A Phase IV Open-label, Single-arm, Single-dose, Multicenter Study to Evaluate the saFEty, toLerability and effIcacy of Gene Replacement Therapy With intravenousOAV101(AVXS101) in Pediatric Patients From Latin America With Spinal Muscular Atrophy (SMA) - OFELIA
Phase: PHASE4
Conditions: Muscular Atrophy, Spinal
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
COAV101A1IC01 / NCT05073133 
Clinical Trial Protocol 
Amendment 1 
A Phase IV Open-label, single-arm, single-dose, multicenter 
study to evaluate the saFEty, toLerability and effIcacy of 
gene replacement therapy with 
intravenousOAV101(AVXS101) in pediatric patients from 
Latin America with spinal muscular atrophy (SMA) – 
OFELIA 
Document type: Clinical Trial Protocol 
Version number: 1.0 
Clinical Trial Phase: IV 
Release date: 24/Mar/2022 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 

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Clinical Trial Protocol (Version No. 01) 
 
Protocol No. COAV101A1IC01 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of abbreviations ............................................................................................................ 6 
Amendment Summary of Changes ...................................................................................... 9 
Glossary of terms ............................................................................................................... 10 
Protocol summary .............................................................................................................. 12 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Purpose .................................................................................................................. 20 
2 
Objectives and endpoints ................................................................................................... 20 
2.1 
Primary endpoints .................................................................................................. 21 
3 
Study design ...................................................................................................................... 22 
4 
Rationale ............................................................................................................................ 23 
4.1 
Rationale for study design ..................................................................................... 23 
4.1.1 
Rationale for choice of background therapy ......................................... 23 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 23 
4.3 
Rationale for use of prednisolone .......................................................................... 23 
4.4 
Purpose and timing of interim analyses ................................................................. 24 
4.5 
Risks and benefits .................................................................................................. 24 
4.6 
Rationale for public health emergency mitigation procedures .............................. 25 
5 
Study Population ............................................................................................................... 25 
5.1 
Inclusion criteria* .................................................................................................. 25 
5.2 
Exclusion criteria ................................................................................................... 26 
6 
Treatment ........................................................................................................................... 27 
6.1 
Study treatment ...................................................................................................... 27 
6.1.1 
Investigational and control drugs .......................................................... 27 
6.1.2 
Additional study treatments .................................................................. 28 
All participants will receive corticosteroids 24 hours prior to the 
infusion of OAV101 and for at least 30 days post-infusion 
(including the day of OAV101 administration). ................................... 28 
6.1.3 
Supply of study treatment ..................................................................... 28 
6.1.4 
Treatment arms/group ........................................................................... 28 
6.1.5 
Treatment duration ................................................................................ 28 
6.2 
Other treatment(s) .................................................................................................. 28 
6.2.1 
Concomitant therapy ............................................................................. 29 
6.2.2 
Prohibited medication ........................................................................... 29 

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Clinical Trial Protocol (Version No. 01) 
 
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6.3 
Participant numbering, treatment assignment, randomization .............................. 30 
6.3.1 
Participant numbering ........................................................................... 30 
6.3.2 
Treatment assignment, randomization .................................................. 30 
6.4 
Treatment blinding ................................................................................................. 30 
6.5 
Dose escalation and dose modification .................................................................. 30 
6.6 
Additional treatment guidance ............................................................................... 30 
6.6.1 
Treatment compliance ........................................................................... 30 
6.6.2 
Recommended treatment of adverse events .......................................... 30 
6.7 
Preparation and dispensation ................................................................................. 31 
6.7.1 
Handling of study treatment and additional treatment .......................... 32 
7 
Informed consent procedures ............................................................................................ 32 
8 
Visit schedule and assessments ......................................................................................... 33 
8.1 
Screening ............................................................................................................... 36 
8.1.1 
Information to be collected on screening failures ................................. 36 
8.2 
Participant demographics/other baseline characteristics ....................................... 36 
8.2.1 
Demographics/medical history.............................................................. 36 
8.2.2 
SMA medical history ............................................................................ 36 
8.2.3 
Physical examination ............................................................................ 37 
8.2.4 
Neurological examination ..................................................................... 37 
 
 37 
8.2.6 
Virus serology ....................................................................................... 37 
8.3 
Efficacy .................................................................................................................. 37 
8.3.1 
Developmental motor milestone checklist ............................................ 37 
8.3.2 
Appropriateness of efficacy assessments .............................................. 38 
8.4 
Safety ..................................................................................................................... 38 
8.4.1 
Laboratory evaluations .......................................................................... 38 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 40 
8.4.3 
Vital signs.............................................................................................. 41 
8.4.4 
Appropriateness of safety measurements .............................................. 41 
8.5 
Additional assessments .......................................................................................... 41 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 41 
 
 42 
 
 43 
9 
Study discontinuation and completion .............................................................................. 43 
9.1 
Discontinuation and completion ............................................................................ 43 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 43 

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9.1.2 
Withdrawal of informed consent ........................................................... 44 
9.1.3 
Lost to follow-up ................................................................................... 44 
9.1.4 
Early study termination by the sponsor ................................................. 44 
9.2 
Study completion and post-study treatment .......................................................... 45 
10 Safety monitoring and reporting ........................................................................................ 45 
10.1 
Definition of adverse events and reporting requirements ...................................... 45 
10.1.1 
Adverse events ...................................................................................... 45 
10.1.2 
Serious adverse events .......................................................................... 47 
10.1.3 
SAE reporting........................................................................................ 47 
10.2 
Additional Safety Monitoring ................................................................................ 48 
10.2.1 
Liver safety monitoring ......................................................................... 48 
10.2.2 
Post-mortem data collection .................................................................. 48 
10.2.3 
Data Monitoring Committee ................................................................. 49 
11 Data Collection and Database management ...................................................................... 49 
11.1 
Data collection ....................................................................................................... 49 
11.2 
Database management and quality control ............................................................ 49 
11.3 
Site monitoring ...................................................................................................... 50 
12 Data analysis and statistical methods ................................................................................ 50 
12.1 
Analysis sets .......................................................................................................... 51 
12.2 
Participant demographics and other baseline characteristics ................................. 51 
12.3 
Treatments ............................................................................................................. 51 
12.4 
Analysis supporting primary objectives ................................................................ 51 
12.4.1 
Definition of primary endpoint(s) ......................................................... 51 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 51 
12.4.3 
Handling of intercurrent events ............................................................. 52 
12.4.4 
Handling of missing values not related to intercurrent event ............... 52 
12.4.5 
Sensitivity analyses ............................................................................... 52 
12.4.6 
Supplementary analysis ......................................................................... 52 
As the sample size is small, data will be only summarized within each subgroup. 
Analysis supporting secondary objectives ............................................................. 52 
12.4.7 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 53 
12.4.8 
Safety endpoints .................................................................................... 53 
 
 54 
12.6 
Interim analyses ..................................................................................................... 55 
12.7 
Sample size calculation .......................................................................................... 55 
12.7.1 
Primary endpoint(s) ............................................................................... 55 

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13 Ethical considerations and administrative procedures ...................................................... 55 
13.1 
Regulatory and ethical compliance ........................................................................ 55 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 55 
13.3 
Publication of study protocol and results............................................................... 56 
13.4 
Quality Control and Quality Assurance ................................................................. 56 
14 Protocol adherence ............................................................................................................ 56 
14.1 
Protocol amendments ............................................................................................. 57 
15 References ......................................................................................................................... 58 
16 Appendices ........................................................................................................................ 61 
16.1 
Appendix ................................................................................................................ 61 
16.1.1 
Clinically notable laboratory values and vital signs ............................. 61 
16.1.2 
Liver monitoring guidelines .................................................................. 63 
16.1.3 
Performance criteria For World Health Organization (WHO) 
developmental motor milestones ........................................................... 65 
List of tables 
Table 1-1 
Spinal Muscular Atrophy Classification ............................................... 18 
Table 2-1 
Objectives and related endpoints .......................................................... 20 
Table 6-1 
Investigational Drug .............................................................................. 27 
Table 6-2 
Pre- and post-infusion corticosteroid use .............................................. 28 
Table 8-1 
Assessment Schedule ............................................................................ 34 
Table 8-2 
Developmental Milestone Checklist and Performance Criteria ............ 41 
Table 16-1 
Liver event and laboratory trigger definitions ...................................... 63 
Table 16-2 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 63 
Table 16-3 
Follow up requirements for liver laboratory triggers - isolated 
hyperbilirubinemia ................................................................................ 65 
  

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List of abbreviations 
AAV 
Adeno-Associated Virus  
AAV2 
Adeno-Associated Virus Serotype 2 
AAV9 
Adeno-Associated Virus Serotype 9 
 
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BiPAP 
Bi-Level Positive Airway Pressure 
BMI 
Body Mass Index 
CB 
Chicken-β-Actin-Hybrid 
cDNA 
Complementary Deoxyribonucleic Acid 
CFR 
Code of Federal Regulations 
CK-MB 
Creatinine Kinase-MB 
CMO&PS  
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CNT 
Can Not Test 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
COVID 
Coronavirus Disease 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DRG 
Dorsal Root Ganglia 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EDC 
Electronic Data Capture 
EOS 
End of Study 
EU 
Europe 
FAS 
FEES 
Full Analysis Set 
Flexible Endoscopic Evaluation of Swallowing 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase 

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GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface antigen 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IT 
Intrathecal 
ITR 
Inverted Terminal Repeats 
IV 
Intravenous 
kg 
Kilogram(s) 
LFT 
Liver function test  
LV EF 
Left Ventricular Ejection Fraction 
LV FS 
Left Ventricular Fractional Shortening 
MAP 
Managed Access Program 
MedDRA 
Medical dictionary for regulatory activities  
 
 
mg 
milligram(s) 
 
 
NfL 
Neurofilament light chain 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcomes 
PT 
Preferred Term 
QMS  
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
RSV 
Respiratory Syncytial Virus 
SAE 
Serious Adverse Event 
SMA 
Spinal muscular atrophy 
SMN1 
Survival of Motor Neuron 1 
SMN2 
Survival of Motor Neuron 2 
SNAP 
Sensory nerve action potential 
SOP 
Standard Operating Procedure(s) 
SoC 
System organ Class 
SoA 
Schedule of Assessment 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 

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TEAE 
Thromboembolic Adverse Events 
TMA 
Thrombotic Microangiopathy 
ULN 
upper limit of normal 
US 
United States 
vg 
Vector Genome 
WHO 
World Health Organization  
WHO-
MGRS 
World Health Organization Multicentre Growth Reference Study 

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Clinical Trial Protocol (Version No. 01) 
 
Protocol No. COAV101A1IC01 
 
 
 
Amendment Summary of Changes 
 
It is listed below the summary of changes of amendment 1 
 
- 
Numbering correction in the Protocol summary section exclusion criteria  
- 
Removal of Canada as a participant country 
- 
Adjustment of project title considering the removal of Canada 
 
 
 
 
 
 
- 
Protocol improvements to confirm that the participants may be discharged 12-48 hours 
after the infusion, based on Investigator judgment 
- 
Protocol improvements to confirm that the safety profile of OAV101 is described in the 
Investigator Brochure (IB) or package insert 
- 
Numbering adjustment performed for items 6.1.2 Additional Study Treatment and 6.1.3 
Supply of study treatment 
- 
Adjustment in the item 8-1 Assessment Schedule – visit window    
 
 

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Clinical Trial Protocol (Version No. 01) 
 
Protocol No. COAV101A1IC01 
 
 
 
Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy; concomitant medications) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant  
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, or 
survives 
Cohort 
A specific group of participants fulfilling certain criteria and generally treated at 
the same time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the participant in a time unit 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from paper source forms used at the point of care 
Enrollment 
Point/time of participant entry into the study at which informed consent must 
be obtained  
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to sponsors and 
other oversight authorities, as appropriate 
Endpoints  
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an endpoints include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 

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Clinical Trial Protocol (Version No. 01) 
 
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Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient about 
the status of a participant's health condition without amendment or 
interpretation of the patient's report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Study treatment 
Any drug or combination of drugs   or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation  
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of 
study consent 
(WoC) 
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data   

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Clinical Trial Protocol (Version No. 01) 
 
Protocol No. COAV101A1IC01 
 
 
 
Protocol summary 
Protocol number 
COAV101A1IC01 
Full Title 
A Phase IV Open-label, single-arm, single-dose, 
multicenter study to evaluate the saFEty, 
toLerability and effIcacy of gene replacement 
therapy with intravenous OAV101 (AVXS-101) in 
pediatric patients from Latin America with spinal 
muscular atrophy (SMA) - OFELIA 
Brief title 
Safety and efficacy of intravenous OAV101 
(AVXS-101) in pediatric patients with spinal 
muscular atrophy (SMA) 
Sponsor and Clinical Phase 
Novartis and Phase 4 
Investigation type 
Participants will receive a single administration 
of OAV101 at 1.1e14 vg/kg 
Study type 
Interventional 
Purpose and rationale 
To evaluate the safety, tolerability and efficacy 
of intravenous administration of OAV101 (AVXS-
101) in patients with SMA with bi-allelic 
mutations in the survival motor neuron 1 (SMN1) 
gene ≤  24 months and weighing ≤ 17 kg, over a 
18-month period post infusion. 
Primary Objective(s)  
 
The primary objective of this study is to assess 
the safety and tolerability of IV OAV101 over a 
18-month period in patients with SMA weighing 
less or equal of 17 kg at the time of dose 
 
Endpoints:  
 
• Evaluation of treatment emergent AEs and 
SAEs 
• Evaluation of important identified and 
important potential risks  
• Evaluate changes from baseline in vital 
signs, cardiac safety assessments, and clinical 
laboratory results  
Secondary Objectives 
To determine the efficacy of IV OAV101 at 6, 12- 
and 18-months post infusion in participants with 
SMA ≤ 24 months and weighing ≤ 17kg as 
measured by change from baseline in: 
Achievement of developmental motor milestones 
according to the World Health Organization-
Multicentre Growth Reference Study (WHO-
MGRS) 
 

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Clinical Trial Protocol (Version No. 01) 
 
Protocol No. COAV101A1IC01 
 
 
 
Study design 
This is an open-label, single arm, multi-center 
study to evaluate the safety, tolerability and 
efficacy of IV OAV101 in SMA participants. The 
study will enroll participants ≤ 24 months that 
weigh ≤ 17 kg. Participants will receive a single 
administration of IV OAV101 at the approved 
dose of 1.1e14 vg/kg. 
Participants who meet eligibility criteria at 
screening and baseline visits will receive a 
single dose of IV OAV101 on Day 1 (Treatment 
period) and will be followed for a period of 
18 months. The study will include a standard 
screening period that can last up to 20 days, 
during which eligibility will be assessed and 
baseline assessments will be performed prior to 
treatment. 
For the study duration, participants will complete 
visits as defined in the Schedule of 
Assessments (SoA). Prednisolone treatment will 
be given per study protocol. On Day –1, 
participants will be admitted to the hospital for 
pre-treatment baseline procedures. On Day 1, 
participants will receive a 1-time IV infusion of 
OAV101 and will undergo in-patient safety 
monitoring over the next 48 hours, after which 
the participant may be discharged, based on 
Investigator judgment. 
Safety monitoring will be performed as per study 
schedule and protocol requirement. Safety for 
the participants enrolled in the study will be 
evaluated by the study team together with Data 
Monitoring Committee (DMC) as described in 
the charter. An interim analysis for safety and 
efficacy maybe performed once the last 
participant completes 6-months of follow-up and 
will include all available data up until that data 
cut-off. Final analysis will be planned after the 
18 months visits (EOS). 
After study completion eligible participants will 
be invited to enroll into a Registry study 
(RESTORE) study to collect additional safety 
and efficacy data. 
Study population 
Participants ≤24 months of age with SMA with 
bi-allelic mutations in the SMN1 gene weighing 
≤17kg, at the time of dosing. 
Key inclusion criteria* 
 
 
 
 
1. Written informed consent/assent obtained 
prior to any assessment performed 
2. Symptomatic SMA diagnosis based on gene 
mutation analysis with bi-allelic SMN1 mutations 
(deletion or point mutations) and any copy of 
SMN2 gene. 
3. Age ≤ 24 months of age at time of treatment 

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*Patients should follow all criteria of the label 
locally approved by Health Authorities. 
3. Weight ≤17 kg at the time of Screening Period 
4. Naive to treatment or have discontinued an 
approved drug/therapy 
5. Up-to date on recommended childhood 
vaccinations and RSV prophylaxis with 
palivizumab (also known as Synagis), per local 
standard of care 
Key exclusion criteria 
Participants meeting any of the following criteria 
are not eligible for inclusion in this study: 
 
1. Previous use of OAV101 or any AAV9 gene 
therapy 
2. BMI < 3rd percentile based on WHO Child 
Growth Standard 
3. Participant with history of aspiration  
pneumonia or signs of aspiration (eg, coughing 
or sputtering of food) within 4 weeks prior to 
Screening 
4. Participant dependent on gastrostomy feeding 
tube for 100% of nutritional intake. 
4. Anti-AAV9 antibody titer > 1:50 as determined 
by ligand binding immunoassay at the time of 
screening 
5. History of gene therapy, hematopoietic 
transplantation, or solid organ transplantation 
6. Inability to take corticosteroids 
7. Concomitant use of immunosuppressive 
therapy, plasmapheresis, immunomodulators 
such as adalimumab, or immunosuppressive 
therapy within 3 months prior to gene 
replacement therapy (eg, cyclosporine, 
tacrolimus, methotrexate, rituximab 
cyclophosphamide, IV immunoglobulin) 
8. Requiring invasive ventilation, tracheostomy 
or daytime non-invasive ventilation (standard of 
care nocturnal BiPAP is not considered 
exclusionary) 
9. Administration of vaccines 2 weeks prior to 
infusion of OAV101 
10. Awake hypoxemia (O2 saturation <95%) or 
awake oxygen saturation level decrease 
between screening and dosing that is clinically 
significant, as per investigator judgment 
11. Clinically significant neurologic or 
neuromuscular conditions other than SMA as 
determined by the principal Investigator 
12. Clinically significant abnormalities in 
laboratory test results at Screening as 
determined by the Investigator 

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13. Hepatic dysfunction (i.e. AST, ALT, bilirubin, 
GGT or GLDH, ≥ ULN; CTCAE ≥ 1) at 
Screening (with the exception of isolated AST 
elevation: in the absence of other liver laboratory 
abnormalities, isolated AST elevation is not 
considered exclusionary) 
14. Excluding SMA, any medically unstable 
condition considered clinically significant by the 
Investigator, including cardiomyopathy, hepatic 
dysfunction, kidney disorder, endocrine disorder, 
GI disorders, metabolic disorders, severe 
respiratory compromise and significant brain 
abnormalities at either Screening or Baseline 
visits that, in the opinion of the investigator, 
would interfere with the overall interpretation of 
safety or efficacy of the study 
15. Presence of a confirmed or suspected active 
infectious process from screening and up to 
dose administration 
16. Previously treated with nusinersen 
(Spinraza®) within 4 months prior to Screening 
17. Previously treated with risdiplam (EvrysdiTM) 
within 15 days prior to Screening (washout 
period of at least 5 half-lives before Screening) 
18. Use of other investigational drugs within 5 
half-lives of enrollment/initiation of study 
treatment (select as appropriate) within 30 days 
(eg, small molecules) / or until the expected 
pharmacodynamic effect has returned to 
baseline (eg, biologics), whichever is longer; or 
longer if required by local regulations. 
19. History of hypersensitivity to any of the study 
treatments or its excipients or to drugs of similar 
chemical classes. 
20. Documented any parental consanguinity (1st 
degree consanguinity). 
Study treatment 
OAV101 will be administered as a single IV 
infusion at 1.1e14 vg/kg over approximately 
60 minutes 
Efficacy assessments 
Developmental Motor Milestones will be 
assessed using relevant definitions obtained 
from the following: 
• 
WHO Multicentre Growth Reference Study 
(WHO-MGRS) 
 
  
 
 
 
 
 
  

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Key safety assessments 
Safety and tolerability of OAV101 treatment 
includes evaluation of AEs, laboratory data, vital 
signs, and ECG and echocardiogram. 
Data analysis 
The primary endpoints include: 
1. Incidence and severity of treatment emergent 
AEs and SAEs 
2. Incidence of adverse events of special 
interest (AESI).  
3. Change from baseline in vital signs, clinical 
laboratory, and procedure (eg ECG, 
echocardiogram) results 
Incidence and severity for treatment emergent 
AEs and SAEs as well as important identified 
and important potential risks will be summarized 
overall in the safety set. The number and 
proportion of participants reporting a treatment 
emergent AE or SAE, including investigator and 
Sponsor causalities will be reported. Summaries 
will also be provided by MedDRA System Organ 
Class and Preferred Term. 
Changes from baseline in vital signs, and clinical 
laboratory, and procedure (eg ECG, 
echocardiogram) results will be summarized 
descriptively overall in the safety set. Mean, 
standard deviation, median, minimum, and 
maximum will be presented. For each applicable 
timepoint, only participants with a baseline and a 
measurement for that timepoint will be included 
in the summary. 
 
The number and proportion of patients achieving 
each Developmental Motor Milestone will be 
presented. 
An interim analysis may be performed once the 
last participant reaches the 6 and 12-month time 
point and will include all available data up until 
that data cut-off. 
There is no formal sample size calculation 
performed for this study. The primary objective 
is to evaluate descriptively the safety and 
tolerability of IV OAV101 over a 18 month post 
infusion period in participants with SMA 
weighing equal or less than 17kg. No hypothesis 
testing will be performed. 

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The sample size is based on recruitment 
estimatives and clinical drug availability. Based 
on this assumption, it is anticipated that 
approximately 15 participants will be enrolled in 
this study. From a medical perspective, this 
number is considered reasonable to provide 
descriptive safety information. 
If the true incidence rate of an AE is 14%, then 
the probability of seeing at least one AE with a 
sample size of 15 participants is approximately 
90%. 
 
 
Key words 
Spinal muscular atrophy, Zolgensma, OAV101, 
AVXS‑101, gene therapy 

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1 
Introduction 
1.1 
Background 
Spinal muscular atrophy is an autosomal recessive, early childhood disease with an incidence 
of approximately 1:10,000 live births, of which approximately 45% to 60% of cases are SMA 
1 (Ogino et al 2004, Sugarman et al 2012, Arnold et al 2015). Spinal muscular atrophy is 
conventionally classified into 4 phenotypes on the basis of age of onset and highest motor 
function achieved, with an additional phenotype (type 0) to describe the severe forms of 
antenatal onset (Kolb and Kissel 2011, Mercuri et al 2012) (Table 1‑1). Prior to the availability 
of effective treatment, SMA was the leading cause of infant mortality due to genetic disease 
(Sugarman et al 2012, Awano et al 2014). 
Table 1-1 
Spinal Muscular Atrophy Classification 
Type 
Age at Symptom Onset 
Maximum 
Motor 
Function 
Life 
Expectancy 
SMN2 Copy 
No. 
0 
Fetal 
Nil 
Days – Weeks 
1 
1 
< 6 months 
1A: Birth – 2 
weeks 1B: < 3 
months 
1C: > 3 
months 
Never sits 
< 2 years 
1, 2, 3 
2 
6 – 18 months 
Never walks 
20 – 40 years 
2, 3, 4 
3 
1.5 – 10 
years 
3A: < 3 years 
3B: > 3 years 
Walks, 
regression 
Normal 
3, 4, 5 
4 
> 35 years 
Slow decline 
Normal 
4-8 
bold = predominant SMN2 copy number that defines the SMA type, the other copy numbers 
represent a small percentage of the designated SMA type. 
Source: Adapted from Kolb and Kissel 2011 and Mercuri et al 2012 
With the recent availability of SMN-targeting therapies, the SMA phenotype is shifting and 
current clinical practice increasingly relies on genotype and age-of-onset when considering 
prognosis and treatment (Mercuri et al 2012, Wirth et al 2020, Wirth 2021). Following the 
development of disease-modifying treatment for SMA, newer categories of nonsitter, sitter, and 
walker phenotypes are increasingly used to better inform disease management 
(Mercuri et al 2012, Finkel et al 2018, Wirth et al 2020, Wijngaarde et al 2020). For example, 
no sitters, the majority of whom have SMA1, typically have 2 copies of SMN2 (approximate 
age range, 1‑3 years) and are unable to sit independently. These patients also have bulbar and 
respiratory 
dysfunction 
requiring 
feeding 
and 
ventilatory 
support, 
respectively 
(Finkel et al 2018, Mercuri et al 2018, Wirth et al 2020). These patients would historically not 
have survived past the age of 2 years, but are now achieving developmental milestones such as 
sitting independently, standing and even walking. 
The serious continuing unmet needs in SMA, all stemming from absence of the SMN protein 
most commonly due to biallelic deletion of the SMN1 gene, is meaningfully addressed by 

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OAV101 (AVXS-101) as the first therapeutic regimen designed to directly address the 
underlying genetic cause of the disease. Most children with SMA have 2 copies of SMN2 and 
have a 97% probability of developing SMA based upon copy number alone 
(Feldkötter et al 2002). The majority of patients with SMA have normal strength at birth but 
exhibit progressive weakness with the onset of symptoms being observed before 6 months of 
age (Shababi et al 2014, Finkel et al 2014). 
OAV101 is a recombinant biological product comprised of replication-incompetent 
recombinant self-complementary AAV9 capsid shell containing the cDNA of the human SMN 
gene. The SMN gene is under the control of the CMV enhancer/CB as well as 2 AAV ITRs 
derived from AAV2 DNA. One of the 2 AAV ITRs has been modified to promote 
intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for 
transcription. This modified ITR, termed a “self-complementary” (sc) ITR, has been shown to 
significantly increase the speed at which the transgene is transcribed, and the resulting human 
SMN protein is produced. Recombinant self-complimentary adeno-associated virus can be 
employed because of the small size of the SMN gene, which enables efficient packaging and 
gene transfer with lower viral titers, compared with prototype single-stranded AAV vectors. All 
DNA from the wild-type AAV9 has been removed and replaced with the genes described above 
(the 2 ITRs are from AAV2). 
Studies using OAV101 show a robust postnatal rescue of SMNΔ7 mice with correction of motor 
function, neuromuscular electrophysiology, and survival after single administration 
(Foust et al 2010). Intravenous OAV101 can transduce neurons, muscle, and vascular 
endothelium, all of which have been proposed as target cells for SMA treatment. In pivotal 
toxicology studies, the main target organs of toxicity were limited to the heart and liver in mice, 
and the brain, dorsal root ganglia (DRG), and associated tissues (spinal cord, peripheral nerves), 
trigeminal ganglion (TG), liver, and heart in cynomolgus monkeys. 
Liver findings in mice were comprised of hepatocellular hypertrophy, Kupffer cell activation, 
and scattered hepatocellular necrosis, while in NHP the findings were limited to single cell 
necrosis of hepatocytes associated with slight mononuclear cell infiltrates. In both species, these 
microscopic findings may have correlated with increased liver enzyme activity. The 
pathogenesis of OAV101 related liver findings has not been specifically studied but is likely 
related to an innate and/or acquired immune response to the viral capsid and/or transgene 
product which is prominently distributed to the liver. OAV101 related findings in the heart 
include ventricular inflammation, edema, and fibrosis, and atrial thrombosis and inflammation 
in mice. In monkeys, slight mixed cell infiltrates and minimal hemorrhage were noted in the 
right atrium of 1 animal 6 weeks post intrathecal (IT) injection at 3e13 vg/animal, with no 
observed alteration of cardiac troponin. The pathogenesis of these heart findings in animals and 
potential translatability to humans is unclear. 
Compared to the natural history of SMA, patients treated with OAV101 in a completed clinical 
study showed significant improvements in survival, attainment of developmental motor 
milestones, respiratory and motor function, and ability to thrive. Results obtained 24 months 
after OAV101 infusion showed that efficacy was durable and either consistent or improved 
compared to earlier analyses conducted when patients had reached at least 13.6 months and 20 
months of age. In a Phase 3 completed clinical study, the co-primary efficacy results 
demonstrated that OAV101 has significant therapeutic benefits in patients with SMA with 

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biallelic mutation of the SMN1 gene and 1 or 2 copies of the SMN2 gene who were < 6 months 
of age at the time of gene replacement therapy. The therapeutic benefit of OAV101 was again 
demonstrated for survival, the achievement of motor milestones, respiratory and motor 
function, and the ability to thrive. Consistent with findings in previous studies, the available 
data from currently ongoing IV studies of OAV101 have also demonstrated clear evidence of 
clinically meaningful efficacy in this otherwise devastating neurodegenerative disease with an 
acceptable safety profile. 
SMA is now recognized as a continuous spectrum of disease with severity determined by both 
genetic and environmental factors, including SMA-modifying therapy (eg, nusinersen and 
risdiplam) and supportive care. As treatment is now available that changes the disease course, 
with older patients now having preserved motor neuron function that can be rescued by gene 
therapy compared to SMA patients in the pre-treatment era. This Phase IV open-label study will 
be conducted in SMA pediatric participants that weigh between 8.5 kg and 17 kg, inclusive. 
This study builds on the established efficacy and safety profile of OAV101 and aims to gather 
additional safety and efficacy information in a cohort of heavier children not previously studied 
in OAV101 clinical trials. 
1.2 
Purpose 
The purpose of the study is to evaluate the safety, tolerability, and efficacy of IV administration 
of OAV101 in participants ≤ 24 months of age with SMA with bi-allelic mutations in the SMN1 
gene weighing up to and equal to 17kg at the time of infusion, during a 18-month post-infusion 
period. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the safety and tolerability of 
IV OAV101 over a 18 month post-
infusion period in participants with SMA 
weighing to ≤ 17 kg. 
• 
Evaluation of treatment emergent AEs and 
SAEs 
• 
Evaluation of important identified and potential 
risks 
• 
Evaluate changes from baseline in vital signs, 
cardiac safety assessments, and clinical 
laboratory results 
 
 
 
 
 
 
 
 

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Objective(s) 
Endpoint(s) 
Secondary objective(s) 
Endpoint(s) for secondary objective 
• 
To evaluate the efficacy of IV OAV101 at 
6, 12, and 18 months post-infusion in 
participants with SMA weighing ≤ 17 kg, 
as measured by the following: 
• 
World Health Organization-
Multicentre Growth Reference 
Study (WHO-MGRS)  
• 
Proportion of participants who achieve 
Development Motor Milestones according to the 
World Health Organization-Multicentre Growth 
Reference Study (WHO-MGRS) at 6, 12, and 18 
months post-infusion 
 
 
2.1 
Primary Endpoint 
The clinical question of interest: What is the safety of single administration of IV OAV101 
treatment in SMA participants ≤ 24 months of age that weigh ≤ 17 kg? 
The primary endpoint is described by the attributes listed below. 
• Population: Participants ≤ 24 months of age with SMA that weigh ≤ 17 kg who meet 
inclusion/exclusion criteria 
• Endpoint:  Evaluation of AEs, laboratory data, vital signs, and ECG and echocardiogram. 
• Binary indicator of having at least one occurrence of TEAE 

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• AESIs  
• Change from baseline in vital signs, cardiac safety assessments, and clinical laboratory 
results 
• Treatment of interest: Treatment strategy includes corticosteroids 24 hours prior to the 
infusion of OAV101 followed by IV OAV101 and corticosteroids for at least 30 days 
post-infusion (including the day of OAV101 administration). 
Handling of intercurrent events: 
The remaining intercurrent events include receiving prohibited concomitant medications. Loss 
to follow-up due to reasons other than death will not impact 1 or 2 above primary variables; for 
primary variable 3 it will be handled by a hypothetical strategy. 
The summary measures include incidence and severity for treatment emergent AEs and SAEs 
as well as important identified and important potential risks and mean for changes from 
baseline in vital signs and clinical laboratory results. 
3 
Study design 
This is an open-label, single arm, multi-center study to evaluate the safety, tolerability, and 
efficacy of IV OAV101 in symptomatic SMA pediatric participants. The study will enroll 
participants that weigh ≤ 17 kg.  
Participants who meet eligibility criteria at Screening and Baseline visits will receive a single 
dose of IV OAV101 on Day 1 (Treatment period) at the approved dose of 1.1e14 vg/kg and will 
be followed for a period of 18months. The study will include a 20 day screening period in which 
there will be 2 Screening visits, during which, eligibility will be assessed (Screening 1), weight 
will be collected for dose calculation (Screening 2), and baseline assessments will be performed 
prior to treatment. For the study duration, participants will be completing visits as defined in 
the Schedule of Assessments (Table 8-1). On Day -1, participants will be admitted to the 
hospital for pre-treatment baseline procedures including prednisolone treatment per study 
protocol. On Day 1, participants will receive a single IV infusion of OAV101. Participants may 
be discharged 12-48 hours after the infusion, based on Investigator judgment. 
Section 6.7 outlines details regarding study drug preparation and administration. 
Safety monitoring will be performed on an ongoing basis per protocol requirement and will be 
evaluated by the clinical safety team as well as DMC. An interim analysis for safety and efficacy 
will be performed once the last participant completes 6-months of follow-up and will include 
all available data up until that data cut-off. Final analysis will be planned once all participants 
have completed Month 18End of Study (EOS) assessments. 
After study completion eligible participants will be invited to enroll into RESTORE registry 
study to collect additional safety and efficacy data. 
 

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4 
Rationale 
4.1 
Rationale for study design 
This Phase IV open-label study builds on the established efficacy and safety profile of OAV101. 
The study is designed as a prospective open-label trial in order to characterize the safety of 
OAV101 in pediatric participants ≤ 17kg with symptomatic SMA.
 
 
  
The study includes 2 Screening visits to facilitate assessment of eligibility (anti-AAV9 antibody 
titers), decrease burden of clinical and laboratory baseline evaluations, and weight-based dose 
calculation closer to infusion day (Day 1). The second Screening visit (Screening 2) will be 
used for weight eligibility and dose calculation. The study will administer OAV101 and monitor 
participants in an inpatient setting for a minimum of 12-48 hours after administration to 
carefully monitor the emergence of acute AEs. Participants will be followed for up to 18 
months, which is considered adequate to characterize safety given clinical experience 
(Section 4.6) and sufficient to evaluate efficacy. 
Inclusion of pediatric participants ≤ 17kg and allows for careful assessment of safety and 
clinical response in a population that has not been previously included in OAV101 clinical 
trials. The study is broad in the inclusion of participants that are treatment naive and “switchers” 
(e.g treatment experienced) reflecting the real-world use of OAV101. The study excludes 
participants who have pre-existing AA9 immunity and who may be at risk for lack of efficacy. 
In order to reduce safety confounders and mitigate known OAV101 safety risks the study 
excludes participants with underlying liver disease, active infections, and immunizations before 
and after administration of OAV101. 
4.1.1 
Rationale for choice of background therapy 
The study allows for standard of care non‑disease modifying SMA therapy, including 
respiratory and nutritional support, physical therapy, occupational therapy, speech-language 
therapy and prevention of infection therapies in accordance to treatment guidelines and local 
practice. This will further mitigate safety and efficacy confounders. 
4.2 
Rationale for dose/regimen and duration of treatment 
OAV101 will be administered in this trial as a single IV infusion. Participants will receive a 
dose of 1.1e14 vg/kg. The total volume is determined by participant body weight. The 
participant will undergo in-patient safety monitoring for 48 hours post-infusion. 
4.3 
Rationale for use of prednisolone 
An immune response to the AAV9 capsid may occur after administration of OAV101. To 
dampen the immune response and in accordance to the market authorization, all participants 
will receive corticosteroids 24 hours prior to the infusion of OAV101 and for at least 30 days 
post-infusion (including the day of OAV101 administration). The participant vaccination 
schedule will be adjusted to accommodate corticosteroid administration. Pre- and post-infusion 
corticosteroids regimen is indicated in Section 6.2 

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4.4 
Purpose and timing of interim analyses 
An interim analysis will be performed once the last participant reaches the 6-month and 12-
month follow-up and will include all available data up until that data cut-off. The interim 
analysis is intended to provide an early safety readout from the study. No study design change 
or adaptation will be implemented based on the outcome of the interim analysis. 
4.5 
Risks and benefits 
Evidence from the completed and ongoing clinical studies continue to demonstrate the efficacy 
of OAV101. Substantial clinical efficacy of OAV101 across multiple endpoints-survival, motor 
function, developmental motor milestones, and ventilatory and nutritional endpoints has been 
established and confirmed in first-in-human and confirmatory studies. Long-term follow-up 
studies continue to support the durability of OAV101 efficacy, and participants continue to 
exhibit the achievement of additional milestones. Data spans pre‑symptomatic and symptomatic 
participants. 
Appropriate eligibility criteria and clinical safety monitoring criteria are included in this 
protocol. The risk to participants in this trial will be minimized by compliance with the 
eligibility criteria and study procedures, as well as close clinical monitoring and evaluation by 
an independent DMC. 
The safety profile of OAV101 is described in the Investigator Brochure (IB) and or package 
insert . The risks and benefits are derived from: 
(1)  Non-clinical toxicology studies 
(2) Clinical studies for the treatment of symptomatic and pre-symptomatic participants with 
SMA who have 1, 2 or 3 copies of the SMN2 gene and bi-allelic SMN1 gene deletions at the 
proposed therapeutic dose of 1.1e14 vg/kg and the dose being proposed in this study 
(3) Long term follow-up study of participants who were administered OAV101 in clinical trials 
(4) US managed access program in participants with serious or life-threatening disease 
(5) Long-term registry of participants diagnosed with SMA 
(6) Post-marketing safety monitoring 
The following are important identified and important potential risks associated with OAV101: 
• Hepatotoxicity 
• Thrombocytopenia 
• Cardiac adverse events 
• Sensory abnormalities suggestive of ganglionopathy 
• Thrombotic microangiopathy 
Further details are outlined in the IB. 
Risk of immunosuppression 
All participants in the study will receive prophylaxis immunosuppression with prednisolone or 
equivalent corticosteroid to mitigate safety risks associated with inflammation (Section 4.3). 

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The chronic use of corticosteroids may be associated with hypothalamic-pituitary-adrenal axis 
suppression, Cushing's syndrome and hyperglycemia which can be mitigate with adequate 
tapering. Increased susceptibility to new infections or exacerbation and dissemination of latent 
infections, as well as elevated blood pressure, salt and water retention, hypokalemia, and 
gastrointestinal perforation have been reported. Risks will be mitigated by close monitoring, 
and implementation of standard prophylaxis and tapering protocol as detailed in Section 6.2 
Risk of phlebotomy (maximum volume over what period of time) 
European Medicines Agency (EMA) Guidelines for Drawing Blood and Best practices in 
Phlebotomy in pediatric participants will be followed. 
Drug-drug interaction 
OAV101 is a gene replacement therapy product for one-time administration, which delivers a 
transgene construct expressing the SMN protein. Drug-drug interactions are not expected with 
OAV101. 
In summary, clinical data strongly suggest OAV101 is safe and well tolerated with an 
acceptable benefit/risk profile when administered to participants with SMA with 2 or 3 SMN2 
copies or a clinical diagnosis of SMA.  
4.6 
Rationale for public health emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic, COVID-19 or natural disaster, mitigation procedures to ensure participant safety and 
trial integrity are listed in relevant sections. Notification of the Public health emergency should 
be discussed with Novartis prior to implementation of mitigation procedures and 
permitted/approved by Local or Regional Health Authorities and Ethics Committees as 
appropriate. 
5 
Study Population 
Approximately 15 pediatric participants ≤ 24 months of age with SMA with bi-allelic mutations 
in the SMN1 gene weighing ≤ 17 kg, at dosing, will be enrolled. 
5.1 
Inclusion criteria* 
*Patients should follow all criteria of the label locally approved by Health Authorities. 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent/assent obtained prior to any assessment performed 
2. Symptomatic SMA diagnosis based on gene mutation analysis with bi-allelic SMN1 
mutations (deletion or point mutations) and any copy of SMN2 gene. 
3. Age ≤ 24 months of age at time of dosing 
4. Weight ≤ 17 kg at the time of Screening Visit 2  
5. Naive to treatment or have discontinued an approved drug/therapy 

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6. Up-to date on recommended childhood vaccinations and RSV prophylaxis with palivizumab 
(also known as Synagis), per local standard of care 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Previous OAV101 use or previous use of any AAV9 gene therapy 
2. BMI < 3rd percentile based on WHO Child Growth Standard 
3. Participant with history of aspiration pneumonia or signs of aspiration (eg, coughing or 
sputtering of food) within 4 weeks prior to screening 
4.  Participant dependent on gastrostomy feed tube for 100% of nutritional intake 
5. Anti-AAV9 antibody titer > 1:50 as determined by ligand binding immunoassay at the time 
of screening 
6. History of gene therapy, hematopoietic transplantation, or solid organ transplantation 
7. Inability to take corticosteroids 
8. Concomitant use of immunosuppressive therapy, plasmapheresis, immunomodulators such 
as adalimumab, or immunosuppressive therapy within 3 months prior to gene replacement 
therapy (eg, cyclosporine, tacrolimus, methotrexate, rituximab cyclophosphamide, IV 
immunoglobulin) 
9 Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation (standard of 
care nocturnal BiPAP is not considered exclusionary) 
10. Administration of vaccines 2 weeks prior to infusion of OAV101 
11. Awake hypoxemia (O2 saturation <95%) or awake oxygen saturation level decrease 
between screening and dosing that is clinically significant, as per investigator judgment. 
12. Clinically significant neurologic or neuromuscular conditions other than SMA as 
determined by the principal Investigator 
13. Clinically significant abnormalities in laboratory test results at Screening as determined by 
the Investigator 
14. Hepatic dysfunction (i.e. AST, ALT, bilirubin, GGT or GLDH, ≥ ULN; CTCAE ≥ 1) at 
Screening (with the exception of isolated AST elevation: in the absence of other liver laboratory 
abnormalities, isolated AST elevation is not considered exclusionary) 
15. Excluding SMA, any medically unstable condition considered clinically significant by the 
Investigator, including cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine 
disorder, GI disorders, metabolic disorders, severe respiratory compromise and significant brain 
abnormalities at either Screening or Baseline that, in the opinion of the investigator, would 
interfere with the overall interpretation of safety or efficacy of the study 
16. Presence of a confirmed or suspected active infectious process from screening and up to 
dose administration 

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17. If previously treated with disease modifying therapy, participants are excluded if they 
received 
• nusinersen (Spinraza®) within 4 months prior to Screening 1. 
• risdiplam (EvrysdiTM) within 15 days prior to Screening 1 (washout period of at least 5 
half-lives before Screening) 
18. Use of other investigational drugs within 5 half-lives of enrollment/initiation of study 
treatment (select as appropriate) within 30 days (eg, small molecules) / or until the expected 
pharmacodynamic effect has returned to baseline (eg, biologics), whichever is longer; or longer 
if required by local regulations. 
19. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes. 
20. Documented any parental consanguinity (1st degree consanguinity) 
6 
Treatment 
6.1 
Study treatment 
The biological product is a non-replicating recombinant AAV9 containing the cDNA of the 
human SMN gene under the control of the CMV enhancer/CB promoter. The AAV ITR has 
been modified to promote intramolecular annealing of the transgene, thus forming a double-
stranded transgene ready for transcription. This modified ITR, termed a “self-complementary” 
(sc) ITR, has been shown to significantly increase the speed of which the transgene is 
transcribed, and the resulting protein is produced. The biological product, called OAV101, 
expresses the human SMN protein in transduced cells. 
Table 6-1 
Investigational Drug 
  
Investigational Product 
Product Name 
OAV101 ( AVXS-101) 
Unit Dose 
1.1e14 vg/kg 
Route of Administration 
Intravenous infusion 
Physical Description 
OAV101 is a clear, colorless to faint white 
solution. 
6.1.1 
Investigational and control drugs 
See Table 6-1. 

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6.1.2 
Additional study treatments 
All participants will receive corticosteroids 24 hours prior to the infusion of OAV101 and for 
at least 30 days post-infusion (including the day of OAV101 administration).  
6.1.3 
Supply of study treatment 
Ex-US non-EU countries where in-country depot is required: IMP is manufactured by the 
Sponsor and supplied to in-country depot. The vials are packaged in a clinical carton (1 vial per 
carton) and shipped out of the in-country depot directly to the clinical sites. The IMP is stored 
at a temperature ≤ -60°C and shipped under dry ice. Once received at the clinical site, the 
material is placed in cold storage (2-8°C) to thaw. 
6.1.4 
Treatment arms/group 
Open label, single treatment arm OAV101 IV. 
6.1.5 
Treatment duration 
OAV101 will be administered as a 1-time IV infusion over approximately 60 minutes. 
6.2 
Other treatment(s) 
In accordance to this protocol, all study participants will receive immunomodulatory therapy 
with prednisolone. Immunomodulatory therapy is intended to mitigate safety risks associated 
with immune response to the AAV9 capsid that may occur after administration of 
OAV101. Immune responses may lead to elevations in liver transaminases or elevations of 
Troponin I. Where feasible, the participant’s vaccination schedule should be adjusted to 
accommodate concomitant corticosteroid administration prior to and following OAV101.  In 
addition to consideration for corticosteroids, vaccinations should be withheld 2 weeks pre and 
4 weeks post OAV101 administration. Prior to initiation of the immunomodulatory regimen 
and prior to administration of OAV101, the participant must be checked for symptoms of active 
infectious disease of any nature. 
Starting 24 hours prior to infusion of OAV101, it is required to initiate an immunomodulatory 
regimen with corticosteroids following the schedule below. 
Table 6-2 
Pre and post-infusion corticosteroid use 
Pre-infusion 
24 hours prior to OAV101 
infusion 
Prednisolone orally 1 
mg/kg/day or equivalent 
Post-infusion 
At least 30 days (including the 
day of OAV101 administration) 
Prednisolone orally 1 
mg/kg/day or equivalent 
Tapering 
Once liver function tests return 
to baseline or after Day 30 if no 
liver function test elevation 
observed 
decrease dose by 0.25 mg/kg 
per week  
Prednisolone treatment of 1 mg/kg/day will be continued post-infusion until liver function tests 
return to baseline. 

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For participants that require steroid dosing longer than 60 days total (including the weaning 
period) Pediatric GI/hepatology specialty evaluation will be considered to address the risk of 
opportunistic infections and to make recommendations for infectious prophylaxis. 
6.2.1 
Concomitant therapy 
The Investigator should instruct the participant and his/her parents/caregivers to notify the study 
site about any new medications he/she takes after the participant was enrolled into the study.  
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) that are ongoing or administered after the participant was enrolled into the 
study must be recorded on the appropriate CRFs. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication (Section 5.2 and Section 6.2.2). If in doubt, the Investigator should contact the 
Novartis medical monitor before enrollment of a participant or allowing a new medication to 
be started. If the participant is already enrolled, contact Novartis to determine if the participant 
should continue participation in the study. 
Participants are encouraged to follow all routinely scheduled immunizations, recommended by 
local health authorities and consistent with Section 6.2.2, throughout the study. Vaccinations 
that include palivizumab prophylaxis (also known as Synagis) to prevent RSV infections are 
also recommended in accordance with the guidance of local health authorities. 
6.2.2 
Prohibited medication 
Except for concomitant medication allowed per protocol (see Section 6.2.1), prednisolone, 
and/or any non-excluded medications which may be required to treat AEs, no medication other 
than study treatment will be allowed from the date the informed consent/assent is signed until 
all of the study completion evaluations have been performed. 
Concomitant use of any of the following medications are prohibited: 
• Concomitant medication with the intent to treat SMA 
• Any investigational medication other than OAV101 
• Use of intravenous immunoglobulins and non-live vaccines 4 weeks after infusion of 
OAV101; unless required for treatment of adverse events. 
• Live vaccines are prohibited while receiving corticosteroids  
• The use of immunosuppressive therapies, including but not limited to, for example, 
cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IVIG, rituximab, and 
adalimumab; unless required for treatment of adverse events 
Given the nature and profile of the treatment, i.e., gene therapy, there are no PK/PD drug 
interactions expected. 
The Investigator should instruct the participant/caregiver to notify the study site about any new 
treatments, including herbal and over the counter medications the participant takes after the 
start of study treatment. All prohibited medications and significant non-drug therapies 
administered after the participant starts study treatment must be recorded in the eCRF. 

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6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent/assent form, the participant is 
assigned to the next sequential Participant No. available. 
Once assigned, the participant No. must not be reused for any other participant and the 
Participant No. for that individual must not be changed unless the participant is re-screened. 
Re-screening is allowed once for participants that were initially screen failures for any reason 
(Section 8.1.1). All eligibility criteria must be re-checked and met prior to enrollment of the 
participant into the study. A new Participant No. should be assigned for all re-screened 
participants. 
A new ICF/ assent will need to be signed if the Investigator chooses to re-screen the participant 
after a participant has screen failed, and the participant will be assigned a new Participant No. 
6.3.2 
Treatment assignment, randomization 
This is an open-label trial and randomization numbers will not be used.  
6.4 
Treatment blinding 
This is an open-label trial. 
6.5 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 
The IV dosage is determined by participant body weight at Screening Visit 2 with a nominal 
recommended dose of 1.1e14 vg/kg. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
OAV101 will be administered as a single IV injection. If the dose is not fully completed the site 
personnel will need to reflect the total volume administered as well as the date and time of 
administration in the eCRF.  
6.6.2 
Recommended treatment of adverse events 
The Investigator will use his/her medical judgement in accordance with standard of care to treat 
AEs. Medication and/or intervention used to medically manage AEs must be recorded on the 
appropriate eCRF. 

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6.7 
Preparation and dispensation 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of prednisolone directly to a participant’s home may be permitted (if allowed by Local 
or Regional Health Authorities and Ethics Committees as appropriate). In the event the 
Investigator decides that an on-site visit by the participant is no longer appropriate or possible, 
and that it is in the interest of the participant’s health to supply the prednisolone even without 
performing an on-site visit, prednisolone will be dispatched from the site to the participant’s 
home and remains under the accountability of the Investigator. Each shipment/provisioning will 
be approximately 2 months’ supply. In this case, regular phone calls or virtual contacts per 
schedule of assessment (Table 8-1) will occur between the site and the participant for 
instructional purposes, safety monitoring, drug accountability, investigation of any AEs, 
ensuring participants continue to benefit from treatment and discussion of the participant´s 
health status until the participants can resume visits at the study site. 
Study drug preparation 
Preparation of OAV101 will be done aseptically under sterile conditions at the site and will be 
received ready for infusion at the bedside. 
The total vector genome dose will be calculated based on the participant’s body weight at 
Screening Period; sites will receive a participant-specific dose for each participant enrolled. 
The dose-delivery vessel will be delivered in the appropriate setting with immediate access to 
acute critical care management.  
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
Study drug administration 
OAV101 infusion will be administered under sterile conditions in an appropriate inpatient 
setting (eg, interventional suite, operating room, dedicated procedure room) with immediate 
access to acute critical care management. OAV101 will be delivered as a single 
treatment through a venous catheter inserted into a peripheral limb vein (arm or leg) at a dose 
of 1.1e14 vg/kg.  OAV101 should be slowly infused over approximately 60 minutes, dependent 
upon volume required, utilizing an infusion set and pump in accordance with the country label. 
Following the administration of the gene replacement therapy, participants should return to an 
appropriate designated setting to ensure close monitoring of vital signs and AEs. Vital signs 
will be continuously monitored throughout the gene replacement therapy infusion as described 
in (Vital Signs/Weight and Height section under Safety Parameters). Participants should be 
maintained in an appropriate inpatient setting from 12 to 48 hours after the start of gene 
replacement therapy based on Investigator judgment. 
 
A unique medication number is printed on the study medication label. 

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6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
OAV101 kits will be stored in a locked, limited access room under the responsibility of the 
Investigator or other authorized persons (eg, pharmacists) in accordance with local regulations, 
policies, and procedures. Control of storage conditions, especially control of temperature (eg, 
refrigerated/freezer storage) and information on in-use stability and instructions for handling 
prepared OAV101 should be managed in accordance with the country label specifications. 
OAV101 will be supplied to each site for each individual study subject after confirmation of 
weight at Screening Visit 2. The OAV101 dose will be administered via a syringe and should 
be delivered by the pharmacist or designated study staff member to the procedure room, 
and administered IV to the patient within 8 hours from preparation. 
Any quality issue noticed with the receipt or use of OAV101 (eg, deficiency in condition, 
appearance, pertaining to documentation, labeling, expiration date, etc.) should be promptly 
reported to the Sponsor. 
Under no circumstances will the Investigator supply OAV101 to a third party, allow OAV101 
to be used other than as directed by this clinical trial protocol, or dispose of OAV101 in any 
other manner. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after IRB/IEC- approved informed 
consent has been provided by a legally acceptable representative(s) or parent of the participant 
(country specific regulations may apply). 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding.  
Novartis will provide to Investigators, in a separate document, a proposed informed consent 
form that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
Investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about known AEs associated with study drug can be found in the IB or in the 
package insert. This information will be included in the participant informed consent and should 
be discussed with the participant during the study as needed. Any new information regarding 
the safety profile of the study drug that is identified between IB updates will be communicated 
as appropriate, for example, via an Investigator notification or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the participant. 
The following informed consents are included in this study: 

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1. Global Model Parent Legal Guardian ICF 
A subsection that requires a separate signature for the ‘Optional Consent for Autopsy’ to allow, 
in the event of the death of a patient, the investigator site to arrange an autopsy and for the 
details of the autopsy and the autopsy report to be shared with the Sponsor 
In case Home Nursing is implemented during the COVID-19 pandemic, a separate Home 
Nursing consent document must be used in addition to the main ICF (in accordance to local 
regulations) 
 
 
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.  
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit,  Investigator may 
conduct the informed consent discussion remotely (eg telephone, videoconference) if allowable 
by a local Health Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (eg the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists type and timing of all assessments. All data obtained 
from these assessments must be supported in the participant’s source documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or within the specified visit window. Missed or rescheduled visits should not lead 
to automatic discontinuation. Participants who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, the AE and concomitant medications 
recorded on the eCRF. 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the Investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (eg tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 

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Table 8-1 
Assessment Schedule 
Period 
Screening 
Baseline 
Treatment 
 
 
Visit Name Screening 
Visit 1 
Screening 
Visit 2 
Baseline Day 
1 
Day 2 Day 3 Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
26 
Week 
 52   
Week 78 
EOS 
Days 
-20 
-0 +5 
-14 
±2 
-1 
1 
2 to 2 3 to 3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±5 
57 
±5 
71 
±14 
85 
±14 
183 
±14 
365 
±21 
547 
±21 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
Inclusion / 
Exclusion criteria 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
 
  
  
 
Height and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Vital Signs 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological 
Examination 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Videodeglutogram 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
SMA Medical 
History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
Medical History 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 

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Period 
Screening 
Baseline 
Treatment 
 
 
Visit Name Screening 
Visit 1 
Screening 
Visit 2 
Baseline Day 
1 
Day 2 Day 3 Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
26 
Week 
 52   
Week 78 
EOS 
Days 
-20 
-0 +5 
-14 
±2 
-1 
1 
2 to 2 3 to 3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±5 
57 
±5 
71 
±14 
85 
±14 
183 
±14 
365 
±21 
547 
±21 
Hematology 
X 
  
X 
  
  
  
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
Chemistry/Liver 
Function Testing 
X 
  
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation panel 
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
Troponin-
I/Troponin T 
  
X 
  
  
  
  
X 
  
  
X 
  
X 
X 
X 
X 
X 
X 
Virus Serology 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
X 
Urinalysis 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
 
  
  
 
Electrocardiogram 
(ECG) 
X 
  
X 
  
  
  
X 
  
  
X 
  
X 
X 
 
X 
X 
X 
Echocardiogram 
X 
  
  
  
  
  
X 
  
  
X 
  
X 
X 
X 
X 
 
X 
Prophylactic 
Prednisolone 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
  
  
 
OAV101 Infusion 
  
  
  
X 
  
  
  
  
  
  
  
  
  
 
  
  
 
Developmental 
Milestone 
Checklist  
  
X 
  
  
  
  
  
  
  
X 
  
  
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
events/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
information 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
X 

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8.1 
Screening 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to enrollment will be considered a screen failure. The reason for screen failure should be 
entered on the applicable eCRF. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure participants. No other data 
will be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a SAE during the screening phase (see SAE section for reporting details, 
Section 10.1.2) or protocol-related AE. 
The Screening assessments will be performed from the time of the ICF signature, as outlined in 
the protocol and SoA. 
The exact sequence of Screening assessments is at the discretion of the Site.  It is recommended 
to obtain the anti-AAV9 antibody screening results first. 
Participants who fail eligibility during the screening process for a temporary condition (eg viral 
illness, concomitant medication, or laboratory values, etc.) may be re-screened at a later time. 
Participants who fail upper weight eligibility at Screening Visit 2 cannot be re-screened. 
In case the screening window has expired, all screening procedures must be repeated. When all 
inclusion and exclusion criteria will have to be re-verified, a new Participant No. will be 
assigned. A participant initially excluded for a condition no longer exclusionary upon a protocol 
amendment may also be re-screened. 
8.2 
Participant demographics/other baseline characteristics 
8.2.1 
Demographics/medical history 
Demographics (including age, sex)/medical history information will be collected at screening 
and captured in the eCRF. 
Any relevant medical history, including relevant hospitalizations from time of birth /current 
medical conditions (until date of signature of informed consent) will be recorded in the eCRF. 
Where possible, the diagnosis and not symptoms should be recorded. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the Section 6.2.1 Concomitant Therapy for 
further details on what information must be recorded on the appropriate page of the eCRF. 
8.2.2 
SMA medical history 
Familial history of SMA including affected siblings or parent carriers will be collected. Any 
relevant SMA medical history, including SMA type and number of copies (if available), will 
be recorded in the eCRF.  

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8.2.3 
Physical examination 
Physical examinations will be conducted by the Investigator or designee as specified in the 
Table 8-1.  The Day 1 physical examination will be performed prior to the start of gene 
replacement therapy infusion. Physical examinations include a review of the following systems: 
(HEENT), lungs/thorax, cardiovascular, abdomen, musculoskeletal, neurologic, dermatologic, 
lymphatic, and genitourinary. 
Physical examination data will be captured on source documentation. 
8.2.4 
Neurological examination 
Neurological examinations will be conducted by the Investigator or designee as specified in the 
Table 8-1. Specifically, the neurological exam should include detailed, age-appropriate sensory 
testing (such as examination of proprioceptive, vibratory, tactile and pain sensation) at each 
visit. Any clinically significant sensory abnormal finding will be recorded in eCRF. 
8.2.6 
Virus serology 
The administration of an AAV vector has the risk of causing immune-mediated 
hepatotoxicity. For participants who have HIV or positive serology for hepatitis B or C, 
administration of the AAV vector may represent an unreasonable risk; therefore negative 
serology testing must be confirmed at screening, prior to treatment. These samples will be 
collected in accordance with the table 8.. 
8.3 
Efficacy 
The efficacy assessments described below have been selected in order to evaluate the effect of 
OAV101 on SMA.  
8.3.1 
Developmental motor milestone checklist 
See Section 8.5.1.1 for details. 

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8.3.2 
Appropriateness of efficacy assessments 
Efficacy assessments for developmental motor milestones is standard for this 
indication/participant population. 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed (Table 8-1). 
Safety parameters include demographics/medical history, physical and neurological 
examinations, vital signs, height and weight measurements, 12-lead ECGs, echocardiograms, 
laboratory assessments, and AE monitoring. 
For details on AE collection and reporting, refer to Section 10.1. 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur based on the Table 8-1 assessment schedule for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 
8.4.1 
Laboratory evaluations 
The site laboratory will be used for analysis of all specimens collected, except for AAV9 
antibodies, that will use central laboratory. Details on the collections, shipment of samples and 
reporting of results by the central laboratory for AAV9 antibodies are provided to Investigators. 
8.4.1.1 
Hematology 
Hematology analysis will include a complete blood count with differential and platelet count. 
Samples will be collected and processed in the local site laboratory. Blood samples for 
hematology analysis will be collected as specified in the Table 8-1. 
Hematology analysis will include the following: 
• Hematocrit 
• Hemoglobin 
• MCH 
• MCHC 
• MCV 
• Platelets 
• Red blood cells 
• White blood cells 
• Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands) 
Hematology analyses required during in-patient dosing, as determined by the Investigator, and 
on Day 2 prior to discharge, will be performed as per investigational site standard procedures 
at the local laboratory.  

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If clinically significant and/or moderate or severe thrombocytopenia and anemia are noted, 
further evaluation to diagnose TMA should be conducted in accordance of standard of care. If 
a clinical diagnosis of TMA is made, a complete complement panel should be obtained per 
standard of care.  
8.4.1.2 
Blood chemistry 
Samples will be collected and processes in the local site laboratory. Blood samples for 
chemistry analysis will be collected as specified in the Schedule of Assessments (Table 8-1). 
Chemistry analysis will include the following: 
• Alkaline phosphatase 
• ALT 
• AST 
• GGT 
• LDH 
• G-LDH 
• Bicarbonate 
• Calcium 
• Phosphorus 
• Chloride 
• Sodium 
• Potassium 
• Creatinine 
• Creatine kinase 
• Direct Bilirubin 
• Indirect Bilirubin 
• Total Bilirubin 
• BUN or Urea 
• Glucose 
Troponin I will be collected as specified in the Schedule of Assessments (Table 8-1) as 
applicable. In case Troponin I is not available at site, Toponin T can be performed. If Troponin-
T is collected at baseline then Tropinin T must be collected for follow up.  
 
If liver aminotransferase elevations occur, the process outlined in Section 10.2.1 should be 
followed. 
8.4.1.3 
Urinalysis 
Urine samples will be collected in accordance with the local laboratory standards at study visits 
in accord with the Schedule of Assessments (Table 8-1).  

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8.4.2 
Electrocardiogram (ECG) 
8.4.2.1 
12-Lead electrocardiogram 
A 12-lead ECG will be performed at times indicated in the Schedule of Assessments. 
In the case of a series of assessments, ECG should be the first assessment obtained while 
participant is at rest. The preferred sequence of cardiovascular data collection during study visits 
is ECG collection first, followed by vital signs, and blood sampling. 
During feasibility, the ECG readout availability should be confirmed at the site for QTcF. If a 
site only has availability to readout in QTcB (Bazett) and NOT QTcF, the ECG machine must 
still be able to provide QT and RR interval values so the Investigator can perform the below 
QTcF (Fridericia) calculation to determine eligibility. The Fridericia QT correction formula 
(QTcF) must be used for clinical decisions. 
Unless auto calculated by the ECG machine, the Investigator must calculate QTcF at the 
Screening and/or Baseline visit(s) (as applicable) to assess eligibility according to the following 
formula: 
 
Triplicate 12-lead ECGs are to be collected with ECG machines available at the site. Each ECG 
tracing must be labeled with study number, participant initials, Participant No., date and time, 
and filed in the study site source documents. The Investigator should document clinical 
evaluation in the source documents. 
The ECG will be interpreted locally by a pediatric cardiologist or designee for immediate safety 
evaluation. If the participant is hemodynamically compromised, the Investigator or a medically 
qualified person must initiate appropriate safety procedures without delay. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the Investigator at 
any time during the study as clinically indicated. A 
Clinically significant ECG findings at baseline must be discussed with Novartis before 
administration of study treatment. 
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate. 
8.4.2.2 
Echocardiogram 
A standard transthoracic ECHO will be performed at times indicated in the Schedule of 
Assessments (Table 8-1); these will be interpreted locally by a cardiologist or a designee for 
immediate safety evaluation. The Novartis physician or designee will be notified of any safety 
concerns from the site review. 

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8.4.3 
Vital signs 
Vital sign parameters include blood pressure, respiratory rate, pulse, temperature, and oxygen 
saturation level. Vital signs will be obtained as specified in the Table 8-1. On Day 1, vital signs 
will be recorded pre-dose and then monitored as specified in the Table 8-1.  
Height and weight will be measured (supine or standing) at each study visit. Screening weight 
shall be obtained ≤ 14 days prior to Day 1. On Day 1, weight and height will be measured pre-
dose.  
8.4.4 
Appropriateness of safety measurements 
Safety assessments such as AEs, clinical laboratory assessments, ECGs, and vital signs are 
standard for this indication/participant population. 
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
COA data (eg, neuromuscular module and multi-dimensional fatigue scale) may be collected 
remotely (eg web portal, telephone interviews) depending on local regulations, technical 
capabilities, and following any applicable training in the required process. 
8.5.1.1 
Developmental Motor Milestone checklist 
Developmental Motor Milestones will be assessed using relevant definition obtained from  
World Health Organization Multicentre Growth Reference Study (WHO-MGRS). 
The Developmental Motor Milestone Checklist will be completed by the qualified site clinical 
evaluator (eg, licensed physical or occupational therapist, or national equivalent) for all 
participants according to the Schedule of Assessments (Table 8-1).  
. 
Table 8-2 
Developmental Motor Milestone  and Performance Criteria 
Developmental Motor Milestone 
Performance Criteria 
Sitting without support (WHO MGRS) 
Child sits up straight with the 
head erect for at least 10 
seconds. Child does not use 
arms or hands to balance 
body or support position. 
Hands-and-knees crawling (WHO MGRS) 
Child alternately moves 
forward or backward on hands 
and knees. The stomach does 
not touch the supporting 
surface. 
There are continuous and 
consecutive movements, at 
least 3 in a row. 

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Standing with assistance (WHO MGRS) 
Child stands in upright position 
on both feet, holding onto a 
stable object (eg, furniture) 
with both hands without 
leaning on it. 
The body does not touch the 
stable object, and the legs 
support most of the body 
weight. 
Child thus stands with 
assistance for at least 10 
seconds. 
Walking with assistance (WHO MGRS) 
Child is in upright position with 
the back straight. 
Child makes sideways or 
forward steps by holding onto 
a stable object (eg, furniture) 
with 1 or both hands. 
One leg moves forward while 
the other supports part of the 
body weight. 
Child takes at least 5 steps in 
this manner. 
Standing alone (WHO MGRS) 
Child stands in upright position 
on both feet (not on the toes) 
with the back straight. 
The legs support 100% of the 
child’s weight. There is no 
contact with a person or 
object. Child stands alone for 
at least 10 seconds. 
Walking alone (WHO MGRS) 
Child takes at least 5 steps 
independently in upright 
position with the back straight. 
One leg moves forward while 
the other supports most of the 
body weight. 
There is no contact with a 
person or object. 
  
 
 

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9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Since this is a single dose study, discontinuation of study treatment is not applicable. 
Because the study treatment is a single administration gene therapy, stopping or reversing the 
study treatment is not possible. Participants who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, they should 
return for the assessments indicated in the Assessment Schedule. If they fail to return for these 
assessments for unknown reasons, every effort (eg telephone, e-mail, letter) should be made to 
contact the participant/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
In the event of study discontinuation, the EOS study should be completed. At a minimum, in 
abbreviated visits, the following data should be collected at clinic visits or via telephone/email 
contact: 
• New / concomitant treatments/medications 
• AEs, including SAEs 

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9.1.1.1 
Replacement policy 
No participant replacement will be done for this study. 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore, 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
In this situation, the Investigator should make a reasonable effort (eg telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. 
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data. 
No further assessments to be conducted, and the data that would have been collected at 
subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the EOS assessments prior to study discontinuation. A 
final evaluation at the time of the participant’s study discontinuation should be made as detailed 
in the assessment table. 
The sponsor will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the Investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, eg dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from DMC after review of safety and efficacy data 
• Discontinuation of study drug development by Novartis 

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• Regulatory Authority recommendation 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The Investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The Investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.  
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An AE is any untoward medical occurrence (eg any unfavorable and unintended sign [including 
abnormal laboratory findings], symptom or disease) in a clinical investigation participant after 
providing written informed consent for participation in the study. Therefore, an AE may or may 
not be temporally or causally associated with the use of a medicinal (investigational) product. 
The Investigator has the responsibility for managing the safety of individual participant and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. Adverse events also may be detected when they are volunteered by the 
participant during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. Severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression of 
underlying illness (i.e. progression of the study indication) the assessment of causality will 

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usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a lack of 
efficacy or progression of underlying illness are not caused by the trial drug, they happen in 
spite of its administration and/or both lack of efficacy and progression of underlying disease 
can only be evaluated meaningfully by an analysis of cohorts, not on a single participant 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All AEs must be treated appropriately. 
6. Its outcome (i.e. recovery status or whether it was fatal) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued until end of study. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 
Based on important identified and potential risks associated with OAV101, AESIs are 
determined and categorized as follows. These will be summarized based on Standardized 
MedDRA terminology: 
• Hepatotoxicity 
• Thrombocytopenia 
• Cardiac adverse events 
• Sensory abnormalities suggestive of ganglionopathy 
• Thrombotic microangiopathy 

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10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
o Life-threatening in the context of a SAE refers to a reaction in which the 
participant was at risk of death at the time of the reaction; it does not refer to a 
reaction that hypothetically might have caused death if it were more severe 
(please refer to the 
International Conference on Harmonisation ICH-E2D Guidelines 2003). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires in-patient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, eg defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
International Conference on Harmonisation ICH-E2D Guidelines 2003). 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. Detailed instructions regarding the submission process and requirements are to be 
found in the Investigator folder provided to each site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 

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within 24 hours of the Investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a CMO & PS Department associate may urgently 
require further information from the investigator for health authority reporting. Novartis may 
need to issue an Investigator Notification to inform all Investigators involved in any study with 
the same study treatment that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with regulatory 
requirements in participating countries. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
OAV101, a standardized process for identification, monitoring and evaluation of liver events 
has to be followed. 
Please refer to Table 16-1 in Appendix 16.1 for complete definition and management of liver 
laboratory abnormalities. 
Table 16-1 should be followed up by the Investigator or designated personnel at the trial site, 
as summarized below. 
If liver function tests are elevated, the following will also be performed: 
• Hospitalization of the participant, if appropriate 
• Causality assessment of the liver event 
• Thorough investigation and follow-up of the liver event. Laboratory investigations may 
include based on Investigator’s discretion: serology and laboratory tests for other causes 
of hepatitis, including viral hepatitis 
• Obtaining a more detailed history of signs and symptoms and prior or concurrent diseases. 
• Obtaining a history of concomitant drug use, including nonprescription medications (eg 
acetaminophen); and herbal and dietary supplement preparations 
• Exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF.  
10.2.2 
Post-mortem data collection 
In the event of a fatal outcome, and if parental consent is obtained, an autopsy should be 
performed when possible, for any participant who receives gene replacement therapy. The 
autopsy will be performed by the clinical site local pathologist, hospital, or other applicable 
location. The autopsy should be performed per local standard of care and local regulations, and 
with particular attention to CNS (eg, DRG), liver, and cardiac examination. 

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Declining an autopsy will not prevent patients from participating in the trial. 
10.2.3 
Data Monitoring Committee 
This study will include a DMC which will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating in 
the study. The DMC will assess at defined intervals the progress of a clinical trial, safety data, 
and critical efficacy variables and recommend to the sponsor whether to continue, modify, or 
terminate a trial. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated Investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the Investigator staff. 
The Investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis will review the data entered by investigational staff for completeness and accuracy. 
Electronic data queries stating the nature of the problem and requesting clarification will be 
created for discrepancies and missing values and sent to the investigational site via the EDC 
system. Designated Investigator site staff are required to respond promptly to queries and to 
make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical (ATC) 
classification system. Medical history/current medical conditions and AEs will be coded using 
the MedDRA terminology. 
Dates of screenings, screen failures, treatment and study completion, as well as drug 
confirmation will be tracked by a system that will be supplied by a vendor, who will also 

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manage the database. The data will be sent electronically to Novartis (or a designated CRO) at 
specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e.  eCRFs) with the 
Investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to GCP, the progress of enrollment, and to ensure that 
study treatment is being stored, dispensed, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits. Continuous 
remote monitoring of each site’s data may be performed by the CRAs. 
The Investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
participant's file. The Investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
The data will be analyzed by Novartis and/or a designated CRO.  
Data from all participating centers will be combined, so that an adequate number of participants 
will be available for analysis.  
Primary safety and efficacy analysis will be conducted on all participant data after all 
participants have completed the Month 18/EOS visit. A final CSR will be produced for the 
primary analysis of the study. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 

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12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned and who received at least one dose of study treatment. Participants will be analyzed 
according to the treatment they have been assigned to. 
The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class (SOC) and preferred term (PT). 
12.3 
Treatments 
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The actual, weight-adjusted dose, in vg/kg, of OAV101 administered during infusion will be 
summarized as well as duration of infusion, whether the entire volume was delivered, and 
whether the infusion was interrupted.Concomitant medications and significant non-drug 
therapies prior to and after the start of the study treatment will be listed and summarized 
according to the ATC classification system. 
12.4 
Analysis supporting primary objectives 
12.4.1 
Definition of primary endpoint(s) 
All safety data, including TEAEs, cardiac safety assessments, clinical laboratory measurements, 
vital signs, are considered primary endpoints.  
12.4.2 
Statistical model, hypothesis, and method of analysis 
No statistical hypothesis testing will be performed.  
Treatment-emergent AEs are defined as any event that begins or worsens in severity after 
infusion of OAV101 through to the last study visit. The incidence of TEAEs will be summarized 
according to MedDRA as follows: overall by SOC and PT, overall, by SOC, PT and severity, 
suspected treatment-related AEs by SOC and PT, SAEs by SOC and PT. 
Adverse events of special interest (AESI) are defined by the important identified risk and 
important potential risk as presented in the effective Risk Management Plan (RMP). MedDRA 
search criteria to retrieve AEs indicative of these risks are updated on a regular basis at the 

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OAV101 program level. The incidence of treatment emergent AESIs will be summarized. 
Descriptive summary statistics for the change from baseline in cardiac safety assessments, 
clinical laboratory measurements, and vital signs will be summarized descriptively by 
visit/timepoint. Mean, standard deviation, median, minimum, and maximum will be presented. 
For each applicable visit/timepoint, only participants with a baseline and a measurement for 
that timepoint will be included in the summary. Categorical cardiac safety assessments, clinical 
laboratory measurements, and vital signs data will be presented as frequencies and percentages.  
12.4.3 
Handling of intercurrent events 
For the analysis of TEAE (including AESI), the treatment effect will be based on a treatment 
policy strategy (i.e. the target of estimation is considered regardless of the occurrence of 
intercurrent events, and the endpoint mirrors the decision to treat a participant rather than the 
effect of the treatment itself).  
The analysis of cardiac safety assessments, clinical laboratory measurements, vital signs will 
take into account the following intercurrent events using a hypothetical strategy: 
• Intake of prohibited concomitant medications 
• Discontinuation from the study due to reasons other than death 
12.4.4 
Handling of missing values not related to intercurrent event 
All available data will be used in the analysis of safety data. No imputation will be done for 
missing safety data. 
12.4.5 
Sensitivity analyses  
Given the descriptive nature of the summary of primary safety endpoints, no sensitivity analysis 
is planned. 
12.4.6 
Supplementary analysis 
 
Subgroup analyses 
Subgroup analyses will be performed on the primary endpoints based on the participant’s 
baseline status: 
• Age 
As the sample size is small, data will be only summarized within each subgroup. Analysis 
supporting secondary objectives 
The secondary objective is: 
• To evaluate the efficacy of IV OAV101 at 6, 12, and 18 months post-infusion in 
participants with SMA weighing ≤ 17 kg, as measured by the following: 
WHO-MGRS 
All secondary efficacy endpoints will be analyzed for the FAS. 

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12.4.7 
Efficacy and/or Pharmacodynamic endpoint(s) 
The number and proportion of participants achieving each WHO developmental milestone will 
be presented at 6-, 12-, and 18- months post-infusion.  
The analysis will take into account the following intercurrent events using a composite strategy: 
• Intake of prohibited concomitant medications 
• Discontinuation from study due to reasons other than death 
This means that if the any of the intercurrent events of interest occur the participant will be 
regarded as a non-responder from when the first intercurrent event of interest occurs. 
12.4.8 
Safety endpoints 
For all safety analyses, the Safety set will be used. 
The overall observation period will be divided into two mutually exclusive segments: 
1. Pre-treatment period: from day of participant’s informed consent to the day before 
infusion of OAV101 
2. On-treatment period: from day of infusion of OAV101 through to the last study visit.  
Adverse events 
Details of the summary of AEs for the primary endpoint are detailed in Section 12.4. 
In addition, separate summaries will be provided for death and other significant TEAEs leading 
to discontinuation. 
All AEs, deaths, and SAEs (including those from the pre-treatment period) will be listed and 
those collected during the pre-treatment period will be flagged. 
Vital signs 
Details of the summary of AEs for the primary endpoint are detailed in Section 12.4. 
12-lead ECG 
Details of the summary of 12-lead ECG (cardiac safety assessment) for the primary endpoint 
are detailed in Section 12.4 
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted (locally). 
2. Categorical Analysis of QT/QTc interval data based on the number of participants meeting 
or exceeding predefined limits in terms of absolute QT/QTc intervals or changes from 
baseline will be presented. 
All ECG data will be summarized by visit/timepoint. 

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Clinical laboratory results 
Details of the summary of clinical laboratory results for the primary endpoint are detailed in 
Section 12.4. 
In addition, shift tables using the low/normal/high/ (low and high) classification will be used to 
compare baseline to the worst on-treatment value. 
Grading of laboratory values will be assigned programmatically as per NCI CTCAE version 
4.03. The calculation of CTCAE grades will be based on the observed laboratory values only, 
clinical assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE version 4.03, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
The following listings/summaries will be generated separately for hematology, and 
biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
version 4.03 grades if applicable and the classifications relative to the laboratory normal 
ranges 
For laboratory tests where grades are defined by CTCAE version 4.03: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant 
will be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE version 4.03 grades to compare baseline to the worst on-
treatment value 
For laboratory tests where grades are not defined by CTCAE version 4.03: 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
 
Other safety evaluations 
Details of the summary of echocardiogram (cardiac safety assessment) for the primary endpoint 
are detailed in Section 12.4. 

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12.6 
Interim analyses 
An interim analysis will be performed once the last participant reaches the 6 and 12-month time 
point and will include all available data up until that data cut-off. The interim analysis is 
intended to provide an early safety readout from the study. No study design change or adaptation 
will be implemented based on the outcome of the interim analysis. 
12.7 
Sample size calculation 
12.7.1 
Primary endpoint(s) 
There is no formal sample size calculation performed for this study. The primary objective is 
to evaluate descriptively the safety and tolerability of IV OAV101 over a 18 month post infusion 
period in participants with SMA weighing equal or less than 17kg. No hypothesis testing will 
be performed. 
The sample size is based on recruitment estimatives and clinical drug availability. Based on this 
assumption, it is anticipated that approximately 15 participants will be enrolled in this study. 
From a medical perspective, this number is considered reasonable to provide descriptive safety 
information. 
If the true incidence rate of an AE is 14%, then the probability of seeing at least one AE with a 
sample size of 15 participants is approximately 90%. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, US CFR 21), and with the ethical principles laid 
down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written informed consent form, consent form updates, 
participant recruitment procedures (eg, advertisements) and any other written information to be 
provided to participants. Prior to study start, the Investigator is required to sign a protocol 

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signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access 
to all relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
Investigator must inform Novartis immediately that this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last participant last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (eg clinicaltrials.gov, EudraCT etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial Investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust QMS that includes all activities involved in quality assurance and 
quality control, to ensure compliance with written SOPs as well as applicable global/local GCP 
regulations and ICH Guidelines. 
Audits of Investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 

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14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 

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15 
References 
References are available upon request 
(2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in 
children and adolescents. Pediatrics p. 555-76. 
(2006) WHO Motor Development Study: windows of achievement for six gross motor 
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16 
Appendices 
16.1 
Appendix 
Appendix 1: Clinically notable laboratory values and vital signs 
Appendix 2: Liver monitoring guidelines 
Appendix 3. Performance criteria for World Health Organization (WHO) developmental 
milestones 
16.1.1 
Clinically notable laboratory values and vital signs 
Clinically relevant laboratory abnormalities 
Age-appropriate, normal laboratory values and clinical measurements should be used in 
pediatric population. Laboratory tests are commonly interpreted in relation to established 
reference intervals. These limits serve to differentiate between normal and pathological 
findings, and to gauge the severity of any abnormal increases or decreases. As far as laboratory 
parameters are known to characteristically vary with age, pediatric test results are usually 
interpreted in relation to these physiological dynamics. Reference intervals for pediatric patients 
have been calculated by partitioning data from a healthy reference population into age groups, 
so that the corresponding subset-specific percentiles would form step functions of age 
(Hirschmann et al 2017). 
Vital signs 
Within vital signs data, height and weight are commonly collected along with heart rate, 
respiratory rate, and blood pressure. The exam and vital sign data can be interpreted only with 
a thorough understanding of normal values. In pediatrics, normal respiratory rate, heart rate, 
and blood pressure have age-specific norms. 
Vital sign 
Value 
 
Patient age at visit 
 
< 18 years 
≥ 18 years 
Systolic blood 
pressure (mmHg) 
High 
 
≥ 95th percentile 
of the age and 
height group1 
≥ 180 with 
increase from 
updated baseline5 
or ≥ 20 mmHg 
Low 
 
≤ 5th percentile of 
the age and 
height group1 
≤ 90 with 
decrease from 
updated baseline5 
or ≥ 20 mmHg 
Diastolic blood 
pressure (mmHg) 
High 
 
≥ 95th percentile 
of the age and 
height group1 
≥ 105 with 
increase from 
updated baseline5 
or ≥ 15 mmHg 
Low 
 
≤ 5th percentile of 
the age and 
height group1 
≤ 50 with 
decrease from 
updated baseline5 
or ≥ 15 mmHg 
High 
 
≥ 38.4 
≥ 39.1 

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Oral body 
temperature (oC) 
Low 
 
≤ 35.0 
≤ 35.0 
Pulse rate (bpm)2 
High 
12-18 months 
> 140 
≥ 120 with 
increase from 
updated baseline5 
or ≥ 15 mmHg 
18-24 hours 
> 135 
2-3 years 
> 128 
3-4 years 
> 123 
4-6 years 
> 117 
6-8 years 
> 111 
8-12 years 
> 103 
12-15 years 
> 96 
≥ 15 years 
> 92 
Low 
12-18 months 
< 103 
≤ 50 with 
decrease from 
updated baseline5 
or ≥ 15 mmHg 
18-24 hours 
< 98 
2-3 years 
< 92 
3-4 years 
< 86 
4-6 years 
< 81 
6-8 years 
< 74 
8-12 years 
< 67 
12-15 years 
< 62 
≥ 15 years 
< 58 
Weight 
High 
 
Increase from 
baseline3 of ≥ 2 
BMI-for-age 
percentile 
cetagories4 
Weight increase 
from updated 
baseline5 of ≥ 
10% 
Low 
 
Decrease from 
baseline3 of ≥ 2 
BMI-for-age 
percentile 
cetagories4 
Weight decrease 
from updated 
baseline5 of ≥ 
10% 
Respiratory rate 
(breath per 
minutes)2 
High 
12-18 months 
> 46 
≥ 30 
18-24 hours 
> 40 
2-3 years 
> 34 
3-4 years 
> 29 
4-6 years 
> 27 
6-8 years 
> 24 
8-12 years 
> 22 
12-15 years 
> 21 
≥ 15 years 
> 20 
Low 
12-18 months 
< 28 
≤ 10 
18-24 hours 
< 25 
2-3 years 
< 22 
3-4 years 
< 21 

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4-6 years 
< 20 
6-8 years 
< 18 
8-12 years 
< 16 
12-15 years 
< 15 
≥ 15 years 
< 13 
bpm=beats per minute 
1 Blood pressure percentiles were calculated for each blood BP record using the method described in 
Appendix B of National High Blood Pressure Education Program Working Group on High Blood 
Pressure in Children and Adolescents 2004 
2 Fleming et al 2011 
3 Baseline BMI-for-age weight status categories are underweight (less than the 5th percentile), healthy 
weight (5th percentile to less than the 85th percentile), overweight (85th to less than the 95th percentile) 
and obese (equal to our greater than 95th percentile). 
4 BMI-for-age percentiles categories (P3, P5, P10, P25, P50, P75, P85, P90, P95, P91) are obtained 
from the WHO Growth Charts (http://www.who.int/childgrowth/en/); For patients less than 2 years old, 
growth charts are based on recumbent length instead of height, which is not collected in the study. As 
an approximation, height collected in the study is considered as equal to the recumbent length 
5 Updated baseline was the last value collected before the 18th birthday. 
16.1.2 
Liver monitoring guidelines 
Table 16-1 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
For ALT and total bilirubin normal at baseline: 
ALT >3 × ULN 
Total bilirubin > 3 × ULN (in the absence of 
known Gilbert syndrome) 
Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN 
[mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN) 
Any clinical event of jaundice (or equivalent 
term) 
Any adverse event potentially indicative of a liver 
toxicity 
Table 16-2 
Follow up requirements for liver laboratory triggers - ALT, AST, TBL 
  
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
  
  
ALT > 3 x ULN 
Normal 
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
Review 
compliance 
with 
immunomodu
latory therapy 
(Protocol 
Section 6.2) 
• 
Measure 
ALT, AST, 
TBIL,Fraction

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ALT 
TBL 
Liver Symptoms 
Action 
ated BIL, 
INR, and 
GLDH in 48-
72 hours. 
• 
Follow-up for 
symptoms. 
  
ALT > 5 x ULN 
Normal 
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
Review 
compliance 
with 
immunomodu
latory therapy 
(Protocol 
Section 6.2) 
• 
Measure 
ALT, AST, 
TBIL, 
Fractionated 
BIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours. 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring 
(hospitalizatio
n when 
appropriate) 
and workup 
for competing 
etiologiesa 
• 
Exclude 
underlying 
liver disease 
• 
Detailed 
history of 
concomitant 
medications 
(e.g 
acetaminoph
en) 
• 
Consult 
pediatric 
Gastroenterol
ogistb 
  
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
  
ALT > 3 x ULN 
TBL > 2 x ULN 
(or INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
  
ALT > 3 x ULN 
Normal or 
elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
  
a Work-up for competing etiologies may include (but not limited to) viral Hepatitis Panel (IgM anti-HAV; 
HBsAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA), Viral panel 
(CMV, EBV, HSV), autoimmune hepatitis (ANA, ASMA titers) 
bConsider appropriate imaging and liver biopsy in consultation with Pediatric Gastroenterologist 

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Table 16-3 
Follow up requirements for liver laboratory triggers - isolated 
hyperbilirubinemia 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin(isolated) 
  
  
>1.5 – 3.0 ULN 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome) 
• 
Repeat LFT within 48-72 
hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, until resolution 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab)in 
the appropriate CRF 
Investigator discretion 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, pediatric gastroenterologist or 
hepatologist’s consultancy; obtaining more detailed history of symptoms and prior or 
concurrent diseases, history of concomitant drug use, exclusion of underlying liver disease. 
16.1.3 
Performance criteria For World Health Organization (WHO) 
developmental motor milestones 
Gross Motor Milestone 
Performance Criteria 
Sitting without support 
Child sits up straight with the head erect for at 
least 10 seconds. Child does not use arms or 
hands to balance body or support position. 
Hands-and-knees crawling 
Child alternately moves forward or backward on 
hands and knees. The stomach does not touch 
the supporting surface. 
There are continuous and consecutive 
movements, at least 3 in a row. 

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Standing with assistance 
Child stands in upright position on both feet, 
holding onto a stable object (eg, furniture) with 
both hands without leaning on it. 
The body does not touch the stable object, and 
the legs support most of the body weight. 
Child thus stands with assistance for at least 
10 seconds. 
Walking with assistance 
Child is in upright position with the back straight. 
Child makes sideways or forward steps by 
holding onto a stable object (eg, furniture) with 1 
or both hands. 
One leg moves forward while the other supports 
part of the body weight. Child takes at least 5 
steps in this manner. 
Standing alone 
Child stands in upright position on both feet (not 
on the toes) with the back straight. 
The legs support 100% of the child’s weight. 
There is no contact with a person or object. 
Child stands alone for at least 10 seconds. 
Walking alone 
Child takes at least 5 steps independently in 
upright position with the back straight. 
One leg moves forward while the other supports 
most of the body weight. There is no contact 
with a person or object. 
WHO = World Health Organization 
Source: World Health Organization Multicentre Growth Reference Trial Group (WHO 2006)