Clinical trial NCT02292654
Conditions: Sphingomyelin Lipidosis
Sponsor: Genzyme, a Sanofi Company
Start date: 2015-05-01; Completion date: 2019-12-09
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

To evaluate the safety and tolerability of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks.

Secondary Objective:

To characterize the pharmacokinetic profile and evaluate the pharmacodynamics and exploratory efficacy of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks.

Detailed description:
The maximum study duration per participant was approximately 18 months (screening period: up to 60 days; treatment period: 64 weeks; post-treatment period: up to 37 days, not applicable if participants enrolled in a long-term extension treatment trial).

Arms: arm 1: Participants received intravenous (IV) infusion of olipudase alfa once every 2 weeks (Q2W) for 64 weeks. Each participant underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 milligram per kilogram (mg/kg). Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 64 treatment weeks.
Interventions: intervention 1: Olipudase alfa
Intervention descriptions: intervention 1: Pharmaceutical form: powder for concentrate for solution for infusion Route of administration: intravenous infusion

Protocol documents:
Prot_000.pdf: 


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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: 
 
 
 
 
Genzyme Corporation 
500 Kendall St 
Cambridge, MA 02142 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: GZ402665 
(olipudase alfa) 
STUDY No: DFI13803 
TITLE 
A phase 1/2, multi-center, open-label, ascending dose study to evaluate the 
safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory 
efficacy of olipudase alfa in pediatric patients aged <18 years with acid 
sphingomyelinase deficiency 
INVESTIGATOR/TRIAL LOCATION 
Multi-national and multi-center. More than one region as needed to allow 
enrollment of sufficient numbers of patients in a reasonable time. Potential 
countries include but are not limited to United States, United Kingdom, Italy, 
Brazil, Germany, and France. 
PHASE OF DEVELOPMENT 
1/2 
STUDY OBJECTIVE(S) 
Primary objective: To evaluate the safety and tolerability of olipudase alfa 
administered intravenously in pediatric patients every 2 weeks for 64 weeks. 
Secondary objective(s): To characterize the pharmacokinetic profile and 
evaluate the pharmacodynamics and exploratory efficacy of olipudase alfa 
administered intravenously in pediatric patients every 2 weeks for up to 64 
weeks. 
STUDY DESIGN 
This is a phase 1/2, multi-national, multi-center, open-label, ascending-dose 
study designed to evaluate the safety, tolerability, pharmacokinetics, 
pharmacodynamics, and exploratory efficacy of olipudase alfa administered 
once every 2 weeks for 64 weeks in pediatric patients, aged <18 years, with 
non-neuronopathic acid sphingomyelinase deficiency (ASMD). 
At least 12 pediatric patients will be enrolled in a staggered fashion into the 
following 3 age cohorts and dose escalated to 3.0 mg/kg olipudase alfa or the 
highest tolerated dose (HTD): 
1. 
Adolescent cohort – patients aged 12 to <18 years  
2. 
Child cohort – patients aged 6 to <12 years  
3. 
Infant/early child cohort – patients from birth to <6 years of age. 
Initiation of dosing will be staggered among the three pediatric age cohorts. The 
adolescent cohort will begin dosing before the child cohort, and the child cohort 
will begin dosing before the infant/early child cohort. Patients in the child and 
infant /early child cohorts will not be dosed until a review of all safety data has 
occurred from the first 3 patients in the respective adolescent and child cohorts 
who completed the dose escalation phase. 
At least 8 additional pediatric patients (<12 years), corresponding to the age 
range of the child and the infant/early child cohorts, will then be enrolled. These 
patients will be enrolled and treated without age cohort staggering.   
After the 64 week-treatment phase, eligible patients may enroll in the long-term 
study LTS13632 to continue receiving olipudase alfa. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria 
I 01. 
The patient and/or patient’s parent(s)/legal guardian(s) must provide 
written informed assent/consent prior to any protocol-related 
procedures being performed. 
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I 02. 
The patient is male or female <18 years of age on the date of informed 
assent/consent. 
 
I 03. 
The patient has documented deficiency of acid sphingomyelinase as 
measured in peripheral leukocytes, cultured fibroblasts, or 
lymphocytes.  
I 04. 
The patient has a spleen volume ≥5 multiples of normal (MN) 
measured by magnetic resonance imaging( MRI); patients who have 
had partial splenectomy will be allowed if the procedure was 
performed ≥1 year before screening and the residual spleen volume is 
≥5 MN. 
I 05. 
The patient’s height is -1 Z-score or lower. 
I 06. 
A negative serum pregnancy test in female patients of childbearing 
potential. 
I 07. 
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. 
Exclusion criteria 
E 01. 
The patient has received an investigational drug within 30 days before 
study enrollment. 
E 02. 
The patient has any of the following medical conditions: 
- 
An active, serious, intercurrent illness; 
- 
Active hepatitis B or hepatitis C infection; 
- 
Infection with human immunodeficiency virus (HIV); 
- 
Cirrhosis (determined by clinical evaluation): 
- 
Significant cardiac disease (eg, clinically significant arrhythmia, 
moderate or severe pulmonary hypertension or valvular 
dysfunction, or <40% left ventricular ejection fraction by 
echocardiogram); 
- 
Malignancy diagnosed within the previous 5 years (except basal 
cell carcinoma); 
- 
Any other extenuating circumstance that can significantly 
interfere with study compliance, including all prescribed 
evaluations and follow-up activities. 
E 03. 
The patient has acute or rapidly progressive neurological 
abnormalities. 
E 04. 
The patients is homozygous for SMPD1 gene mutations R496L, 
L302P, and fs330 or any combination of these 3 mutations. 
E 05. 
The patient has a delay of gross motor skills.  
E 06. 
The patient has had a major organ transplant (eg, bone marrow, liver). 
E 07. 
The patient requires use of invasive ventilatory support. 
E 08. 
The patient requires use of noninvasive ventilatory support while 
awake and for >12 hours a day. 
E 09. 
The patient, in the investigator’s opinion, is unable to adhere to the 
requirements of the study. 
E 10. 
The patient has a platelet count <60 × 103/µL (based on the average 
of 2 screening samples obtained greater than 24 hours apart). 
E 11. 
The patient has alanine aminotransferase or aspartate 
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aminotransferase >250 IU/L or total bilirubin >1.5 mg/dL. 
E 12. 
The patient has an international normalized ratio (INR) >1.5. 
 
E 13. 
The patient is unwilling or unable to abstain from ingesting alcohol the 
day before through 3 days after each infusion of olipudase alfa during 
the treatment period. Measuring alcohol concentration in blood is not 
required. 
E 14. 
The patient is scheduled during the study for in-patient hospitalization 
including elective surgery 
E 15. 
The patient requires medication(s) that may decrease olipudase alfa 
activity (eg, fluoxetine, chlorpromazine; tricyclic antidepressants 
[eg, imipramine, or desipramine]). 
E 16. 
The patient is breast-feeding. 
Total expected number of patients 
A total of at least 20 patients with ASMD <18 years of age will be enrolled. 
• At least 12 patients with ASMD who are able to tolerate 2 consecutive doses 
of 0.3 mg/kg olipudase alfa will be enrolled to 3 age cohorts.  A minimum of 
3 patients each will be enrolled in the adolescent and child cohorts; a 
minimum of 2 patients will be enrolled in the infant/early child cohort. 
• At least 8 additional patients with ASMD will be enrolled in the child and 
infant/early child cohorts, who are able to tolerate 2 consecutive doses of 
0.3mg/kg olipudase alfa.  A minimum of 4 patients will be enrolled in the 
child cohort; a minimum of 2 patients will be enrolled in the infant/early child 
cohort. 
STUDY TREATMENT(s) 
 
Investigational medicinal product(s) 
 
Olipudase alfa (GZ402665, recombinant human acid sphingomyelinase or 
rhASM) 
Formulation 
Sterile, lyophilized cake 
Route(s) of administration 
Intravenous infusion 
Dose regimen 
Olipudase alfa will be administered every 2 weeks for 64 weeks. All patients will 
receive an initial dose of 0.03 mg/kg olipudase alfa, which will then be followed 
by one dose of 0.1 mg/kg, and two consecutive doses at 0.3 mg/kg. Patients 
tolerating 2 consecutive doses of 0.3 mg/kg will be dose escalated step-wise to 
receive 2 consecutive doses at 0.6 mg/kg, which will be followed by infusions at 
1.0 mg/kg and 2.0 mg/kg, and to the final target dose of 3.0 mg/kg, which is to 
be maintained for the remaining duration of the treatment period. Patients 
unable to tolerate 3.0 mg/kg olipudase alfa will receive the highest tolerable 
dose every 2 weeks until the end of the treatment period.  
Patients unable to tolerate 2 consecutive doses of 0.3 mg/kg olipudase alfa will 
be replaced. 
Noninvestigational medicinal 
product(s) (if applicable) 
Not applicable. 
ENDPOINT(S) 
 
Primary endpoint:  
Data pertaining to the safety and tolerability of olipudase alfa: 
• 
Assessment of adverse events/treatment-emergent adverse events 
(TEAEs), including infusion-associated reactions  
• 
Physical examinations  
• 
Neurological examinations 
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• 
Clinical laboratory evaluations  
• 
Vital sign measurements 
• 
Electrocardiograms (ECGs) 
• 
Safety biomarkers 
• 
Doppler echocardiography  
• 
Liver ultrasound Doppler  
• 
Immune response assessments 
Secondary endpoint(s):   
Pharmacokinetics:  
• 
Plasma parameters include Cmax, AUC0-last, AUC, t1/2, CL and Vss 
following the first infusion of olipudase alfa at 0.3 mg/kg, 1.0 mg/kg, 
and 3.0 mg/kg and with olipudase alfa infusion at Week 52. 
Exploratory efficacy 
• 
Spleen volume and liver volume (in multiples of normal [MN]), as 
measured by abdominal magnetic resonance imaging (MRI). 
• 
Infiltrative lung disease scoring as measured by high resolution 
computed tomography (HRCT) and by chest x-ray (at selected sites).  
• 
Linear patient growth by height Z-score. 
• 
Pulmonary function testing endpoints. 
• 
Bone age by hand x-ray. 
• 
Cycle ergometry endpoints. 
• 
Physician’s global assessment. 
• 
Efficacy biomarkers. 
• 
Lipid profile. 
• 
Bone biomarkers. 
• 
Health outcome questionnaires. 
• 
Cognitive and adaptive function testing. 
Pharmacodynamics 
• 
Sphingomyelin and sphingomyelin metabolite levels. 
ASSESSMENT SCHEDULE 
Screening assessments are to be completed within 60 days of Day 1.  
The timing for safety and tolerability, pharmacokinetic, pharmacodynamic and 
exploratory efficacy assessments is presented in the Study Flow Chart. 
Patients who do not enroll into the long-term study, LTS13632, or lag treatment 
between studies will be followed-up with a telephone call 30 to 37 days after the 
last olipudase alfa infusion. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: The sample size set for this study was 
based on empirical considerations; no calculations were performed. 
Analysis Population: The safety analysis set will include all patients who 
receive at least 1 infusion (partial or total) of olipudase alfa. 
The pharmacokinetic analysis set includes all patients who receive at least 
1 infusion of study medication and have evaluable pharmacokinetic data. 
The modified intent-to-treat analysis set is the same as the safety set and is 
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used as the primary population for the efficacy analysis.  
The pharmacodynamic population includes all patients who have at least 1 
infusion of study medication and have at least 1 evaluable pharmacodynamic 
data.measurement available post-baseline.  
 
Safety Analysis: Safety analyses will include a summary of treatment 
duration, the total number of infusions received, and the total amount of 
olipudase alfa received. Frequencies (number and percentage) of patients with 
one or more treatment-emergent adverse events (TEAEs) will be summarized 
according to the Medical Dictionary for Regulatory Activities (MedDRA) System 
Organ Class (SOC) and Preferred Term (PT) overall and by age group. All 
TEAEs, including those potentially related to study drug, those leading to 
treatment discontinuation and study discontinuation, infusion-associated 
reactions, serious adverse events (SAEs), and all AEs with fatal outcome 
(including fatal TEAEs) will be summarized overall and by age group. Other 
safety variables, including laboratory parameters and vital signs, will be 
summarized overall and by age group. 
Pharmacokinetic Analysis: The pharmacokinetic analysis will be 
conducted on the pharmacokinetic analysis set. Plasma concentration-time data 
will be analyzed by non-compartmental methods, nonlinear mixed effects 
modeling, or by population-based analysis, based upon patient age and data 
suitability. Pharmacokinetic parameters will be calculated for each patient and 
summarized by age group, by dose (0.3, 1.0, 3.0 mg/kg), and by time point, and 
by manufacturing scale, including the week 52 visit. 
Exploratory Efficacy Analysis: An assessment of exploratory efficacy 
will be conducted on the modified intent-to-treat analysis set. Efficacy 
summaries will include descriptive statistics of the observed value and/or 
change or percentage change (eg, spleen volume, liver volume, platelet count, 
etc.) from baseline to week 52 or week 64, as appropriate, including 
95% confidence intervals. Categorical variables (eg, pulmonary imaging, chest 
X-ray) will be summarized using frequencies and percentages according to time 
points collected from screening or baseline to week 52 or week 64, as 
appropriate. Analysis will be performed overall and by manufacturing scale as 
appropriate. 
Pharmacodynamic Analysis: The pharmacodynamic analysis will be 
conducted on the pharmacodynamic analysis set. Concentration of 
sphingomyelin and its metabolites will be summarized by dose and time point, 
and manufacturing scale as appropriate, using descriptive statistics. 
Pharmacodynamic-Pharmacokinetic Analysis: Exploratory 
analyses may be performed to elucidate exposure-response relationships with 
biomarkers of safety and/or efficacy. 
DURATION OF STUDY PERIOD (per 
patient)  
Per patient, the maximum study duration is approximately 18 months: 
• 
Screening period: up to 60 days 
• 
Treatment period: 64 weeks 
• 
Post-treatment period:  up to 37 days. Not applicable if patient enrolls 
in LTS13632. 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
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Screening 
Treatment Perioda, b 
Post-treatment 
Observations 
DAY/WEEK (Wk) 
Day -60 
to Day -1 
Day1 
/Wk0 
Wk 2 to Wk 
10 
W12 
QV 
Wk 14 to Wk 
24 
Wk 26 
QV 
Wk 28 to Wk 
36cWk 40 to Wk 
50, 
Wk 54 to WK 62 
Wk 38 
QV 
Wk 52  
QV 
Wk 64 
 
Withdrawal 
Follow-up 
if released from the hospital, patients will be required to return as needed for evaluation and collection of samples at 48h and 96h. After the second infusion at the highest tolerable dose, patients will be observed 
for a minimum of 3 hours following infusion completion, and discharged at the investigator’s discretion. 
b Unless specified otherwise, assessments are completed before starting the olipudase alfa infusion. See Flow Chart 1.3 and protocol Section 10 for sample collection windows. When multiple assessments are 
required, the order should be vital signs before ECG before PK or blood draw. 
c If dose escalation is extended beyond Week 26, visit assessments should match the Week 14 to Week 24 column content. 
d Assessment not required if historical results available.  
e Not required if assessment previously collected within 12 weeks prior to the post-treatment withdrawal follow-up visit. 
f 
Assessment not required in patients >2 years of age.  
g See Flow Chart Section 1.3 and Section 1.4 for sample collection details per each age cohort.  
h Pre-infusion ECG in triplicate.  
i 
Females achieving menarche will have serum test for pregnancy at Screening, a urine β-hCG test up to 24 hours before day 1/week 0 infusion and every 4 weeks thereafter. 
j 
Patients are required to fast from solid foods (liquids such as water, milk, juice allowed) for 6 hours before an abdominal MRI to reduce the effect of a meal on MRI data.    
k Assessment not required in patients <5 years of age at day 1/week 0.  
l 
Chest x-ray to be performed at selected sites.  
m Assessment not required in patients ≤ 6 years of age or < 120 cm in height at day 1/week 0.    
n Assessment not required in patients ≤ 2 years of age.  
o Assessment not required in patients ≥ 6 years of age at day 1/week 0.  
p See Flow Chart Section 1.5 for sample collection details. 
Abbreviations:  AE = adverse event;  ASM = acid sphingomyelinase; β-hCG = beta-human chorionic gonadotropin; BMI = body mass index; DBS = dried blood spot; CRIM = cross reactive immune material;  
ECG = electrocardiography; HRCT = high resolution computed tomography;  Ig = immunoglobulin; MRI = magnetic resonance imaging; PK = pharmacokinetics; QV = Quarterly Visit; ; SAE = serious adverse event; 
TEAE = treatment-emergent AE; UGT1A1 = uridine diphospho-glucuronosyltransferase 1 family, polypeptide A1; Wk = week. 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 04 ..............................................................................................1 
1 
FLOW CHARTS...............................................................................................................................8 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................8 
1.2 
STUDY FLOW CHART ..................................................................................................................10 
1.3 
SUPPLEMENTAL FLOWCHART - DOSE ESCALATION VISITS, SECOND INFUSION AT 
THE HIGHEST TOLERATED DOSE, QUARTERLY VISIT AND WEEK 64 
ASSESSMENTS: PATIENTS IN THE ADOLESCENT COHORT, CHILD COHORT AND 
PATIENTS AGED 3 TO < 6 YEARS..............................................................................................14 
1.4 
SUPPLEMENTAL FLOWCHART - DAY 1/WEEK 0, DOSE ESCALATION VISITS, 
SECOND INFUSION AT THE HIGHEST TOLERATED DOSE, QUARTERLY VISIT AND 
WEEK 64 ASSESSMENTS IN PATIENTS ≤ 2 YEARS OLD ........................................................15 
1.5 
SUPPLEMENTAL FLOWCHART - PHARMACOKINETIC SAMPLES FOR FIRST 
INFUSIONS AT 0.3MG/KG, 1.0 MG/KG, 3.0 MG/KG AND AT WEEK 52 BY AGE 
COHORT........................................................................................................................................16 
2 
TABLE OF CONTENTS ................................................................................................................17 
3 
LIST OF ABBREVIATIONS ..........................................................................................................23 
4 
INTRODUCTION AND RATIONALE.............................................................................................25 
4.1 
INTRODUCTION............................................................................................................................25 
4.2 
STUDY RATIONALE......................................................................................................................27 
5 
STUDY OBJECTIVES ...................................................................................................................28 
5.1 
PRIMARY.......................................................................................................................................28 
5.2 
SECONDARY ................................................................................................................................28 
6 
STUDY DESIGN ............................................................................................................................29 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................29 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................30 
6.2.1 
Duration of study participation for each patient .............................................................................30 
6.2.2 
Determination of end of clinical study (all patients) .......................................................................30 
6.3 
STUDY COMMITTEES..................................................................................................................30 
6.4 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS .............................31 
6.4.1 
Specific parameters rationale ........................................................................................................33 
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6.4.1.1 
Safety .............................................................................................................................................33 
6.4.1.2 
Exploratory efficacy........................................................................................................................34 
7 
SELECTION OF PATIENTS..........................................................................................................35 
7.1 
INCLUSION CRITERIA..................................................................................................................35 
7.2 
EXCLUSION CRITERIA ................................................................................................................35 
8 
STUDY TREATMENTS .................................................................................................................37 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................37 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS.....................................................................37 
8.3 
PREPARATION AND ADMINISTRATION OF TREATMENTS .....................................................37 
8.3.1 
Investigational medicinal product preparation ...............................................................................37 
8.3.2 
Investigational medicinal product administration ...........................................................................38 
8.3.3 
Infusion delays or missed infusions ...............................................................................................38 
8.3.4 
Escalation schema including dose-limiting toxicity criteria and maximally tolerated dose 
determination .................................................................................................................................39 
8.3.4.1 
Dose escalation schema................................................................................................................39 
8.3.4.2 
Dose-limiting toxicity criteria ..........................................................................................................39 
8.4 
BLINDING PROCEDURES............................................................................................................40 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................41 
8.6 
PACKAGING AND LABELING ......................................................................................................41 
8.7 
STORAGE CONDITIONS AND SHELF LIFE................................................................................41 
8.8 
RESPONSIBILITIES ......................................................................................................................41 
8.8.1 
Treatment accountability and compliance......................................................................................42 
8.8.2 
Return and/or destruction of treatments ........................................................................................42 
8.9 
CONCOMITANT MEDICATION.....................................................................................................42 
8.9.1 
Treatment of infusion-associated reactions ...................................................................................43 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................44 
9.1 
PRIMARY ENDPOINT - SAFETY..................................................................................................44 
9.1.1 
Physical examination .....................................................................................................................44 
9.1.2 
Neurological Examination ..............................................................................................................44 
9.1.3 
Adverse events ..............................................................................................................................44 
9.1.3.1 
Infusion associated reactions.........................................................................................................45 
9.1.4 
Vital signs.......................................................................................................................................45 
9.1.5 
Electrocardiograms ........................................................................................................................45 
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9.1.6 
Doppler echocardiogram................................................................................................................46 
9.1.7 
Liver ultrasound Doppler................................................................................................................46 
9.1.8 
Clinical laboratory evaluations .......................................................................................................47 
9.1.9 
Safety biomarkers ..........................................................................................................................47 
9.1.10 
Immune response assessments ....................................................................................................48 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................48 
9.2.1 
Pharmacokinetics...........................................................................................................................48 
9.2.1.1 
Sampling time ................................................................................................................................48 
9.2.1.2 
Number of pharmacokinetic samples.............................................................................................48 
9.2.1.3 
Pharmacokinetics handling procedure...........................................................................................48 
9.2.1.4 
Bioanalytical method......................................................................................................................49 
9.2.1.5 
Pharmacokinetics parameters .......................................................................................................49 
9.2.2 
Exploratory efficacy........................................................................................................................50 
9.2.2.1 
Abdominal magnetic resonance imaging.......................................................................................50 
9.2.2.2 
Pulmonary imaging by high resolution computed tomography......................................................51 
9.2.2.3 
Pulmonary function testing.............................................................................................................51 
9.2.2.4 
Chest X-ray ....................................................................................................................................52 
9.2.2.5 
Hand x-ray......................................................................................................................................52 
9.2.2.6 
Cycle ergometry.............................................................................................................................52 
9.2.2.7 
Physician’s global assessment of change .....................................................................................53 
9.2.2.8 
Efficacy biomarkers........................................................................................................................53 
9.2.2.9 
Lipid profile.....................................................................................................................................53 
9.2.2.10 Bone biomarkers............................................................................................................................53 
9.2.2.11 Health outcome questionnaires .....................................................................................................53 
9.2.2.12 Cognitive and adaptive function.....................................................................................................55 
9.2.3 
Pharmacodynamics........................................................................................................................55 
9.2.4 
Pharmacogenetic assessments.....................................................................................................55 
9.2.4.1 
Genotyping of SMPD1, CHIT1, UGT1A1 and genes.....................................................................55 
9.3 
OTHER ASSESSMENTS ..............................................................................................................55 
9.3.1 
Demographic information and medical/surgical history .................................................................55 
9.3.2 
Acid sphingomyelinase enzyme activity.........................................................................................56 
9.3.3 
Tanner staging ...............................................................................................................................56 
9.3.4 
Cross-reacting immunological material..........................................................................................56 
9.3.5 
Patient photographs.......................................................................................................................56 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................56 
9.5 
SAMPLED BLOOD VOLUME ........................................................................................................57 
10 
STUDY PROCEDURES ................................................................................................................61 
10.1 
VISIT SCHEDULE..........................................................................................................................61 
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10.2 
SCREENING AND INCLUSION PROCEDURES..........................................................................61 
10.3 
TREATMENT PERIOD PROCEDURES........................................................................................62 
10.3.1 
Hospitalization................................................................................................................................62 
10.3.2 
Day 1/Week 0 procedures (Quarterly visit schedule) ....................................................................62 
10.3.3 
Dose escalation visits and 2nd infusion at 3.0 mg/kg or highest tolerated dose procedures .........63 
10.3.4 
Quarterly visit procedures at Week 12 and Week 38 ....................................................................64 
10.3.5 
Quarterly visit procedures at Week 26 and Week 52 ....................................................................65 
10.3.6 
Non-dose escalation, non-quarterly visits occurring before Week 26 ...........................................67 
10.3.7 
Non-dose escalation, non-quarterly visit occurring after Week 26 ................................................67 
10.3.8 
Visit procedures at Week 64..........................................................................................................68 
10.3.9 
Alcohol consumption......................................................................................................................68 
10.3.10 Pregnancy......................................................................................................................................69 
10.4 
DEFINITION OF SOURCE DATA..................................................................................................69 
10.5 
HANDLING OF TEMPORARY OR PERMANENT TREATMENT DISCONTINUATION...............69 
10.5.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................70 
10.5.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................70 
10.5.3 
List of criteria for permanent treatment discontinuation.................................................................70 
10.5.4 
Handling of patients after permanent treatment discontinuation ...................................................71 
10.5.5 
Procedure and consequence for patient withdrawal from study....................................................71 
10.5.6 
Replacement of patients ................................................................................................................71 
10.6 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................71 
10.6.1 
Definitions of adverse events.........................................................................................................71 
10.6.1.1 Adverse event ................................................................................................................................71 
10.6.1.2 Serious adverse event ...................................................................................................................72 
10.6.1.3 Adverse event of special interest...................................................................................................73 
10.6.1.4 Definitions for criteria of adverse events........................................................................................74 
10.6.2 
General guidelines for reporting adverse events ...........................................................................76 
10.6.3 
Instructions for reporting serious adverse events ..........................................................................77 
10.6.4 
Guidelines for reporting adverse events of special interest...........................................................77 
10.6.4.1 Reporting of adverse events of special interest with immediate notification .................................77 
10.6.4.2 Reporting of adverse events of special interest without immediate notification ............................78 
10.6.5 
Guidelines for management of specific laboratory abnormalities ..................................................78 
10.7 
PREGNANCY REPORTING..........................................................................................................79 
10.8 
OBLIGATIONS OF THE SPONSOR .............................................................................................80 
10.9 
ADVERSE EVENTS MONITORING..............................................................................................80 
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11 
STATISTICAL CONSIDERATIONS..............................................................................................81 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................81 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................81 
11.3 
ANALYSIS POPULATIONS...........................................................................................................82 
11.3.1 
Safety population ...........................................................................................................................82 
11.3.2 
Pharmacokinetic population...........................................................................................................82 
11.3.3 
Modified intent-to-treat population .................................................................................................82 
11.3.4 
Pharmacodynamic population........................................................................................................82 
11.4 
STATISTICAL METHODS .............................................................................................................82 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................82 
11.4.1.1 Compliance ....................................................................................................................................82 
11.4.2 
Analyses of safety endpoints .........................................................................................................82 
11.4.2.1 Adverse events ..............................................................................................................................83 
11.4.2.2 Clinical laboratory tests..................................................................................................................84 
11.4.2.3 Vital signs.......................................................................................................................................85 
11.4.2.4 Electrocardiogram..........................................................................................................................86 
11.4.2.5 Physical examinations and neurological examinations..................................................................87 
11.4.2.6 Echocardiogram and liver ultrasound Doppler...............................................................................87 
11.4.2.7 Safety biomarkers ..........................................................................................................................87 
11.4.2.8 Anti-olipudase alfa IgG antibodies, neutralizing antibodies, and other immune response 
assessments ..................................................................................................................................87 
11.4.3 
Pharmacokinetic analyses .............................................................................................................87 
11.4.4 
Pharmacodynamic analyses..........................................................................................................87 
11.4.5 
Exploratory efficacy analyses ........................................................................................................88 
11.4.6 
Pharmacokinetic-pharmacodynamic analyses ..............................................................................88 
11.5 
INTERIM ANALYSIS......................................................................................................................88 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................89 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................89 
12.2 
INFORMED CONSENT .................................................................................................................89 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............90 
13 
STUDY MONITORING...................................................................................................................91 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................91 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................91 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................92 
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13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................92 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................92 
14 
ADDITIONAL REQUIREMENTS...................................................................................................93 
14.1 
CURRICULUM VITAE....................................................................................................................93 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................93 
14.3 
CONFIDENTIALITY .......................................................................................................................93 
14.4 
PROPERTY RIGHTS.....................................................................................................................94 
14.5 
DATA PROTECTION.....................................................................................................................94 
14.6 
INSURANCE COMPENSATION....................................................................................................94 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................95 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................95 
14.8.1 
By the sponsor ...............................................................................................................................95 
14.8.2 
By the Investigator .........................................................................................................................96 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................96 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................96 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................97 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................98 
 
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3 
LIST OF ABBREVIATIONS 
 
ABAS: 
Adaptive Behavior Assessment System 
ACE: 
angiotensin-converting enzyme 
AE: 
adverse event 
ALT: 
alanine aminotransferase 
AP: 
alkaline phosphatase 
APR: 
acute phase reaction 
ASM: 
acid sphingomyelinase 
ASMD: 
acid sphingomyelinase deficiency 
ASMKO: 
acid sphingomyelinase knock out 
AST: 
aspartate aminotransferase 
CCL18: 
chemokine (CC-motif) ligand 18 
CRIM: 
cross-reactive immunological material 
CRS: 
cytokine release syndrome 
CS: 
clinically significant 
DBS: 
dried blood spots 
DLT: 
dose limiting toxicity 
DMC: 
Data Monitoring Committee 
DP-3: 
Development Profile-3 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EOS: 
end of study 
FDA: 
Food and Drug Administration 
FVC: 
forced vital capacity 
HIV: 
immunodeficiency virus 
HR: 
heart rate 
HRCT: 
high resolution computed tomography 
hsCRP: 
high sensitivity C reactive protein 
HTD: 
highest tolerated dose 
IAR: 
infusion-associated reaction 
ICH: 
International Conference on Harmonisation 
IgE: 
immunoglobulin E 
IgG: 
immunoglobulin G 
IL: 
interleukin 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRB/IEC: 
Institutional Review Board/Independent Ethics Committee 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MN: 
multiples of normal 
MRI: 
magnetic resonance imaging 
NCS: 
not clinically significant 
NOAEL: 
no observable adverse effect level 
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NPD: 
Niemann Pick disease 
NPD A: 
Niemann Pick disease type A 
NPD B: 
Niemann Pick disease type B 
PCSA: 
potentially clinically significant abnormality 
PedsQL: 
Pediatric Quality of Life Inventory 
PFT: 
pulmonary function testing 
Protime: 
prothrombin time 
PT: 
preferred term 
PTT: 
partial thromboplastin time 
rhASM: 
recombinant human acid sphingomyelinase 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SMPD1: 
acid sphingomyelinase gene 
SOC: 
system organ class 
TEAEs: 
treatment-emergent adverse events 
ULN: 
upper limit of normal 
β-HCG: 
beta-human chorionic gonadotropin 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Human acid sphingomyelinase deficiency (ASMD) is a serious, rare, 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 SMPD1, the gene encoding acid 
sphingomyelinase, whose transcription and translation results in a defective acid 
sphingomyelinase (ASM) enzyme. Inactivity of ASM leads to the lysosomal accumulation of 
sphingomyelin and, secondarily, increases in cholesterol and other related lipids, mostly in the 
organs spleen, liver, lung, and bone marrow. 
Historically, ASMD has been diagnosed as Niemann-Pick Disease (NPD) and of either types A or 
B disease. Type A (NPD A) is characterized as the early-onset and acute neuronopathic form of 
Niemann-Pick disease 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 and is also a 
childhood disease. The most common disease manifestation is hepatosplenomegaly; other, more 
variable features include liver dysfunction, pulmonary disease, retinal stigmata, and growth 
retardation. NPD 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. Being an autosomal recessive single gene disease, ASMD is acknowledged to generate 
a spectrum of phenotypes. Accordingly, cases classified as intermediate to the A and B extremes, 
have been reported. Patients with this intermediate form (NPD A/B) may develop neurologic 
symptoms during childhood and have a chronic neurodegenerative disease course. 
Genzyme is developing a potential enzyme therapy for ASMD with recombinant human acid 
sphingomyelinase (rhASM; olipudase alfa) for the treatment of the non-neurological 
manifestations of ASMD. This recombinantly-derived enzyme is expressed in Chinese hamster 
ovarian cells transfected with olipudase alfa complementary DNA that encodes a 627-residue 
peptide chain. The resulting gene-product retains the enzymatic activity and lysosomal targeting 
of the native protein. 
Proof of concept for olipudase alfa 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 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 animal model is limited as 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, pharmacokinetic, 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, toxicity was 
observed in ASMKO mice given single high bolus doses of olipudase alfa (≥10 mg/kg). The same 
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single high doses did not cause toxic effects in normal mice, 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 
3 days later) prevented the toxicity associated with the single initial high doses. These findings 
suggest that the observed toxicity is related to the rate of substrate degradation and that step-wise 
removal of substrate likely mitigates toxicity. Furthermore, repeat, high doses of olipudase alfa 
(30 mg/kg every 2 weeks for 7 doses) administered after a 7-day debulking period (3 mg/kg on 
Days 1, 3, 5, and 7), also did not cause toxicity. 
In the completed Phase 1 study (5), 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 
post-dose 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 
AEs (SAEs) related to olipudase alfa treatment were not reported. The sponsor terminated the 
study subsequent to the single patient dosed at 1.0 mg/kg olipudase alfa presenting with 
hyperbilirubinemia and an acute-phase reaction with clinical symptoms. Of note, this patient was 
subsequently confirmed to have Gilbert’s syndrome. Because there were no other signs of liver 
toxicity or hemolysis, the observed hyperbilirubinemia may have been secondary to specific 
inhibition of bilirubin uptake into hepatocytes and/or glucuronide conjugation of bilirubin within 
hepatocytes. 
In a Phase 1b, open-label, multi-center, 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). Patients received an initial intravenous dose of 0.1 mg/kg olipudase alfa and then 
dose-escalated in a step wise manner to a final target intravenous dose of 3.0 mg/kg. All patients 
remained 3.0 mg/kg for the remainder of the treatment period. Upon completion of the study, all 
patients enrolled into an open-label, long term treatment study (LTS13632) (7).  
Results from this trial demonstrated that the progressive, within-patient olipudase alfa dose 
escalation regimen was well tolerated in adult ASMD patients. No serious or severe AEs or deaths 
were reported in the study. Related AEs consisted predominantly of infusion-associated reactions 
(IARs), the majority of which were mild in severity with all patients recovering without sequelae. 
At the end of the 6 month treatment period, a positive response to treatment with olipudase alfa 
was observed in several individual efficacy parameters. This included mean decreases in spleen 
and liver volumes by 25.3% and 17.1%, respectively; decreased interstitial lung disease scores; 
increased percent predicted  DLCO; reduction in serum chitotriosidase, chemokine (CC-motif) 
ligand 18 (CCL18) and angiotensin-converting enzyme (ACE); a positive trend towards a less 
pro-atherogenic lipid profile; and trends for improvement in quality of life assessments for fatigue 
and pain.  
A complete summary of nonclinical and clinical experience with olipudase alfa can be found in 
the Investigator’s brochure. 
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4.2 
STUDY RATIONALE 
The sponsor believes that cumulative data from the single-dose Phase 1 study (5) and repeat-dose 
Phase 1b study (6) demonstrate both the safety and tolerability of the olipudase alfa dose 
escalation regimen and repeat dosing at 3.0 mg/kg; such data support the conduction of this 
repeat, ascending dose study of olipudase alfa in pediatric patients with ASMD.  
This Phase 1/2, open-label, multi-center, multi-national study is designed to evaluate the safety 
and tolerability of olipudase alfa in pediatric patients less than 18 years of age with  
non-neuronopathic ASMD. Olipudase alfa will be administered every 2 weeks using a 
progressive, within-patient dose escalation regimen, with dose escalation starting at 0.03 mg/kg 
and ending at 3.0 mg/kg. This study was also designed to characterize olipudase alfa 
pharmacokinetics, pharmacodynamics and exploratory efficacy throughout a 64-week treatment 
period.  
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is to evaluate the safety and tolerability of olipudase alfa 
administered intravenously in pediatric patients every 2 weeks for 64 weeks. 
5.2 
SECONDARY 
The secondary objectives of this study are to characterize the pharmacokinetic profile and 
evaluate the pharmacodynamics and exploratory efficacy of olipudase alfa administered 
intravenously in pediatric patients every 2 weeks for up to 64 weeks. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
DFI13803 is a Phase 1/2, multi-center, open-label, ascending dose study to evaluate the safety, 
tolerability, pharmacokinetics, pharmacodynamics and exploratory efficacy of olipudase alfa 
administered once every 2 weeks for 64 weeks in pediatric patients less than 18 years of age with 
non-neuronopathic ASMD. At least 12 patients will be enrolled in a staggered fashion into 3 age 
cohorts, with a minimum of 3 patients aged from 12 to <18 years (adolescent cohort), 3 patients 
aged from 6 to <12 years (child cohort), and 2 patients with ages ranging from birth to <6 years 
(infant/early child cohort).  
In this study, intravenous infusions of olipudase alfa will be administered every 2 weeks for 
64 weeks. Patients will begin with a dose of 0.03 mg/kg olipudase alfa, which will be followed 
with dose escalation to 0.1mg/kg and then to 0.3 mg/kg olipudase alfa. Patients able to tolerate 
2 consecutive doses of 0.3 mg/kg olipudase alfa will continue to dose escalate step-wise as 
indicated in Section 1.1 to 0.6 mg/kg, 1.0 mg/kg, 2.0 mg/kg, and the final target dose of 3.0 mg/kg 
olipudase alfa. Patients unable to tolerate 2 consecutive doses of 0.3 mg/kg olipudase alfa will be 
replaced. Patients unable to tolerate the target 3.0 mg/kg dose will receive the highest dose 
tolerable every 2 weeks for the remainder of the 64-week treatment period.  
Patient enrollment and initiation of dosing will be staggered among the three pediatric age cohorts 
for the first 12 patients. The study will begin with the enrollment of patients from the adolescent 
cohort (ages 12 to less than 18 years). Subsequently, a Data Monitoring Committee (DMC) and 
the sponsor will review all safety data collected from the first 3 patients in the adolescent cohort 
who have completed the dose escalation phase, reflecting the most critical point in olipudase alfa 
safety. Pending the outcome of the DMC and sponsor review, patients from the child cohort (6 to 
less than 12 years) will be enrolled. When the first 3 patients in the child cohort complete the dose 
escalation phase, another DMC and sponsor review will be conducted. Pending the outcome of the 
DMC and sponsor review of safety data from the child cohort, the study will be opened for 
enrollment of the infant/early child cohort (patients younger than 6 years of age).  
To open enrollment in younger age cohorts, the sponsor and DMC will review at a minimum the 
following safety data: AEs/treatment emergent AEs (TEAEs) including IARs, clinical laboratory 
results including but not limited to hematology and clinical chemistry, electrocardiograms 
(ECGs), vitals, and any available immunology results as applicable. 
Following enrollment in the youngest age cohort, an additional group of at least 8 patients <12 
years will be enrolled.  These patients will be included in the appropriate age cohort (at least 4 
patients in the child cohort and at least 2 patients in the infant/early child cohort) without 
staggering of enrollment/ treatment. 
 
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Eligible patients may enroll in a long-term study (LTS13632) following completion the 64-week 
treatment period to continue receiving olipudase alfa. Patients not enrolling in the long-term 
study, or those with a treatment gap between the end of the 64-week treatment period of 
DFI13803 and enrollment in the long-term study, will undergo a final safety follow-up assessment 
by telephone 30 to 37 days after the last infusion in this study. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
Per patient, the maximum study duration is approximately 18 months: 
• 
Screening period: up to 60 days 
• 
Treatment period: 64 weeks 
• 
Post-treatment period: up to 37 days, which is not applicable if patient enrolls in 
LTS13632 
6.2.2 Determination of end of clinical study (all patients)  
The end of the clinical study is defined as the day that the last patient completes his/her last visit 
at the end of the treatment period as planned in the protocol.  
6.3 
STUDY COMMITTEES 
An independent DMC appointed by the sponsor will review the protocol and will thereafter 
provide medical and ethical guidance related to the conduct of this study. The DMC will review 
safety information as outlined in the DMC Charter, which is maintained separately from the study 
protocol.  
A formal safety review will be performed by the DMC:  
• 
When 3 patients in the adolescent cohort complete the dose escalation phase.  
• 
Approximately every 12 weeks after the first DMC meeting until study end. Frequency 
can be adapted based on availability of patient data and key visits. 
• 
When 3 patients in the child cohort complete the dose escalation phase.  
• 
With all relevant data at the end of the study. 
Relevant data for DMC reviews will be, at a minimum, AEs including IARs, clinical laboratory 
results including, but not limited to, hematology and clinical chemistry, ECG, vitals, and any 
available immunology results as applicable. 
The DMC will also review data on an ad hoc basis to assist in determining if AEs should preclude 
continued treatment with olipudase alfa and if stopping rules apply. The report of a potential dose 
limiting toxicity (DLT) to the sponsor or the occurrence of any safety related issues identified by 
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the DLT 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. Should any 
major safety issues arise, final decisions regarding the study will be made by the sponsor, taking 
into consideration the DMC opinion (as applicable). 
6.4 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS 
The following points were taken into consideration in the design of the study:  
Rationale for dose selection and escalation: The starting dose of 0.03 mg/kg in this pediatric 
clinical trial is 10 times below the no observable adverse effect level (NOAEL) in single dose 
studies in ASMKO mice, and 1000 times below the NOAEL in repeat dose studies in ASMKO 
mice following a sphingomyelin debulking regimen. In addition, the starting dose of 0.03 mg/kg 
is 3 times lower than the highest dose that was not associated with any related AEs in the Phase 1 
single-dose study, 0.1 mg/kg (5).  
The target dose of 3.0 mg/kg olipudase alfa was selected to evaluate a dose effect for olipudase 
alfa to clear sphingomyelin from the lungs in patients with ASMD. In nonclinical studies, 
treatment of ASMKO mice with olipudase alfa led to dose dependent reductions of sphingomyelin 
in tissues, with the liver and spleen clearing substantially more substrate than the lung, suggesting 
the need for a higher dose and/or longer treatment duration to effectively treat the lung. As noted 
previously, chronic dosing in the ASMKO animal model is limited by the animal’s shortened 
lifespan of approximately 6 to 8 months, a direct consequence of complete ASMD. 
The highest repeat-dose for this study, 3.0 mg/kg, is supported by nonclinical repeat-dose 
toxicology data and experience from the adult Phase 1b trial. This dose is 10 times less than the 
30 mg/kg repeat dose NOAEL in ASMKO mice after a debulking regimen, and is 3.3 times less 
than the 10 mg/kg single dose, at which significant toxicity and deaths were observed in ASMKO 
mice without prior debulking. In the Phase 1b study, the safety and tolerability of within-patient 
dose escalation of olipudase alfa administered intravenously every two weeks for 26 weeks was 
studied. In this trial, 5 adult patients with NPD B were given ascending doses of olipudase alfa 
administered intravenously every two weeks, as tolerated, according to the following dose 
escalation schedule: 0.1, 0.3, 0.3, 0.6, 1.0, 2.0, and 3.0 mg/kg. The olipudase alfa dose was 
increased if the patient experienced no or only mild AEs at the lower dose. Patients were 
monitored in-hospital prior to and for at least 72 hours after olipudase alfa infusion during the 
dose escalation period, and during the first 2 doses at the maximum tolerable dose; thereafter 
patients were maintained at their maximum tolerable dose until the end of the 26-week treatment 
period and discharged after dosing and a 3-hour minimum observational period. Study 
assessments included continuous AE reporting and periodic evaluations of safety, 
pharmacokinetics, pharmacodynamics, and efficacy parameters.  
All 5 patients completed the dose escalation regimen, receiving 3.0 mg/kg olipudase alfa, the 
highest dose allowed per protocol, and remained at that dose for the remainder of the study. Three 
patients completed the dose escalation regimen without a dose reduction or repeat. One patient 
had a dose reduction following a moderate IAR with the first olipudase alfa dose at 1.0 mg/kg; 
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subsequently, this patient continued dose escalation to 2.0 and 3.0 mg/kg olipudase alfa. One 
patient repeated the 2.0 mg/kg olipudase alfa dose following a moderate IAR and subsequently 
dose escalated to 3.0 mg/kg. Adverse events were mild or moderate with those considered related 
to olipudase alfa administration generally occurring between 12 and 48 hours post-dose. The most 
commonly reported of these events were headache, arthralgia, abdominal pain, and nausea. 
Plasma ceramide levels typically peaked 48 hours post-dose and attenuated with repeat dosing. 
The dose of 3.0 mg/kg will only be administered once a patient has safely escalated through the 
lower doses following the progressive dose escalation regimen. By comparison, the same dose of 
olipudase alfa that caused toxic effects in ASMKO mice (ie, 10 mg/kg), did not cause toxic effects 
in normal mice, Sprague Dawley rats, or cynomolgus monkeys, suggesting that a sphingomyelin 
catabolite (eg, ceramide, sphingosine, sphingosine-1-phosphate, or phosphocholine) was 
responsible for the toxic effects, and not olipudase alfa itself. 
Open label, no placebo control: Given that the primary purpose of the study is to understand the 
safety, tolerability, pharmacokinetics, pharmacodynamics and exploratory efficacy of repeat 
olipudase alfa dosing in pediatric patients with ASMD, the study is designed as an open-label, no 
comparator group trial. 
Inclusion of infant/early child ASMD patients: Given the rarity of ASMD and that patients with 
the non-neuronopathic form of the disease can be diagnosed as early as birth, the age for the study 
includes patients from birth to <18 years of age.  
Sixty-four week treatment period: The 64-week treatment period will allow for a broader 
understanding of olipudase alfa safety and tolerability in a patient population rapidly changing 
physiologically relative to shorter studies. Depending on the assessment, change from baseline in 
exploratory efficacy parameters will be evaluated through 52 weeks or 64 weeks of olipudase alfa 
administration. In addition, long term olipudase alfa safety and tolerability will also be further 
explored via the extension study LTS13632.  
Patient enrollment between age cohorts: Enrollment of patients in DFI13803 for the first 12 
patients will begin with adolescent patients (ages 12 to less than 18 years), followed by enrollment 
of child patients (6 to less than 12 years) and ending with the enrollment of infant/early child 
patients (patients below 6 years of age) as described in Section 6.1. The most critical phase for 
olipudase alfa safety is the dose escalation phase as indicated by Phase 1b study data (6). For this 
reason, enrollment of child cohort patients will commence once 3 patients in the adolescent cohort 
complete the dose escalation phase, and resulting safety data reviewed by the DMC and sponsor. 
The same process will occur with the enrollment of infant/early child patients based upon 
complete dose escalation safety data from 3 child cohort patients. Following enrollment in the 
youngest age cohort, an additional group of at least 8 patients <12 years will be enrolled.  These 
patients will be included in the appropriate age cohort without staggering of enrollment/ 
treatment. 
Number of patients: A sample size power calculation was not performed for this study. The 
sample size approximation of 20 pediatric patients is based upon empirical considerations. 
At least 12 patients will be enrolled in a staggered fashion to 3 age cohorts with a minimum of 3 
patients aged from 12 to <18 years, 3 patients aged from 6 to <12 years, and 2 patients with ages 
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ranging from birth to <6 years; followed by at least 8 additional patients <12 years enrolled 
without staggering. Out of the 8 additional patients, at least 4 patients in the child cohort and at 
least 2 patients in the infant/early child cohort will be enrolled. 
Number of investigator sites: In order to fully enroll the study, this will be a multi-center, 
multi-national trial. ASMD is an orphan disease with a limited number of patients available to 
participate in clinical trials. Multiple sites will allow for the inclusion of patients from multiple 
regions. 
6.4.1 Specific parameters rationale 
6.4.1.1 Safety 
Data collected in the phase 1 single ascending dose study with olipudase alfa in ASMD adult 
patients demonstrated dose-related increases in ceramide, bilirubin, hsCRP, and other acute phase 
reactants that peaked 24 to 48 hours post-dose and resolved by Day 14 (5). With the use of a 
progressive dose escalation regimen in the Phase 1b adult ASMD, such increases in ceramide, 
bilirubin, hsCPR and other acute phase reactants were attenuated, with the majority of AEs being 
mild (6).  
As a result, safety biomarkers for the monitoring of olipudase alfa in pediatric patients include, 
but are not limited to, hsCRP, ceramide, iron, ferritin, cardiac-specific troponin I, calcitonin, 
interleukin (IL)-6 and IL-8. 
An immune reaction against an exogenously administered recombinant protein plays a critical role 
in the safety of such compounds. Therefore, safety assessments will also include blood samples 
for anti-olipudase alfa immunoglobulin G (IgG) antibodies and neutralizing antibody formation in 
patients testing positive for IgG.  
In the event that a patient experiences a moderate, severe, or recurrent IAR suggestive of 
hypersensitivity reactions, additional blood samples will be collected for the evaluation of: 
• 
circulating immune complex detection; and 
• 
immunoglobulin E (IgE), serum tryptase, and complement activation. 
Additionally, skin testing may be performed, as appropriate, in patients who experience an IAR 
that meets the following criteria: 
• 
Infusion associated reaction is suggestive of IgE-mediated hypersensitivity reaction, with 
persistent symptoms of bronchospasm, hypotension and/or urticaria requiring intervention;  
• 
or any other signs or symptoms at the discretion of the investigator or the sponsor. 
Skin testing may be another predictor of IgE-mediated reaction and may be suggested for 
confirmation of the IgE results. 
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6.4.1.2 Exploratory efficacy 
Exploratory efficacy of olipudase alfa in pediatric patients will be assessed by evaluating changes 
in organomegaly, lung function and pulmonary imaging parameters, exercise testing, lipid profile, 
bone biomarkers, linear growth, and biomarkers known to be elevated in ASMD. Such biomarkers 
include chitotriosidase, CCL18, and ACE (8). Several of the above assessments have been 
identified as potential indicators of clinical outcome in ASMD (9). 
Levels of the olipudase alfa enzymatic substrate sphingomyelin and sphingomyelin metabolites 
will also be evaluated throughout the treatment period in plasma and/or dried blood spots.  
Changes in quality of life, fatigue and pain levels will be evaluated using age- appropriate scales, 
including the Pediatric Quality of Life Inventory (PedsQL), the PedsQL Multidimensional Fatigue 
Scale and the PedsQL Pediatric Pain Questionnaire. Changes in cognitive function will be 
evaluated in ASMD patients younger than 6 years with the Development Profile-3 (DP-3) 
assessment tool.  Changes in adaptive function will be evaluated in ASMD patients less than 
6 years using the Adaptive Behavior Assessment System (ABAS).  
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
To enter this study, patients must fulfill the following criteria: 
I 01. The patient and/or patient’s parent(s)/legal guardian(s) must provide written informed 
assent/consent prior to any protocol-related procedures being performed. 
I 02. The patient is male or female <18 years of age on the date of signed informed 
assent/consent.  
I 03. The patient has documented deficiency of ASM consistent with NPD, as measured in 
peripheral leukocytes, cultured fibroblasts, and/or lymphocytes. 
I 04. The patient has a spleen volume ≥5 multiples of normal (MN) measured by magnetic 
resonance imaging (MRI); patients who have had partial splenectomies will be allowed if 
the procedure was performed ≥1 year before screening and the residual spleen volume is 
≥5 MN. 
I 05. The patient’s height is -1 Z-score or lower.  
I 06. Female patients of childbearing potential must have a negative serum pregnancy test for 
beta-human chorionic gonadotropin (β-hCG). 
I 07. Female patients of childbearing potential and male patients are required to practice true 
abstinence in line with their preferred and usual lifestyle or use two acceptable effective 
methods of contraception, a barrier method such as a condom or occlusive cap (diaphragm 
or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository and an established 
non-barrier method such as oral, injected, or implanted hormonal methods, an intrauterine 
device or intrauterine system for the duration of the study. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the 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 the 30 days before study 
enrollment. 
E 02. The patient has any of the following medical conditions: 
a) An active, serious, intercurrent illness; 
b) Active hepatitis B or hepatitis C infection; 
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c) Infection with human immunodeficiency virus (HIV); 
d) Cirrhosis (determined by clinical evaluation); 
e) Significant cardiac disease (eg, clinically significant arrhythmia, moderate or severe 
pulmonary hypertension or valvular dysfunction, or <40% left ventricular ejection 
fraction by echocardiogram); 
f) 
Malignancy diagnosed within the previous 5 years (except basal cell carcinoma); 
g) Any other extenuating circumstance that can significantly interfere with study 
compliance, including all prescribed evaluations and follow-up activities. 
E 03. The patient has acute or rapidly progressive neurological abnormalities. 
E 04. The patient is homozygous for SMPD1 gene mutations R496L, L302P, and fs330 or any 
combination of these 3 mutations. 
E 05. The patient has delayed gross motor skills.  
E 06. The patient has had a major organ transplant (eg, bone marrow, liver). 
E 07. The patient requires use of invasive ventilatory support. 
E 08. The patient requires use of noninvasive ventilatory support while awake and for >12 hours 
a day. 
E 09. The patient, in the investigator’s opinion, is unable to adhere to the requirements of the 
study. 
E 10. The patient has a platelet count <60 × 103/µL (based on the average of 2 screening samples 
obtained greater than 24 hours apart). 
E 11. The patient has alanine aminotransferase or aspartate aminotransferase >250 IU/L or total 
bilirubin >1.5 mg/dL. 
E 12. The patient has an international normalized ratio (INR) >1.5. 
E 13. The patient is unwilling or unable to abstain from ingesting alcohol the day before through 
3 days after each infusion of olipudase alfa during the treatment period. Measuring alcohol 
concentration in blood is not required. 
E 14. The patient is scheduled during the study for in-patient hospitalization including elective 
surgery. 
E 15. The patient requires medication(s) that may decrease olipudase alfa activity (eg, fluoxetine, 
chlorpromazine; tricyclic antidepressants [eg, imipramine, or desipramine]). 
E 16. The patient is breast-feeding. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
The study drug, 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. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS 
Not applicable. 
8.3 
PREPARATION AND ADMINISTRATION OF TREATMENTS 
8.3.1 Investigational medicinal product preparation  
Detailed information on preparation and administration of olipudase alfa is provided in the 
pharmacy manual. 
Study drug or investigational medicinal product (IMP) infusions must be prepared by a qualified, 
authorized pharmacist (or designee) using aseptic technique. The pharmacist or designee will 
determine the quantity of vials required based on the patient’s weight and dose. Olipudase alfa 
doses should be adjusted every 4 weeks to account for patient growth.  
The study drug will be reconstituted with 5.1 mL of Sterile Water for Injection to yield a 
concentration of 4.0 mg/mL olipudase alfa. The study drug will be further diluted in 0.9% sodium 
chloride for injection solution to a specific volume based on dose. 
All infusions will be prepared based on patient weight (kg) and dose (ranging from 0.03 mg/kg to 
3.0 mg/kg). Therefore, the total volume of the infusion will be dependent on the patient's weight 
and total dose, as recommended in the pharmacy manual.  
The diluted solution should be filtered through a 0.2 – 0.22 micron, low protein-binding, in-line 
filter during administration to remove any visible particles. 
Olipudase alfa should not be infused in the same intravenous line with other products. 
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8.3.2 Investigational medicinal product administration 
For all dose levels, dosing with olipudase alfa is by intravenous infusion every 2 weeks (±3 days). 
The dose escalation phase and the 64-week treatment period begin with the first intravenous 
infusion of 0.03 mg/kg olipudase alfa on Day 1/Week 0 (Section 1.1). All subsequent olipudase 
alfa administrations are to be scheduled relative to the Day 1/Week 0 visit. The dose escalation 
phase ends with the first infusion at 3.0 mg/kg or with the identification of a patient-specific 
highest tolerated dose.  
Patients who tolerate the 0.03 mg/kg dose at Day 1/Week 0 (one re-challenge of the 0.03 mg/kg 
dose is allowed) will receive a dose of 0.1 mg/kg 2 weeks later. Patients who tolerate the 
0.1 mg/kg dose (one re-challenge of the first 0.1 mg/kg dose is allowed) will receive a dose of 
0.3 mg/kg dose 2 weeks later. Patients tolerating 2 consecutive doses of 0.3 mg/kg will be dose 
escalated step-wise to receive 2 consecutive doses at 0.6 mg/kg, followed by infusions at 
1.0 mg/kg and 2.0 mg/kg, and to the final target dose of 3.0 mg/kg, which is maintained for the 
remaining duration of the treatment period. Patients unable to tolerate 3.0 mg/kg olipudase alfa 
will receive the highest tolerable dose every 2 weeks until the end of the treatment period. (Refer 
to Section 8.3.4.2.1 for patient stopping criteria.) 
Decisions regarding dose escalations may be made by discussion between the investigator and the 
sponsor upon review on an individual patient basis. See Section 8.3.4 for dose escalation criteria.  
All infusions will take place in a monitored setting with ready access to emergency resuscitation 
equipment and medications.  
Patients will receive intravenous olipudase alfa over a period of approximately 20 minutes to 
4.5 hours, depending on the dose. The length of the infusion time may be adjusted based on the 
patient’s tolerance of the infusion. 
Infusions should be administered at approximately the same time of the day. There are no 
restrictions on the infusion timing with respect to meals.  
8.3.3 Infusion delays or missed infusions  
During the treatment period, patients are infused with olipudase alfa every 2 weeks (±3 days) with 
all olipudase alfa infusions scheduled relative to the first study infusion on Day 1/Week 0. If any 
olipudase alfa infusion is delayed by more than 3 days, the infusion is considered a missed 
infusion. Missed infusions should not be administered. The patient should return to the clinic for 
their next scheduled visit and receive their last previously tolerated dose level of olipudase alfa. If 
more than 1 infusion is missed during dose escalation, the next dose will be decreased by 1 level. 
If more than 1 infusion is missed after the patient has completed dose escalation, the last 
previously tolerated dose level of olipudase alfa may be administered or the dose may be 
decreased by 1 level at the investigator’s discretion.  
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8.3.4 Escalation schema including dose-limiting toxicity criteria and maximally tolerated 
dose determination 
8.3.4.1 Dose escalation schema 
During dose escalation, patients will undergo in-patient hospitalization as indicated in 
Section 10.3.1. The following criteria will determine the next dose of olipudase alfa to be 
administered, provided the patient does not experience an AE that meets the patient stopping 
criteria (see Section 8.3.4.2.1). 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. Note: Re-challenge for 
patients with a moderate AE at a dose of 0.03 or 0.1 mg/kg olipudase alfa is permitted 
only once before the patient is discontinued from the study and replaced.  
3. If the patient experiences a severe AE, decrease to the prior dose. Note: Patients with a 
severe AE at a dose of 0.03 mg/kg or 0.1 mg/kg olipudase alfa will be discontinued from 
the study and replaced. Re- challenge for patients with a severe AE at a dose of 0.3 mg/kg 
olipudase alfa is permitted only once (at the lower dose of 0.1 mg/kg) before the patient is 
discontinued and replaced. 
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 criteria (Section 8.3.4.2.1), the olipudase alfa 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 8.3.3.  
8.3.4.2 Dose-limiting toxicity criteria 
For the purpose of this study, the events listed under patient stopping criteria 
(see Section 8.3.4.2.1) are considered indicative of a potential DLT  for olipudase alfa 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 6.3). Screening for 
eligible patients may continue during DMC review of patient or study stopping events. 
When olipudase alfa dosing is temporarily halted for a particular patient, safety monitoring of the 
patient will continue. If the AE(s) is/are reversible and the clinical laboratory tests (including liver 
function tests) have reached pre-event levels, the patient will resume dosing and receive the 
previously-tolerated lower dose. Depending on the patient's response, dose escalation will either 
continue (as described in Section 8.3.4.1) or the patient will remain at the previously tolerated 
dose (ie, the patient’s highest tolerated dose [HTD]). 
The investigator is responsible for notifying his/her Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) in writing when a potential DLT is being evaluated at his/her 
investigative site. 
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8.3.4.2.1 Dose limiting toxicity patient stopping criteria 
If any of the following AEs occur, dosing will be temporarily stopped for the specific patient who 
experienced the AE:  
• 
Any SAE, not related to the patient’s underlying condition and considered related to the 
study treatment. 
• 
Any increase in aspartate aminotransferase (AST), alanine aminotransferase (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, 
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. 
8.3.4.2.2 Study stopping criteria 
If either of these criteria are met: 
• 
Two 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.  
After consideration of DMC recommendations, final decisions regarding discontinuation of study 
drug for all or selected clinical trial patients will be made by the Sponsor. 
In the event a significant safety concern arises, the Sponsor may immediately decide to 
discontinue study drug dosing in all clinical trial patients prior to receipt of DMC 
recommendation. 
If the study is temporarily or permanently halted, the Sponsor will notify the health authorities of 
the halt by a substantial amendment in regions where this applies. 
8.4 
BLINDING PROCEDURES 
Not applicable. This is an open-label study design.  
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8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
This is a single-arm treatment study whereby patients who comply with all inclusion/exclusion 
eligibility criteria will be enrolled. Investigator sites will access an interactive response system to 
confirm patient enrollment.  
8.6 
PACKAGING AND LABELING 
Olipudase alfa is packaged and labeled according to good manufacturing practices and local 
regulatory specifications and requirements. Refer to the pharmacy manual for additional details.  
8.7 
STORAGE CONDITIONS AND SHELF LIFE 
All clinical trial material must be kept in a secure area with restricted access, and stored under 
adequate refrigerated temperature conditions, 2 to 8°C (36 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. 
8.8 
RESPONSIBILITIES 
The investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
study drug will be responsible for ensuring that the study drug used in the clinical trial is securely 
maintained as specified by the sponsor and in accordance with applicable regulatory requirements. 
All study drug will be dispensed in accordance with the investigator's prescription and it is the 
investigator’s responsibility 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) should 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 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 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. 
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8.8.1 Treatment accountability and compliance 
Compliance to the treatment regimen will be monitored in terms of the percentage of scheduled 
infusions the patient receives through the treatment period. No infusions should be missed. 
Noncompliance is defined as missing 2 consecutive infusions (not for cause, such as when the 
missed infusions are required by the protocol due to a DLT) or 4 total infusions per the 64-week 
treatment period. As they are identified, the investigator should discuss noncompliant patients on 
a case by case basis with the sponsor.  
The investigator or designee will keep an accurate record of all study drug received, dispensed, 
and returned on a per patient basis using a study drug or IMP accountability log. 
8.8.2 Return and/or destruction of treatments 
Reconciliation of all used, partially-used or unused treatments must be performed at the site by the 
investigator and the monitoring team using treatment log forms. 
Authorization for destruction will be given by the sponsor once the reconciliation has been 
completed. This destruction can be performed at the site depending on local regulations and site 
specific capabilities; alternatively, study drug may be returned to the sponsor or designee for 
destruction. 
8.9 
CONCOMITANT MEDICATION 
Medications and therapeutic procedures received by the patient in the 30 days prior to their first 
infusion until the final visit will be recorded on the Prior and Concomitant Medication electronic 
case report form (e-CRF) 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 30 days prior to the first 
infusion of olipudase alfa in this study. 
• 
Concomitant medications will be defined as medications that are taken after the first 
infusion of olipudase alfa in this study. 
During the 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 a list of concomitant medications that may decrease olipudase alfa activity. 
Cationic amphiphilic antihistamines, such as loratadine, desloratadine, astemizole, ebastine, 
terfenadine, and clemastine, may decrease olipudase alfa activity. Therefore, the need for their use 
in oral or IV administration should be carefully considered. There is no restriction on topical 
antihistaminics.  
Pretreatment in general is not recommended for prophylactic management of IARs. For patients 
who experience moderate to severe or recurrent IARs suggestive of hypersensitivity (as defined in 
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Section 10.6.1.3.2.1), pre-treatment regimens (eg, antihistamines, antipyretics, glucocorticoids) 
may be prescribed by the investigator as per clinical judgment.  In particular, the need for cationic 
amphiphilic antihistamines administered orally or IV should be carefully considered given the 
potential risk for functional inhibition of olipudase alfa activity by such drugs. 
8.9.1 Treatment of infusion-associated reactions  
For management of mild IARs, infusion rate reductions (eg, reduced to half the rate) or temporary 
interruptions may mitigate the reaction. For moderate to severe or recurrent IARs, the investigator 
may consider the use of pre-treatment medications (eg, antihistamines, antipyretics, and/or 
glucocorticoids), if the symptoms are suggestive of hypersensitivity reaction, in addition to 
infusion rate reductions, interruptions, or discontinuation.  In particular, the need for cationic 
amphiphilic antihistamines administered orally or IV should be carefully considered given the 
potential risk for functional inhibition of olipudase alfa activity by such drugs. 
Patients experiencing symptoms suggestive of hypersensitivity reactions, including anaphylactic 
or anaphylactoid reactions, during olipudase alfa infusion should be managed according to the 
general standards of care consistent with the treatment of such reactions. If anaphylaxis or other 
severe allergic reactions occur, immediate discontinuation of the infusion should be considered, 
and appropriate medical treatment should be initiated. Because of the potential for severe IARs, 
appropriate medical personnel and equipment to perform resuscitation must be readily available in 
the event of a hypersensitivity reaction. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT - SAFETY 
Primary safety endpoints include data pertaining to the safety and tolerability of olipudase alfa: 
assessment of AEs/TEAEs, including IARs; physical examinations; neurological examinations; 
clinical laboratory evaluations; vital sign measurements; ECGs; safety biomarkers; Doppler 
echocardiography and liver ultrasound Doppler; and immune response assessments.  
A site physician will assess safety findings as normal, abnormal but not clinically significant 
(NCS), or abnormal and clinically significant (CS). Any abnormal findings that meet the 
definition of an AE per Section 10.6 will be recorded on the AE e-CRF. 
9.1.1 Physical examination 
Complete physical examinations will be completed as indicated in Section 1.2 and will include the 
following observations/measurements: general appearance, examination of the skin; head, eyes, 
ears, nose, and throat; lymph nodes; heart, lungs, and abdomen; extremities and joints and body 
mass index. The patient’s weight will be measured without shoes and wearing the lightest possible 
clothing. At visits where height is measured, the patient will be measured without shoes. While 
patient height is included as part of the physical examination, z-score for height will be evaluated 
as an exploratory efficacy parameter.  
An abbreviated physical examination will assess only the general appearance of the patient and is 
only required when a complete exam is not indicated. 
Whenever possible, the same physician should perform the physical examination at all study 
visits.  
9.1.2 Neurological Examination 
Neurological examinations will be performed as specified in Section 1.2. Assessments include, 
but are not limited to the patient’s mental status, posture, cranial nerves, motor system including 
muscle atrophy, tone and power, reflexes, sensory system, coordination, gait, and age-appropriate 
responses. The examination should be performed by the same neurologist throughout the study, 
if possible. 
9.1.3 Adverse events 
See Section 10.6 for details.  
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9.1.3.1 Infusion associated reactions  
For a moderate/severe or recurrent IAR that is suggestive of a hypersensitivity reaction (as 
defined in Section 10.6.1.3.2.1), 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 clinically indicated. 
• 
For IgE anti-olipudase alfa antibody testing the same pre-infusion serum sample drawn for 
anti-olipudase alfa IgG testing (every 4 weeks) may be used if the IAR occurs at that study 
visit. If a pre-infusion sample was not drawn on that day, the patient should return to the 
study site or local laboratory 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 manual for guidelines on the collection and shipping of samples.  
• 
Skin testing may be performed if necessary following consultation between the 
investigator and the sponsor in patients who experience an IAR that meet the following 
criteria: 
- 
Assessed as moderate or severe in intensity, or recurrent, by the investigator AND. 
- 
Suggestive of an IgE-mediated hypersensitivity reaction (ie, persistent and intractable 
symptoms of hypersensitivity [as described in Section 10.6.1.3.2.1] as assessed by the 
investigator). 
Refer to the study manual for skin testing procedures. 
9.1.4 Vital signs 
Vital signs will be evaluated as indicated in Section 1.2. More specifically, vitals are to be 
measured at every visit before, halfway through, and after infusion (±10 minutes). Postinfusion 
vital signs are measured every 30 minutes for the first 2 hours, hourly for 2 to 6 hours 
postinfusion, and then once every 8 hours until the patient is discharged (±10 minutes). Vital signs 
will include heart rate (HR, beats/minute), systolic and diastolic blood pressure (mmHg), and 
body temperature (°F or °C).  
9.1.5 Electrocardiograms 
Standard 12-lead ECGs will be recorded using an electrocardiographic device at the visits and 
timepoints specified in Section 1.2 and Section 1.3 after at least 5 minutes in supine position, and 
prior to any blood collections.  
For Day 1/Week 0, triplicate ECG (3 ECGs) will be recorded within 5 minutes with at least 
1 minute between 2 replicates prior to IMP administration.  
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Each ECG consists of a 10-second recording of the 12 leads simultaneously, leading to: 
• 
A single 12-lead ECG (25 mm/s, 10 mm/mV) printout with heart rate, PR, QRS, QT, QTc 
automatic correction evaluation, including date, time, initials, and patient number 
(ie, 9 digits) , signature of the research physician, and at least 3 complexes for each lead. 
This printout will be retained at the site. 
• 
A digital storage that enables eventual further reading by an ECG reading center: each 
digital file will be identified by theoretical day and time, real date and real time (recorder 
time), sponsor study code, patient number (ie, 3 digits), date of birth, and site and country 
numbers, if relevant. The digital recording, data storage, and transmission (whenever 
requested) need to comply with all applicable regulatory requirements (ie, FDA 21 CFR, 
part 11).  
The study site cardiologist should review the ECGs in a timely manner to determine if there are 
any safety concerns and for clinical management of the patient. In the event of any CS or NCS 
abnormal findings that meet the definition of an AE (see Section 10.6 for definitions and 
reporting), the investigator will continue to monitor the patient with additional ECGs until the 
ECG returns to baseline or the investigator determines that follow-up is no longer necessary. The 
investigator’s or cardiologist’s assessments are to be captured in the e-CRF. 
All ECGs will also be collected and read centrally by a third party independent reviewer. 
9.1.6 Doppler echocardiogram 
A 2-dimensional and M-mode echocardiograph with Doppler will be performed at the visits 
specified in Section 1.2.  
Examination will include but not be limited to: left ventricular cavity size, left ventricular mass, 
valve characterization, ejection fraction, ventricular wall thickness, regional wall motion, systolic 
and diastolic functions, pericardium characterization and congenital abnormalities. Pulmonary 
artery pressure will be determined by Doppler ultrasound. 
The review of these assessments will be performed locally by a certified cardiologist.  Whenever 
possible, the same cardiologist will perform all evaluations per patient.   
Wherever possible, the same physician should review all echocardiographs for a given patient.  
9.1.7 Liver ultrasound Doppler 
Liver ultrasound Doppler 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 that may be examined include the network of intrahepatic portal veins, the 
main and intrahepatic arteries, the hepatic veins, the main and intrahepatic portal veins, the 
intrahepatic portion of the inferior vena cava, collateral venous pathways, and transjugular 
intrahepatic portosystemic shunts. Liver ultrasound Doppler will be performed using methods that 
are compatible with the standard institutional procedures of the investigational site. 
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9.1.8 Clinical laboratory evaluations 
The following hematology, chemistry, serology and urine analyses will be evaluated as indicated 
in Section 1.2, Section 1.3 and Section 1.4. 
• 
Hematology: complete blood count  including white blood cell count, platelet count, 
hemoglobin, and hematocrit with absolute and percentage differential cell counts of 
lymphocytes, monocytes, neutrophils, basophils, eosinophils, and (if applicable) abnormal 
cells. 
• 
Clinical chemistry: sodium, potassium, chloride, blood urea nitrogen, glucose, uric acid, 
calcium, phosphorus, magnesium, albumin, total protein, creatinine, AST, ALT, total 
bilirubin, direct bilirubin, AP. 
• 
Coagulation: prothrombin time (Protime), partial thromboplastin time (PTT), INR, and  
D-dimer. 
• 
Serology tests: hepatitis B antigen, hepatitis C antibodies, anti-human immunodeficiency 
virus-1 and anti-human immunodeficiency virus-2 antibodies. 
• 
Urinalysis: dipstick for pH, ketones, glucose, bilirubin, protein and blood.  
• 
If female of child bearing potential, β-hCG serum or urine test as appropriate per 
Section 1.2 and Section 10.3. 
Analysis of all safety laboratory parameters will be conducted by a central laboratory. Procedures 
for handling and shipment of all central laboratory samples will be included in the information 
provided by the central laboratory. Specimens will be processed appropriately by the central 
laboratory facility and laboratory reports will be made available to the study investigator in a 
timely manner to assure appropriate clinical review. 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
The study investigator must score all abnormal laboratory values as either CS or NCS. Because 
some laboratory values may be outside of the normal value range due to the underlying disease, 
the study investigators should use clinical judgment when considering clinical significance. 
Clinical significance is defined as any change in laboratory parameters from baseline, which has 
medical relevance. If CS worsening of laboratory values from screening levels is noted, the 
changes will be documented as an AE and scored per Section 10.6.1.4.3. The study investigator 
will continue to monitor the patient with additional laboratory assessments until (1) values have 
reached normal range and/or screening levels, or, (2) in the judgment of the study investigator, 
abnormal values are not related to the administration of IMP or other protocol-specific 
procedures. 
9.1.9 Safety biomarkers 
Biomarkers for monitoring the safety of olipudase alfa include, but are not limited to hsCRP, 
ceramide, iron, ferritin, cardiac-specific troponin I, calcitonin, IL-6 and IL-8. Samples will be 
collected as specified in Section 1.2 and Section 1.3 study flow charts.  
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9.1.10 Immune response assessments 
Samples will be collected as specified in Section 1.2 for the evaluation of anti-olipudase alfa IgG 
antibodies. IgG seropositive patient serum will be subsequently assessed for neutralizing IgG 
antibodies to olipudase alfa.  
9.2 
SECONDARY ENDPOINTS 
9.2.1 Pharmacokinetics  
9.2.1.1 Sampling time 
Pharmacokinetic sampling will occur with the first infusion at 0.3, 1.0 and 3.0 mg/kg olipudase 
alfa and at Week 52. Specific time points and collection time windows are detailed in Section 1.5 
for each age cohort. To minimize the amount of blood drawn, post-dose time points have been 
selected for sparse sampling of pharmacokinetic parameters and microsampling methods 
(volumes ≤0.5 mL) may be used.   
If a patient receives only a partial infusion (eg, due to a safety concern), pharmacokinetic 
sampling will be repeated the next time the patient receives that dose. 
Depending on patient age, blood samples will be drawn for pharmacokinetic assessments using an 
indwelling catheter from an arm that is not used for olipudase alfa infusions. The exact time of 
olipudase alfa infusions (start and stop times of infusion), rate of infusion, time of infusion rate 
changes, and dose will be recorded along with exact sampling times. 
9.2.1.2 Number of pharmacokinetic samples 
Table 1 - Approximate number of plasma samples by age cohort 
 
Adolescent cohort 
Child cohort 
Infant/early child cohort 
By patient 0.3 mg/kg  
7 
6 
5 
By patient 1.0 mg/kg 
7 
6 
5 
By patient 3.0 mg/kg 
7 
6 
5 
By patient Week 52 
7 
6 
5 
Total by patient 
28 
24 
20 
 
9.2.1.3 Pharmacokinetics handling procedure 
Special procedures for collection, storage, and shipment are provided in the study manual. 
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9.2.1.4 Bioanalytical method 
Plasma olipudase alfa concentrations will be determined using a validated enzyme-linked 
immunosorbent assay (ELISA) method. 
9.2.1.5 Pharmacokinetics parameters 
Plasma concentration-time data will be analyzed by noncompartmental methods, nonlinear mixed 
effects modeling or by population-based analysis, based upon patient age and data suitability. 
Pharmacokinetic parameters listed in Table 2 will be calculated using noncompartmental methods 
from plasma olipudase alfa concentrations. 
Table 2 - List of pharmacokinetic parameters and definitions 
Parameters 
Drug/Analyte 
Matrix 
Definition/Calculation 
Ceio 
olipudase alfa 
Plasma 
Concentration at end of infusion 
Cmax 
olipudase alfa 
Plasma 
Maximum plasma concentration observed 
tmax 
olipudase alfa 
Plasma 
Time to reach Cmax 
AUClast 
olipudase alfa 
Plasma 
Area under the plasma concentration versus time curve calculated using the 
trapezoidal method from time zero to the real time 
AUC 
olipudase alfa 
Plasma 
Area under the plasma concentration versus time curve extrapolated to infinity 
according to the following equation:  
z
C
AUC
AUC
last
last
D
+
=
 
 
Values with a percentage of extrapolation >20% will not be taken into account 
in the descriptive statistics 
t1/2z 
olipudase alfa 
Plasma 
Terminal half-life associated with the terminal slope (λz) determined according 
to the following equation: 
z
1/2Z
0.693
 
t
λ
=
 
 
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. 
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Parameters 
Drug/Analyte 
Matrix 
Definition/Calculation 
CL 
olipudase alfa 
Plasma 
 Total body clearance of a drug from the plasma calculated using equations 
below: 
CL = Dose / AUC after the first dose 
or CLss = Dose / AUC0-τ after repeated dose; where CLss is the clearance 
estimated for steady state after repeated doses. 
Vss 
olipudase alfa 
Plasma 
Volume of distribution at steady state after the first dose calculated using the 
equation: 
 
Where, MRT is the mean residence time a molecule resides in body calculated 
using the equation: 
 
where, Tinf  is the duration of infusion and AUMC is the area under the curve of 
moments calculated with the trapezoidal method according to the equation: 
 
After repeated doses, Vss = CLss · MRT 
 
9.2.2 Exploratory efficacy 
For MRI, high resolution computed tomography (HRCT), and chest x-ray, a site physician will 
review and assess as normal, abnormal but not clinically significant (NCS), or abnormal and 
clinically significant (CS). Any abnormal findings that meet the definition of an AE per 
Section 10.6 will be recorded on the AE. 
9.2.2.1 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 Section 1.2. Patients are required 
to fast from solid foods (liquids such as water, milk, juice allowed) for 6 hour prior to the MRI to 
reduce the effect of a meal.  
Magnetic resonance imaging data will be collected and read centrally by a third party blinded to 
patient number and study visit. Procedures for abdominal MRI are detailed in the study manual. 
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9.2.2.2 Pulmonary imaging by high resolution computed tomography 
High resolution computed tomography scans of the chest will be obtained as specified in 
Section 1.2 to quantitate the degree of possible infiltrative lung disease. 
High resolution computed tomography will be performed using methods that are compatible with 
the standard institutional procedures of the investigational site. Images will be collected centrally 
by a medical imaging core laboratory where they will be digitized and coded, and read by a third 
party blinded to patient number and study visit. The mean density will be calculated at each lung 
level using standard HRCT software. The lung fields will be assessed by a central reader and 
scored subjectively for the degree of interstitial lung disease (0 = normal, 1 = mild, 2 = moderate, 
or 3 = severe) (10). 
The bilateral lung boundaries are determined from the following 4 pre-defined levels on the 
HRCT images (10). 
• 
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 will be made of the interstitial, reticular, nodular and pleura areas of the 
right and left lungs based on the following criteria: 
• 
0 = No disease 
• 
1 = Mild (affecting 1 to 25% of the lung volume) 
• 
2 = Moderate (affecting 26 to 50% of the lung volume) 
• 
3 = Severe (affecting 51 to 100% of the lung volume) 
• 
NE = Not evaluable 
Procedures for HRCT are detailed in the study manual.  
9.2.2.3 Pulmonary function testing 
Pulmonary function testing (PFT) will be performed at the time points specified in Section 1.2 in 
patients ≥5 years old on day 1/week 0. Completion of PFT may also depend upon patient age 
and/or cooperation.  
The PFT administration protocol is standardized across sites in accordance with American 
Thoracic Society/European Respiratory Society guidelines. Pulmonary function testing will 
include but will not be limited to the assessment of forced vital capacity (FVC), forced expiratory 
volume in the 1st second of the FVC maneuver and total lung capacity. Diffusing capacity of 
carbon monoxide will be used to measure gas exchange across the alveolocapillary membrane. 
Pulmonary function testing should occur at the same time of day across study visits (±2 hour of 
the screening assessment).  
A trained physician should review the PFTs in a timely manner for clinical management of the 
patient. The investigator will continue to monitor the patient until the parameter returns to 
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baseline or until the investigator determines that follow-up is no longer medically necessary. 
Procedures for PFTs are detailed in the study manual. 
9.2.2.4 Chest X-ray 
A chest X-ray (posterior-anterior and lateral views) will be performed as indicated in Section 1.2 
at selected sites.  
A study site physician, such as the investigator, a pneumologist or a radiologist should review the 
chest X-ray in a timely manner to determine if there are any safety concerns, and for clinical 
management of the patient. Chest X-rays will be collected at the site and sent to a medical 
imaging core laboratory where they will be digitized (if not already done at the site), coded, and 
read by a third party reader blinded to patient number and study visit. The lung fields will be 
scored subjectively for the degree of infiltrative lung disease (10): 
• 
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) 
Procedures for chest x-ray scoring are detailed in the study manual. 
9.2.2.5 Hand x-ray 
Patients will have an x-ray performed on their left hand, fingers and wrist as indicated in 
Section 1.2.  
X-rays will be collected at the site and sent to a medical imaging core laboratory where they will 
be digitized (if not already done at the site), coded, and read by a third party blinded to patient 
number and study visit. Bone age will be calculated using the Greulich & Pyle Atlas.  
9.2.2.6 Cycle ergometry 
Cycle ergometry will be performed within 1 week after infusion at the time points specified in 
Section 1.2. This assessment is not required in patients that are ≤6 years of age or <120 cm in 
height on day 1/week 0. Completion of the assessment may depend upon patient cooperation. 
Cardiopulmonary status will be assessed using a stationary one-wheeled cycle used as an 
ergometer to measure a person's work output under controlled conditions. Patients will be asked to 
ride the cycle at increasing workload levels until they can no longer proceed. Patients will breathe 
through a tube connected to a one-way valve for continuous measurements of oxygen (O2) uptake, 
carbon dioxide (CO2) output, and tidal volume throughout the test. Heart rate, respiratory rate, and 
digital O2 saturation will also be continuously monitored. Steady state levels for each workload 
will be calculated for O2 uptake, CO2 output, tidal volume, ventilation, and respiratory exchange 
ratio. Maximum workload achieved will be recorded and expressed as percent predicted. In 
addition, percent predicted maximum will be calculated for O2 uptake and heart rate.  Note that 
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cycle ergometry assessments must occur at the same time for each assessment (ie, ±2 hours of the 
screening assessment). 
Procedures for cycle ergometry assessments are detailed in the study manual. 
9.2.2.7 Physician’s global assessment of change 
The physician's global assessment of the patient’s progress will be evaluated prior to infusion at 
the time points specified in Section 1.2. 
At Week 26 and Week 52, the investigator will also evaluate the patient’s current clinical status 
compared with screening (baseline) by marking 1 of the following 7 categories: marked 
improvement, moderate improvement, mild improvement, no change, mild worsening, moderate 
worsening, or marked worsening. 
9.2.2.8 Efficacy biomarkers 
Chitotriosidase, CCL18, and ACE levels will be evaluated as indicated in Section 1.2. 
9.2.2.9 Lipid profile 
A lipid profile will be assessed as an efficacy parameter as specified in Section 1.2. 
Blood will be collected prior to infusion for lipids including total cholesterol, low density 
lipoprotein, high density lipoprotein, very low density lipoprotein, triglycerides, apolipoprotein B, 
apolipoprotein A1, and lipoprotein [a]. 
9.2.2.10 Bone biomarkers 
Serum bone-specific alkaline phosphatase and C-telopeptide levels will be evaluated as indicated 
in Section 1.2. 
9.2.2.11 Health outcome questionnaires 
Health outcome measures will be evaluated as specified in Section 1.2 using the assessment tools 
summarized by age range in Table 3. Completion of questionnaires may depend upon patient age 
and/or cooperation. 
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9.2.2.12 Cognitive and adaptive function 
Cognitive function will be evaluated using the DP-3 assessment tool as specified in Section 1.2. 
Patients that are ≥ 6 years of age on day 1/week 0 are not required to complete this assessment.  
Adaptive function will be evaluated as specified in Section 1.2 using the ABAS. Patients that are 
≥6 years on day 1/week 0 are not required to complete this assessment.  
Refer to the study manual for further details. Completion of the above assessments may depend 
upon patient age and/or cooperation. 
9.2.3 Pharmacodynamics 
Sphingomyelin and sphingomyelin metabolites including but not limited to ceramide, 
lyso-sphingomyelin, and sphingosine-1-phosphate will be quantified in plasma and/or dried blood 
spots (DBS) as appropriate using samples collected as detailed in Section 1.2 and Section 1.3. 
Procedures, preparation, and sample shipment guidelines for plasma and DBS sampling are 
provided in the study manual.  
9.2.4 Pharmacogenetic assessments 
9.2.4.1 Genotyping of SMPD1, CHIT1, UGT1A1 and genes 
The acid sphingomyelinase gene (SMPD1), the chitotriosidase gene (CHIT1) and the uridine 
diphosphoglucuronosyltransferase 1 family, polypeptide A1 gene (UGT1A1) will be sequenced if 
historical results are not available.  
A blood sample will be sent to a centralized laboratory where it will be extracted to yield DNA. 
The DNA will be amplified by polymerase chain reaction using gene specific primers and the 
resulting PCR products will be sequenced for the identification of mutations and genetic variation 
(polymorphisms and associated haplotypes) within the genes. The chitotriosidase gene will be 
analyzed for the presence or absence of the 24-base pair duplication mutation. SMPD1 mutations 
of patients participating in this study will be summarized and may be compared to those 
previously identified in ASDM patients from historical data outside of this study. Mutations will 
be annotated according to the guidelines of the Human Genome Variation Society (12). 
9.3 
OTHER ASSESSMENTS 
9.3.1 Demographic information and medical/surgical 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. Additional data to be collected 
include ASMD family history and smoking and alcohol drinking history. 
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9.3.2 Acid sphingomyelinase enzyme activity 
Acid sphingomyelinase activity will be measured as specified in Section 1.2 in peripheral 
leukocytes in patients for whom these results are not available. A central laboratory may conduct 
the analysis of the samples and will provide reports. Sample processing, storage, and shipment 
guidelines are provided in the study manual. 
9.3.3 Tanner staging 
Patient puberty stage will be evaluated according to Tanner staging (13, 14). Tanner stage for 
genitals (male, stage I though V), breasts (females, stage I though V) and pubic hair (both 
genders, stage I through V) will be documented at times specified in Section 1.2.  
9.3.4 Cross-reacting immunological material  
A Western blot assay will be developed to evaluate cross-reactive immunological material 
(CRIM) on peripheral blood mononuclear cells to determine each patient’s CRIM status. An 
alternative method may be considered pending sufficient cell counts in patient blood samples. 
This assessment is to be performed as specified in Section 1.2 and is not required in patients that 
are >2 years of age.  
Sample processing, storage, and shipment guidelines are provided the study manual.  
9.3.5 Patient photographs 
Photographs (eg, abdominal) will be taken as specified in Section 1.2 of patients who volunteer to 
provide visual context of the disease. 
9.4 
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 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 than the one used during the study 
(ie, subject ID). They will be transferred to a Sanofi site (or a subcontractor site) which can be 
located outside of the country where the study is conducted. The sponsor has included safeguards 
for protecting subject confidentiality and personal data (see Section 14.3 and Section 14.5). 
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Table 7 - Approximate sampled blood volume per infusion following moderate, severe, or recurrent 
infusion associated reactions suggestive of hypersensitivity reactions 
Type 
Volume per sample (mL) 
Circulating immune complex 
3.5 mL 
IgE antibodies 
3.5 mL 
Serum tryptase 
3.5  mL 
Complement 
2 mL 
Total per infusion 
12.5 mL 
 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
 Section 1.2 summarizes the schedule of study events for all patients enrolled in the study, with 
specific requirements based upon patient age and gender. Details on the timing of study 
assessments are provided below and in Section 1.3, Section 1.4, Section 1.5 and in Section 10.3.2 
through Section 10.3.7. Individual evaluations are also described in Section 9.  
10.2 
SCREENING AND INCLUSION PROCEDURES 
During screening, the patient or a patient representative will receive information on the study 
objective(s) and procedures from the investigator. The patient and/or patient representative (parent 
or legal guardian) will have to sign the informed assent/consent prior to any action related to the 
study. Screening assessments as specified in Section 1.2 may need several out-patient visits to the 
site or in-patient hospitalization may be required to proceed with all screening or baseline 
assessments. Two samples are to be collected greater than 24 hours apart during the screening 
period for platelet count assessments. The mean platelet count is to be used for determining 
patient eligibility.  
Patients who meet all the inclusion criteria and none of the exclusion criteria will be eligible for 
inclusion into the study. 
Retesting of any screening parameter is limited to a maximum of 3 times and with a minimum of 
14 days in between reassessments. Unless indicated otherwise, the last retest value will be 
considered as the baseline value and reported in the e-CRF. 
Screening procedures will be carried out within 60 days prior to the start of 64-week treatment 
period of DFI13803. 
If a patient does not meet all inclusion criteria or meets one or more exclusion criterion within 
60 days prior to the start of the treatment period, the patient may rescreen for the study once. For 
screening failures, the following data obtained during screening will be transferred to the e-CRF 
and entered into the database: patient’s demographic data, inclusion and exclusion criteria, 
relevant medical history and surgical history (if available), previous and concomitant medications 
(if available), AE data (if available) and reason for failure. 
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10.3 
TREATMENT PERIOD PROCEDURES 
Final inclusion in the study will be performed just before study drug infusion at Day 1/Week 0 of 
the treatment period.  
Retesting of parameters during the treatment period is limited to one time, except for when the 
measurement has not been obtained in accurate conditions.  
The dose escalation phase and the 64-week treatment period begins with the first intravenous 
infusion of 0.03 mg/kg olipudase alfa on Day 1/Week 0.The dose escalation phase ends with the 
first infusion at 3.0 mg/kg or with the identification of a patient-specific highest tolerated dose. 
Day 1/Week 0 and Week 12 assessments and samples are to be collected per quarterly visit 
specifications, even though patients are actively dose escalating at these clinical visits. Samples 
are not to be collected in duplicate (ie, Week 12 quarterly visit and dose escalation visit) under 
such circumstances.  
10.3.1 Hospitalization 
In-patient hospitalization will be required before and for at least 24 hours after infusion for all 
infusions during the dose escalation process through the second infusion at the highest tolerated 
dose. Patients may be required to stay in the hospital for additional time for safety purposes at the 
investigator’s discretion. If discharged 24 hours after infusion, patients are required to return to 
the clinical site for assessments at 48 hours post infusion, and at 96 hours post infusion if 
necessary for pharmacokinetic samples.  
After the second infusion at the highest tolerable dose, patients will be observed for a minimum of 
3 hours following infusion completion, and may be discharged at the investigator’s discretion. For 
quarterly visits at Week 26, Week 38 and Week 52 patients will be observed for a minimum of 
3 hours following infusion completion, and may be discharged at the investigator’s discretion. 
However, patients are required to return to the clinical site for assessments at 24 hours and 
48 hours post infusion, and at 96 hours if necessary for pharmacokinetic samples.  
10.3.2 Day 1/Week 0 procedures (Quarterly visit schedule)  
After a patient (or parent or guardian) has provided informed consent, met all inclusion and none 
of the exclusion criteria, the following assessments are to be completed at Day 1/Week 0 as 
follows:  
• 
Complete physical exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Neurological exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Body weight, height, BMI: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Vital signs: Before (within 30 minutes prior) infusion, halfway through infusion, and after 
infusion (±10 minutes). Postinfusion vital signs are measured every 30 minutes for the first 
2 hours, hourly for 2 to 6 hours postinfusion, and then once every 8 hours until the patient 
is discharged (±10 minutes). 
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• 
ECG: in triplicate within 24 hours prior to olipudase alfa infusion (pre-infusion); in single 
analysis at the end of infusion (within 10 minutes following end of infusion), 24 and 
48 hours following end of infusion (±3 hours). 
• 
Clinical laboratory samples for liver function testing, clinical chemistry, hematology, and 
coagulation: as indicated by age cohort in Section 1.3 and Section 1.4. Preinfusion samples 
to be collected within 24 hours prior to olipudase alfa infusion. Post infusion samples to be 
collected ±3 hours from scheduled time.  
- 
Urinalysis: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Urine β-hCG pregnancy test: within 24 hours prior to olipudase alfa infusion 
(pre-infusion). 
• 
Safety biomarkers: as indicated by age cohort in Section 1.3 and Section 1.4. Preinfusion 
samples to be collected within 24 hours prior to olipudase alfa infusion. Post infusion 
samples to be collected ±3 hours from scheduled time.  
• 
Immunogenicity samples: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Efficacy biomarkers: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Lipid profile: as indicated by age cohort in Section 1.2.  Preinfusion samples to be 
collected within 24 hours prior to olipudase alfa infusion.  
• 
Bone biomarkers: as indicated by age cohort in Section 1.2, within 24 hours prior to 
olipudase alfa infusion (pre-infusion).  
• 
Plasma and/or DBS sphingomyelin and metabolites: as indicated by age cohort in 
Section 1.3 and Section 1.4. Preinfusion samples to be collected within 24 hours prior to 
olipudase alfa infusion. Post infusion samples to be collected ±3 hours from scheduled 
time.  
10.3.3 Dose escalation visits and 2nd infusion at 3.0 mg/kg or highest tolerated dose 
procedures 
The following assessments are to be completed for each dose escalation visit: 
• 
Abbreviated physical exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Doppler echocardiogram: within 24 hours prior to the first infusion of 3.0 mg/kg olipudase 
alfa or highest tolerated dose (pre-infusion). 
• 
Body weight, height, BMI: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
ECG: with each new dose ≥0.3 mg/kg; within 24 hours prior to olipudase alfa infusion 
(pre-infusion), at the end of infusion (within 10 minutes following end of infusion), 
24 hours and 48 hours following end of infusion (±3 hours). 
• 
Vital signs: Every visit. Before (within 30 minutes prior) infusion, halfway through 
infusion, and after infusion (±10 minutes). Postinfusion vital signs are measured every 
30 minutes for the first 2 hours, hourly for 2 to 6 hours postinfusion, and then once every 
8 hours until the patient is discharged (±10 minutes). 
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• 
Liver function testing: as indicated by age cohort in Section 1.3 and Section 1.4. 
Preinfusion samples to be collected within 24 hours prior to olipudase alfa infusion. Post 
infusion samples to be collected ±3 hours from scheduled time. 
• 
Urine β-hCG pregnancy test: within 24 hours prior to olipudase alfa infusion (pre-infusion, 
every 4 weeks). 
• 
Safety biomarkers: as indicated by age cohort in Section 1.3 and Section 1.4. Preinfusion 
samples to be collected within 24 hours prior to olipudase alfa infusion. Post infusion 
samples to be collected ±3 hours from scheduled time. 
• 
Plasma and/or DBS sphingomyelin and metabolites: as indicated by age cohort in 
Section 1.3 and Section 1.4. Preinfusion samples to be collected within 24 hours prior to 
olipudase alfa infusion. Post infusion samples to be collected ±3 hours from scheduled 
time. 
• 
Immunogenicity samples: within 24 hours prior to olipudase alfa infusion (pre-infusion) 
every 2 weeks from Day 1/Week 0 through Week 16. 
• 
Pharmacokinetics: with the first infusion at 0.3, 1.0 and 3.0 mg/kg. See Section 1.5 for 
sample collection times per age cohort.  
10.3.4 Quarterly visit procedures at Week 12 and Week 38 
The following assessments are to be completed for the Week 12 and Week 38 visit: 
• 
Tanner staging: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Complete physical exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Neurological exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Body weight, height, BMI: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Vital signs: Before (within 30 minutes prior) infusion, halfway through infusion, and after 
infusion (±10 minutes). Postinfusion vital signs are measured every 30 minutes for the first 
2 hours, hourly for 2 to 6 hours postinfusion, and then once every 8 hours until the patient 
is discharged (±10 minutes). 
• 
ECG: within 24 hours prior to olipudase alfa infusion (pre-infusion), at the end of infusion 
(within 10 minutes following end of infusion), 24 hours and 48 hours following end of 
infusion (±3 hours). 
• 
Clinical laboratory samples for liver function testing, clinical chemistry, hematology, and 
coagulation: as indicated by age cohort in Section 1.3 and Section 1.4. Preinfusion samples 
to be collected within 24 hours prior to olipudase alfa infusion. Post infusion samples to be 
collected ±3 hours from scheduled time.  
- 
Urinalysis: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Urine β-hCG pregnancy test: within 24 hours prior to olipudase alfa infusion (Week 12 
only, pre-infusion). 
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• 
Safety biomarkers: as indicated by age cohort in Section 1.3 and Section 1.4. Preinfusion 
samples to be collected within 24 hours prior to olipudase alfa infusion. Post infusion 
samples to be collected ±3 hours from scheduled time. 
• 
Immunogenicity samples: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Lipid profile: as indicated by age cohort in Section 1.2.  Preinfusion samples to be 
collected within 24 hours prior to olipudase alfa infusion.  
• 
Pharmacokinetics: if applicable at Week 12 with the first infusion at 1.0 mg/kg. 
See Section 1.5 for sample collection times per age cohort.  
• 
Plasma and/or DBS sphingomyelin and metabolites: as indicated by age cohort in 
Section 1.3 and Section 1.4. Preinfusion samples to be collected within 24 hours prior to 
olipudase alfa infusion. Post infusion samples to be collected ±3 hours from scheduled 
time. 
10.3.5 Quarterly visit procedures at Week 26 and Week 52 
The following assessments are to be completed for Week 26 and Week 52 visits: 
• 
Tanner staging: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Complete physical exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Neurological exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Body weight, height, BMI: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Patient photos: within 24 hours prior to olipudase alfa infusion (Week 52, pre-infusion, 
optional). 
• 
Doppler echocardiogram: within 24 hours prior to olipudase alfa infusion (Week 52 only, 
pre-infusion).Vital signs: Before (within 30 minutes prior) infusion, halfway through 
infusion, and after infusion (±10 minutes). Postinfusion vital signs are measured every 
30 minutes for the first 2 hours, hourly for 2 to 6 hours postinfusion, and then once every 
8 hours until the patient is discharged (±10 minutes). 
• 
Vital signs: Before (within 30 minutes prior) infusion, halfway through infusion, and after 
infusion (±10 minutes). Postinfusion vital signs are measured every 30 minutes for the first 
2 hours, hourly for 2 to 6 hours postinfusion, and then once every 8 hours until the patient 
is discharged (±10 minutes). 
• 
ECG: within 24 hours prior to olipudase alfa infusion (pre-infusion), at the end of infusion 
(within 10 minutes following end of infusion), 24 hours and 48 hours following end of 
infusion (±3 hours). 
• 
Clinical laboratory samples:  
- 
Liver function testing, clinical chemistry and coagulation: as indicated by age cohort in 
Section 1.3 and Section 1.4. Preinfusion samples to be collected within 24 hours prior 
to olipudase alfa infusion. Post infusion samples to be collected ±3 hours from 
scheduled time.  
- 
Hematology  
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a) Week 26: within 24 hours prior to olipudase alfa infusion (pre-infusion), 24 hours 
(adolescent cohort only) and 48 hours following end of infusion (±3 hours).  
b) Week 52:  
- 
Pre-infusion: Two (2) samples to be collected greater than 12 hours but less than 
24 hours apart. The first sample can be collected up to 24 hours prior to olipudase 
alfa administration at Week 52. If necessary, the second sample may be collected 
following olipudase alfa infusion at Week 52.  
- 
24 hours following end of infusion (adolescent cohort only, ±3 hours). 
- 
48 hours following end of infusion (±3 hours). 
c) Urinalysis: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Urine β-hCG pregnancy test: within 24 hours prior to olipudase alfa infusion (Week 52 
only, pre-infusion). 
• 
Safety biomarkers: as indicated by age cohort in Section 1.3 and Section 1.4. Preinfusion 
samples to be collected within 24 hours prior to olipudase alfa infusion. Post infusion 
samples to be collected ±3 hours from scheduled time. 
• 
Immunogenicity samples: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Spleen and liver volume by MRI: within 7 days after Week 26 or Week 52 olipudase alfa 
infusion. 
• 
Pulmonary imaging by HRCT (Week 52 only): within 7 days after Week 52 olipudase alfa 
infusion. 
• 
Pulmonary function testing: within 7 days after Week 26 or Week 52 olipudase alfa 
infusion. 
• 
Chest X-ray (at selected sites, Week 52 only): within 7 days after Week 52 olipudase alfa 
infusion. 
• 
Hand X-ray (Week 52 only): within 7 days after Week 52 olipudase alfa infusion. 
• 
Cycle ergometry: within 7 days after Week 26 or Week 52 olipudase alfa infusion. 
• 
Liver ultrasound Doppler: within 7 days after Week 52 olipudase alfa infusion. 
• 
Physician global assessment: within 24 hours prior to Week 26 or Week 52 olipudase alfa 
infusion. 
• 
Efficacy biomarkers: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Lipid profile: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Bone biomarkers: as indicated by age cohort in Section 1.2, within 24 hours prior to 
olipudase alfa infusion (pre-infusion). 
• 
Plasma and/or DBS sphingomyelin and metabolites: as indicated by age cohort in Section 
1.3 and Section 1.4. Preinfusion samples to be collected within 24 hours prior to olipudase 
alfa infusion. Post infusion samples to be collected ±3 hours from scheduled time. 
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• 
Health outcome questionnaires: within 7 days after Week 26 and Week 52 olipudase alfa 
infusion. 
• 
Cognitive and adaptive function testing: within 7 days after Week 26 and Week 52 
olipudase alfa infusion. 
• 
Pharmacokinetics (Week 52 only): See Section 1.5 for sample collection times per age 
cohort.  
10.3.6 Non-dose escalation, non-quarterly visits occurring before Week 26 
The following assessments are to be completed:  
• 
Abbreviated physical exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Body weight, height, BMI: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Vital signs: Before (within 30 minutes prior) infusion, halfway through infusion, and after 
infusion (±10 minutes). Postinfusion vital signs are measured every 30 minutes for the first 
2 hours, hourly for 2 to 6 postinfusion, and then once every 8 hours until the patient is 
discharged (±10 minutes). 
• 
Liver function testing: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Urine β-hCG pregnancy test: within 24 hours prior to olipudase alfa infusion 
(pre-infusion), every 4 weeks. 
• 
Safety biomarkers: as indicated by age cohort in Section 1.3 and Section 1.4, within 
24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Plasma and/or DBS sphingomyelin and metabolites: as indicated by age cohort in 
Section 1.3 and Section 1.4, within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Immunogenicity samples: every 2 weeks from Day 1/Week 0 through Week 16 
(pre-infusion). 
10.3.7 Non-dose escalation, non-quarterly visit occurring after Week 26 
The following assessments are to be completed:  
• 
Abbreviated physical exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Body weight, height, BMI: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Vital signs: Before (within 30 minutes prior) infusion, halfway through infusion, and after 
infusion (±10 minutes). Postinfusion vital signs are measured every 30 minutes for the first 
2 hours, hourly for 2 to 6 hours postinfusion, and then once every 8 hours until the patient 
is discharged (±10 minutes). 
• 
Urine β-hCG pregnancy test: within 24 hours prior to olipudase alfa infusion  
(pre-infusion), every 4 weeks.  
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10.3.8 Visit procedures at Week 64  
The following assessments are to be completed:  
• 
Abbreviated physical exam: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Body weight, height, BMI: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Vital signs: Before (within 30 minutes prior) infusion, halfway through infusion, and after 
infusion (±10 minutes). Postinfusion vital signs are measured every 30 minutes for the first 
2 hours, hourly for 2 to 6 postinfusion, and then once every 8 hours until the patient is 
discharged (±10 minutes). 
• 
Clinical laboratory samples:  
- 
Liver function testing, clinical chemistry and coagulation: as indicated by age cohort in 
Section 1.3 and Section 1.4. Preinfusion samples to be collected within 24 hours prior 
to olipudase alfa infusion.  
- 
Urinalysis: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Urine β-hCG pregnancy test: within 24 hours prior to olipudase alfa infusion 
(pre-infusion). 
• 
Safety biomarkers: as indicated by age cohort in Section 1.3 and Section 1.4, within 
24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Plasma and/or DBS sphingomyelin and metabolites: as indicated by age cohort in 
Section 1.3 and Section 1.4, within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Immunogenicity samples: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Efficacy biomarkers: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Lipid profile: within 24 hours prior to olipudase alfa infusion (pre-infusion). 
• 
Bone biomarkers: as indicated by age cohort in Section 1.2, within 24 hours prior to 
olipudase alfa infusion (pre-infusion). 
10.3.9 Alcohol consumption 
Patients must be willing to abstain from the use of alcohol for 1 day before and 3 days after each 
olipudase alfa infusion for the duration of the treatment period. Note: blood alcohol levels are not 
required.  
Patients should be counseled to limit alcohol consumption for the entire duration of the study: 
male patients to a maximum of 30 g alcohol per day; female patients to a maximum of 15 g 
alcohol per day. Per the investigator’s discretion, patients who fail to limit alcohol may be 
discontinued from the study. 
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10.3.10 
Pregnancy 
Pregnancy will lead to permanent 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. In addition, these patients are 
required to have a negative urine β-hCG pregnancy test every 4 weeks before undergoing visit 
specific assessments and receiving olipudase alfa.  
Every effort should be made to prevent pregnancy during this study. Female patients of 
childbearing potential and male patients are required to practice true abstinence in line with their 
preferred and usual lifestyle or use two acceptable effective methods of contraception, a barrier 
method such as a condom or occlusive cap (diaphragm or cervical/vault cap) with spermicidal 
foam/gel/film/cream/suppository and an established non-barrier method  such as oral, injected, or 
implanted hormonal methods, an intrauterine device or intrauterine system for the duration of the 
study. 
10.4 
DEFINITION OF SOURCE DATA 
Source data includes all information in original records and certified copies of original records of 
clinical findings, observations, or other activities necessary for the reconstruction and evaluation 
of the trial. Source data are contained in source documents. 
Source documents are original documents, data and records (eg, hospital records, clinical and 
office charts, laboratory reports and notes, memoranda, patient diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcripts 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, X-rays, patient files, and records kept at the pharmacy, at the 
laboratories, and at medical-technical departments) involved in the clinical study. Source 
documentation must be maintained to support information provided in the e-CRF. 
10.5 
HANDLING OF TEMPORARY OR PERMANENT TREATMENT DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the source and e-CRF. In 
any case, the patient should remain in the study as long as possible.  
Pregnancy will lead to treatment discontinuation in all cases. 
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10.5.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation decided by the investigator corresponds to more than 
1 infusion not administered to the patient. 
Temporary treatment discontinuation (also referred to as treatment interruption) may be 
considered by the investigator because of suspected AEs. 
Re-initiation of treatment with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the investigator has considered to his/her best medical judgment that 
the selection criteria for the study are still met (refer to 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 is required (see Section 8.3.3 and Section 8.3.4). 
For all temporary treatment discontinuations, the duration should be recorded by the investigator 
in the appropriate screens of the e-CRF. 
10.5.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the investigator or the patient not to re-expose the patient to the IMP at 
any time. 
10.5.3 List of criteria for permanent treatment discontinuation 
The patient may withdraw from treatment with the IMP if he/she decides to do so, at any time and 
irrespective of the reason, or this may be the investigator’s or sponsor’s decision. All efforts 
should be made to document the reasons for treatment discontinuation and this should be 
documented in the e-CRF. 
Patients should discontinue the IMP for the following reasons: 
• 
Unacceptable toxicity (see Section 8.3.4.2). 
• 
The need for intervention or therapy precluded by protocol, and determination by the 
investigator that it is medically necessary to do so. 
• 
Patient noncompliance with treatment or if the patient wishes to be withdrawn from 
treatment. 
• 
The patient is no longer deriving clinical benefit, in the opinion of the investigator. 
• 
Pregnancy  
In addition, the sponsor may decide to discontinue the trial prematurely for any other reason.  
Any abnormal laboratory value or ECG parameter relevant to the situation will be immediately 
rechecked for confirmation before making a decision of permanent discontinuation of the IMP for 
the concerned patient.  
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10.5.4 Handling of patients after permanent treatment discontinuation 
If a patient or parent/legal guardian decides to discontinue participation in the study, he should be 
contacted by the study investigator in order to obtain information about the reason(s) for 
discontinuation and collection of any potential AEs. 
When possible, all tests and evaluations listed in Section 1.2 for the post treatment withdrawal 
visit should be carried out within 2 weeks of the last olipudase alfa infusion. If a patient fails to 
return for the necessary visits, every effort must be made to contact the patient and determine the 
reason(s) and recorded 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. 
10.5.5 Procedure and consequence for patient withdrawal from study 
If possible, the patients are assessed using the procedure indicated for study withdrawal in 
Section 1.2. 
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. 
10.5.6 Replacement of patients  
The minimum number of patients to be evaluated by age cohort is specified in Section 6.1. Once 
these are met, if a patient prematurely discontinues the study after tolerating 2 consecutive doses 
of olipudase alfa at 0.3 mg/kg, an additional patient may be enrolled. 
10.6 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.6.1 Definitions of adverse events  
10.6.1.1 Adverse event 
An 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. 
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10.6.1.2 Serious adverse event 
An 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 should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is not 
intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
a) Allergic bronchospasm, 
b) Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
c) Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence 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 (only if judged 
unusual/significant by the investigators in oncology studies) 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the investigators). 
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10.6.1.3 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. 
AESIs include the following: 
10.6.1.3.1 Pregnancy 
Pregnancy of a female patient entered in the study as well as pregnancy occurring in female 
partner of a male patient enrolled in this study. See Section 10.7 for additional details.  
10.6.1.3.2 Infusion-associated reactions 
Some AEs may be manifestations of IARs, including hypersensitivity reaction, acute phase 
reactions (APR), and cytokine release syndrome (CRS), as described in Section 10.6.1.3.2.1, 
Section 10.6.1.3.2.2, and Section 10.6.1.3.2.3, respectively. However, original signs and 
symptoms must be reported as AEs. In the e-CRF, investigators are asked to identify whether a 
specific AE represents a clinical manifestation of the IAR. 
Infusion-associated reactions are defined as AEs that occur during the infusion or within up to 
24 hours after the start of infusion and are considered as related or possibly related to the study 
treatment by the investigator or the sponsor. An event occurring ≥24 hours after the start of an 
infusion may be judged an IAR at the discretion of the investigator or sponsor. For this study of 
olipudase alfa, IARs may present as different types of reactions, such as hypersensitivity 
reactions, APRs, and CRS. 
10.6.1.3.2.1 
Hypersensitivity reactions 
Infusion-associated hypersensitivity reactions seen with other enzyme replacement therapies are 
typically immunoglobulin-mediated (IgG/IgE) and occur after sensitization. After subsequent 
exposure to the antigen typically early into or shortly after the infusion, a “sensitized” patient may 
experience a broad range of allergic reactions that can be mild to severe or life threatening. 
Anaphylaxis (or anaphylactic reaction) is a serious, IgE mediated allergic reaction that is rapid in 
onset, and may cause death (15). 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, APRs and CRS include fever, hypotension, tachycardia, nausea, vomiting, 
pain, and headache. 
There were no IAR suggestive of hypersensitivity in the Phase 1b trial (6). 
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10.6.1.3.2.2 
Acute phase reactions 
Acute phase reactions observed in the phase 1 and phase 1b studies are considered as one type of 
IAR, specific to the infused olipudase alfa therapy (5, 6). From observations in both studies the 
APR reactions typically occurred within 12-72 hours following an infusion of olipudase alfa and 
were indicative of an inflammatory response. APRs were associated with elevations in hsCRP and 
changes acute phase reactants including, but not limited to, neutrophils, iron, ferritin, fibrinogen, 
D-dimer, transferrin, albumin, protime, and partial thromboplastin time. Patient AEs associated 
with the APR included (but are not limited to) pyrexia, nausea, vomiting, fatigue, and pain. Acute 
phase reaction is determined based on combined significant laboratory findings and clinical 
symptoms. 
10.6.1.3.2.3 
Cytokine release syndrome 
Cytokine release syndrome is another type of IAR, attributed to the release of excessive amounts 
of cytokines shortly after the 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 possibility of cytokine release syndrome. The Phase 1 single 
dose study (5) demonstrated increases in IL-8 and IL-6; macrophage inflammatory protein 1, 
alpha component; macrophage inflammatory protein 1, beta component; and other cytokines and 
biomarkers (based Myriad Rules-Based Medicine Human Multi-Analyte Profile® antigen panel) 
after a single dose of ≥0.3 mg/kg olipudase alfa. In the Phase 1b trial, increases in mean IL-6 and 
IL-8 values were associated with the first administrations of olipudase alfa at doses 0.6 mg/kg 
through 2.0 mg/kg and tended to be concurrent with acute phase responses (6). Unlike 
immunoglobulin-mediated hypersensitivity reactions, no prior antigen exposure is required for the 
development of CRS. Symptoms of CRS develop soon after exposure, and range from mild to 
severe. Although CRS shares some symptoms with other IARs (ie, hypersensitivity reactions and 
APRs), symptoms typical of CRS include pyrexia, nausea, vomiting, fatigue, pain, myalgia, and in 
severe cases, multi-organ system dysfunction or failure, severe headache, and pulmonary edema. 
Cytokine release syndrome is determined based on combined significant laboratory findings and 
clinical symptoms. 
10.6.1.4 Definitions for criteria of adverse events 
10.6.1.4.1 Definition of a protocol-related adverse event 
A protocol-related AE is an AE occurring during a clinical study that is not product related (either 
investigational or control), but is considered by the investigator or the Medical Monitor to be 
related to the research conditions (ie, related to the fact that a patient is participating in the study). 
For example, a protocol-related AE may be an untoward event occurring during a washout period 
of a treatment other than the investigational product or an event related to a medical procedure 
required by the protocol. 
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10.6.1.4.2 Relationship to study treatment 
Assessment of the association between the AE and study exposure is important for regulatory 
reporting. This assessment is to be made in blinded studies and also for known comparators. For 
each AE/SAE the investigator is to determine whether there is a reasonable possibility 
demonstrated by evidence which suggests a causal relationship between the study treatment and 
the AE according to the categories below: 
• 
Not Related: There is no suspicion of a causal relationship between exposure and the AE. 
• 
Unlikely Related: There is no evidence for a causal relationship between exposure and the 
AE; however, such a relationship cannot be ruled out. 
• 
Possibly Related: There is some evidence supporting the possibility of a causal 
relationship between exposure and the AE. 
• 
Related: There is strong evidence that there is a causal relationship between exposure and 
the AE. 
A relationship to the investigational product must be assigned for each AE/SAE recorded, even if 
there is only limited information at the time. The investigator may change his/her opinion of 
causality in light of follow-up information, amending the AE/SAE report accordingly. 
10.6.1.4.3 Severity of adverse event scoring 
Note that “severity” is not the same as “seriousness”, which is defined in Section 10.6.1.2. 
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 
10.6.1.4.4 Outcome 
Outcome describes the status of the AE. The investigator will provide information regarding the 
patient outcome of each AE. Definitions for possible results of an AE include: 
• 
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. 
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10.6.1.4.5 Action taken regarding the investigational product 
The investigator will be required to provide the action taken regarding investigational product 
(eg, active, comparator) in response to the AE. Options include:  
• 
Dose increased: Increase in the frequency, strength or amount of investigational product 
administered. 
• 
Dose not changed: No change in administration of the investigational product. 
• 
Dose reduced: Reduction in the frequency, strength or amount of investigational product 
administered. 
• 
Drug (investigational product) interrupted: Temporary interruption in administration of the 
investigational product. 
• 
Drug (investigational product) withdrawn: Administration of the investigational product 
terminated (no further dosing). 
• 
Not applicable: Determination of a value is not relevant in the current context. 
• 
Unknown: Not known, not observed, not recorded, or refused. 
10.6.2 General guidelines for reporting adverse events 
• 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the e-CRF. 
• 
Except for IARs, whenever possible, diagnosis or single syndrome should be reported 
instead of symptoms. For IARs, all symptoms must be separately recorded. 
• 
The investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP. 
• 
The investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. 
• 
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 IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI (see Section 10.6.1.3) 
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10.6.3 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 e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the investigator within the e-CRF or after a standard delay. 
• 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the sponsor. For laboratory results, include the laboratory normal ranges. 
• 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 
• 
A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work.  
Any SAE brought to the attention of the investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.6.4 Guidelines for reporting adverse events of special interest   
10.6.4.1 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 10.6.3, even if not fulfilling a seriousness criterion, using the corresponding 
screens in the e-CRF. 
• 
Pregnancy 
- 
Pregnancy occurring in a female patient included in the clinical trial as well as 
pregnancy occurring in a female partner of a male patient enrolled in the study. 
Pregnancy will be recorded as an AESI with immediate notification in all cases. It will 
be qualified as an SAE only if it fulfills the SAE criteria. 
- 
In the event of pregnancy, study drug should be discontinued. 
- 
Follow-up of the pregnancy is mandatory until the outcome has been determined. 
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• 
Infusion-associated reaction (see Section 10.6.1.3.2), which include: 
- 
Hypersensitivity reactions (see Section 10.6.1.3.2.1) 
- 
Acute-phase reaction (see Section 10.6.1.3.2.2) 
- 
Cytokine release syndrome (see Section 10.6.1.3.2.3) 
• 
Symptomatic overdose with IMP 
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. 
• 
The following laboratory values and symptoms (see also Patient Stopping Criteria in 
Section 8.3.4.2), as follows: 
- 
Any increase in AST, ALT, total bilirubin, or AP >3x baseline (before 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 ULN combined with an increase in ALT or AST 
>2x baseline (prior to olipudase alfa therapy), with symptoms of fatigue, nausea, 
vomiting, 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. 
10.6.4.2 Reporting of adverse events of special interest without immediate notification 
• 
Asymptomatic overdose with IMP (see Section 10.6.4.1 for definition of an overdose). 
10.6.5 Guidelines for management of specific laboratory abnormalities 
Not applicable.  
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Table 8 - Summary of adverse event reporting instructions 
CASE REPORT FORM COMPLETION 
EVENT 
CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS IN 
THIS CATEGORY 
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 10.6.1.2  
Yes 
Yes 
No 
 
 
ALT ≥ 3 ULN  
Yes 
Yes 
No 
Adverse Event of 
Special Interest  
Expedited  
(within 24 hours) 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
 
 
 
 
 
 
Infusion associated reactions 
(IAR)/Hypersensitivity 
reactions 
Yes 
Yes 
 No 
 
 
Pregnancy 
Yes 
Yes 
Yes 
AE: adverse event; AESI: adverse event of special interest; SAE: serious adverse event; ULN: upper limit of normal 
10.7 
PREGNANCY REPORTING 
Female patients will be instructed to notify the investigator immediately if they discover they are 
pregnant. Pregnant female patients will be discontinued from the study.  
Male patients will be instructed to notify the investigator immediately if they discover that their 
sexual partner is pregnant. 
If the investigator learns of a report of pregnancy at any time after signing the informed consent, 
the investigator should follow the instructions in Section 10.6.4.1 to contact the sponsor within 
24 hours. The investigator is to complete the AE form, the Safety Complementary form and the 
Pregnancy forms. The patient will be followed until the outcome of the pregnancy is known (eg, 
live birth or stillbirth). The investigator will be responsible for this follow-up. 
If not otherwise established, the investigator will inform the patient that the sponsor is required to 
gather information regarding the course and outcome of the pregnancy after exposure to a study 
product. The progress of the pregnancy must be followed until the outcome of the pregnancy is 
known (ie, delivery, elective termination, or spontaneous abortion). If the pregnancy results in the 
birth of a child, additional follow-up information may be requested. 
The investigator will be asked to obtain follow-up information no later than 2 months after the 
gestational period to obtain maternal/fetal/neonatal outcome and any other relevant information. 
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Follow-up information may be requested at additional time points. All study related visits/contacts 
involving a known pregnancy should include pregnancy status assessment until pregnancy 
outcome is known. 
Please note that pregnancy in and of itself is not an AE or an SAE. Pregnancy should not be 
entered into the e-CRF as an AE unless the investigator suspects an interaction between the study 
treatment and the contraceptive method. Additionally all information received will be assessed for 
any AEs and SAEs and processed per study guidelines. If the patient is discontinued because of 
pregnancy, pregnancy will be documented as the reason for study discontinuation. Spontaneous 
abortions and stillbirths are reported as SAEs. 
10.8 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the sponsor will report in an expedited manner: 
• 
All SAEs that are both unexpected and at least reasonably related to the IMP (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 the IMPs to the health 
authorities, according to local regulations. 
The sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.9 
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 
A SAP will be written and finalized prior to database lock to give guidance to the statistical 
analysis. It will be in compliance with the International Conference on Harmonisation (ICH) and 
Food and Drug Administration’s (FDA) Guidance for Industry: Statistical Principles for Clinical 
Trials. 
The sponsor or its designee will perform the statistical analysis of the data from this study. The 
analysis will be performed using the SAS® statistical software system Version 9.1 2 or higher. 
11.1 
DETERMINATION OF SAMPLE SIZE 
No formal sample size calculations have been performed. Sample size for this study was based 
upon empirical considerations.  
A total of at least 20 patients with ASMD < 18 years of age will be enrolled.  
At least 12 patients will be enrolled in a staggered fashion to 3 age cohorts with a minimum of 3 
patients aged from 12 to <18 years (adolescent cohort), 3 patients aged from 6 to <12 years (child 
cohort), and 2 patients with ages ranging from birth to <6 years (infant/early child cohort); 
followed by at least 8 additional patients <12 years enrolled without staggering. Out of the 8 
additional patients, at least 4 patients in the child cohort and at least 2 patients in the infant/early 
child cohort will be enrolled. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who signed the informed consent, signed informed 
assent or whose parent or guardian signed informed consent. 
Enrolled patients are defined as those who meet the inclusion criteria and none of the exclusion 
criteria. 
All patients who receive an infusion of olipudase alfa (total or partial) will be included in the 
summary of patient disposition.  
The number of patients screened, enrolled, treated, completing the study, and not completing 
study along with primary reason for discontinuation will be presented. The number of screen 
failures, and the reason for screen failure, will also be presented. Patient disposition data will also 
be listed. 
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11.3 
ANALYSIS POPULATIONS 
11.3.1 Safety population 
All patients who were exposed to IMP, regardless of the amount of treatment administered (partial 
or total).  
11.3.2 Pharmacokinetic population 
The pharmacokinetic population includes all patients who receive at least 1 infusion of study 
medication and have evaluable pharmacokinetic data.  
11.3.3 Modified intent-to-treat population 
The modified intent-to-treat population is the same as the safety population, and is used as the 
primary population for the efficacy analysis.  
11.3.4 Pharmacodynamic population 
The pharmacodynamic population includes all patients who  have at least 1 infusion of study 
medication and have at least one evaluable pharmacodynamics measurement available post-
baseline. 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure will be assessed and descriptive statistics will be presented 
for all patients who receive an infusion of olipudase alfa (total or partial) as detailed in the SAP. 
11.4.1.1 Compliance 
A given administration will be considered noncompliant if the patient did not take/complete the 
planned infusions as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (n, mean, standard deviation [SD], median, minimum, and maximum). The 
percentage of patients with compliance is <80% will be summarized.  
11.4.2 Analyses of safety endpoints 
Olipudase alfa safety evaluation will be based upon the review of the individual values (clinically 
significant abnormalities), descriptive statistics (summary tables, graphics). Safety analyses will 
be performed using the safety population. Since the safety population includes patients who are 
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withdrawn due to intolerance of 0.1 or 0.3 mg/kg olipudase alfa, their safety data will be reported 
up to and including the time of withdrawal, and follow-up for AEs, where applicable.  
The baseline value is defined generally as the last available value before study drug 
administration. 
Selected safety data may be presented by manufacturing scale. 
For all safety data, the observation period will be divided into three segments: 
• 
The pre-treatment period is defined as the time between when the patient gives informed 
consent and the start of the first IMP administration (excluded);  
• 
The on-treatment period will be defined as the time from the start of IMP administration 
(included) and till end of Week 64, or end of study (EOS); 
• 
The post-treatment period is defined as the time after the EOS visit (excluded). 
The following definitions will be applied to laboratory parameters, vital signs and ECG. 
• 
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, vital signs, and ECG. 
• 
Potentially clinically significant abnormality criteria will determine which patients had at 
least 1 PCSA during the treatment emergent period, taking into account all evaluations 
performed during the treatment emergent period, including unscheduled or repeated 
evaluations. The number of all such patients will be the numerator for the treatment 
emergent PCSA percentage. 
• 
Treatment period: the treatment period used for quantitative analysis is defined as the time 
from first infusion to the last study drug infusion + 14 Days. 
11.4.2.1 Adverse events 
The definitions in Section 10.6.1 will be used for AEs. Pre-treatment AEs will be listed and 
presented separately from treatment-emergent AEs. 
Adverse events will be coded according to the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Adverse event incidence tables will be presented by MedDRA 
system organ class (SOC) (sorted by internationally agreed order) and preferred term (PT) sorted 
in decreasing number of patients within SOCs and further alphabetical order within the same 
number of patients over different PTs for each age group, the number (n) 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 for the entire study and each age group cohort. 
Adverse events will be classified into pre-defined standard categories according to chronological 
criteria: 
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• 
Pre-treatment AEs: AEs that occurred or worsened during the pre-treatment period; 
• 
Treatment-emergent AEs (TEAEs): AEs that occurred or worsened during the on-
treatment period); 
• 
Post-treatment AEs: AEs that occurred or worsened during the post-treatment period. 
If the start date of an AE is incomplete or missing, then the AE will be considered as a TEAE 
unless a partial date shows it as a pre- or post-treatment event. 
All AEs reported in the study will be listed, sorted by patient, and onset date. 
11.4.2.1.1 Treatment-emergent adverse events 
Patients presenting TEAEs will be listed sorted by age group, SOC and PT. 
The number and the percentage of patients with at least one TEAE, severe TEAE, serious TEAE 
and TEAE leading to treatment discontinuation will be summarized by age group. 
Treatment-emergent AEs will be summarized, tabulating: 
• 
The number and percent of patients with at least one TEAE within each and overall 
SOC(s); 
• 
The number and percent of patients experiencing each PT in each SOC; 
• 
The number of occurrences of all PTs within each and overall SOC(s); 
• 
The number of occurrences of each PT in each SOC. 
11.4.2.1.2  Deaths, serious, and other significant adverse events 
Any deaths and SAEs will be listed. 
11.4.2.1.3 Adverse events leading to treatment discontinuation 
Any AEs leading to treatment discontinuation will be listed. 
11.4.2.1.4 Adverse events of special interest (AESI) 
Adverse events of special interest will be listed, including IAR, APR and CRS.  
11.4.2.2 Clinical laboratory tests 
The values to be used as baselines will be the values collected on Day 1/Week 0 (D1) pre-infusion 
assessment with the exception of white blood cell count, platelet count, and hemoglobin. If any of 
the scheduled baseline tests are repeated for any patient, the last rechecked values will be 
considered as baseline, provided they were done pre- infusion. 
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Baseline white blood cell count, platelet count, and hemoglobin values will be calculated using 
the mean of 2 samples collected greater than 24 hours apart during the screening period. 
Abnormalities analyses 
For parameters with laboratory ranges and/or abnormality criteria, an on-treatment analysis will 
be performed using all post-baseline assessments done during the on-treatment period, including 
rechecked values. Counts of patients with PCSAs will be provided in summary tables showing 
shifts from normal and abnormal baselines to post-baseline abnormalities, presented by age group 
the PCSA occurred in. The same type of summary tables will be provided for out-of-normal 
laboratory range values. 
A listing of liver function data for patients who experienced at least one occurrence of ALT 
≥3 ULN and at least one occurrence of total bilirubin ≥2 ULN during the study with at least one of 
them being post first infusion will be also provided. 
Descriptive statistics 
For laboratory parameters, observed raw data, change from baseline and percent change from 
baseline will be summarized in descriptive statistics. 
Listings 
All individual data, including rechecked values, for planned hematology and biochemistry 
evaluations, will be listed. If any, data from unscheduled laboratory tests will be also listed. In 
these listings, individual data will be flagged when lower or higher than the lower or upper 
laboratory limits and/or when reaching the absolute limit of PCSA criteria, when defined. A data 
listing of individual post-baseline abnormalities by patient and time point will be provided. 
11.4.2.3 Vital signs 
Heart rate and blood pressure 
Heart rate and blood pressure, systolic and diastolic, will be analyzed as observed parameter value 
and change from baseline. 
The values to be used as the baselines will be the Day 1/Week 0 pre-infusion value. If any of the 
scheduled baseline tests are repeated for any patient, the last rechecked values will be considered 
as baselines, provided they were done pre-infusion. 
Abnormality analysis 
For all parameters, an “on-treatment” analysis will be performed using all post-baseline 
assessments done during the on-treatment period, including rechecked values. Counts of patients 
with post-baseline PCSAs will be provided in summary tables regardless of the normal or 
abnormal status of the baseline by age group. 
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Descriptive statistics 
For heart rate (in beats/minute) and blood pressure (in mmHg) observed raw data and change 
from baseline will be summarized in descriptive statistics, for each type of measurement, 
parameter and time point. 
Listings 
All individual data, including rechecked values, will be listed by type of measurement. In the 
listings, values will be flagged when reaching the limits of the PCSA criteria, when defined. A 
data listing of individual post-baseline abnormalities by patient will be provided. 
Comments related to vital sign evaluations will also be listed, if any. 
11.4.2.4 Electrocardiogram 
Heart rate (in bpm), PR (in ms), QRS (in ms), QT-intervals (in ms) and corrected QT-intervals 
(QTc) will be analyzed as raw parameter values and change from baseline (for HR, PR, QT, QTc). 
Outlier summaries for the ECG parameters (eg, QTc) will also be created. 
The values to be used as the baselines will be the mean of the triplicate measurements on 
Day 1/Week 0 pre-IMP values. If any of the scheduled baseline tests are repeated for any patient, 
the last rechecked values will be considered as baselines, provided they were done prior to the 
first olipudase alfa infusion. 
Abnormality analysis 
For all parameters, an “on-treatment” analysis will be performed using all post-baseline 
assessments done during the on-treatment period, including rechecked values. Counts of patients 
with post-baseline PCSAs will be provided in summary tables regardless of the normal or 
abnormal status of the baseline by age group. 
Descriptive statistics 
For all parameters, raw data and changes from baseline will be summarized in descriptive 
statistics for each time point.  
Listings 
All individual data, including rechecked values, will be listed by type of measurement. In the 
listings, values will be flagged when reaching the limits of the PCSA criteria, when defined. A 
data listing of individual post-baseline abnormalities by patient will be provided. 
Comments related to vital sign evaluations will also be listed, if any. 
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11.4.2.5 Physical examinations and neurological examinations 
The frequencies and percent of patients with normal/abnormal findings at baseline and successive 
visits will be summarized. 
11.4.2.6 Echocardiogram and liver ultrasound Doppler  
Echocardiogram and liver ultrasound Doppler data will be presented for appropriate visits using 
raw data in listings and/or by descriptive statistics. Likewise, categorical data will be summarized 
using frequencies and percents at appropriate visits. 
11.4.2.7 Safety biomarkers 
For safety biomarkers of ceramide, cardiac troponin I, hsCRP, calcitonin, iron, ferritin, IL-6 and 
IL-8 raw values and change from baseline will be summarized using descriptive statistics by age 
group cohort, time point, highest tolerated dose and overall time point. 
11.4.2.8 Anti-olipudase alfa IgG antibodies, neutralizing antibodies, and other immune 
response assessments 
Percentage of patients who seroconverted to olipudase alfa, time to seroconversion and peak IgG 
antibody titer will be summarized using descriptive statistics. IgG antibody titer values will be 
summarized using descriptive statistics at each study visit. All data will be presented in listings for 
each patient. 
By patient listings will also display results of neutralizing antibody, circulating immune complex, 
anti-olipudase alfa IgE antibody, serum tryptase activity, complement activation, and skin testing 
performed. Descriptive summaries may also be provided as appropriate. 
11.4.3 Pharmacokinetic analyses 
Plasma concentration-time data will be analyzed by non-compartmental methods, nonlinear mixed 
effects modeling or by population-based analysis, based upon patient age and data suitability. 
Values will be reported for individual subjects and summarized using descriptive statistics by 
dose level and study week as appropriate.  These will use the pharmacokinetic population. 
11.4.4 Pharmacodynamic analyses 
Pharmacodynamic endpoints are defined in Section 9.2.3. 
Concentration-time data for sphingomyelin and metabolite levels (eg, ceramide, 
lyso-sphingomyelin) will be summarized using descriptive statistics. If appropriate, the following 
parameters will also be assessed: Cmax, Tmax, and area under the effect-time curve. Individual and 
descriptive statistics will be presented. 
Pharmacodynamic parameters will be summarized using descriptive statistics using the 
pharmacodynamics population. Change from baseline will be calculated and summarized. 
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Exploratory correlation analyses will be attempted to evaluate relationships between different 
pharmacodynamic markers and between sphingomyelin levels from different sources. 
These analyses will be conducted by age cohort – in overall population as well as by 
manufacturing scale, as appropriate. 
11.4.5 Exploratory efficacy analyses 
Efficacy assessments are described in Section 9.2.2. 
Efficacy analyses will be performed on the modified intent-to-treat analysis set. For each 
exploratory efficacy assessment, observed measures, change from baseline and/or percent 
change from baseline to week 52 or 64,  as appropriate, will be listed and summarized using 
descriptive statistics overall and separately by timepoint and age cohort, including 
95% confidence intervals. 
Categorical variables (eg, pulmonary imaging, chest X-ray) will be summarized using 
frequencies and percentages according to time points collected from screening or baseline to 
Week 52 (or last study assessment). 
The same efficacy analyses will also be performed by manufacturing scale. 
11.4.6 Pharmacokinetic-pharmacodynamic analyses 
Exploratory PK-PD analyses may be performed to elucidate exposure-response relationships 
with biomarkers of safety and/or efficacy. The PK-PD relationships may be explored 
graphically. If a relationship is apparent, PK-PD modeling may be attempted and results 
reported, as appropriate.  
11.5 
INTERIM ANALYSIS 
Analysis of data, including summary tables, figures and listings, may be conducted intermittently 
during the study and upon completion of a cohort’s key milestones, eg, week 26 or 52 efficacy 
assessments.  
 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
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 free, publicly accessible, internet-based registries, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The investigator (according to applicable regulatory requirements), or a person designated by the 
investigator, and under the investigator’s responsibility, should fully inform the patient (and the 
parent[s] or guardian[s]) of all pertinent aspects of the clinical trial including the written 
information given approval/favorable opinion by the ethics committee (IRB/IEC). All participants 
should be informed to the fullest extent possible about the study in language and terms they are 
able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s parents or by the 
patient’s legally acceptable representative, and by the person who conducted the informed consent 
discussion. If only 1 one parent or guardian signs the consent form, the investigator must 
document the reason why only 1 parent or guardian’s signature. A copy of the signed and dated 
written informed consent form will be provided to the patient.  
Participants who can read the assent form will do so before writing their name and dating or 
signing and dating the form. 
Participants who can write but cannot read will have the assent form read to them before writing 
their name on the form. 
Participants who can understand but who can neither write nor read will have the assent form read 
to them in the presence of an impartial witness, who will sign and date the assent form to confirm 
that assent was given. 
The informed consent form used by the investigator for obtaining the patient's informed consent 
must be reviewed and approved by the sponsor prior to submission to the appropriate Ethics 
Committee (IRB/IEC) for approval/favorable opinion. 
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In relation with the population of patients exposed in the trial ie, pediatric/minor patients, the 
IRB/IEC should ensure proper advice from specialist with pediatrics expertise (competent in the 
area of clinical, ethical and psychosocial problems in the field of pediatrics) according to national 
regulations. This should be documented. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the investigator or the sponsor must submit this clinical trial 
protocol to the appropriate 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 IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
IMP 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 should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
investigator’s Brochure will be sent to the IRB/IEC. 
A progress report is sent to the 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 is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the sponsor (including security rules). The 
investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the e-CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient’s data to be transferred. 
The investigator may appoint such other individuals as he/she may deem appropriate as 
subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All subinvestigators shall be appointed and listed in a timely manner. The 
subinvestigators will be supervised by and work under the responsibility of the investigator. The 
investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-CRFs. Thus, the main duty of 
the monitoring team is to help the investigator and the sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-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 e-CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the investigator to maintain adequate and accurate e-CRFs (according to 
the technology used) designed by the sponsor to record (according to sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the sponsor may generate additional requests (DRF) to 
which the investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF.  
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the sponsor and investigator study files. 
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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 prior to the 
beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The investigator must notify the sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the investigator shall inform the sponsor and the relevant records shall be transferred to a mutually 
agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the e-CRFs, the investigator’s Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (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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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the sponsor or its designee are and remain the 
sole property of the sponsor. 
The investigator shall not and shall cause the delegated investigator staff/subinvestigator not to 
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, shall 
be treated by both the sponsor and the investigator in compliance with all applicable laws 
and regulations. 
• 
Subject race or ethnicity (ethnicity: not Hispanic or Latino; race: American Indian or 
Alaska native, Asian, Black, Native Hawaiian or other Pacific Islander, White and “not 
reported”) will be collected in this study because these data are required by several health 
authorities. 
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 any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory 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 is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The investigator will make every effort to help 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 will inform 
the sponsor and authorize the sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the investigator to the sponsor. 
The investigator shall take appropriate measures required by the sponsor to take corrective actions 
for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 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; 
• 
The investigator has received from the sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
• 
Non-compliance of the investigator or sub-investigator, 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. 
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14.8.2 By the Investigator 
The investigator may terminate his/her participation upon thirty (30) days’ prior written notice if 
the study site or the investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the investigator. The coordinating investigator who will sign off on the study 
report will be the investigator who first enrolled the largest number of patients in the trial.  
14.10 PUBLICATIONS AND COMMUNICATIONS 
The investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the sponsor’s written consent, being understood that the sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the sponsor agrees that, consistent with scientific 
standards, a primary presentation or publication of the study results based on global study 
outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (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 in agreement with 
other investigators and stakeholders. The investigator shall provide the sponsor with a copy of any 
such presentation or publication 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 justified 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 of 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 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. Schuchman EH, Desnick RJ. Niemann-Pick Disease Types A and B: Acid Sphingomyelinase 
Deficiencies. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio 
A, et al, editors. OMMBID - The Online Metabolic and Molecular Bases of Inherited Diseases. 
New York (NY): McGraw-Hill; 2013.[cited 2014 Jul 29]. Available from: 
http://ommbid.mhmedical.com/content.aspx?bookid=474&Sectionid=45374145 
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, 
but not neurological, correction of the pathophysiology. FASEB J. 2000;14(13):1988-95. 
4. Dhami R, He X, Gordon RE, Schuchman EH. Analysis of the lung pathology and alveolar 
macrophage function in the acid sphingomyelinase-deficient mouse model of Niemann-Pick 
disease. Lab Inves. 2001;81(7):987-99. 
5. Genzyme, a Sanofi company. A phase 1, single-center, single-dose, dose escalation study of 
recombinant human acid sphingomyelinase (rhASM) in adults with acid sphingomyelinase 
deficiency (ASMD). Study No. SPHINGO00605. 
6. Genzyme, a Sanofi company. An open-label, multicenter, ascending dose study of the 
tolerability and safety of recombinant human acid sphingomyelinase (rhASM) in patients with 
acid sphingomyelinase deficiency (ASMD). Study No. DFI13412 (Genzyme Study No. 
SPHINGO00812). 
7. Genzyme, a Sanofi company. A long-term study to assess the ongoing safety and efficacy of 
recombinant human acid sphingomyelinase in patients with acid sphingomyelinase deficiency. 
Study No. LTS13632. 
8. Brinkman J, Wijburg FA, Hollak CE, Groener JE, Verhoek M, Scheij S, et al. Plasma 
chitotriosidase and CCL18: early biochemical surrogate markers in type B Niemann-Pick 
disease. J Inherit Metab Dis. 2005;28(1):13-20. 
9. 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 
B. Pediatrics. 2008;122(2):341-9. 
10. Mendelson DS, Wasserstein MP, Desnick RJ, Glass R, Simpson W, Skloot G, et al. Type B 
Niemann-Pick disease: findings at chest radiography, thin-section CT, and pulmonary function 
testing. Radiology. 2006;238(1):339-45. 
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11. Varni JW, Burwinkle TM, Seid M. The PedsQL as a pediatric patient-reported outcome: 
reliability and validity of the PedsQL Measurement Model in 25,000 children. Expert Rev 
Pharmacoecon Outcomes Res. 2005; 5(6):705-19. 
12. Guidelines of the Human Genome Variation Society. Available at: http://www.hgvs.org/. 
Accessed at 2014 Jul 29. 
13. Marshal WA and Tanner JM. Variations in the Pattern of Pubertal Changes in Boys. Arch Dis 
Child. 1970;45(239):13–23. 
14. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969; 44(235):291-303. 
15. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis; Summary report — 
second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. Ann Emerg Med. 2006;47(4):373-80. 
  
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SAP_001.pdf: 


Statistical Analysis Plan  
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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 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 9 
1.4 
STUDY PLAN ................................................................................................................................... 9 
1.5 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL ............................ 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ....................... 9 
2 
STATISTICAL AND ANALYTICAL PROCEDURE ....................................................................... 11 
2.1 
SUBJECT DESCRIPTION ............................................................................................................. 11 
2.1.1 
Disposition of subjects ................................................................................................................... 11 
2.1.2 
Protocol deviations ......................................................................................................................... 11 
2.2 
ANALYSIS POPULATIONS ........................................................................................................... 12 
2.2.1 
Safety population ........................................................................................................................... 12 
2.2.2 
Modified intent-to-treat population ................................................................................................. 12 
2.2.3 
Pharmacokinetic population ........................................................................................................... 12 
2.2.4 
Pharmacodynamic population ........................................................................................................ 12 
2.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................. 12 
2.3.1 
Subject demographic characteristics, medical history, and diagnoses ......................................... 12 
2.3.2 
Baseline safety parameters ........................................................................................................... 13 
2.3.3 
Baseline pharmacodynamics parameters ...................................................................................... 14 
2.4 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE ........................................ 14 
2.5 
PRIOR AND CONCOMITANT MEDICATION/THERAPY ............................................................. 15 
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2.6 
ANALYSIS OF SAFETY DATA ...................................................................................................... 16 
2.6.1 
Adverse events .............................................................................................................................. 16 
2.6.1.1 
Definitions ...................................................................................................................................... 16 
2.6.1.2 
Treatment-emergent adverse events ............................................................................................. 18 
2.6.1.3 
Adverse events of special interest ................................................................................................. 18 
2.6.1.4 
Adverse events of other interest .................................................................................................... 20 
2.6.1.5 
Serious adverse events ................................................................................................................. 20 
2.6.1.6 
Adverse events leading to permanent treatment discontinuation .................................................. 20 
2.6.1.7 
Deaths ............................................................................................................................................ 20 
2.6.1.8 
Potential Quantifiable Dose Limiting Toxicities .............................................................................. 21 
 
 
2.6.2 
Physical examinations ................................................................................................................... 21 
2.6.3 
Neurological examinations ............................................................................................................. 21 
2.6.4 
Weight, height, BMI ........................................................................................................................ 21 
2.6.5 
Clinical laboratory evaluations ....................................................................................................... 22 
2.6.6 
Vital signs ....................................................................................................................................... 23 
2.6.7 
Electrocardiogram .......................................................................................................................... 23 
2.6.8 
Doppler echocardiogram ................................................................................................................ 23 
2.6.9 
Liver ultrasound Doppler ................................................................................................................ 24 
2.6.10 
Safety biomarkers .......................................................................................................................... 24 
2.6.11 
Immune response assessments .................................................................................................... 24 
2.7 
ANALYSIS OF PHARMACOKINETIC DATA ................................................................................. 27 
2.7.1 
Pharmacokinetic parameters ......................................................................................................... 27 
2.7.2 
Statistical analysis .......................................................................................................................... 27 
2.8 
ANALYSIS OF EXPLORATORY EFFICACY VARIABLES ........................................................... 28 
2.8.1 
Spleen and liver volumes ............................................................................................................... 28 
2.8.2 
Height z-score ................................................................................................................................ 29 
2.8.3 
Pulmonary function testing ............................................................................................................. 29 
2.8.4 
Platelet count and hemoglobin ....................................................................................................... 31 
2.8.5 
Pulmonary imaging by high resolution computed tomography ...................................................... 31 
2.8.6 
Chest X-ray .................................................................................................................................... 32 
2.8.7 
Bone age by hand X-ray ................................................................................................................ 32 
2.8.8 
Cycle ergometry ............................................................................................................................. 32 
2.8.9 
Physician’s global assessment of change ..................................................................................... 33 
2.8.10 
Efficacy biomarkers ........................................................................................................................ 34 
2.8.11 
Lipid profile ..................................................................................................................................... 34 
2.8.12 
Bone biomarkers ............................................................................................................................ 34 
2.8.13 
Health outcome questionnaires ..................................................................................................... 34 
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2.8.14 
Cognitive and adaptive function testing ......................................................................................... 37 
 
 
2.9 
ANALYSIS OF PHARMACODYNAMIC VARIABLES .................................................................... 39 
2.9.1 
Description of pharmacodynamic variables ................................................................................... 39 
2.9.2 
Statistical analysis .......................................................................................................................... 39 
2.10 
PATIENT NARRATIVES ................................................................................................................ 39 
2.11 
DATA HANDLING CONVENTIONS .............................................................................................. 40 
2.11.1 
General conventions ...................................................................................................................... 40 
2.11.2 
Missing data ................................................................................................................................... 40 
2.11.3 
Windows for time points ................................................................................................................. 41 
2.11.4 
Unscheduled visits ......................................................................................................................... 41 
2.11.5 
Potentially clinically significant abnormalities (PCSA) criteria ....................................................... 42 
3 
INTERIM ANALYSIS ..................................................................................................................... 48 
4 
SOFTWARE DOCUMENTATION ................................................................................................. 49 
5 
REFERENCES ............................................................................................................................... 50 
6 
APPENDICES ................................................................................................................................ 51 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ABAS-3: 
Adaptive Behavior Assessment System, Third Edition 
ACE: 
angiotensin-converting enzyme 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AP: 
alkaline phosphatase 
APR: 
acute phase reaction 
ASM: 
acid sphingomyelinase 
ASMD: 
acid sphingomyelinase deficiency 
AST: 
aspartate aminotransferase 
AUC: 
area under the plasma concentration curve 
AUC0-inf: 
area under the concentration versus time curve from time 0 textraoplated to 
infinity 
BMI: 
body mass index 
BUN: 
blood urea nitrogen 
CCL18: 
chemokine (CC-motif) ligand 18 
Ceio: 
concentration at end of infusion 
CHITO: 
chitotriosidase 
CL: 
total body clearance 
Cmax: 
maximum plasma concentration 
CRS: 
cytokine release syndrome 
CSR: 
clinical study report 
CV: 
coefficient of variation 
DBP: 
diastolic blood pressure  
DBS: 
dried blood spots 
DLCO: 
diffusing capacity of the lung for carbon monoxide 
DP-3: 
Developmental Profile 3 
ECG: 
electrocardiogram 
ECHO: 
echocardiogram 
e-CRF: 
electronic case report form 
FEV1: 
forced expiratory volume in the 1st second of the FVC maneuver 
FVC: 
forced vital capacity 
Hb: 
hemoglobin 
HDL: 
high density lipoprotein 
HIV: 
human immunodeficiency virus 
HR: 
heart rate 
HRCT: 
high resolution computed tomography 
hsCRP: 
high sensitivity C-reactive protein 
IAR: 
infusion-associated reaction 
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IgE: 
immunoglobulin E 
IgG: 
immunoglobulin G 
IL: 
interleukin 
INR: 
international normalized ratio 
ITT: 
Intent-to treat 
IV: 
intravenous 
LDL: 
low density lipoprotein 
LLOQ: 
Lower Limit of Quantification 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
Modified intent-to-treat 
MN: 
multiples of normal 
MRI: 
magnetic resonance imaging 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic(s) 
PedsQL: 
Pediatric Quality of Life 
PFT: 
pulmonary function testing 
PK: 
pharmacokinetc(s) 
PKDM: 
pharmacokinetics, dynamics and metabolism 
Protime: 
prothrombin time 
PT: 
preferred term 
PTT: 
partial thromboplastin time 
QOL: 
Quality of Life 
QTc: 
corrected QT-interval 
QTcB: 
QTc interval corrected by Bazett 
QTcF: 
QTc interval corrected by Fridericia 
RBC: 
red blood cell 
rhASM: 
recombinant human acid sphingomyelinase 
SAE: 
serious adverse event 
SAP: 
Statistical Analysis Plan 
SAS: 
Statistical Analysis System 
SBP: 
systolic blood pressure  
SD: 
standard deviation 
SEM: 
standard error of the mean 
SI: 
international system of units, international system of units 
SMPD1: 
acid sphingomyelinase gene, acid sphingomyelinase gene 
SOC: 
system organ class 
t1/2z: 
terminal half-life 
TEAE: 
treatment-emergent adverse event 
TLC: 
total lung capacity 
tmax: 
time to reach Cmax, time to reach Cmax 
ULN: 
upper limit of normal 
VAS: 
visual analogue scale 
VLDL: 
very low density lipoprotein 
VSS: 
volume of distribution at steady state. 
WBC: 
white blood cell 
WHO: 
World Health Organization 
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WHO-DRUG: 
World Health Organization Drug dictionary 
WMW: 
Wilcoxon-Mann-Whitney 
β-HCG: 
beta-human chorionic gonadotropin 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical techniques to be used to analyze data from DFI13803, a study of 
GZ402665/olipudase alfa, recombinant human acid sphingomyelinase [rhASM] in pediatric 
patients; it is based on Amended Clinical Trial Protocol 4, dated 21-Aug-2017. The purpose of the 
SAP is to ensure the credibility of the study findings by pre-specifying the statistical approaches 
to the analysis of study data prior to database lock. This version replaces the previous versions of 
the SAP. 
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is a Phase 1/2, multi-center, open-label, ascending dose study to evaluate the safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and exploratory efficacy of 
olipudase alfa in pediatric patients less than 18 years of age with non-neuronopathic acid 
sphingomyelinase deficiency (ASMD). At least 12 patients were initially planned to be enrolled in 
3 age cohorts with a minimum of 3 patients aged from 12 to <18 years (adolescent cohort), a 
minimum of 3 patients aged from 6 to <12 years (child cohort), and at least 2 patients aged from 
birth to <6 years (infant/early child cohort). At least 8 additional pediatric patients <12 years will 
be enrolled following protocol amendment 04 (dated 21-Aug-2017). There will be at least 20 
patients enrolled in the study in total. 
For each patient, study participation will consist of a screening/baseline period (up to 60 days) and 
a 64-week treatment period with intravenous (IV) infusions of olipudase alfa administered every 
2 weeks for 64 weeks. Patients will go through a dose escalation period with target dose of 
3.0mg/kg; for further details see protocol Section 1.1. 
Eligible patients may enroll in a long-term study (LTS13632) following completion of the 
64-week treatment period to continue receiving olipudase alfa. Patients not enrolling in the  
long-term study will undergo a final safety follow-up assessment by telephone 30 to 37 days after 
the last infusion in this study; patients with a treatment gap between the end of the 64-week 
treatment period of DFI13803 and enrollment in the long-term study, depending on the length of 
the gap, may also undergo a final safety follow-up assessment by telephone 30 to 37 days after the 
last infusion in this study.  
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objective of this study is to evaluate the safety and tolerability of olipudase alfa 
administered intravenously in pediatric patients every 2 weeks for 64 weeks. 
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1.2.2 Secondary objectives  
The secondary objectives of this study are to characterize the pharmacokinetic profile and 
evaluate the pharmacodynamics and exploratory efficacy of olipudase alfa administered 
intravenously in pediatric patients every 2 weeks for up to 64 weeks.   
1.3 
DETERMINATION OF SAMPLE SIZE  
A sample size power calculation was not performed for this study. The study sample size is based 
upon empirical considerations.  
1.4 
STUDY PLAN  
Refer to Protocol Section 1.2 for the study plan.  
1.5 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL  
In the section of statistical considerations of the protocol, the baseline for white blood cell count, 
platelet count, and hemoglobin was defined as the mean of 2 samples collected greater than 24 
hours apart during the screening period. The baseline definition is modified in the SAP as the 
average of all measurements taken before the first infusion. 
The statistical considerations of the protocol mentions that Infusion Associated Reactions (IAR), 
Acute phase reaction (APR) and cytokine release syndrome (CRS) will be listed as part of adverse 
events of special interest (AESI). However, per protocol, AESIs are reported as original signs and 
symptoms and only IARs were specifically identified in the eCRF. Consequently, APR and CRS 
cannot specifically be listed, but the details of these AESIs will be provided in patient narratives, 
and discussed in the clinical study report (CSR) as necessary. 
In the section of statistical considerations of the protocol, the post-treatment period was defined as 
the time after the EOS visit. However, no data are expected to be collected after the EOS visit. 
Therefore, the post-treatment period has been removed from this SAP. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
The main modifications made in this version of SAP compared to the previously approved version 
(Version 2, Dated 17-Aug-2016) are listed as follows. 
 The modified intent-to-treat population was added in Section 2.2.2 to be consistent with 
the protocol. 
 The per protocol population and completer population were removed from Section 2.2 as 
they are not pre-defined in the protocol and also are not needed for this study. 
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 Derivations for classifications of the different SMPD1, CHIT1 and UGT1A1 genotypes 
were added in Section 2.3.1 in order to provide summaries on number of patients and 
percentages.  
 Protocol-defined potential dose limiting toxicities that are considered AESIs have been 
added in Section 2.6.1.3 to be consistent with the protocol. 
 Specific analyses on infections and bleeding have been updated in Section 2.6.1.4 
following interactions with health authorities. 
 
. 
 
 
 
 The paired t-test has been updated to analysis of covariance with baseline included as 
covariate for exploratory efficacy variables in order to adjust for baseline, since baseline is 
highly correlated with change from baseline values. See Section 2.8. 
 Platelet count and hemoglobin were added as exploratory efficacy endpoints in order to be 
consistent with other ASMD studies for compound GZ402665/olipudase alfa. See 
Section 2.8.4. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURE  
Data collected in this study will be presented using summary tables, figures, and by-patient data 
listings. Descriptive statistics for categorical variables will be provided using frequencies (n) and 
percentages (%). Descriptive statistics for continuous variables will be provided using number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum. 
If appropriate, p-values and 95% confidence intervals (CI) from analysis of covariance with 
baseline as covariate may be provided for change from baseline values. All data used in tabular 
summaries or figures will be supported by listings of underlying data – raw and/or derived, and all 
figures will be supported by relevant summary information.  
2.1 
SUBJECT DESCRIPTION  
2.1.1 Disposition of subjects  
Screened patients are defined as any patients who signed the informed consent or whose parent or 
guardian signed informed consent. 
Enrolled patients are defined as those who meet the inclusion criteria and none of the exclusion 
criteria. 
The number of patients screened, enrolled, treated (receiving at least one study infusion), 
completing the study, and not completing study along with primary reason for discontinuation will 
be presented.   
2.1.2 Protocol deviations  
During the review of the database, compliance with the protocol will be examined with regard to 
inclusion and exclusion criteria, treatment, prohibited therapies, and timing and availability of 
planned assessments. Protocol deviations will be identified by the study team before database lock 
and classified as minor, major or critical deviations. A listing of major or critical protocol 
deviations for all treated patients will be produced.   
In addition to the above, the two conditions listed below will be evaluated:  
 Noncompliance: Missing 2 or more consecutive infusions (excluding for cause missed 
doses, such as when the missed infusions are required by the protocol due to a dose 
limiting toxicity) or a total of 4 or more infusions for the 64-week treatment period. 
Whether a missed infusion is for-cause or not will be reviewed and determined by the 
clinical team; the decision will be used in the determination of noncompliance.  
 Prohibited medications intake: A list of medications which potentially modify the effect of 
olipudase alfa are identified and provided by the clinical team. This list is updated 
regularly with change of World Health Organization (WHO) Drug dictionary (WHO-
DRUG) versions. Any use of such medications in the clinical database will be reviewed by 
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the clinical team before data base lock with special attention to start and/or stop date of 
these medications compared to start/stop date of study treatment. The clinical team will 
review the prohibited medication intake and decide whether it is minor, major or critical 
protocol deviation. 
2.2 
ANALYSIS POPULATIONS  
2.2.1 Safety population  
All subjects who were exposed to the study treatment, olipudase alfa, ie, who received at least one 
infusion of study treatment (total or partial), will be included in the safety population. 
2.2.2 Modified intent-to-treat population  
The modified intent-to-treat (mITT) population is the same as the safety population and is used as 
the primary population for the efficacy analysis. 
2.2.3 Pharmacokinetic population  
The pharmacokinetic population includes all patients who receive at least 1 infusion of olipudase 
alfa and have evaluable pharmacokinetic data available post-baseline.  
2.2.4 Pharmacodynamic population  
Pharmacodynamic population includes all patients who are treated and have at least one evaluable 
pharmacodynamics measurement available post-baseline.  
2.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS  
2.3.1 Subject demographic characteristics, medical history, and diagnoses  
Demographic, disease characteristics and medical/surgical history information will be summarized 
by age group cohorts and overall using the safety population. No formal hypothesis testing will be 
performed to compare differences between age group cohorts. 
Demographic and baseline characteristic parameters include the following: gender, race, ethnicity, 
ancestry, age (in years and months) at Week 0/Day 1, human immunodeficiency virus (HIV) 
antibody testing, and Hepatitis tests (B surface antigen and C antibody tests). 
Baseline disease characteristic parameters include the following: age at ASMD symptom onset 
(years and months if available), age at ASMD diagnosis (years and months if available), spleen 
status, ASMD symptoms present at disease onset, ASMD family history, genotyping of acid 
sphingomyelinase gene (SMPD1), CHIT1, UGT1A1, severe splenomegaly and severe % predicted 
DLco adjusted for hemoglobin. Genotype of acid sphingomyelinase gene (SMPD1), CHIT1 and 
UGT1A1 as well as acid sphingomyelinase (ASM) activity in peripheral leukocytes and CRIM 
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testing from screening evaluations will be included in data listings. Severe splenomegaly is 
defined as the baseline spleen volume (MN) > 15 MN; severe % predicted DLco adjusted for 
hemoglobin is defined as the baseline value < 40%.  
The SMPD1 variant type (i.e., 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”. 
Medical/surgical history will be collected by body system as Yes/No/Unknown, and if Yes, the 
current status will be collected. These data will be summarized by body system, by age group 
cohorts and overall. Additional medical/surgical history regarding specific disease of interest will 
be collected and summarized. 
Smoking and alcohol drinking history data will be provided in data listings. 
2.3.2 Baseline safety parameters  
Baseline for safety parameters (weight, height, body mass index (BMI), physical exam, vital 
signs, echocardiograms, immune response assessments, and safety biomarkers) in general is 
defined as the last available non-missing value for the parameter before the first infusion. Most of 
the baseline values will thus be Day 1/Week 0 pre-infusion assessments with the exception of 
hematology parameters and possibly electrocardiogram (ECG). Hematology 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. Another 
exception may be the ECG parameters – Day 1/Week 0 (the first infusion visit) is to collect ECG 
in triplicate before the infusion; if 2 or more than 2 of these triplicate collections of ECG are 
before the first infusion, the average of these ECG parameter results will be considered as the 
baseline value; otherwise, the baseline value of ECG parameters will be taken from the latest 
observation before the first infusion.  
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Baseline safety data will be presented along with subsequent values assessed during or after 
olipudase alfa dosing using safety population. 
2.3.3 Baseline pharmacodynamics parameters  
Baseline values for sphingomyelin and sphingomyelin metabolites, including, but not limited to, 
ceramide in dried blood spots (DBS), lyso-sphingomyelin and sphingosine-1-phosphate in plasma 
and/or DBS will be the last available value before first infusion; typically these will be the 
screening values.  
Baseline pharmacodynamic data will be presented along with subsequent pharmacodynamics 
values assessed during or after olipudase alfa dosing using pharmacodynamic population. 
2.4 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE  
The extent of study treatment exposure will be assessed and will be summarized using safety 
population. The duration of exposure is defined as the number of weeks between first infusion and 
disposition date (ie, the end of study date) in the study: (disposition date of the study – first 
infusion date + 1)/7. The number of infusions received and the duration of exposure will be 
summarized by age cohorts and overall. 
The distribution of weeks on study treatment (<12 weeks, >=12 weeks to <26 weeks, >=26 weeks 
to <38 weeks, >=38 weeks to <52 weeks, >=52 weeks to <64 weeks, and >=64 weeks) will be 
provided using number and percentage of patients by age group cohorts and overall. 
Compliance to the treatment regimen will be monitored in terms of the percentage of scheduled 
infusions the patient receives during the treatment period. A patient is considered noncompliant if 
the patient missed 2 or more consecutive infusions (not-for-cause, such as when the missed 
infusions are required by the protocol due to a dose limiting toxicity) or a total of 4 or more 
infusions for the 64-week treatment period. Whether a missed infusion is for-cause or not will be 
reviewed and determined by the clinical team; the decision will be used in the analysis of 
compliance.  
Overall Compliance = 100% x Total number of infusions received / Total number of expected 
infusions 
where total number of expected infusions refers to the number of infusions expected between the 
first infusion and the date of withdrawal or date of completion. It is calculated as the integer part 
of (Date of withdrawal – Date of the first infusion)/14. For a patient who completes the 64-week 
treatment period, the total number of expected infusions is 33. 
Compliance excluding for-cause = 100% x Total number of infusions received / Total number of 
expected infusions (excluding for-cause missing infusions) 
where total number of not-for-cause expected infusions refers to the number of infusions expected 
between the first infusion and the date of withdrawal or date of completion, excluding the  
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for-cause missed dose. It is calculated as the integer part of [(Date of withdrawal – Date of the 
first infusion)/14] – number of for-cause missed infusions.  
Overall compliance and compliance excluding for-cause will be summarized descriptively as 
quantitative variable by age group cohorts and overall using safety population. The numbers and 
percentages of patients whose compliance are <80%, >=80% to <90%, >=90% to <100% and 
>=100% will be provided. Number and percentage of patients in the following two categories will 
be presented: 
 Missed 2 or more not-for-cause consecutive infusions. 
 Missed 4 or more scheduled infusions. 
2.5 
PRIOR AND CONCOMITANT MEDICATION/THERAPY  
Medications and therapeutic procedures received by the patient in the 30 days prior to their first 
infusion until the final visit will be recorded on the Prior and Concomitant Medication the 
electronic case report form (e-CRF). Medications, including over-the-counter and herbal products 
as well as supplements, and therapeutic procedures will be collected. Prior and concomitant 
medications will be coded using the World Health Organization Drug dictionary version dated 
March of 2019. 
 Prior medications will be defined as medications that are taken prior to the first infusion of 
olipudase alfa in this study. 
 Concomitant medications will be defined as medications that are taken on or after the first 
infusion of olipudase alfa in this study. 
A medication that was started before the first infusion but continued beyond the first infusion will 
be categorized as both prior and concomitant.  In case the start/stop date of the medication is 
missing or incomplete preventing the unambiguous determination of the medication status, the 
medication will be categorized as both prior and concomitant. 
Medication summaries will be presented by WHO-DRUG Anatomic Class and by WHO-DRUG 
Therapeutic Class for each age group cohort and overall using safety population. Tables will 
show all medications used during the study, sorted by most prevalent Anatomic Class and then by 
descending frequency of Therapeutic Class within Anatomic Class based on the prevalence within 
the overall column.  
Prohibited medications include those that are taken during the study and may decrease olipudase 
alfa activity (eg, fluoxetine, chlorpromazine; tricyclic antidepressants [eg, imipramine, or 
desipramine]). The medications list with potential prohibited medications will be provided by the 
data management and will be merged with the concomitant medication data in the database to 
identify any use of it. Whether the use of such medication constitute a protocol deviation that 
interferes with assessment of effect of olipudase alfa will be determined by clinical review before 
the database lock of all prohibited medication intake during the study. 
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2.6 
ANALYSIS OF SAFETY DATA  
Safety endpoints include data pertaining to the safety and tolerability of olipudase alfa: 
assessment of adverse events (AEs)/treatment-emergent adverse events (TEAEs), including 
AESIs (eg, infusion-associated reactions (IARs), symptomatic overdose, etc.); physical 
examinations; neurological examinations; clinical laboratory evaluations; vital sign 
measurements; ECGs; Doppler echocardiography;  liver ultrasound Doppler; safety biomarkers; 
and immune response assessments. For laboratory endpoints, the summaries will use both the 
international system of units (SI) and US conventional units; figures will use the international 
system of units (SI); data listings will provide the results in original units as well as in standard 
units, where applicable. 
All the safety analyses will be performed using the safety population. Patients will be summarized 
and displayed by age group cohorts and overall. Safety data will be reported up to and including 
the time of treatment withdrawal, and follow-up for AEs, where applicable. The baseline value is 
the last available value before the first infusion of olipudase alfa, except for white blood cell 
count, platelet count, hemoglobin and possibly ECG parameters. For complete definition of 
baseline, refer to Section 2.11.1. 
For all safety data, the observation period will be divided into 2 segments: 
 The pretreatment period is defined as the time between when the patient gives informed 
consent and the start of the first infusion (excluded).  
 The on-treatment period is defined as the time from the start of the first infusion 
(included) till the end of the study. 
The following definitions regarding potentially clinically significant abnormality (PCSA) will be 
applied to laboratory parameters, vital signs and ECG: 
The PCSA values are defined as abnormal values considered medically important by the sponsor 
according to predefined criteria/thresholds based on literature review and defined by the sponsor 
for clinical laboratory tests, vital signs, and ECG. These values are provided in Section 2.11.5.  
 PCSA criteria will determine which patients had at least 1 PCSA taking into account all 
evaluations performed, including unscheduled or repeated evaluations. 
 Before determining a value as PCSA, the value will be rounded to the precision that the 
PCSA criterion is defined. 
2.6.1 Adverse events  
2.6.1.1 Definitions  
AEs are defined in protocol Section 10.6.1. AEs will be coded according to the version of Medical 
Dictionary for Regulatory Activities (MedDRA) in use at the time of database lock. Adverse 
event summaries will include the number of events (N), number (n) and percentage (%) of 
patients experiencing an adverse event. The denominator for computation of percentages is the 
safety population for the entire study and for each age group cohort. Sorting order will follow the 
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internationally agreed MedDRA system organ class (SOC) order, then by decreasing number of 
patients overall in preferred terms (PTs) within SOCs, and further alphabetically within the same 
number of patients over different PTs.  When more than one PT has same number of events within 
the same SOC, the order of presentation will be alphabetical in PTs.  
The AEs will be classified into different periods of occurrence as follows: 
 Pre-treatment adverse events: AEs that started before the start of the first infusion. 
 TEAEs: AEs that started during the on-treatment period. 
If an AE date/time of onset is incomplete, an imputation algorithm will be used to classify the 
adverse event within the appropriate adverse event period. The algorithm for imputing date/time 
of onset will be conservative and will classify an adverse event as treatment emergent unless there 
is definitive information to determine otherwise. Details on classification of AEs with missing or 
partial onset dates are provided in Section 2.11.2. If an AE worsens in severity, only the worst 
severity is captured on the AE log page in the e-CRF. 
The AE log page in the e-CRF captures the date when the event become serious. If and when this 
date is non-missing, it indicates that the AE started as non-serious and became serious after few 
days. 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 primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pre-treatment adverse events will be listed separately. 
Start day of a pre-treatment AE = Start date of AE – first infusion date. 
Start day of treatment emergent AE relative to first infusion = Start date of AE – first infusion 
date + 1. 
Start day of treatment emergent AE relative to last infusion = Start date of AE – last infusion date 
+ 1. 
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2.6.1.2 Treatment-emergent adverse events  
An overview of TEAEs will be provided by age group cohorts and overall 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 the worst severity.  
 TEAEs leading to treatment discontinuation.  
 TEAEs leading to study withdrawal. 
 TEAEs leading to dose reduction. 
 TEAEs leading to study treatment interruption. 
 Protocol-defined IARs. 
 Algorithm-defined IARs. 
 Treatment-emergent serious adverse events.  
 Treatment-emergent serious adverse events potentially related to study treatment. 
 TEAEs with fatal outcome (Deaths). 
 Treatment-emergent pregnancies. 
 TEAEs which are considered symptomatic overdose. 
 Dose-limiting toxicities (collected in the adverse event log page in e-CRF, see protocol 
Section 8.3.4.2.1 for details). 
The following summaries will be produced by primary SOC and PT, by age group cohorts and 
overall: 
 TEAEs.  
 TEAEs by the worst severity (ie, mild, moderate, or severe).  
 TEAEs potentially related to study treatment.   
The most common TEAEs are defined as those with percentage of events >= 2% and number of 
patients >=2 in all age cohorts combined. The most common TEAEs by SOC and PT will be 
provided in descending order of overall incidence by age group cohorts and overall. 
TEAEs by the latest infusion dose immediately preceding the start of AE will be provided by SOC 
and PT, by age group cohorts and overall. 
2.6.1.3 Adverse events of special interest  
The following are AEs of special interest: 
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Protocol-defined IAR: Any AE that is considered related or possibly related to study treatment as 
judged by the investigator or the sponsor is defined as a protocol-defined IAR. Sponsor 
identification will reconcile with investigator identification of IAR before the database lock. 
The following summaries will be produced by primary SOC and PT, by age group cohorts and 
overall: 
 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. 
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.  
The following summaries will be produced by primary SOC and PT, by age group cohorts and 
overall: 
 Algorithm-defined IARs (including any TEAEs with missing time but happened on the 
same day or the day after the infusion) 
 
A subset of protocol-defined IARs will also be defined programmatically by searching for 
preferred terms within Hypersensitivity SMQs (identified using SMQ code 20000214 Broad and 
Narrow scope). The summaries of Hypersensitivity IARs will be provided by primary SOC and 
PT. 
Pregnancy: Pregnancy of a female patient entered 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. In addition, 
e-CRF provides urine pregnancy test results as positive or negative. Labs provide serum 
pregnancy test results. Pregnancies will be provided in the overview of AE summary and the 
pregnancy test results will be provided as part of patient narrative.  
Symptomatic overdose: This is captured as an adverse event in this study. For details, please see 
Section 10.6.4.1 in the protocol. The symptomatic overdose data will be provided as part of 
patient narrative. 
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Asymptomatic overdose: This is captured as an adverse event with verbatim term as 
‘Asymptomatic overdose’. Asymptomatic overdose data will be provided as part of patient 
narrative. 
 
Laboratory values: The following protocol-defined potential dose limiting toxicities are also 
considered AESIs:  
 Any increase in AST, ALT, total bilirubin, or AP >3x baseline (before 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 ULN combined with an increase in ALT or AST >2x 
baseline (prior to olipudase alfa therapy), with symptoms of fatigue, nausea, vomiting, 
fever, rash, or eosinophilia (> ULN).  
2.6.1.4 Adverse events of other interest  
Infections:  TEAEs of infections are defined under the system organ class of Infections and 
Infestations. These TEAEs will be included in the summary of all TEAEs by primary SOC and 
PT. 
Bleeding:  TEAEs of bleeding are defined under the standard MedDRA queries (SMQs) of 
Hemorrhages (identified using SMQ code 20000038 Broad and Narrow scope). Bleeding AE data 
will be summarized by SOC and PT for each age cohort and overall. 
2.6.1.5 Serious adverse events  
The following summaries will be provided by primary SOC and PT, by age group cohorts and 
overall: 
 Treatment-emergent serious adverse events. 
2.6.1.6 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. AEs leading to permanent treatment discontinuation will be provided as part of the 
patient narrative. 
2.6.1.7 Deaths  
Death is reported as a fatal outcome on the AE log page in the e-CRF. All deaths reported in the 
trial will be provided as part of the patient narrative. 
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2.6.1.8 Potential Quantifiable Dose Limiting Toxicities  
Potential quantifiable Dose Limiting Toxicities will be provided in a by patient data listing. 
2.6.1.9 
  
 
 
 
 
 
 
 
 
 
2.6.2 Physical examinations  
Complete physical examinations data will be collected at screening, Day 1/Week 0, Week 12, 26, 
38 and 52 (or at withdrawal if withdrawn prematurely and not done within 12 weeks prior to 
withdrawal). These examinations will include the evaluation of normal versus abnormal in 
following body systems: general appearance, examination of the skin; head, eyes, ears, nose, and 
throat; lymph nodes; heart, lungs, and abdomen; extremities and joints. Complete physical 
examination (except overall neurological exam) will be classified as normal or abnormal. 
Frequency shift tables will be provided.   
An abbreviated physical examination will assess only the general appearance with evaluation of 
normal versus abnormal of the patient and is only required prior to each infusion when a complete 
exam is not indicated. A listing of the abbreviated physical examination data will be provided.  
Tanner stage for physical gender-related development will be assessed at Screening, Week 12, 
Week 26, Week 38 and Week 52 (or at withdrawal if withdrawn prematurely and not done within 
12 weeks prior to withdrawal). A data listing will be provided.  
2.6.3 Neurological examinations  
Neurological examinations assessments will be collected at screening, Day 1/Week 0, Week 12, 
26, 38, and 52 (or at withdrawal if withdrawn prematurely). They will include, but are not limited 
to the patient’s mental status, posture, cranial nerves, motor system including muscle atrophy, 
tone and power, reflexes, sensory system, coordination, gait, and age-appropriate responses. 
Neurological examinations will be classified as normal/abnormal findings. Frequency shift table 
will be provided.  
2.6.4 Weight, height, BMI  
The weight, height (standing height will be used for patients >2 years of age and supine height 
will be used for patients <=2 years of age) and BMI will be collected at Screening and within 
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24 hours prior to every infusion visit from Day 1/Week 0 to Week 64 (or withdrawal if withdrawn 
prematurely).  
BMI = weight in kilograms / (height in meters)2 
For these three parameters, change from baseline, in addition to observed values, will be 
calculated and summarized for all scheduled visits by age group cohorts and overall.   
Age-appropriate growth in height is a matter of efficacy; please see Section 2.8.2 for analysis of 
height z-scores.  
2.6.5 Clinical laboratory evaluations  
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Analysis of all safety laboratory parameters will be conducted by a central laboraty. 
The following clinical laboratory evaluations will be assessed by the site as specified in 
Section 1.2 to 1.4 of the study protocol. The laboratory parameters will be classified as follows: 
 Hematology: Complete blood count including white blood cell (WBC, leukocytes) count, 
platelet count, hemoglobin, hematocrit, red blood cell (RBC , erythrocytes) count, WBC 
differentials (absolute and percentage of lymphocytes, monocytes, neutrophils, basophils, 
eosinophils, and (if applicable) abnormal cells). Platelet count and hemoglobin will also be 
analyzed as exploratory efficacy endpoints. See details in Section 2.8.4. 
 Clinical Chemistry: sodium, potassium, chloride, blood urea nitrogen (BUN), glucose, uric 
acid, calcium, phosphorus, magnesium, albumin, total protein, creatinine.  
 Liver function tests: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
total bilirubin, direct bilirubin and alkaline phosphatase (AP). 
 Coagulation: prothrombin time (Protime), partial thromboplastin time (PTT), international 
normalized ratio (INR) and D-dimer. 
 Urinalysis: dipstick for pH, ketones, glucose, bilirubin, protein and blood.  
 If female of child bearing potential, β-human chorionic gonadotropin (β-HCG) serum or 
urine test as appropriate per Protocol Sections 1.2 and 10.3. 
Observed values, change from baseline and percent change from baseline to scheduled study time 
points will be summarized by age group cohorts and overall. By patient plots of hemoglobin, 
platelets, WBC, ALT, AST, total bilirubin will be provided. 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 hematology, 
liver function tests and clinical chemistry will be provided by age group cohorts and overall. 
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PCSA values for hematology, liver function tests and clinical chemistry (provided in 
Section 2.11.5) during the study (from first infusion start to last available observation) will be 
summarized by age group cohorts and overall.  PCSA values for hematology, liver function test 
and clinical chemistry parameters will be provided in separate listings.  
2.6.6 Vital signs  
Vital signs are to be measured at every visit before, halfway through, and after infusion 
(±10 minutes). Post-infusion vital signs are measured every 30 minutes for the first 2 hours, 
hourly for 2 to 6 hours post-infusion, and then once every 8 hours until the patient is discharged 
(±10 minutes). Refer to Section 2.11.1 for the baseline definition. 
Vital signs will include heart rate (HR, beats/minute), systolic and diastolic blood pressure 
(SBP/DBP, mmHg), and body temperature (°F or °C). Each vital sign parameter will be 
summarized as observed parameter value and change from baseline per-infusion, 3 hours post-
infusion, 24 hours post-infusion, 48 hours post-infusion, 72 hours post-infusion and end of 
infusion at each scheduled visit by age group cohorts and overall. 
PCSA values during the study (from first infusion start to last available observation) will be 
summarized by age group cohorts and overall.  
2.6.7 Electrocardiogram  
Standard 12-lead ECGs will be recorded at the visits and time points specified in Protocol 
Sections 1.2 and 1.3, and prior to any blood collections.  For Day 1/Week 0, triplicate ECGs will be 
recorded within 5 minutes with at least 1 minute between 2 replicates prior to the study treatment 
administration. 
Heart rate (in beats per minute, PR (in milliseconds), QRS (in milliseconds), QT-intervals (in 
milliseconds) and corrected QT-intervals (QTc) will be analyzed as observed parameter values 
and change from baseline (for HR, PR, QT, QTc). The corrected QT-interval (QTc) data will be 
analyzed using the Bazett (QTcB) and Fredericia (QTcF) methods.  
For all parameters, the observed data and change from baseline will be summarized for each time 
point by age group cohorts and overall.  
PCSA values will be summarized during the study (from first infusion start to last available 
observation) by age group cohorts and overall.   
2.6.8 Doppler echocardiogram  
A standard 2-dimensional and M-mode Echocardiogram (ECHO) with Doppler will be conducted 
at Screening, with the first infusion at 3.0 mg/kg or highest tolerated dose during Week 14 to 
Week 24 or whenever dose escalation is reached, and at Week 52. Examination will include but 
not be limited to: left ventricular cavity size, left ventricular mass, valve characterization, ejection 
fraction, ventricular wall thickness, regional wall motion, systolic and diastolic functions, 
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pericardium characterization and congenital abnormalities. Pulmonary artery pressure will be 
determined by Doppler ultrasound. 
Shift tables will be created for valve characterization (including aortic regurgitation, mitral 
regurgitation, pulmonic regurgitation, tricuspid regurgitation). Summary of change from baseline 
in ejection fraction (%) and pulmonary artery systolic pressure will be provided. By-patient plots 
of left ventricular calculated ejection fraction (%) will be provided. 
2.6.9 Liver ultrasound Doppler  
Liver ultrasound Doppler will be performed at Screening and Week 52 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 that may be examined include the network of intrahepatic portal veins, the 
main and intrahepatic arteries, the hepatic veins, the main and intrahepatic portal veins, the 
intrahepatic portion of the inferior vena cava, collateral venous pathways, and transjugular 
intrahepatic portosystemic shunts. Liver ultrasound Doppler will be performed using methods that 
are compatible with the standard institutional procedures of the investigational site. 
Liver ultrasound Doppler data will be provided in listings.  
2.6.10 Safety biomarkers  
Biomarkers for monitoring the safety of olipudase alfa include, but are not limited to, high 
sensitivity C reactive protein (hsCRP), plasma ceramide, iron, ferritin, cardiac-specific troponin-1, 
calcitonin, interleukin (IL)-6 and IL-8. Samples will be collected at the visits specified in Protocol 
Sections 1.2 and 1.3. 
Observed values, change from baseline and percent change from baseline will be summarized by 
age group cohorts and overall at each time point. Summary plots over time will also be presented 
for observed values as appropriate. 
2.6.11 Immune response assessments  
An immune reaction against an exogenously administered recombinant protein plays a critical role 
in the safety of such compounds. Therefore, safety assessments will also include blood samples 
for anti-olipudase alfa immunoglobulin G (IgG) antibodies and neutralizing antibody formation in 
patients testing positive for ADA when appropriate.  
In the event that a patient experiences a moderate, severe, or recurrent IAR suggestive of 
hypersensitivity reactions, additional blood samples will be collected for the evaluation of: 
 Circulating immune complex detection; and, 
 Immunoglobulin E (IgE) ADA, serum tryptase, and complement activation. 
Additionally, skin testing may be performed, as appropriate, in patients who experience an IAR 
that meets the following criteria: 
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 IAR is suggestive of IgE ADA – mediated hypersensitivity reaction, with persistent 
symptoms of bronchospasm, hypotension and/or urticaria requiring intervention, 
 Or any other signs or symptoms at the discretion of the investigator or the sponsor. 
For ADA summaries, the baseline is the last non-missing ADA assessment prior to the first IMP. 
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 ADA titer value is reported as <xx, the numeric value will be 
imputed as xx, the minimum required dilution (MRD), and used for summary purposes. Listing 
will provide results as reported as well as results as imputed. 
A patient with at least one anti-drug antibody (ADA) response available in the database is 
considered evaluable. 
A patient whose ADA status is positive at baseline is considered to have pre-existing ADA. 
A patient whose ADA status is positive anytime post-baseline and is negative or missing at 
baseline is considered to have treatment-induced ADA.  
A patient whose ADA status is positive at baseline (pre-existing ADA) and the ADA titer level 
anytime post-baseline is significantly higher than that at baseline is considered to have treatment-
boosted ADA. A difference in titer values between 2 samples representing greater than or equal to 
twice the dilution level is considered significant. In other words, if the post-baseline titer value 
divide by the baseline titer value is greater than or equal to 4, then the patient is considered to 
have treatment boosted ADA. 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: 
 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 last ADA-positive samples (irrespective of any negative samples in 
between) are separated by a period less than 16 weeks, and the subject’s last sampling time 
point is ADA-negative. 
Persistent ADA response: 
 Treatment-induced ADA detected at two or more sampling time points post-baseline, 
where the first and 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. 
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The following sub-classifications for persistent ADA response will be considered as well. 
 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 ADA 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:  
 Only the last sampling time point is positive and all previous samples are negative. 
Pre-existing ADA and ADA Incidence rate are defined as follows: 
Pre-existing ADA = 100*(Number of patients 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 by age group cohorts and overall:  
 Number of ADA evaluable patients  
 Number (%) of patients with ADA positive/negative at baseline 
 Number (%) of patients that never develop ADA at any time (i.e, ADA always negative 
during baseline and post-baseline ) 
 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 
ADA titer of treatment induced ADA positive patients 
 Number (%) of patients with positive neutralizing antibody (NAb) 
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- 
NAb inhibition of catalytic activity 
- 
NAb inhibition of cellular uptake 
2.7 
ANALYSIS OF PHARMACOKINETIC DATA  
All the pharmacokinetic analyses will be performed using the pharmacokinetic population. 
Pharmacokinetic sampling will occur with the first infusion at 0.3, 1.0 and 3.0 mg/kg olipudase 
alfa and at Week 52. Specific time points are detailed in protocol Section 1.5 for each age cohort. 
To minimize the amount of blood drawn, post-dose time points have been selected for sparse 
sampling of pharmacokinetic parameters and microsampling methods (volumes ≤0.5 mL) will be 
used.  If a patient receives only a partial infusion (eg, due to a safety concern), pharmacokinetic 
sampling will be repeated the next time the patient receives that dose.    
2.7.1 Pharmacokinetic parameters  
Plasma concentration-time data will be analyzed by noncompartmental methods, or nonlinear 
mixed effects modeling, based upon patient age and data suitability. Pharmacokinetic parameters 
if calculated using noncompartmental methods from plasma olipudase alfa concentrations may 
include, but are not limited to, Ceio, Cmax, tmax, AUClast, AUC0- ᴛ, t1/2z, CL and VSS. 
Pharmacokinetic parameters if derived from population PK model may include Cmax, tmax, AUC0-ᴛ, 
CL and V.  
2.7.2 Statistical analysis  
Plasma concentration-time data will be analyzed by non-compartmental methods, or nonlinear 
mixed effects modeling, based upon patient age and data suitability. Values will be reported for 
individual patient and summarized by age group cohorts, dose level, 
 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 
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visit, dose level and age group cohort under the responsibility of Pharmacokinetics, Dynamics and 
Metabolism (PKDM) using Phoenix WinNonlin Professional, Version 5.2 or above.  
Associations between IgG ADA variables and PK of olipudase alfa may be explored. If applicable, 
plot of olipudase alfa PK (e.g., AUC) versus PK visit may be provided by ADA classifications. 
2.8 
ANALYSIS OF EXPLORATORY EFFICACY VARIABLES  
All exploratory efficacy analyses to assess changes in organomegaly (spleen and liver), infiltrative 
lung disease, linear patient growth, pulmonary function, bone age, cycle ergometry endpoints, 
physician’s global assessment, efficacy biomarkers, lipid profile, bone biomarkers, health 
outcome questionnaires, cognitive functioning and adaptive functioning will be performed using 
the mITT population. For each exploratory efficacy assessment, observed measures and changes 
from baseline, as appropriate, will be listed and summarized, including the p-value from analysis 
of covariance with baseline as covariate and 95% CIs as appropriate, separately by time point, age 
group cohorts and overall. 
 
 
Baseline for exploratory efficacy variables will be defined as the last non-missing value before the 
first infusion. 
2.8.1 Spleen and liver volumes  
Spleen and liver volumes will be measured by abdominal magnetic resonance imaging (MRI) to 
quantitate the degree of splenomegaly and hepatomegaly at Screening, Week 26 and Week 52 
(or at withdrawal if withdrawn prematurely and not done within 12 weeks prior to withdrawal).   
MRIs will be collected and read centrally by a third party blinded to patient number and study 
visit.  
Spleen volume >=5 multiples of normal (MN) is an inclusion criterion. For screening purpose, the 
external vendor will provide the spleen volume in the unit of MN to the site. The computation will 
use the same formula as below. However, the report from the external vendor will be part of the 
source document of the site and will not be included in the clinical data base. Spleen and liver 
volumes collected in cm^3 unit (including those from the screening visit) will be converted to 
multiples of normal (MN) unit for analyses using the following formula: 
Spleen Volume (MN) = Spleen Volume (cm^3) / [2*Weight (kg)]. 
Liver Volume (MN) = Liver Volume (cm^3) / [25*Weight (kg)]. 
Change from baseline and percent change from baseline for both cm^3 and MN units, in addition 
to observed values, will be calculated and summarized for all scheduled visits by age group 
cohorts and overall. The analysis of covariance (ANCOVA) with baseline as the covariate and 
Wilcoxon-Mann-Whitney (WMW) test p-values for the change from baseline and percent change 
from baseline will be provided in the summary tables for spleen/liver volumes in MN unit. Box 
plots of observed values over time for spleen and liver volumes in MN unit will be provided. 
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Summary plots for the mean spleen/liver volumes (MN) over time will be provided. By-patient 
plots of the observed spleen/liver volumes (MN) over time will be provided. 
Additional sensitivity analyses to assess the effect of age group cohorts: Analysis of covariance 
(ANCOVA) will be used for the mITT population for spleen/liver volumes in MN unit with the 
following model: 
Percent change from baseline at Week 26 or 52 volume (MN) = Age group cohorts + Baseline 
value 
The observed values, change from baseline and percent change from baseline on spleen volume 
(MN) will also be summarized by the following disease severity: 
 Spleen volume by baseline spleen volume severity (severe vs not severe). Severity is 
defined as baseline spleen volume > 15 MN. 
In addition, the summary of spleen/liver volumes (MN) over time will be provided to exclude 
patients who satisfy the noncompliance condition in Section 2.1.2 as a sensitivity analysis if 
applicable.  
2.8.2 Height z-score  
As stated in Section 2.6.4, patient height will be collected at screening and within 24 hours prior 
to every infusion visit from Day 1/Week 0 to Week 64 (or withdrawal if withdrawn prematurely). 
Z-score for height will be evaluated as an exploratory efficacy parameter. This parameter reflects 
failure to thrive. 
Height z-score will be calculated and categorized using the number and percentage of patients in 
<= -4, > -4 to <= -3.5, > -3.5 to <= -3, > -3 to <= -2.5, > -2.5 to <= -2, > -2 to <= -1.5, > -1.5 to 
<= -1 and > -1. The categories will be summarized for baseline, Week 12, Week 26, Week 38 and 
Week 52 by age group cohorts and overall. Change from baseline at Week 52 (as improved, same, 
and worsened) will also be summarized using the number and percentage of patients. A bar chart 
for the percentage of patients in each category at baseline and Week 52 will be provided. By-
patient plot on height z-score over time will be provided. 
Observed values and change from baseline values for height z-score will be summarized at 
baseline, Week 12, Week 26, Week 38 and Week 52 by age group cohorts and overall. In 
addition, change from baseline in height z-score will be analyzed with analysis of covariance 
(ANCOVA) model with baseline height z-score as covariate. 
2.8.3 Pulmonary function testing  
Pulmonary function testing (PFT) will be performed at Screening, Week 26 and Week 52 (or at 
withdrawal if withdrawn prematurely and not done within 12 weeks prior to withdrawal)  in 
patients ≥5 years old at Day 1/Week 0.  PFT will include, but may not be limited to the 
assessment of forced vital capacity (FVC), forced expiratory volume in the 1st second of the 
FVC maneuver (FEV1), total lung capacity (TLC), and diffusing capacity of carbon monoxide 
(DLCO). Completion of the assessment may depend upon patient cooperation. The tests are done 
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in local labs and hence do not use a standardized approach for calculation of percent predicted 
values. For analyses, we use the following standard formula (height and hemoglobin values are 
from available ones closest to the PFT evaluation date/time, age is calculated at the PFT 
evaluation date, and sex=0 for female and 1 for male) to calculate the percent predicted values. 
The percent predicted values captured in the e-CRF will remain in the database, but will not be 
used for analysis. 
Percent predicted values of FEV1 and FVC will use the Global Lung Initiative (GLI) 2012 
reference equations (1). 
Predicted TLC (Liters) will use the following formula (Koopman et al. corrected version [2]): 
Predicted TLC = exp(24.67 - 4.91*ln(Height[cm]) – 7.16*ln(Age[months]) + 0.059*Sex + 
1.47*ln[Height]*ln[Age]) 
Percent predicted TLC = 100*Observed TLC / Predicted TLC 
Predicted DLco will be calculated in the unit of mmol/min/kPa as follows (Koopman et al. 
corrected version [2]): 
Predicted DLco (mmol/min/kPa) = exp(34.80 - 6.89*ln(Height[cm]) – 8.66*ln(Age[months]) + 
0.10*Sex + 1.79*ln[Height]*ln[Age]) 
Unit conversion (Macintyre et al. [3]): mL CO/min/mmHg = mmol/min/kPa*2.987  
Hemoglobin-adjustment factor (Macintyre et al. [3]) (to be applied to DLco in unit of mL 
CO/min/mmHg) 
= 1.7*Hemoglobin (g/dL) / (10.22+Hemoglobin) for patients >=15 years of age. 
= 1.7*Hemoglobin (g/dL) / (9.38+Hemoglobin) for patients <15 years of age. 
Patients’ age at screening will be used to decide which formula to use for the hemoglobin-
adjusted factor. 
Adjusted DLco = Observed DLco (mL CO/min/mmHg) / Hemoglobin-adjusted factor 
Percent predicted Hemoglobin-adjusted DLco is calculated as follows: 
Percent predicted Hemoglobin-adjusted DLco = 100 * Adjusted DLco / Predicted DLco in unit of 
mL CO/min/mmHg. 
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For all 4 tests, FVC (L), FEV1 (L), TLC (L) and DLCO (mL/min), percent (%) predicted values 
will be summarized for observed values, change from baseline and percent change from baseline 
using the mITT population by age group cohorts and overall at scheduled study visit. The analysis 
of covariance (ANCOVA) with baseline as covariate and WMW test p-values for the change from 
baseline and percent change from baseline will be provided in the summary tables for all 4 tests. 
Box plots of observed values over time for these 4 tests will be provided for the mITT population. 
By-patient plots for all 4 tests over time will be provided. 
Additional sensitivity analyses to assess the effect of age group cohorts: ANCOVA will be used 
for the mITT population for the 4 tests with the following model: 
Percent change from baseline at Week 26 or 52 = Age group cohorts + Baseline value. 
The summary of percent predicted DLco adjusted for hemoglobin over time will be provided to 
exclude patients who satisfy the noncompliance condition in Section 2.1.2 as a sensitivity analysis 
if applicable. In addition, sensitivity analysis to account for missing data of percent predicted 
DLco adjusted for hemoglobin at baseline or post-baseline visits may be conducted after 
appropriate imputations.  
2.8.4 Platelet count and hemoglobin  
Observed values, change from baseline and percent change from baseline for platelet count and 
hemoglobin at pre-infusion time point will be summarized by age group cohorts and overall. The 
ANCOVA with baseline as covariate will be used to assess the change from baseline. 
Additionally, the ANCOVA with age group cohorts and baseline value as covariates will be used 
to assess the age effect. 
2.8.5 Pulmonary imaging by high resolution computed tomography  
Pulmonary imaging of the chest using high resolution computed tomography (HRCT) will be 
assessed at Screening and Week 52 (or at withdrawal if withdrawn prematurely and not done 
within 12 weeks prior to withdrawal) to quantitate the degree of possible infiltrative lung disease.   
The bilateral lung boundaries are determined from 4 pre-defined levels of 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, and Level 4 is 1 cm above the hemidiaphragm. 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 the following criteria: 0 = No 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), and NE = Not evaluable.  
For all 4 features, the mean and standard deviation will be provided for observed values and 
change from baseline by each side at each level. The mean scores at each scheduled visit are 
calculated as follows: 
Mean score across 4 levels for left (or right) lung = Sum of scores for 4 levels/4. 
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Mean score across 4 levels and both lungs = (Mean score across 4 levels for left lung + Mean 
score across 4 levels for right lung)/2. 
Summary of the above two types of mean scores and change from baseline for each feature will 
be provided by age group cohorts and overall. A box plot for the mean scores across 4 levels and 
both lungs of each feature will be provided. The mean pixel density will be provided in a data 
listing. 
2.8.6 Chest X-ray  
A chest X-ray (posterior-anterior and lateral) will be performed at Screening and Week 52 (or at 
withdrawal if withdrawn prematurely and not done within 12 weeks prior to withdrawal) at 
selected sites.  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): 
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), or 3 = Severe (affecting 51 to 100% of the lung 
volume).  
For chest x-ray imaging, interstitial provides an overall assessment of interstitial lung disease with 
reticular and nodular may provide more supportive information on type of interstitial 
involvement. Consolidation provides a measure of air space disease and is assessed in addition to 
interstitial involvement. As HRCT provides a more robust characterization of the diffuse lung 
disease, only interstitial (overall ILD) of the chest X-ray will be analyzed; however data for all 
features will be provided in data listings. 
Summary of mean scores and change from baseline for interstitial will be provided by age group 
cohorts and overall.  
2.8.7 Bone age by hand X-ray    
Patients will have a hand X-ray performed on their left hand, fingers and wrist at Screening and 
Week 52 (or at withdrawal if withdrawn prematurely and not done within 12 weeks prior to 
withdrawal).  Bone age will be provided by the central vendor – 
; they will use 
calculations based on the Greulich & Pyle Atlas (4). A listing of these data will be provided. 
For each patient at each scheduled baseline and post-baseline visits, the difference between the 
bone age and actual age at that visit will be calculated. Then the change from baseline in the bone 
age and actual age difference will be analyzed with analysis of covariance (ANCOVA) model 
with baseline bone age and actual age difference as covariate. 
2.8.8 Cycle ergometry  
Cycle ergometry will be performed at Screening and within 1 week after infusion at Week 26 and 
Week 52 (or at withdrawal if withdrawn prematurely and not done within 12 weeks prior to 
withdrawal). This assessment is not required in patients that are ≤6 years of age or <120 cm in 
height on Day 1/Week 0. Completion of the assessment may depend upon patient cooperation. 
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Cycle ergometry assessments will include maximum workload (watts), percent predicted 
maximum workload (%), working time (min), maximum heart rate (breaths/min), maximum 
percent predicted heart rate (%), maximum O2 saturation (%), maximum respiratory rate 
(breaths/min), maximum ventilation (L/min), maximum O2 uptake (mL/min), maximum percent 
predicted O2 uptake (%), maximum CO2 output (mL/min), and maximum respiratory exchange 
ratio. 
Assessments will be summarized at each time point along with change from baseline by age group 
cohorts and overall. 
2.8.9 Physician’s global assessment of change  
The physician’s global assessment of the patient’s progress will be evaluated prior to infusion at 
Screening, Week 26 and Week 52 (or at withdrawal if withdrawn prematurely), as mild, moderate 
and severe.  At Week 26 and Week 52 the investigator will also evaluate the patient’s current 
clinical status compared with 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”.  
Frequency shift table for physician’s global assessment of patient progress (mild, moderate, 
severe) from the baseline to Week 26 and Week 52 will be provided by age group cohorts and 
overall. Frequencies and percentages of patients at each clinical status at Week 26 and Week 52 
will be provided by age group cohorts and overall. 
7 categories of Physician’s global assessment of patient’s current clinical status compared with 
screening (baseline) will be converted to numeric values as follows: 
 “Marked improvement of daily activities” = 3. 
 “Moderate improvement of daily activities” = 2. 
  “Mild improvement of daily activities” = 1. 
  “No change” = 0. 
  “Mild worsening of daily activities” = -1. 
  “Moderate worsening of daily activities” = -2. 
 “Marked worsening of daily activities” = -3. 
Observed numeric values at each post-baseline visits will be analyzed using analysis of 
covariance (ANCOVA) model with baseline as covariate. The baseline value will be Physician’s 
global assessment of severity at screening with value of 1=mild, 2=moderate, 3=severe. 
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2.8.10 Efficacy biomarkers  
Efficacy biomarkers of chitotriosidase activity ([CHITO]nmol/hr/mL), chemokine (CC-motif) 
ligand 18 (CCL18) (ug/L), and angiotensin-converting enzyme (ACE) (uKat/L) will be evaluated 
at Day 1/Week 0, Week 26, Week 52, and Week 64 (or at withdrawal if withdrawn prematurely).  
Observed values, change from baseline and percent change from baseline will be summarized by 
age group cohorts and overall at each time point. Summary plots of observed values and percent 
change from baseline over time for each efficacy biomarker will be provided. 
Chitotriosidase values will be normalized prior to study analyses based on the patient's 
chitotriosidase genotype: 
Chitotriosidase Genotype 
Normalization of Chitotriosidase Activity 
Normal 
None (reported value was used) 
Heterozygous 
Value multiplied by 2 
Homozygous mutation 
Value set to “no value” 
2.8.11 Lipid profile  
A lipid profile will be assessed at Screening, Day 1/Week 0 (not required in patients <=2 years of 
age), Week 12 (not required in patients <=2 years of age), Week 26, Week 38, Week 52 and 
Week 64 (or at withdrawal if withdrawn prematurely).  Blood will be collected prior to infusion 
for lipids including total cholesterol (mmol/L), low density lipoprotein (LDL)(mmol/L), high 
density lipoprotein (HDL)(mmol/L), very low density lipoprotein (VLDL)(mmol/L), triglycerides 
(mmol/L), apolipoprotein B (g/L), apolipoprotein A1 (g/L), and lipoprotein-[a] (g/L).  
Results will be analyzed and presented for observed values and change from baseline values by 
age group cohorts and overall at each scheduled time point. Summary plots of observed values 
over time of lipid profile parameters will be provided. 
2.8.12 Bone biomarkers  
Bone biomarkers of serum bone-specific alkaline phosphatase (ug/L) and C-telopeptide (ug/L) 
will be evaluated at Day 1/Week 0, Week 26, Week 52 and Week 64 (or at withdrawal if 
withdrawn prematurely) for patients >2 years of age.  
Observed values and change from baseline will be summarized by age group cohorts and overall 
at each scheduled time point. Summary plots of observed values over time for each bone 
biomarkers will be provided. 
2.8.13 Health outcome questionnaires  
Health outcome measures were evaluated using questionnaires designed to measure general 
quality of life (QOL) with the Pediatric Quality of Life (PedsQL) scale, fatigue with the PedsQL 
Multidimensional Fatigue Scale, and pain with the PedsQL Pediatric Pain Questionnaire. These 
will be evaluated at Screening, Week 26 and Week 52 (or at withdrawal if withdrawn prematurely 
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and not done within 12 weeks prior to withdrawal), and will be analyzed in accordance to the tool 
manuals. 
PedsQL Generic Core Scales 
The PedsQL includes a child self-report for patients age 5 to 18 years and a report for parents of 
patients age birth to 18 years. For patients age 5 to 18 years, the 23-item PedsQL Generic Core 
Scales for both patient and parent reports include four Scales,  Physical Functioning (8 items), 
Emotional Functioning (5 items), Social Functioning (5 items),  and School Functioning (5 items). 
For patients age 2 to 4 years, the 21-item PedsQL Generic Core Scales for the parent reports 
include 8 items in Physical Functioning Scale, 5 items in Emotional Functioning Scale, 5 items in 
Social Functioning Scale, and 3 items in School Functioning Scale. 
The PedsQL Infant Scales include two age-appropriate versions for ages 1-12 months and  
13-24 months, and assess parents’ perceptions of their infant’s generic Health-Related Quality of 
Life. The 36-item PedsQL Infant Scales 1-12 months Version encompasses 5 scales: (1) Physical 
Functioning (6 items), (2) Physical Symptoms (10 items), (3) Emotional Functioning (12 items), 
(4) Social Functioning (4 items), and (5) Cognitive Functioning (4 items). The 45-item PedsQL 
Infant Scales 13-24 months Version contains the same 5 scales and the same 36 items as the  
1-12 months Version with 9 additional age-appropriate items: (1) Physical Functioning (9 items), 
(2) Physical Symptoms (10 items), (3) Emotional Functioning (12 items), (4) Social Functioning 
(5 items), and (5) Cognitive Functioning (9 items). The format, instructions, Likert response scale, 
and scoring method for the PedsQL Infant Scales are identical to the PedsQL Generic Core Scales 
for ages 2-18 years.  
Each item in every Scale in both parent report and patient report in the above age ranges uses the 
4-point rating scale (0=never to 4=almost always). The items of the four Scales are grouped 
together on the actual questionnaire. The algorithm of Scale Scores (5) is as follows. 
1. On the PedsQL Generic Core Scales, for ease of interpretability, items are reversed scored 
and linearly transformed to a 0-100 scale, so that higher scores indicate better Health-
Related Quality of Life. 
2. To reverse score, transform the 0-4 scale items to 0-100 as follows: 
 
  0=100, 1=75, 2=50, 3=25, 4=0. 
3. To create Scale Scores, if more than 50% of the items in the scale are missing, the Scale 
Score will not be computed. If 50% or more of the items in the scale are completed, 
compute the Scale Score using the sum of non-missing items scores divided by the number 
of items answered.  
4. The PedsQL Generic Core Scales for ages 2-18 years: to create the Psychosocial Health 
Summary Score, the mean is computed as the sum of the items scores over the number of 
items answered in the Emotional, Social, and School Functioning Scales; the Physical 
Health Summary Score is the same as the Physical Functioning Scale Score.  
5. The PedsQL Infant Scales 1-12 months and 13-24 months: the Physical Health Summary 
Score is computed as the sum of the items scores over the number of items answered in the 
Physical Functioning and Physical Symptoms Scales; the Psychosocial Health Summary 
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Score is computed as the sum of the items scores over the number of items answered in the 
Emotional, Social, and Cognitive Functioning Scales. 
6. To create the Total Scale Score, the mean is computed as the sum of all the items scores 
over the number of items answered on all the Scales. 
 
Response Choices 
Never 
Almost Never 
Sometimes 
Often 
Almost 
Always 
Raw Scores 
0 
1 
2 
3 
4 
0-100 Scale Scores 
100 
75 
50 
25 
0 
Scale Scores, Psychosocial Health Summary Score, Physical Health Summary Score and the Total 
Scale Score will be calculated based on the 0-100 scale scores. Their computed values and 
changes from baseline will be summarized by age group cohorts at each scheduled time point. 
PedsQL Multidimensional Fatigue Scale 
The PedsQL Multidimensional Fatigue Scale is an 18-item instrument encompassing three scales: 
(1) General Fatigue (6 items), (2) Sleep/Rest Fatigue (6 items), and (3) Cognitive Fatigue 
(6 items). It includes a child self-report for patients ages 5-7, 8-12 and 13-18 years and a report for 
parents of patients ages 2-4, 5-7, 8-12 and 13-18 years.  
For parent reports of patients ages 2-4, 5-7, 8-12 and 13-18 years and child self-reports of patients 
ages 2-4, 8-12 and 13-18, a 5-point Likert-type response scale is utilized (0 = never a problem;  
1 = almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = almost always a 
problem). The child self-reports of patients ages 5 to 7 years was simplified to a 3-point scale to 
increase the ease of use (0 = not at all a problem; 2 = sometimes a problem; 4 = a lot of a 
problem).  
The format, instructions, response scale, and scoring method are identical to the PedsQL Generic 
Core Scales (6). Items in all child self-reports and parent reports are reverse-scored and linearly 
transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that higher scores indicate 
better Health-Related Quality of Life. Scale Scores are computed as the sum of item scores 
divided by the number of answered items. If more than 50% of the items in the scale are missing, 
the Scale Score is not computed. If less than 50% of the items in the scale are missing, use the 
same method for the PedsQL Generic Core Scales to impute the Scale Score. The Total Scale 
Score is computed as the sum of all the item scores divided by the number of items answered on 
all the Scales. 
Scale Scores and the Total Scale Score will be calculated based on the 0-100 scale scores. Their 
computed values and changes from baseline will be summarized by age group cohorts at each 
scheduled time point. 
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PedsQL Pediatric Pain Questionnaire 
The PedsQL Pediatric Pain Questionnaire consists of 3 items and includes a child self-report for 
patients age 5 to 18 years and a proxy report for parents of patients age 5 to 18 years. 
The first item is the degree of present pain, the second item is the degree of the worst pain, and the 
third item refers to the localization of pain and is not scored. The first two items will be scaled 
using visual analogue scales (VAS) from 0 (Not hurting / No discomfort / No pain) to 100 mm 
(Hurting a whole lot / Very uncomfortable / Severe pain). The present pain and worst pain are 
scored separately. The scores are based on line length to the nearest 5mm. There is no imputation 
process since these are single item VAS scales.   
For the first two items, the observed scores based on the 100 mm VAS and the change from 
baseline will be summarized by age group cohorts at each scheduled time point. 
2.8.14 Cognitive and adaptive function testing  
Developmental Profile 3 (DP-3): 
Cognitive function will be evaluated using the Developmental Profile 3 (DP-3) (7) assessment 
tool at Screening, Week 26 and Week 52 (or at withdrawal if withdrawn prematurely and not done 
within 12 weeks prior to withdrawal) for patients <6 years of age at Day 1/Week 0. The number 
of items to be answered on each content area of the DP-3 depends on the patient’s age and 
functional level. For each content area (Physical, Adaptive Behavior, Social-Emotional, 
Cognitive, Communication), the raw score indicates the number of developmental items the 
subject is credited for being able to complete.  
The DP-3 assessments are centrally scored to generate the General Development Score.  For each 
content area and the General Development Score, standard scores, confidence intervals, 
descriptive categories, and percentile ranks are generated.  For each content score, age-
equivalence is generated.   
Adaptive Behavior Assessment System, Third Edition (ABAS-3): 
Adaptive function will be evaluated at the same time points as cognitive function for patients 
<6 years of age at Day 1/Week 0 using the Adaptive Behavior Assessment System, Third Edition 
(ABAS-3) (8).  The ABAS-3 consists of several age-specific rating forms; for this study, the 
Parent/Primary Caregiver Form (Ages 0-5) and Parent Form (Ages 5-21) will be used. The 
ABAS-3 measures adaptive behavior at three different levels.  At the highest level is the General 
Adaptive Composite, which is composed of all measured skill areas. The next level are three 
adaptive domains, each comprising multiple individual skill areas; these domains are Conceptual, 
Social, and Practical. At the third level are individual adaptive skill areas. For each adaptive skill 
area, the raw score is the sum of item behavior frequency ratings for all items.   
The ABAS-3 assessments are centrally scored to generate scaled scores for each adaptive skill 
area.  The scaled scores are utilized to generate a standard score, percentile rank, and confidence 
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interval for the General Adaptive Composite and three adaptive domains (Conceptual, Social, and 
Practical).  
Analysis: 
A listing of DP-3 and ABAS-3 raw and generated scores will be provided. 
For the DP-3, by-patient bar graphs will be generated to demonstrate subject’s performance over 
time using percentile rank and standard score for each content area (Physical, Adaptive Behavior, 
Social-Emotional, Cognitive, Communication) and General Development Score at the 3 study 
time points (baseline, Week 26, and Week 52).   
For the ABAS-3, by-patient bar graphs will be generated to demonstrate subject’s performance 
over time using percentile rank and standard scores for the General Adaptive Composite and three 
adaptive domains (Conceptual, Social, and Practical) at the 3 study time points (baseline, Week 
26, and Week 52).   
In addition, to illustrate patient’s performance on the DP-3 and ABAS-3 collectively, group 
graphs by patient age will be developed showing tool standard scores of patients over time.  One 
graph for the ABAS-3 General Adaptive Composite Standard Score and one graph for the DP-3 
General Development Score Standard Score.  
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2.9 
ANALYSIS OF PHARMACODYNAMIC VARIABLES  
All the pharmacodynamic analyses will be performed using the pharmacodynamic population.  
2.9.1 Description of pharmacodynamic variables  
Sphingomyelin and sphingomyelin metabolites, including, but not limited to the following:   
 Ceramide in DBS. 
 Lyso-sphingomyelin and sphingosine-1-phosphate in plasma and/or DBS. 
Refer to protocol Section 1.2 and 1.3 for more details. 
2.9.2 Statistical analysis  
Concentration-time data for sphingomyelin and metabolite levels (eg, ceramide, 
lyso-sphingomyelin and sphingosine-1-phosphate), observed, change from baseline and percent 
change from baseline, will be summarized by age group cohorts and overall. Summary plots over 
time will be provided. 
2.10 
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 2.6.1.3) 
- 
Pregnancy of female patient or partner of a male patient 
- 
Symptomatic overdose of study drug 
- 
Any increase in AST, ALT, total bilirubin, or AP >3x baseline (prior to olipudase alfa 
therapy) and > ULN 
- 
Any increase in total bilirubin or AP >1.5x baseline in the presence of AST or ALT > 
2x ULN 
- 
Any increase in ALT or AST >3x the ULN combined with an increase in ALT or AST 
>2x baseline (prior to olipudase alfa therapy) with symptoms of fatigue, nausea, 
vomiting, fever, rash, or eosinophilia (> ULN) 
- 
asymptomatic overdose of study drug 
Patients who meet these criteria will be listed and provided to the medical writer. 
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2.11 
DATA HANDLING CONVENTIONS  
2.11.1 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.   
The pre-infusion hematology value at Week 52 will be the average of the two samples collected 
within 24 hours.  
Age at ASMD diagnosis = number of years between the date of birth and the date of ASMD 
diagnosis. 
If the date of birth is missing or incomplete, then the patient’s age collected in year and month at 
screening will be compared to the screening date to derive which year and month the patient was 
born, and then the corresponding year and the 1st day of the month will be assigned as the birth 
date. 
2.11.2 Missing data  
In general, no imputation is planned for missing data. The following approaches are default 
methods for missing data handling. Some exploratory analyses can be planned with different 
strategies for treating missing outcomes.  
 Categorical data at baseline will be summarized for each age group cohort using counts (n) 
and percentages (%). The number of patients with missing data may be mentioned, but 
will not be included in the denominator for the calculation of percentages unless otherwise 
specified. When relevant, the number of patients with missing data is presented. 
 Continuous data: The analyses and summaries for variables with continuous scales will be 
based on observed data only.  
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing   
For the calculation of the treatment duration, the date of the last dose of study treatment is 
reported on the last infusion page in e-CRF.  If this date is missing, the exposure duration will be 
left as missing.  
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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.  
 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. 
2.11.3 Windows for time points  
Statistical analysis will be based on the nominal visit which should follow schedule defined in 
protocol Section 1.2. Visits will not be windowed for analysis purposes, except for unscheduled 
visits in some cases as described in Section 2.11.4. 
2.11.4 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 or PCSA. If a scheduled post-baseline visit measurement of an exploratory efficacy 
parameter is missing, but an unscheduled visit value for the same parameter is available in close 
proximity of time, the windowing of unscheduled visit to substitute the missing scheduled visit 
value is defined in the following table. Laboratory, vital signs, ECG and PD parameters are 
collected at several times during a visit with respect to the infusion time, therefore a window for 
an unscheduled visit to substitute missing schedule values will not be considered. 
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Parameter 
Scheduled 
Visit/Target Days 
Analysis Visit 
Window, in Study 
Days 
Spleen volume, liver volume, pulmonary imaging with 
HRCT, PFT, cycle ergometry, physician’s global 
assessment, health outcome questionnaires 
Week 26/183 days 
92 days to 274 days 
 
 
Week 52/365 days 
275 days to 456 days 
Chest X-ray, bone age by hand X-ray 
Week 52/365 days 
275 days to 456 days 
Efficacy biomarker, serum bone-specific ALP and  
C-telopeptide 
Week 26/183 days 
92 days to 274 days 
 
Week 52/365 days 
275 days to 407 days 
 
Week 64/449 days 
408 days to 463 days 
Lipid profile 
Week 12/85 days 
43 days to 134 days 
 
Week 26/183 days 
135 days to 225 days 
 
Week 38/267 days 
226 days to 316 days 
 
Week 52/365 days 
317 days to 407 days 
 
Week 64/449 days 
408 days to 463 days 
2.11.5 Potentially clinically significant abnormalities (PCSA) criteria  
In the safety data analysis, patients included in the PCSA analysis for a given parameter will be 
defined as subjects: 
 Exposed to study treatment, 
 With at least one parameter result after study treatment administration, and, 
 With available laboratory limits when required for analysis. 
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Liver function tests 
ALT 
> 3 ULN 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
AST 
> 3 ULN 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
Alkaline phosphatase 
> 1.5 ULN 
Total bilirubin 
>= 1.3 ULN 
ALT and total bilirubin 
ALT > 3 ULN and total bilirubin > 2 ULN 
Hematology 
WBC 
Birth/0 to 27 days old (Neonates) 
<4.0 GIGA/L 
>25.0 GIGA/L 
28 days/1 month to 23 months old (Infants) 
<4.0 GIGA/L 
>20.0 GIGA/L  
24 months/2 years to <6 years old (Children) 
<3.0 GIGA/L 
>16.0 GIA/L 
6 to <12 years old (Children) 
<5.0 GIGA/L 
>17.0 GIGA/L  
12 to 16/18 years old (Adolescents) 
<4.5 GIGA/L 
>13.5 GIGA/L  
Lymphocytes Birth/0 to 27 days old (Neonates) 
<1.2 GIGA/L 
>17.0 GIGA/L 
28 days/1 month to 23 months old (Infants) 
<2.0 GIGA/L 
>13.5 GIGA/L 
24 months/2 years to <6 years old (Children) 
<1.0 GIGA/L 
>9.5 GIGA/L 
6 to <12 years old (Children) 
<1.0 GIGA/L 
>8.0 GIGA/L 
12 to 16/18 years old (Adolescents) 
<0.6 GIGA/L 
>6.0 GIGA/L 
 
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Neutrophils 
Birth/0 to 27 days old (Neonates) 
<4.0 GIGA/L (1 day old) 
<1.5 GIGA/L (2 – 7 days old) 
<1.25 GIGA/L (>7 day – 1 month old) 
>1 ULN 
28 days/1 month to 23 months old (Infants) 
<1.0 GIGA/L (1 – 3 months) 
<1.2 GIGA/L (3 – 24 months) 
>1 ULN 
24 months/2 years to <6 years old (Children) 
<1.2 GIGA/L 
>1 ULN 
6 to <12 years old (Children) 
<1.2 GIGA/L 
>1 ULN 
12 to 16/18 years old (Adolescents) 
<1.2 GIGA/L 
>1 ULN  
Eosinophils 
All age ranges 
>0.5 GIGA/L  
Or >ULN if ULN ≥0.5 GIGA/L 
Hemoglobin 
Birth/0 to 27 days old (Neonates) 
<12.0 g/dL and 20% decrease from 
baseline, or decrease from baseline >=2 
g/dL 
28 days/1 month to 23 months old (Infants) 
<9.0 g/dL and 20% decrease from 
baseline, or decrease from baseline >=2 
g/dL 
24 months/2 years to <16/18 years old (Children, 
Adolescents) 
<10.0 g/dL and 20% decrease from 
baseline, or decrease from baseline >=2 
g/dL  
Hematocrit 
Birth/0 to 27 days old (Neonates) 
<0.39 l/l or 40% 
>0.61 l/l or 47% 
 
28 days/1 month to 23 months old (Infants) 
<0.29 l/l or 29% 
>0.42 l/l or 42% 
 
24 months/2 years to <16/18 years old (Children, 
Adolescents) 
<0.32 l/l or 32% 
>0.47 l/l or 47% 
Platelets 
All age ranges 
<100 GIGA/L and 20% decrease from 
baseline 
>=700 GIGA/L  
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ECG parameters 
HR 
Birth/0 to 27 days old (Neonates) 
<=90 bpm and decrease from baseline 
>=20 bpm 
>=190 bpm and increase from baseline 
>=20 bpm 
28 days/1 month to 23 months old (Infants) 
<=80 bpm and decrease form baseline 
>=20 bpm 
>=175 bpm and increase from baseline 
>=20 bpm 
24 months/2 years to <6 years old (Children) <=75 bpm and decrease from baseline 
>=20 bpm 
>=140 bpm and increase from baseline 
>=20 bpm 
6 to <12 years old (Children) 
<=50 bpm and decrease from baseline 
>=20 bpm 
>=120 bpm and increase from baseline 
>=20 bpm 
12 to 16/18 years old (Adolescents) 
<=50 bpm and decrease from baseline 
>=20 bpm  
>=120 bpm and increase from baseline 
>=20 bpm 
PR 
Birth/0 to 27 days old (Neonates) 
>=120 ms  
28 days/1 month to 23 months old (Infants) 
>=140 ms 
24 months/2 years to <6 years old (Children) >=160 ms 
6 to <12 years old (Children) 
>=170 ms 
12 to 16/18 years old (Adolescents) 
>=180 ms 
QRS Birth/0 to 27 days old (Neonates) 
>=85 ms 
28 days/1 month to 23 months old (Infants) 
>=85 ms 
24 months/2 years to <6 years old (Children) >=95 ms 
6 to <12 years old (Children) 
>=100 ms 
12 to 16/18 years old (Adolescents) 
>=110 ms 
QTc 
Birth/0 to <12 years old (Neonates, Infants, 
Children) 
Absolute values (ms) 
Borderline: 431 – 450 ms 
Prolonged: >450 ms 
Additional: >=500 ms 
 
Increase from baseline 
Borderline: Increase from baseline  
30 – 60 ms 
Prolonged: Increase from baseline >60 ms 
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12 to 16/18 years old (Adolescents) 
Absolute values (ms) 
Borderline: 431 – 450 ms (Boys);  
451 – 470 ms (Girls) 
Prolonged: >450 ms (Boys);  
>470 ms (Girls) 
Additional: >=500 ms 
 
Increase from baseline 
Borderline: Increase from baseline  
30 – 60 ms 
Prolonged: Increase from baseline >60 ms 
Clinical chemistry 
Creatinine 
Birth/0 to <6 years old (Neonates, Infants, 
Children) 
>53 µmol/L or 0.6 mg/dL 
6 years to <12 years old (Children) 
>=90 µmol/L or 1.1 mg/dL 
12 years to 16/18 years old (Adolescents) 
>=132 µmol/L or 1.5 mg/dL 
Blood urea 
nitrogen (BUN) 
Birth/0 to 27 days old (Neonates) 
>=4.3 mmol/L or 12 mg/dl 
28 days/1 month to 16/18 years old (Infants, 
Children, Adolescents) 
>=6.4 mmol/L or 18 mg/dl 
Chloride 
All age ranges 
<80 mmol/L 
>115 mmol/L 
Sodium 
All age ranges 
<=129 mmol/L 
>=150 mmol/L 
Potassium 
Birth/0 to 27 days old (Neonates) 
<=3.0  mmol/L 
>=7.0 mmol/L 
28 days/1 month to 23 months old (Infants) 
<=3.5 mmol/L 
>=6.0 mmol/L 
24 months/2 years to 16/18 years old 
(Children, Adolescents) 
<=3.5 mmol/L 
>=5.5 mmol/L 
Glucose 
     
All age ranges 
Hypoglycaemia <2.7 mmol/L 
Hyperglycaemia >=7 mmol/L (fasted 
after >12 hours of fast);  
>=10.0 mmol/L (unfasted) 
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Vital signs 
Heart rate 
Birth/0 to 27 days old (Neonates) 
<=90 bpm and decrease from baseline >=20 bpm 
>=190 bpm and increase from baseline >=20 bpm 
28 days/1 month to 23 months old 
(Infants) 
<= 80 bpm and decrease form baseline >=20 bpm 
>= 175 bpm and increase from baseline >= 20 bpm 
24 months/2 years to <6 years old 
(Children) 
<= 75 bpm and decrease from baseline >=20 bpm 
>= 140 bpm and increase from baseline >= 20 bpm 
6 to <12 years old (Children) 
<=50 bpm and decrease from baseline >=20 bpm 
>=120 bpm and increase from baseline >=20 bpm 
12 to 16/18 years old (Adolescents) <=50 bpm and decrease from baseline >=20 bpm  
>=120 bpm and increase from baseline >=20 bpm 
Systolic BP 
Birth/0 to 27 days old (Neonates) 
<=60 mmHg and decrease from baseline >=20 mmHg 
>=85 mmHg and increase from baseline >=20 mmHg 
28 days/1 month to 23 months old 
(Infants) 
<=70 mmHg and decrease from baseline >=20 mmHg 
>=98 mmHg and increase from baseline >=20 mmHg 
24 months/2 years to <6 years old 
(Children) 
<=70 mmHg and decrease from baseline >=20 mmHg 
>=101 mmHg and increase from baseline >=20 mmHg 
6 to <12 years old (Children) 
<=80 mmHg and decrease from baseline >=20 mmHg 
>=108 mmHg and increase from baseline >=20 mmHg 
12 to 16/18 years old (Adolescents) <=90 mmHg and decrease from baseline >=20 mmHg 
>=119 mmHg and increase from baseline >=20 mmHg 
Diastolic BP Birth/0 to 27 days old (Neonates) 
<=34 mmHg and decrease from baseline >=10 mmHg 
>=50 mmHg and increase from baseline >=10 mmHg 
28 days/1 month to 23 months old 
(Infants) 
<=34 mmHg and decrease from baseline >=10 mmHg 
>=54 mmHg and increase from baseline >=10 mmHg 
24 months/2 years to <6 years old 
(Children) 
<=34 mmHg and decrease from baseline >=10 mmHg 
>=59 mmHg and increase from baseline >=10 mmHg 
6 to <12 years old (Children) 
<=48 mmHg and decrease from baseline >=10 mmHg 
>=72 mmHg and increase from baseline >=10 mmHg 
12 to 16/18 years old (Adolescents) <=54 mmHg and decrease from baseline >=10 mmHg 
>=78 mmHg and increase from baseline >=10 mmHg 
 
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3 
INTERIM ANALYSIS  
Analysis of data, including summary tables, figures and listings, may be conducted intermittently 
during the study and upon completion of a cohort’s key milestones, eg, week 26 or 52 efficacy 
assessments. However, due to the nature of the open label study, these potential analyses will have 
no impact on primary and secondary objectives of this study. 
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4 
SOFTWARE DOCUMENTATION  
The analysis of clinical data will be performed using Statistical Analysis System (SAS®) (version 
9.4 or higher, SAS Institute, NC USA). Statistical analysis of pharmacokinetic parameters will be 
performed using Phoenix WinNonlin Professional, Version 5.2 or above.  
  
 
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5 
REFERENCES  
1. Global Lung Initiative (GLI) reference [Online]. [cited 2019 Nov 05]. Available from: URL: 
http://www.ers-education.org/guidelines/global-lung-function-initiative.aspx 
2. Koopman, M, Zanen P, Kruitwagen CL, van der Ent CK, Arets HG. Corrigendum to 
“Reference values for pediatric pulmonary function testing: The Utrecht dataset”. Respiratory 
Medicine. 2011;105:1970-1. 
3. Macintyre, N, Crapo RO, Vieqi 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. 
4. Greulich, WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd 
ed. Standford, Calif.: Standford University Press; 1959. 
5. PedsQL Generic Core Scales scoring algorithm [Online]. [cited 2019 Nov 05]. Available from: 
URL: http://www.pedsql.org/ 
6. Varni JW, Beaujean AA, Limbers CA. Factorial invariance of pediatric patient self-reported 
fatigue across age and gender: a multigroup confirmatory factor analysis approach utilizing 
the PedsQL™ Multidimensional Fatigue Scale. Qual Life Res. 2013;22:2581-94. 
7. Aplern, GD. Developmental Profile 3 (DP-3) [Manual]. Torrance, CA: Western Psychological 
Services. [Online]. 2007 [cited 2019 Nov 05]. Available from: 
URL:https://www.wpspublish.com/store/p/2743/dp-3-developmental-profile-3 
8. Harrison PL, Oakland T. Adaptive Behavior Assessment System, Third Edition [Manual]. 
Torrance, CA: Western Psychological Services. [Online]. 2015 [cited 2019 Nov 05]. Available 
from: URL: http://www.wpspublish.com/store/p/3234/abas-3-adaptive-behavior-assessment-
system-third-edition  
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6 
APPENDICES  
Adjustment of DLco measurements 
1 Introduction 
Adjustments of DLco measurements are described in detail the 2005 ERS/ATS statement. In the 
paper, however, the adjustment is described as a change of the DLco predicted values. After 
several discussions with opinion leaders, we have to conclude that it is more common to compute 
a DLadj value that is computed from the measured DLco value. This DLadj value is then 
compared to the (unchanged) predicted values. The following table describes this: 
Comment 
Parameter 
Predicted 
% Predicted 
 
DLcomeas 
DLcopred 
DLcopred/DLcomeas 
ERS/ATS statement 
DLcomeas 
DLcopred*α 
DLcopred*α/DLcomeas 
EasyOne pro 
DLadj = DLcomeas*β 
DLcopred 
DLcopred/(DLcomeas*β) 
As can be seen from the table above, the % Predicted is the same if β = 1/α. This means that the 
equations of the ERS/ATS statement have to be inverted (ie, the factor is multiplied instead of 
divided). If compared to the original formulas in the ERS/ATS statement, the following formulas 
are therefore ‘inverted’ (multiplication instead of division and vice versa).  
2 Adjustment for hemoglobin 
The following formula is applied to correct for hemoglobin (Hb): 
Male adults (age >=15):                                         DLadj = DLco/(1.7*Hb/(10.22+Hb)) Hb in g/dL 
Female and children (age<15):                               DLadj = DLco/(1.7*Hb/(9.38+Hb)) Hb in g/dL 
Unit conversion:                                                     Hb [g/dL] = Hb [mmol/L] /0.616  
                                                                               (according to other sources the factor is 0.6206) 
Allowed range for Hb:                                            0 to 100 g/dL 
Default value for male adults (age >=15):              14.6 g/dL (9.00 mmol/L) 
Default value for female and children (age <15):   13.4 g/dL (8.26 mmol/L) 
© ndd Medizintechnik AG, 03-2013, CB 
 
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