=15% 
at Week 52, then this patient will be a responder.  
Responder analyses for SRS, BFI scale - Item 3, BPI scale - Item 3 and FACIT-Dyspnea 
symptom score 
Thresholds for meaningful within-patient improvement on the SRS, BFI scale - Item 3, 
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the DFI12712 study (methods described in PRO Psychometric Statistical Analysis Plan). The 
primary and secondary improvement thresholds for each measure are as follows: 
 SRS: Primary threshold is change from baseline at Week 52 <= -12.5 points; Secondary 
threshold is change from baseline at Week 52 <= -18 points. 
 BFI scale - Item 3: Primary threshold is change from baseline at Week 52 <= -1.7 points; 
Secondary threshold is change from baseline at Week 52 <= -2.5 points. 
 BPI scale - Item 3: Primary threshold is change from baseline at Week 52 <= -2.5 points; 
Secondary threshold is change from baseline at Week 52 <= -4.0 points. 
 FACIT-Dyspnea symptom score: Primary threshold is change from baseline at Week 52 
<= -7.0 points; Secondary threshold is change from baseline at Week 52 <= -5.6 points.  
Responder analyses will be conducted using these thresholds. For each measure, patients who 
meet or exceed the meaningful change threshold at Week 52 will be considered a responder and 
those who do not meet or exceed the threshold will be considered non-responders. For patients 
who have missing data at Week 52, they will be considered as non-responder. Separate responder 
analyses will be conducted using the primary and secondary thresholds for each measure.  
Cumulative distribution functions (CDFs) will be generated by treatment group for SRS, 
BFI scale - Item 3, BPI scale - Item 3 and FACIT-Dyspnea symptom score. The CDFs will show 
the cumulative percent of patients on the y-axis and change from baseline to Week 52 scores on 
the x-axis. The CDFs will allow a visual inspection of the cumulative proportion of patients in 
each treatment group who achieved various levels of change on the PRO measure at Week 52. 
2.4.5.6 Compliance of eDiary data during PAP 
In addition, to assess the compliance for eDiary data including SRS, BFI scale - Item 3, and 
BPI scale - Item 3, the following summaries will be provided for each treatment group. 
 The number and percentage of patient with >=4 days of non-missing diary entries at each 
baseline and post-baseline collection visits up to Week 52 separately. 
 The number and percentage of patient with >=4 days of non-missing diary entries at both 
baseline and Week 52. 
 The number and percentage of patient with >=4 days of non-missing diary entries at 
baseline and all scheduled post-baseline visits up to Week 52. 
Compliance on the FACIT-Dyspnea symptom score will be calculated as (a) the number and 
percentage of patients who have non-missing values at baseline and each post-baseline visits up to 
Week 52 separately, (b) the number and percentage of patients who have non-missing values at 
both baseline and Week 52, and (c) the number and percentage of patients who have non-missing 
values at baseline and all scheduled post-baseline visits up to Week 52. 
2.4.5.7 Additional efficacy analyses in PAP 
No multiplicity adjustment will be conducted for additional efficacy endpoints. Nominal p-values 
will be reported in the tables. No sensitivity analyses will be performed for the additional efficacy 


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endpoints. All of the analyses specified below will be done in mITT population using data 
obtained before initiation of rescue therapy.  
Liver function tests 
The percentage change in ALT, AST, direct bilirubin, and total bilirubin from baseline up to 
Week 52 at pre-infusion time point will be analyzed using MMRM model described in 
Section 2.4.5.1. Data collected at quarterly visits will be included in the MMRM model.  
Pulmonary function tests 
The percentage change in FEV1 (% predicted), FVC (% predicted) and TLC (% predicted) from 
baseline up to Week 52 will be analyzed using the MMRM model described in Section 2.4.5.1. 
Pulmonary imaging - HRCT 
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. 
The change in the two types of mean scores for each feature from baseline up to Week 52 will be 
analyzed using the MMRM model described in Section 2.4.5.1. 
Pulmonary function 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 for each side of lungs, as explained in Section 2.1.4.3.  
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. 
The change in mean scores across two lungs for interstitial, which provides a measure of overall 
interstitial involvement, from baseline up to Week 52 will be analyzed using the MMRM model 
described in Section 2.4.5.1. 
Treadmill ergometry 
The parameters of cycle ergometry assessments are noted in Section 2.1.4.3. The change in 
percent predicted values (or observed values if the percent predicted value is not available) from 
baseline up to Week 52 will be analyzed using the MMRM model described in Section 2.4.5.1. 


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Fasting lipids (including lipoproteins of interest) 
The percentage change from baseline up to Week 52 values will be analyzed using MMRM model 
described in Section 2.4.5.1. Summary plots of the LS means from the MMRM of the change 
from baseline up to Week 52 with 95% CIs will be provided. 
Hematology 
Platelet and hemoglobin are efficacy parameters. Baseline definitions of hematology parameters 
are defined in Section 2.6.1. In the visits where two samples are to be collected, the average of 
two results will be used for summary and plots. Analysis of platelets has already been described 
under secondary efficacy parameters. For hemoglobin, the MMRM model as used in the primary 
analysis of spleen volume under primary efficacy endpoints will be used to compare treatment 
groups for percentage change from baseline up to Week 52, using mITT population. Data 
collected at quarterly visits will be included in the MMRM model.  
Bone disease assessments  
Bone marrow burden 
The change from baseline to the last observation during PAP will be analyzed using ANCOVA 
including covariates of baseline and treatment for total BMB score, femur score and spine score 
separately. 
DXA parameters 
The change from baseline to the last observation during PAP will be analyzed using ANCOVA 
model including covariates of baseline and treatment for BMD, T-score and Z-score by the region 
of femur and spine separately. 
Bone biomarkers 
Bone-specific alkaline phosphatase and C-telopeptide are bone biomarkers. The change from 
baseline to Week 52 for these bone biomarkers will be analyzed using MMRM model described 
in Section 2.4.5.1. 
Efficacy biomarkers 
Normalized values of serum chitotriosidase, and results from ligand 18 (CCL-18), and 
angiotensin-converting enzyme (ACE) are efficacy biomarkers. The percentage change from 
baseline up to Week 52 for efficacy biomarkers will be analyzed using MMRM model described 
in Section 2.4.5.1.  


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Physician’s global assessment  
At the scheduled post-baseline visits, the investigator will also evaluate the patient’s current 
clinical status compared to screening (baseline) by marking 1 of 7 categories and those 
7 categories 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 MMRM model 
described in Section 2.4.5.1. And in the MMRM model, the baseline value will be Physician’s 
global assessment of severity at screening with value of 1=mild, 2=moderate, 3=severe. 
In addition, as supportive analysis, at Week 52, patients will be categorized as responder if having 
numeric value of 3, 2, or 1, otherwise, patient will be categorized as non-responder if having 
numeric value of 0, -1, -2, -3 or missing. This binary measure of responder (yes vs no) at Week 52 
will be analyzed with logistic regression including treatment group and baseline as covariates.  
NMR of HDL 
The NMR of HDL data will be provided in data listings. 
Liver function via echo-Doppler ultrasound 
A frequency shift table for detected signs of portal vein hyperpressure will be provided. 
2.4.5.8 PAP+ETP efficacy analyses 
All of the efficacy endpoints throughout the study treatment epoch including all longitudinal time 
points from both PAP and ETP will be summarized by randomized treatment groups in PAP, 
using mITT population and the same baseline definition for both randomized treatment groups 
(latest observation prior to the first infusion of the IMP in the study, see Section 2.6.1 for the 
details of hematology parameters and possibly ECG parameters). ANCOVA model with baseline 
and treatment group as covariates will be used to assess the means of each treatment group and 
the 95% CIs of both treatment groups as well as the difference between two groups at each time 
point. It is understood that all patients in ETP are on olipudase alfa. Summary plots and by-patient 
plots will be provided as appropriate.  
For the primary efficacy endpoints, in addition to the above summaries, the descriptive summaries 
over time while patients are treated with olipudase alfa using mITT population will be provided. 


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Since patients who were randomized to placebo group start receiving olipudase alfa when they 
enter the ETP, their baseline will be defined as the latest observation prior to the first infusion of 
olipudase alfa. 
2.4.6 Analyses of safety data 
The summary of safety results will be presented by actual treatment received using safety 
population. The epochs for safety analysis have been defined in Section 2.1.5. The assessment of 
safety measures 
 will be conducted through pooled 
analyses and presented in the integrated summary of safety (ISS). 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
 The baseline value is defined as the last available value before the first infusion of the 
study drug, except for hematology parameters and possibly ECG parameters. For complete 
definition of baseline, refer to Section 2.6.1. 
 The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned.  
The potentially clinically significant abnormality (PCSA) values are defined by the Sponsor 
according to predefined criteria/thresholds based on literature review for clinical laboratory tests, 
vital signs, and ECG; this list is provided in Section 7.2. 
 PCSA criteria will determine which patients had at least 1 PCSA during the 
treatment-emergent adverse event period, taking into account all evaluations performed 
during the treatment-emergent adverse event period, including unscheduled or repeated 
evaluations. The number of all patients with any post-baseline evaluation will be the 
numerator for the on-treatment PCSA percentage. 
 The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period by treatment group on the safety population. 
 Before determining a value as PCSA, the value will be rounded to the precision that the 
PCSA criterion is defined. 
2.4.6.1 Adverse events 
Pre-treatment adverse events are defined as those that have an onset date/time before the first 
infusion date/time of the patient. Treatment emergent adverse events are those that have an onset 
date/time in the treatment epoch. Any AE reported in the database with onset date after the end of 
the treatment epoch will be classified as post-treatment. 


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The epochs for safety analysis have been defined in Section 2.1.5. Treatment-emergent adverse 
events will be presented for different periods under different treatment groups as follows (and as 
appropriate): 
1. Adverse events started in PAP treatment epoch, by randomized treatment group.  
2. Adverse events started in either PAP or in ETP while taking olipudase alfa. This will be 
presented by randomized treatment group as well as combined (ie, all patients treated with 
olipudase alfa). 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events. 
Pretreatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, or 
treatment-emergent. 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 
it is pretreatment. Details on classification of adverse events with missing or partial onset dates 
are provided in Section 2.6.2. If an AE worsens in severity, two AEs of same verbatim but with 
different start/end dates and different severity are captured separately on the AE log page in the 
eCRF. 
The AE log page in the eCRF 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. 
The adverse events summary will be presented by SOC and PT sorted by the internationally 
agreed SOC order and decreasing frequency of PTs within SOCs within the olipudase alfa 
treatment arm, unless otherwise specified. Multiple occurrences of the same event in the same 
patient will be counted only once in the tables within a particular treatment phase. The 
denominator for computation of percentages is the safety population within each treatment group. 
Start day of treatment emergent AE relative to first infusion = Start date of AE – first infusion 
date + 1 


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Start day of pre-treatment AE relative to first infusion = Start date of AE – first infusion date  
2.4.6.1.1 Treatment-emergent adverse events 
An overview of treatment-emergent adverse events (TEAEs) for PAP will be provided to include 
(potentially related is defined as either ‘related’ or ‘possibly related’ as assessed by the 
investigator): 
 TEAEs 
 TEAEs potentially related to study treatment 
 TEAEs by 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  
 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 the eCRF, see protocol 
Section 8.1.6 for details) 
The following summaries will be produced by primary SOC and PT: 
 TEAEs  
 TEAEs by 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 are defined as those with percentages of events >=2% and number of 
patients >=2 in the olipudase alfa treatment group and in addition, the percentage of patients with 
the specific TEAEs in olipudase alfa treatment group is greater than placebo. The most common 
TEAEs by SOC and PT will be provided in descending order of olipudase alfa incidence, 
followed by placebo incidence.  
Summary of TEAEs by the latest infusion dose immediately preceding the start of AE will be 
provided by SOC and PT. 


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Post-rescue PAP TEAEs by SOC and preferred term will be provided separately in a data listing 
using the rescue population. 
2.4.6.1.2 Adverse events of special interest 
Protocol-defined IAR: The following summaries will be produced by primary SOC and PT, and 
by treatment group for PAP:  
 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 
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. 
A subset of protocol-defined IARs will also be defined programmatically by searching for 
preferred terms within Hypersensitivity reaction SMQs (identified using SMQ code 20000214 
Broad and Narrow scope). The summaries of Hypersensitivity IARs will be provided by primary 
SOC and PT. 
Algorithm-defined IAR: Summary of algorithm-defined IARs by primary SOC and PT will be 
provided for PAP.   
2.4.6.1.3 Adverse events of other interest 
Infections: Infection AEs are already part of system organ class of Infections and Infestations in 
all TEAE displays. No separate display is planned. 
Bleeding: Bleeding related TEAEs will be summarized using the standard MedDRA queries 
(SMQs) Hemorrhages (identified using SMQ code 20000038 broad and narrow scope). 
2.4.6.1.4 Serious adverse events 
The following summaries will be provided by primary SOC and PT for PAP: 
 Treatment-emergent serious adverse events 


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2.4.6.1.5 Adverse events leading to permanent treatment discontinuation 
In this study, if the treatment is discontinued permanently, the patient is withdrawn from the 
study. A temporary dose interruption is not considered permanent discontinuation of study 
treatment. Any AEs leading to permanent treatment discontinuation will be summarized by 
primary SOC and PT - for PAP, ETP and cumulative over PAP and ETP. The listing of such AEs 
will include the olipudase alfa dose of the infusion prior to or during the occurrence of the AE 
leading to treatment discontinuation. Any AE leading to discontinuation of study treatment 
post-rescue in PAP will be provided in data listing. 
2.4.6.1.6 Adverse events leading to dose reduction 
Any AEs leading to dose reduction will be listed including the olipudase alfa dose of the infusion 
prior to or during the occurrence of the AE leading to dose reduction, where applicable. 
2.4.6.1.7 Adverse events leading to drug interruption 
Any AEs leading to drug interruption will be listed including the olipudase alfa dose of the 
infusion prior to or during the occurrence of the AE leading to drug interruption, where 
applicable. 
2.4.6.2 Laboratory data  
For parameters that are reported as below the quantification limit (BQL), the results often convey 
a clinically meaningful change. Therefore, a numerical value is necessary to be imputed for 
including these in descriptive statistics calculations. For all these parameters either the lower limit 
of quantification (LLOQ) is available in the database, or the result is reported as <xx. The numeric 
value for results of BQL will be imputed as LLOQ/2; the numeric value for results reported as 
<xx will be imputed as xx/2. 
In hematology, platelets and hemoglobin are part of efficacy parameters, and have been described 
under Section 2.1.4. For the rest of hematology parameters, the baseline will be defined the same 
way (Section 2.6.1), and any visit which is scheduled to collect two samples pre-infusion for 
WBC, the average of the two values will be used as pre-infusion value. 
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 2.4.5), liver function tests, coagulation, etc. as described in Section 2.1.5 (excluding lipids 
which have been described as part of efficacy, Section 2.4.5.7). Summary plots over time will also 
be provided as needed.  
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. 


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PCSA values for clinical chemistry, hematology and liver function tests (provided in Section 7.2) 
during the study (from first infusion to last available observation) will be summarized. PCSA 
values for hematology, liver function test and clinical chemistry parameters will be provided in 
separate listings.  
2.4.6.3 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 (provided in Section 7.2) during the study (from first infusion start to last available 
observation) will be summarized. 
2.4.6.4 Electrocardiogram variables 
For ECG parameters, the baseline is defined in Section 2.6.1. The observed data and change from 
baseline will be summarized at each scheduled time point.  
PCSA values (provided in Section 7.2) will be summarized during the study (from first infusion 
start to last available observation).  
2.4.6.5 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 cardiac index, ejection fraction (%), pulmonary artery systolic pressure will be provided.  
2.4.6.6 Physical examinations 
Complete physical examinations will be classified as normal or abnormal. Shifts from baseline to 
scheduled time points, any time during the on-treatment period and the last available value, in the 
abnormality of any complete physical examinations (except overall neurological exam - please see 
Section 2.4.6.7) 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.  
2.4.6.7 Extended neurological examinations 
Neurological examinations (Section 2.1.5.6) will be classified as normal/abnormal findings. 
Frequency shift table will be provided. The overall evaluation of neurological exam collected in 
the eCRF under physical exam will be included in this section. 


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2.4.6.8 Liver biopsy 
Liver biopsy is planned at screening, Week 52 and Week 104. 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 will 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.  
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 accumulation in liver tissue that is assessed from liver biopsy will be summarized 
under pharmacodynamic endpoints (Section 2.1.7).  
2.4.6.9 Liver function via echo-Doppler ultrasound 
Liver ultrasound Doppler data will be provided in listings. 
2.4.6.10 Inflammatory and vascular biomarkers 
Results of inflammatory and vascular biomarkers will be provided in data listings. IL-6 and IL-8 
are part of safety biomarkers and will not be included here; for details of IL-6/IL-8 analysis, 
please refer to Section 2.4.6.11.  
2.4.6.11 Safety biomarkers 
Observed values, change from baseline and percent change from baseline will be summarized at 
each scheduled time point. Summary plot for the mean ceramide levels in plasma over time also 
be presented. By-patient plots for the observed values over time will be provided for the highly 
sensitive C-Reactive protein, iron, ferritin, troponin I, calcitonin, Interleukin 6 and Interleukin 8 
will be provided.  
2.4.6.12 Immune response assessments 
For ADA summaries during PAP period, the baseline is the last non-missing ADA assessment 
prior to the first IMP. For ADA summaries during PAP+ETP for duration on olipuase alfa 
exposure, the baseline is the last non-missing ADA assessment prior to the first oliupdase alfa 
infusion. 
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. 


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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. 
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. 


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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 
 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 
 
will be conducted through pooled analyses and presented in the integrated summary of 
immunogenicity. The assessment of immunogenicity and safety 
 will be presented in 
the integrated summary of safety (ISS). 
2.4.6.13 Subgroup analyses for key safety measures in PAP 
The following subgroup analyses for key safety measures will be performed:  
 Baseline ALT or AST abnormality (ALT or AST ≥1 ULN vs ALT and AST <1 ULN) 
 Baseline total bilirubin abnormality (total bilirubin ≥1.5 ULN vs total bilirubin <1.5 ULN) 
The key safety measures that will be analyzed by the above subgroup include the followings: 


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 Overview of treatment-emergent adverse events 
 Summary of treatment-emergent adverse events by primary SOC and PT  
 Summary of protocol-defined infusion-associated reactions by primary SOC and PT  
2.4.6.14 PAP+ETP safety analyses 
For categorical measures, such as AE, data throughout both PAP and ETP will be summarized as 
three groups: 
 Previous placebo group includes patients who are randomized to placebo. For patients in 
this group, only the data during olipudase alfa exposure at ETP will be summarized. The 
baseline will be defined as the last non-missing value prior to first olipudase alfa infusion 
at ETP. 
 Previous olipudase alfa group includes patients who are randomized to olipudase alfa. 
For patients in this group, all the data during PAP and ETP with olipudase alfa exposure 
will be summarized. The baseline will be defined as the last non-missing value prior to 
first olipudase alfa infusion at PAP. 
 Overall Olipudase alfa group includes patients from previous placebo group and 
Previous Olipudase alfa group. 
For continuous measures collected at longitudinal time point, such as labs and vital signs, data 
throughout both PAP and ETP will be summarized as two groups: 
 Placebo/olipudase alfa group includes patients who are randomized to placebo. For 
patients in this group, all data during PAP and ETP will be summarized at each 
longitudinal time point. The baseline will be defined as the last non-missing value prior to 
first infusion of IMP at PAP. 
 Olipudase alfa/Olipudase alfa group includes patients who are randomized to olipudase 
alfa. For patients in this group, all the data during PAP and ETP with olipudase alfa 
exposure will be summarized at each longitudinal time point. The baseline will be defined 
as the last non-missing value prior to first infusion of IMP at PAP. 
2.4.7 Analyses of pharmacokinetic and pharmacodynamic variables 
2.4.7.1 Pharmacodynamic analysis 
Pharmacodynamic endpoints include sphingomyelin and its metabolites, including 
sphingomyelin accumulation in liver tissue. These endpoints will be analyzed using 
pharmacodynamics population. Observed, change from baseline values and percent change 
from baseline values will be summarized at scheduled visits. Summary plots of the mean 
values over time for all pharmacodynamics endpoints will be provided. 


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2.4.7.2 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 dose level, process materials 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, and dose level under the responsibility of pharmacokinetics, dynamics and metabolism 
(PKDM) using WinNonlin Professional, or Phoenix, 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 the olipudase alfa treatment group 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.  
2.4.8 Analyses of quality of life (patient reported outcome)/health economics variables 
All of the analyses specified below will be done in mITT population. Observations collected after 
the initiation of the rescue therapy will be excluded from the analysis. Exploratory p-values will 
be provided, if applicable, from MMRM model described in Section 2.4.5.1 for analyses of data 
from PAP.  
Brief fatigue inventory  
The change from baseline up to Week 52 on severity and interference of fatigue as measured by 
BFI (individual questions as well as scale score) will be analyzed using the MMRM model 
described in Section 2.4.5.1. 
Brief Pain Inventory – Short Form (BPI-SF) 
The change from baseline up to Week 52 on severity (average of Questions 3, 4, 5, 6) and 
interference (Q9) of pain as measured by BPI-SF (individual questions as well as scale score) will 
be analyzed using the MMRM model described in Section 2.4.5.1. 


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SF-36 
The change from baseline up to Week 52 on 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 analyzed using the MMRM model described in Section 2.4.5.1. 
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 last three months of each scheduled time point, the following measures will be summarized: 
the number of physician visits (total number of physician visits by adding up all the visits from 
different specialists), the number of emergency room visits, the number of days of paid caregiver 
assistance and the number of DAYS of care/help from a family member(s) and/or friend(s). For 
symptom in the last three months of each scheduled time point, frequency and level of bothersome 
of each symptom will be listed. For physical activity in the last three months of each scheduled 
time point, the number and percentage of patients at each frequency of physical activities will be 
summarized.  
FACIT-Dyspnea 
The symptom scores have been discussed under secondary efficacy endpoints. Functional 
limitation scores will be provided in data listing. 
Health-related productivity 
Each question (about employment, household chores, homework/classes) will be summarized 
separately at each scheduled time point. At each scheduled time point, the following number of 
hours missed due to ASMD or its treatment will be summarized: the number of hours missed of 
work, the number of hours missed of house hold chores, the number of hours missed of homework 
or class. If the answer for ASMD or its treatment(s) keep you from work, house hold chores, 
homework or class is “no”, then number of hours missed will be imputed as 0 for the summary.  
EQ-5D-5L 
Each question on a 1-5 scale (for mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression), higher score indicating worse, will be summarized separately at each scheduled 
time point, providing number and % of patients at each level. The change from baseline up to 
Week 52 on the VAS scale score on “your health today” (0 indicating the worst, and 100 indicating 
the best) will be analyzed using the MMRM model described in Section 2.4.5.1. 
PGIS/PGIC 
For PGIC, 7 categories of response will be converted to the following numeric values:  
 Very much Better = 3 
 Moderately Better = 2 


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 A Little Better = 1 
 No Change = 0 
 A Little Worse = -1  
 Moderately Worse = -2 
 Very much Worse =-3  
Observed numeric values at each post-baseline visits will be analyzed using MMRM model 
described in Section 2.4.5.1. And in the MMRM model, the baseline value will be PGIS at 
screening with value of 0=none, 1=mild, 2=moderate, 3=severe, 4=very severe. 
In addition, as supportive analysis, at week 52, patients will be categorized as responder if having 
numeric value of 3, 2, or 1, otherwise, patient will be categorized as non-responder if having 
numeric value of 0, -1, -2, -3 or missing. This binary measure of responder (yes vs no) at Week 52 
will be analyzed with logistic regression including treatment and baseline as covariates. 
The PGIS at baseline and post-baseline visits will be converted to a numeric score on 0-4 scale 
(0=none, 1=mild, 2=moderate, 3=severe, 4=very severe). Therefore, change from baseline at each 
post-baseline visits using MMRM model described in Section 2.4.5.1. 
2.4.8.1 PAP+ETP quality of life analyses 
All of the quality of life endpoints throughout the study treatment epoch including all longitudinal 
time points from both PAP and ETP will be summarized by randomized treatment group in PAP, 
using mITT population. ANCOVA model with baseline and treatment group as covariates will be 
used to assess the means of each treatment group and the 95% CIs of both treatment groups as 
well as the difference between two groups at each time point. It is understood that all patients in 
ETP are on olipudase alfa. 
2.5 
PATIENT NARRATIVES 
Patient narratives criteria for this study are as follows: 
 Deaths 
 Serious adverse event  
 Adverse Events leading to permanent treatment discontinuation 
 Adverse events of special interest including the followings: 
- 
Protocol defined IARs (as specified in Section 2.1.5.1) 
- 
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 


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- 
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 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, 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. 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 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.  
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 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. 
 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 the eCRF.   


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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. Further, if the PAP or ETP period 
could not be determined, this AE will be considered as TEAE in PAP. 
 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 before any missing data imputation algorithm is implemented. 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. If these two unscheduled visits happened in the same distance to 
the target visit date with one before and one after, the one before the target visit date will be used. 
Laboratory, vital signs, ECG and pharmacodynamic 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. For ADA analyses, unscheduled visits 
will be included in the by-visit summaries. 


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2.6.5 Pooling of centers for statistical analyses 
Not applicable to the primary analysis. Investigation of the effects of geographic regions may be 
performed on an exploratory basis. 
2.6.6 Statistical technical issues 
A sensitivity analysis of the primary efficacy endpoints using a pattern mixture model and 
different imputations for values missing during the on-treatment period versus values missing 
after treatment discontinuation is planned. The description of the analysis refers to the DLco 
endpoint; differences in the implementation for the spleen volume and splenomegaly-related 
scores are noted. On-treatment period is defined as the time period between the start of 
first infusion of the study drug up to the day of last infusion in PAP +13 days for patients who did 
not continue in ETP, or up to the day before first infusion in ETP if the patient continued into 
ETP.  
A pattern-mixture model sensitivity analysis of the percentage change in DLco (% predicted) 
from baseline to 52 weeks will be conducted, with a different imputation strategy applied for 
missing DLco values during the on-treatment period and missing DLco values after treatment 
discontinuation (ie, after the day of last infusion +13 days) based on the following assumptions: 
 Patients within 13 days of their last IMP infusion would continue to show benefit from 
treatment similar to that observed at the scheduled time point. Therefore, DLco values 
missing during the on-treatment period will be considered “Missing At Random” and 
imputed using a model estimated using all samples collected on-treatment. 
 Patients who stop taking their study treatment will no longer benefit from it in the future, 
and thus will tend to have DLco values returning to baseline. Thus DLco values missing 
after treatment discontinuation will be imputed based on a patient’s own baseline value. 
Missing DLco values will be imputed 100 times to generate 100 complete data sets. The percent 
change from baseline to 52 weeks will be derived from observed and imputed DLco at this time 
point. The complete data sets will be analyzed using an ANCOVA model with treatment group, 
baseline DLco and baseline age as covariates. The results from the 100 analyses will be combined 
using Rubin’s formulae. 
Imputation of missing data during the on-treatment period 
Missing DLco values during the on-treatment period will be imputed from other on-treatment 
measurements assuming MAR, using SAS® PROC MI. 
Only DLco values collected during the on-treatment period will be included in the imputation 
model. This way, missing DLco values during the on-treatment period will be imputed based 
solely on observed on-treatment calculated DLco values. 
The imputation model will include baseline DLco, baseline age and all observed DLco values at 
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pattern of missing data could be non-monotone, a MCMC method will be used. A minimum value 
of 0 will be specified in order to avoid negative imputed DLco values. 
Sample SAS code is provided below: 
proc mi data=DATAIN out=DATAOUT nimpute=100 minimum=0; 
  var DLCO_BASE AGE_BASE DLCO_W26 DLCO_W52; 
  by TRTPN; 
run; 
For the splenomegaly-related score endpoint which is collected at Weeks 14, 26, 38 and 52, the 
above code will be modified accordingly. 
As stated above, the input dataset DATAIN will include only DLco values collected during the 
on-treatment period. Any DLco values collected after the treatment discontinuation (after last 
infusion +13 days) will be excluded from the input dataset. In practice, the MI procedure will 
generate imputed values for all missing values (whether on-treatment or post-treatment), but only 
imputed values during the-on-treatment period will be kept in the final datasets that will be 
analyzed using ANCOVA. Imputed values during the post-treatment period will be discarded and 
replaced by imputed values described in the next section. 
Imputation of missing data after treatment discontinuation 
Missing DLco values during the post-treatment period will be imputed assuming DLco values 
will, on average, return to baseline values. 
For each patient, missing post-treatment DLco values will be imputed 100 times, using a random 
draw from a normal distribution, with mean equal to a patient’s own baseline value and variance 
equal to the conditional variance at the specific time-point, given the baseline value. 
Let Y0 and Y1 denote the DLco at baseline and at the specific time-point respectively. Since 
Y0 and Y1 are assumed to have a bivariate normal distribution, the conditional variance of Y1 
given Y0 is: 
)
1(
)
(
2
2
1
0
0
1




y
Y
Y
Var
 
where denotes the variance of Y1 and ρ the coefficient of correlation between Y0 and Y1. 
The conditional variance will be estimated from observed data within the same treatment arm at 
the specific time-point. 
During the random generation process, a minimum value of 0 will also be applied in order to 
avoid negative imputed DLco values. 
 


Statistical Analysis Plan  
4-Nov-2019 
GZ402665-DFI12712 - olipudase alfa 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 69 
3 
INTERIM ANALYSIS 
There is no formal interim analysis before the primary timepoint (Week 52). Periodic unblinded 
safety data review is carried out by an external Data Monitoring Committee, aided by external 
vendor providing statistics and programming support. Efficacy will be assessed when all patients 
complete 52 weeks in PAP and data are unblinded to the study team in preparation for the CSR 
for PAP. For ETP data, efficacy analysis is exploratory. 


Statistical Analysis Plan  
4-Nov-2019 
GZ402665-DFI12712 - olipudase alfa 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 70 
4 
DATABASE LOCK 
The database is planned to be locked within 6 weeks after the last patient last visit in PAP. 


Statistical Analysis Plan  
4-Nov-2019 
GZ402665-DFI12712 - olipudase alfa 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 71 
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. 


Statistical Analysis Plan  
4-Nov-2019 
GZ402665-DFI12712 - olipudase alfa 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 72 
6 
REFERENCES 
1. Crapo RO, Morris AH. Standardized single breath normal values for carbon Monoxide 
Diffusing Capacity. Am Rev Respir Dis. 1981;123:185-9. 
2. 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. 
3. 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. 
4. Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting 
the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT 
recommendations. J Pain. 2008;9(2):105-21. 
5. 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;86:1848-55. 
6. Cleeland CS, Ryan KM. Pain assessment: Global use of the Brief Pain Inventory. Ann Acad 
Med Singapore. 1994;23(2):129-38. 
7. Cleeland, CS. The brief pain inventory. MD Anderson, TX. Copyright: 2009. 
8. Choi SW, Victorson DE, Yount S, Anton S, Cella D. Development of a conceptual 
framework and calibrated item banks to measure patient-reported dyspnea severity and 
related functional limitations. Value Health. 2011;14(2):291-306. 
9. Global Lung Initiative (GLI) reference. Available from: URL: http://www.ers-
education.org/guidelines/global-lung-function-initiative.aspx 
10. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et al. National Lipids 
Assocation recommendations for patient-centered management for dyslipidemia: Part 1- full 
report. J Clin Lipidol. 2015;9:129-69. 
11. Thurberg BL, Wasserstein MP, Schiano T, O'Brien F, Richards S, Cox GF, et al. Liver and 
skin histopathology in adults with acid sphingomyelinase deficiency (Niemann-Pick Disease 
Type B). Am J Surg Pathol. 2012;36(8):1234-46. 
12. Kammerman LA, Cappelleri J, Bartlett J. Patient-Reported Outcomes. Wiley StatsRef: 
Statistics Reference. [Online]. 2017. DOI: 10.1002/9781118445112.stat07929 
13. Sloan JA, Dueck AC, Erikson PA et al. Analysis and interpretation of results based on 
patient-reported outcomes. Value Health. 2007;10(2):S106-15. 


Statistical Analysis Plan  
4-Nov-2019 
GZ402665-DFI12712 - olipudase alfa 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 73 
14. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey: Conceptual 
framework and item selection. Med Care. 1992;30(6):473-83. 
15. Maruish ME. User’s Manual for the SF-36v2 Health Survey. 3rd ed. Lincoln, RI: 
QualityMetric, Inc; 2011.  
16. EQ-5D User guide. Available from: URL:https://euroqol.org/wp-
content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf 
17. Mallinckrodt CH, Lane PW, Schnell, D, Peng Y, Mancuso JP.  Recommendations for the 
Primary Analysis of Continuous Endpoints in Longitudinal Clinical Trials. Drug Information 
Journal. 2008;42:303-19. 
18. Siddiqui O, Hung HMJ, O’Neill R.  MMRM vs. LOCF: A comprehensive comparison based 
on simulation study and 25 NDA datasets. J Biopharm Stat. 2009;19:227-46. 
19. Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics.1997;53:983-97. 
20. Samuel-Cahn E. Is the Simes improved Bonferroni procedure conservative? Biometrika. 
1996;83(4):928-33. 
21. Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M, et al. Therapeutic goals in 
the treatment of Gaucher Disease. Semin Hematol. 2004;41(4 Suppl 5):4-14. 
22. Xaubet A, Molina-Molina M, Acosta O, Bollo E, Castillo D, Fernández-Fabrellas E, et al. 
Guidelines for the medical treatment of idiopathic pulmonary fibrosis. Arch Bronconeumol. 
2017;53(5):263-9. 
23. Cottin V, Crestani B, Cadranel J, Cordier JF, Marchand-Adam S, Prévot G, et al. French 
practical guidelines for the diagnosis and management of idiotpathic pulmonary fibrosis - 
2017 update. Full-length version. Rev Mal REspir. 2017;34(8):900-68. 
24. Khanna D, Mittoo S, Aggarwal R, Proudman SM, Dalbeth N, Matteson EL, et al. Connective 
Tissue diseases associated interstitial lung diseases (CTD-ILD) -- report from OMERACT 
CTD-ILD working group. J Rheumatol. 2015;42(11):2168-71. 
25. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative 
strategies for lung function tests. Eur Respir J. 2005;26(5):948-68. 
26. Horita N, Miyazawa N, Kojima R, Inoue M, Ishigatsubo Y, Kaneko T. Minimum clinically 
important difference in diffusing capacity of the lungs for carbon monoxide among patients 
with severe and very severe chronic obstructive pulmonary disease. COPD. 2015;12(1):31-7. 
27. Punjabi NM, Shade D, Patel AM, Wise RA. Measurement variability in single-breath 
difusing capacity of the lung. Chest. 2003;123(4):1082-9. 


Statistical Analysis Plan  
4-Nov-2019 
GZ402665-DFI12712 - olipudase alfa 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 74 
7 
LIST OF APPENDICES 
7.1 
FACIT-DYSPNEA SHORT FORM - CONVERSION FROM RAW TO SCALE SCORES  
 
Raw dyspnea score 
Scale score 
SE 
Raw functional 
limitations score 
Scale score 
SE 
0 
27.7 
4.7 
0 
29.7 
4.7 
1 
32.8 
3.7 
1 
34.9 
3.4 
2 
36.1 
3.2 
2 
38.0 
3.0 
3 
38.6 
2.8 
3 
40.3 
2.7 
4 
40.6 
2.6 
4 
42.1 
2.5 
5 
42.3 
2.4 
5 
43.8 
2.4 
6 
43.8 
2.2 
6 
45.2 
2.3 
7 
45.2 
2.2 
7 
46.5 
2.2 
8 
46.4 
2.1 
8 
47.8 
2.2 
9 
47.6 
2.1 
9 
49.0 
2.2 
10 
48.8 
2.0 
10 
50.1 
2.1 
11 
50.0 
2.0 
11 
51.2 
2.1 
12 
51.1 
2.0 
12 
52.3 
2.1 
13 
52.1 
1.9 
13 
53.4 
2.1 
14 
53.2 
1.9 
14 
54.4 
2.0 
15 
54.2 
1.9 
15 
55.4 
2.0 
16 
55.2 
1.9 
16 
56.4 
2.0 
17 
56.2 
1.9 
17 
57.4 
2.0 
18 
57.2 
1.9 
18 
58.4 
2.0 
19 
58.1 
1.9 
19 
59.4 
2.0 
20 
59.2 
1.9 
20 
60.4 
2.1 
21 
60.2 
2.0 
21 
61.4 
2.1 
22 
61.2 
2.0 
22 
62.4 
2.1 
23 
62.3 
2.0 
23 
63.5 
2.2 
24 
63.5 
2.1 
24 
64.7 
2.2 
25 
64.8 
2.1 
25 
66.0 
2.3 
26 
66.1 
2.3 
26 
67.3 
2.4 
27 
67.7 
2.4 
27 
68.9 
2.6 
28 
69.5 
2.6 
28 
70.7 
2.8 
29 
71.9 
3.0 
29 
73.0 
3.2 
30 
75.9 
4.0 
30 
76.7 
4.1 


Statistical Analysis Plan  
4-Nov-2019 
GZ402665-DFI12712 - olipudase alfa 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 75 
7.2 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA  
 
Liver function tests 
ALT 
>3 x ULN 
>5 x ULN 
>10 x ULN 
>20 x ULN 
AST 
>3 x ULN 
>5 x ULN 
>10 x ULN 
>20 x ULN 
Alkaline Phosphatase 
>1.5 x ULN 
Total Bilirubin 
>1.5 x ULN 
>2 x ULN 
ALT and Total Bilirubin 
ALT >3 x ULN and Total Bilirubin >2 x ULN 
Hematology 
WBC 
<3.0 GIGA/L (non-Black), <2.0 GIGA/L (Black), 
>=16.0 GIGA/L 
Lymphocytes 
>4.0 GIGA/L 
Neutrophils 
<1.5 GIGA/L (non-Black) 
<1.0 GIGA/L (Black) 
Monocytes 
>0.7 GIGA/L 
Basophils 
>0.1 GIGA/L 
Eosinophils 
>0.5 GIGA/L or 
> ULN if ULN >=0.5 GIGA /L 
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) 
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 
RBC 
>=6 TERA/L 
Platelets 
<100 GIGA/L and 20% decrease from baseline 
>=700 GIGA/L 
 


Statistical Analysis Plan  
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Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 76 
ECG – PCSA criteria 
HR 
<=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 
QRS 
>=120 ms 
QTc 
Absolute values (ms)       
 
Males  
Females 
 
431-450ms 
451-470 ms 
 
>450 ms 
 >470 ms 
 
≥500 ms 
≥500 ms 
Increase from baseline (Males and Females) 
30-60 ms 
>60 ms 
Clinical chemistry  
Creatinine 
>=150 µmol/L (Adults) 
>=30% increase from baseline 
>=100% increase from baseline 
Blood Urea Nitrogen 
>=17 mmol/L 
Chloride 
<80 mmol/L 
>115 mmol/L 
Sodium 
<=129 mmol/L 
>=160 mmol/L 
Potassium 
<3 mmol/L 
>=5.5 mmol/L 
Glucose 
    Hypoglycemia 
    Hyperglycemia 
 
<=3.9 mmol/L and < LLN 
>=11.1 mmol/L (unfasted), >7 mmol/L (fasted) 
Albumin 
<=25 g/L 
Vital signs  
Heart rate 
<=50 bpm and decrease from baseline >=20 bpm 
>=120 bpm and increase from baseline >=20 bpm 
Systolic BP 
<=95 mmHg and decrease from baseline >=20 mmHg 
>=160 mmHg and increase from baseline >=20 mmHg 
Diastolic BP 
<=45 mmHg and decrease from baseline >=10 mmHg 
>=110 mmHg and increase from baseline >=10 mmHg 
Urinalysis  
pH 
<=4.6 
>=8 
 
 


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