A Phase IIIb, 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 With Spinal Muscular Atrophy (SMA)
Phase: PHASE3
Conditions: Spinal Muscular Atrophy
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
OAV101 
Clinical Trial Protocol COAV101A12306 / NCT04851873  
A Phase IIIb, 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 with spinal 
muscular atrophy (SMA)  
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-005995-37 
Version number: 
01 (Clean) 
Clinical Trial Phase: 
IIIb 
Release date: 
28-Feb-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 (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................. 9 
Amendment 01 (28-Feb-2022) .......................................................................................... 10 
Amendment Rationale ....................................................................................................... 10 
Changes to Protocol ........................................................................................................... 10 
Protocol summary .............................................................................................................. 17 
1 
Introduction ....................................................................................................................... 20 
1.1 
Background ............................................................................................................ 20 
1.2 
Purpose .................................................................................................................. 22 
2 
Objectives and endpoints ................................................................................................... 22 
2.1 
Primary estimands ................................................................................................. 23 
2.2 
Secondary estimands ............................................................................................. 23 
3 
Study design ...................................................................................................................... 24 
4 
Rationale ............................................................................................................................ 25 
4.1 
Rationale for study design ..................................................................................... 25 
4.1.1 
Rationale for choice of background therapy ......................................... 26 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 26 
4.3 
Rationale for use of prednisolone .......................................................................... 26 
 
 26 
4.5 
Purpose and timing of interim analyses ................................................................. 27 
4.6 
Risks and benefits .................................................................................................. 27 
4.7 
Rationale for public health emergency mitigation procedures .............................. 28 
5 
Study Population ............................................................................................................... 28 
5.1 
Inclusion criteria .................................................................................................... 28 
5.2 
Exclusion criteria ................................................................................................... 28 
6 
Treatment ........................................................................................................................... 30 
6.1 
Study treatment ...................................................................................................... 30 
6.1.1 
Investigational and control drugs .......................................................... 30 
6.1.2 
Additional study treatments .................................................................. 30 
6.1.3 
Supply of study treatment ..................................................................... 30 
6.1.4 
Treatment arms/group ........................................................................... 31 
6.1.5 
Treatment duration ................................................................................ 31 
6.2 
Other treatment(s) .................................................................................................. 31 
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Protocol No. COAV101A12306 
 
6.2.1 
Concomitant therapy ............................................................................. 31 
6.2.2 
Prohibited medication ........................................................................... 32 
6.3 
Participant numbering, treatment assignment, randomization .............................. 32 
6.3.1 
Participant numbering ........................................................................... 32 
6.3.2 
Treatment assignment, randomization .................................................. 33 
6.4 
Treatment blinding ................................................................................................. 33 
6.5 
Dose escalation and dose modification .................................................................. 33 
6.6 
Additional treatment guidance ............................................................................... 33 
6.6.1 
Treatment compliance ........................................................................... 33 
6.6.2 
Recommended treatment of adverse events .......................................... 33 
6.7 
Preparation and dispensation ................................................................................. 33 
6.7.1 
Handling of study treatment and additional treatment .......................... 35 
7 
Informed consent procedures ............................................................................................ 35 
8 
Visit schedule and assessments ......................................................................................... 37 
8.1 
Screening ............................................................................................................... 41 
8.1.1 
Information to be collected on screening failures ................................. 41 
8.2 
Participant demographics/other baseline characteristics ....................................... 42 
8.2.1 
Demographics/medical history.............................................................. 42 
8.2.2 
SMA medical history ............................................................................ 42 
8.2.3 
Physical examination ............................................................................ 42 
8.2.4 
Neurological examination ..................................................................... 42 
 
 42 
8.2.6 
Virus serology ....................................................................................... 43 
8.3 
Efficacy .................................................................................................................. 43 
8.3.1 
Hammersmith Functional Motor Scale-Expanded (HFMSE) ............... 43 
8.3.2 
Revised Upper Limb Module (RULM)................................................. 43 
8.3.3 
Developmental milestone checklist ....................................................... 43 
8.3.4 
Video evidence ...................................................................................... 43 
 
 44 
8.3.6 
Appropriateness of efficacy assessments .............................................. 44 
8.4 
Safety ..................................................................................................................... 44 
8.4.1 
Laboratory evaluations .......................................................................... 44 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 46 
8.4.3 
Vital signs.............................................................................................. 48 
8.4.4 
Other safety evaluations ........................................................................ 48 
8.4.5 
Appropriateness of safety measurements .............................................. 48 
8.5 
Additional assessments .......................................................................................... 48 
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8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 48 
 
 50 
 
 51 
 
 51 
8.5.5 
Pharmacokinetics .................................................................................. 51 
 
 51 
9 
Study discontinuation and completion .............................................................................. 53 
9.1 
Discontinuation and completion ............................................................................ 53 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 53 
9.1.2 
Withdrawal of informed consent ........................................................... 53 
9.1.3 
Lost to follow-up ................................................................................... 54 
9.1.4 
Early study termination by the sponsor ................................................. 54 
9.2 
Study completion and post-study treatment .......................................................... 54 
10 Safety monitoring and reporting ........................................................................................ 55 
10.1 
Definition of adverse events and reporting requirements ...................................... 55 
10.1.1 
Adverse events ...................................................................................... 55 
10.1.2 
Serious adverse events .......................................................................... 56 
10.1.3 
SAE reporting........................................................................................ 57 
10.2 
Additional Safety Monitoring ................................................................................ 58 
10.2.1 
Liver safety monitoring ......................................................................... 58 
10.2.2 
Post-mortem data collection .................................................................. 59 
10.2.3 
Data Monitoring Committee ................................................................. 59 
11 Data Collection and Database management ...................................................................... 59 
11.1 
Data collection ....................................................................................................... 59 
11.2 
Database management and quality control ............................................................ 59 
11.3 
Site monitoring ...................................................................................................... 60 
12 Data analysis and statistical methods ................................................................................ 60 
12.1 
Analysis sets .......................................................................................................... 60 
12.2 
Participant demographics and other baseline characteristics ................................. 61 
12.3 
Treatments ............................................................................................................. 61 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 61 
12.4.1 
Definition of primary endpoint(s) ......................................................... 61 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 61 
12.4.3 
Sensitivity analyses for primary endpoint/estimand ............................. 62 
12.4.4 
Supplementary analysis ......................................................................... 62 
12.4.5 
Supportive analyses ............................................................................... 62 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 62 
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12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 62 
12.5.2 
Safety endpoints .................................................................................... 62 
 
 62 
 
 63 
 
 63 
 
 63 
 
 63 
 
 63 
12.7 
Interim analyses ..................................................................................................... 63 
12.8 
Sample size calculation .......................................................................................... 63 
12.8.1 
Primary endpoint(s) ............................................................................... 63 
13 Ethical considerations and administrative procedures ...................................................... 63 
13.1 
Regulatory and ethical compliance ........................................................................ 63 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 64 
13.3 
Publication of study protocol and results............................................................... 64 
13.4 
Quality Control and Quality Assurance ................................................................. 64 
14 Protocol adherence ............................................................................................................ 64 
14.1 
Protocol amendments ............................................................................................. 65 
15 References ......................................................................................................................... 66 
16 Appendices ........................................................................................................................ 69 
16.1 
Appendix ................................................................................................................ 69 
16.1.1 
Clinically notable laboratory values and vital signs ............................. 69 
16.1.2 
Liver monitoring guidelines .................................................................. 69 
16.1.3 
Performance criteria For Bayley scales infant and toddler 
developmental motor milestones (Bayley-III) ...................................... 71 
16.1.4 
Performance criteria For World Health Organization (WHO) 
developmental motor milestones ........................................................... 71 
List of tables 
Table 1-1 
Spinal Muscular Atrophy Classification ............................................... 20 
Table 2-1 
Objectives and related endpoints .......................................................... 22 
Table 6-1 
Investigational Drug .............................................................................. 30 
Table 6-2 
Pre and post-infusion corticosteroid use ............................................... 31 
Table 8-1 
Assessment Schedule ............................................................................ 38 
Table 8-2 
Developmental Milestone Checklist and Performance Criteria ............ 49 
Table 16-1 
Liver event and laboratory trigger definitions ...................................... 69 
Table 16-2 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 69 
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Table 16-3 
Follow up requirements for liver laboratory triggers - isolated 
hyperbilirubinemia ................................................................................ 70 
List of figures 
Figure 3-1 
Study design .......................................................................................... 25 
 

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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 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BiPAP 
Bi-Level Positive Airway Pressure 
BLQ 
Below the lower limit of quantitation 
BMI 
Body Mass Index 
CB 
Chicken-ȕ-Actin-Hybrid 
cDNA 
Complementary Deoxyribonucleic Acid 
CFR 
Code of Federal Regulations 
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 
Full Analysis Set 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface antigen 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HFMSE 
Hammersmith Functional Motor Scale - Expanded 
HIV 
Human immunodeficiency virus 
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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 
IRT 
Interactive Response Technology 
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 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
 
 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcomes 
PT 
Prothrombin Time 
QMS  
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
RSV 
Respiratory Syncytial Virus 
RULM 
Revised Upper Limb Module 
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) 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
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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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  
Estimand  
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 estimand 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. 
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-
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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
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  
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   
 
Amendment 01 (28-Feb-2022) 
Amendment rationale 
 
The main purpose of this amendment is to correct an error in the schedule of assessment in 
protocol Section 8. By error, virus serology has been added to visits Week 13, 26, 39 and 52 
Week/EOS. Virus serology should be performed at screening to rule out specific viral 
infections before study start as mentioned in protocol Section 8.2.6. There is no reason, from a 
safety perspective, why this assessment would be repeatedly tested in a low-risk pediatric 
population such as children with SMA. As these assessments are performed through serum,  
blood draw volume should be limited, especially in pediatric patients so as to not create an 
anemia risk. Thus, virus serology assessments for the above-mentioned visits are removed. In 
addition to this, a local change, only applicable for Germany has been added.  As requested by 
Paul-Ehrlich Institut, hematology assessments have been added to Week 4 and Week 10 in the 
schedule of assessments in protocol Section 8, to be consistent with platelet monitoring 
requirements in the SmPC. Furthermore, language regarding the collection of additional 
information from screening failures and for the use of remaining serum samples for the 
potential development of companion diagnostic assays has been added. 
 
Changes to the Protocol 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
• Protocol Summary: 
• Key Exclusion Criteria, #13 Hepatic Dysfunction: Wording changed from ‘≥ ULN; 
CTCAE ≥ 1’ to ‘> ULN ’ for clarification.  
• Key Exclusion Criteria, #16 Previous Treatment: Updated formatting for clarification. 
• Data Analysis: Addition of ‘WHO-MGRS & Bayley Scale of Infant and Toddler 
Development’ to clarify the assessment included in Secondary Endpoints. 
• Section 1.1, Background: 
• Removed reference to Foust et al study due to data discrepancies.  

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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
x UpGDWHGWRUHSODFHµOLNHO\¶ZLWKµSRWHQWLDOO\¶LQWKH$&2RI(8UHQHZDOZKHQ
describing acquired immune response to the viral capsid and/or transgene product, as 
there is no evidence that liver findings are caused by immune response.  
x Section 3, Study Design:  
x Added language on remote visits and off-site study procedures offered to certain 
countries and site locations as determined by Novartis based on national and local 
regulations.  
x Section 4.1, Rationale for study design: 
x $GGHGµSODQQHGLPPXQL]DWLRQV¶LQH[FOXVLRQDU\FULWHULD:RUGLQJFKDQJHGIRU
clarification purposes. 
x Section 4.6, Risks and benefits 
x Potential risks associated with OAV101: Wording changed from ‘Sensory 
DEQRUPDOLWLHVVXJJHVWLYHRIJDQJOLRQRSDWK\¶WRµ'RUVDOURRWJDQJOLDWR[LFLW\¶-to align 
to risk description in the Investigator Brochure (version 9). 
x Updated the language of drug-drug interaction to clarify “There might be 
pharmacodynamic drug-drug interactions with other therapeutic agents for the 
treatment of SMA,
 
x Section 5.2, Exclusion criteria 
x #13, Hepatic Dysfunction: Changed “ 8/1´WR³!8/1´WRIL[DPLVWDNH5HPRYHG 
µ&7&$(JUDGHRUJUHDWHU¶WRKHSDWLFG\VIXQFWLRQH[FOXVLRQFULWHULDIRUFODULILFDWLRQ 
x Section 6.2.2, Prohibited medication:  
x 5HPRYHGµLQWUDYHQRXVLPPXQRJOREXOLQV¶IURPOLVWRISURKLELWHGFRQFRPLWDQW
medication. Editorial error, this language is covered by the last bullet in same section 
(IVIG). 
x Removed “PD” from the drug interaction sentence to clarify there might be PD drug-
drug interactions with other therapeutic agents for the treatment of SMA. 
x Section 6.3.1, Participant numbering:  
x Added language to clarify that a new patient number will be assigned if a patient is re-
screened as a result of screen failure. 
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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
x Section 7, Informed consent procedures: 
 
 
 this study includes a 
mandatory DNA sample for SMA confirmation,
   
x Added language on off-site study procedures, including clarification that a separate 
consent would be required to allow for this, in order to align with standardized 
template language on COVID-19 mitigation procedures.  
x Section 8, Visit schedule and assessments: 
x Table 8-1, Assessment schedule: 
x Virus Serology: Removed assessments from Week 13, Week 26, Week 39, and Week 
52/EOS visits, as these were originally added in error. 
x Hematology assessment at Day 2 has been added to align SoA with Section 8.4.1.1  
x Footnote 4 to specify that Day 2 assessment of hematology should be performed 
locally and that platelet counts should be monitored for the first week after infusion, 
has been added, to be consistent with the SmPC. 
x Hematology assessments at Week 4 and Week 10 have been added as per Paul-
Ehrlich Institut request consistent with the summary of Product Characteristics 
(SmPC). This change is only applicable for Germany which is specified in Footnote 
5. 
x Subsequent footnotes after Footnote 5 have been renumbered for consistency. 
 

 
 
x HFSME, RULM: Footnote 9 was added in line with Section 8.5.1.2 to both HFSME 
and RULM assessments, as this assessment is not applicable to all patients. Footnote 
10 clarifies that physical assessments may occur over the span of more than one day 
within the visit window, but must not exceed 4 days.  
 
x Section 8.1.1, Information to be collected on screening failures: 
x Collection of additional information on screening samples has been added for 
following eCRF pages if applicable and available: Diagnosis_SMA , Withdrawal of 
consent,  Assessments, Rescreen, Anti-AAV9 Antibody Testing (Blood), 5q 
SMA Genetic Testing (SMN1 and SMN2), AE page is seriousness criteria is Death. 
x In addition, the request to enter available anti-AAV9 Antibody testing results and 5q 
SMA Genetic Testing (SMN1 and SMN2) into the Novartis database has been added.  
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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
x Added language to specify that participants who fail eligibility criteria for a 
temporary condition may be re-tested/re-assessed within the screening window up to 
two times, and re-screened once.   
x Added clarification that participants who fail upper weight eligibility at Screening 
Visit 2 cannot be re-tested or re-screened. 
x Section 8.4.1, Laboratory evaluations: 
x Added language clarifying that safety samples may be collected remotely (through 
local lab) during a Public Health emergency as declared by local or regional 
authorities in order to provide a potential pandemic mitigation strategy. 
x Added language clarifying that participants may visit local lab for lab assessments if 
they cannot visit primary institution in order to provide a potential pandemic 
mitigation strategy. 
x Section 8.4.1.1, Hematology:  
x Language to specify that platelet counts should be monitored for the first week after 
infusion, has been added, consistent with the SmPC. 
x Section 8.4.1.2, Coagulation panel:  
x Added Coagulation panel as a new section. Renumbered subsequent sections for 
consistency. 
x Added language clarifying that coagulation testing, including prothrombin time and 
INR and activated partial thromboplastin time, will be performed prior to OAV101 
dosing. This was left out of original document by mistake. 
x Section 8.4.2.1, 12-Lead Electrocardiogram:  
x Updated language regarding ECG readout availability, as study sites will only use one 
ECG model. Language is not applicable for site. 
x Section 8.4.3, Vital signs:  
x Wording for screening weight changed from ‘14 days priRUWR'D\¶WRµDW
screening visit 2¶DVDFRUUHFWLRQ 
x Section 8.4.4, Other safety evaluations: 
x Updated language to specify that SNAP data will be read locally but reviewed 
centrally by an external expert to ensure consistent implementation and quality 
control of the neurophysiology data. This language is aligned with the sensory nerve 
conduction studies manual. 
x Added guidance to consult the sensory nerve conduction studies manual for details on 
SNAP assessments and quality checks. 
x Section 8.5.1.1, Hammersmith Functional Motor Scale-Expanded:  
x Additional assessment details added for clarification, including further support 
regarding reasoning behind assessment selection as well as details surrounding 
scoring for how a change over time will be reflected to support the secondary 
objectives. 
x Section 8.5.1.2, Revised Upper Limb Module:  
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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
• Additional assessment details added for clarification, including further support 
regarding reasoning behind assessment selection as well as details surrounding 
scoring for how a change over time will be reflected to support the secondary 
objectives. 
• It has been added that the site clinical evaluator must be trained for clarification 
• DNA Samples (mandatory): Subheading has been clarified as “DNA samples for 
genetic confirmation of SMA (mandatory)” for consistency. Added clarification that 
current planned SMA testing may to detect SMN1 point mutation. 
 
 
• Section 10.1.1, Adverse Events:  
• Wording changed from ‘Sensory abnormalities suggestive of ganglionopathy’ to 
‘Dorsal root ganglia toxicity’ to align with Investigator Brochure (Edition 9). 
• Section 10.1.3, SAE Reporting:  
• Updated SAE reporting language to provide more specific instructions on reporting 
SAEs to Novartis safety immediately and no later than within 24 hours of obtaining 
knowledge of events, or if more stringent, per local regulations for reporting 
timelines. 
• Section 10.2.1, Liver Safety Monitoring:  
• Clarification in line with Section 16.1.2 has been added: “If elevated, repeated liver 
chemistry tests (i.e. ALT, AST, BIL, Fractionated BIL, INR, and GLDH) will be 
performed within 48-72 hours to confirm elevation. If results will not be available 
from the central laboratory, then repeated testing should be performed at a local 
laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with 
this event should have results recorded on the appropriate eCRF page.” 
• Clarification to consider based on Investigator judgement imaging, such as 
ultrasound/Fibroscan, and pathology assessments in case of a liver event has been 
added. 

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x Clarification to consider based on Investigator judgement pediatric gastroenterology 
or hepatology consultation has been added 
x Section 12.5.1, Efficacy and/or Pharmacodynamic endpoint(s):  
x Updated full title of ‘WHO-MGRS & Bayley Scale of Infant and Toddler 
'HYHORSPHQW¶IRUFODULILFDWLRQ 
 
  
 
 
x Section 15, References:  
x Added Flynn et al (2017), as exam and vital sign data can only be interpreted with a 
thorough understanding of normal values. Addition of this reference provides age-
specific norms for pediatric blood pressure. 
x Removed Foust et al (2010), as this study is no longer relevant to the document. 
Additional text related to this study throughout the document was removed. 
x Section 16.1.1, Potentially notable variables and vital signs:  
x :RUGLQJFKDQJHGWRµ3RWHQWLDOO\FOLQLFDOO\¶DVGHILQLWLRQRIFOLQLFDOUHOHYDQFHPLJKW
be subjective. 
x Vital signs:  
x Added Flynn, et al reference, as exam and vital sign data can only be interpreted 
with a thorough understanding of normal values. Addition of this reference 
provides age-specific norms for pediatric blood pressure. 
x Deleted table containing normal range of lab values for vital signs  and refer to 
align with AAP 2017 guidelines (Flynn et al 2017) for simplification. 
x General grammatical, spelling, linking and referencing corrections and updates were made 
throughout the document. 
 
 
 
 
PPD
PPD

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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC and Health Authority approval according to local 
regulations prior to implementation. The changes herein affect the Informed Consent. Sites 
are required to update and submit for approval a revised Informed Consent that takes into 
account the changes described in  this protocol amendment. 
 

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Protocol summary 
Protocol number 
COAV101A12306 
Full Title 
A Phase IIIb, 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 with spinal muscular atrophy (SMA) 
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 IIIb  
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 weighing ≥ 8.5 kg and ≤ 21 kg, over a 12 month period. 
Primary Objective(s)  To assess the safety and tolerability of intravenous (IV) OAV101 over a 12-month 
period in participants with SMA weighing ≥ 8.5 kg and ≤  21 kg  
Secondary 
Objectives 
To determine the efficacy of IV OAV101 at 6 and 12 months post dose in participants 
with SMA weighing ≥ 8.5 kg and ≤ 21 kg as measured by change from baseline in: 
● Achievement of development motor milestones according to the World Health 
Organization-Multicentre Growth Reference Study (WHO-MGRS) and Bayley Scales 
of Infant and Toddler Development-Third Edition (Bayley-III) criteria (See Table 2-1 for 
details) 
● Hammersmith Functional Motor Scale - Expanded (HFMSE) 
● Revised Upper Limb Module (RULM), as appropriate according to participant age. 
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 that 
weigh ≥ 8.5 kg and ≤ 21 kg. An even weight distribution across the desired range will 
be achieved by aiming to enroll approximately 6-10 participants across 3 weight 
brackets (≥ 8.5-13 kg, > 13-17 kg, > 17-21 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 12 months. The study will include a standard screening period that can last 
up to 45 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. 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 clinical and 
safety team together with Data Monitoring Committee (DMC) as described in the 
charter. An interim analysis for safety and efficacy may 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 after the 12 months visits (EOS). 
After study completion eligible participants will be invited to enroll into Long Term 
follow-up study to collect additional safety and efficacy data. 
Study population 
Participants with SMA with bi-allelic mutations in the SMN1 gene weighing ≥ 8.5 kg 
and ≤ 21 kg, at the time of Screening Visit 2. 

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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 survival of motor neuron 2 
(SMN2) gene. 
3. Weight ≥ 8.5 kg and ≤ 21 kg at the time of Screening Visit 2  
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 OAV101 use or previous use of any adeno-associated virus serotype 9  
(AAV9) gene therapy 
2. BMI < 3rd percentile based on WHO Child Growth Standard 
3. Participant with history of aspiration pneumonia or signs of aspiration (e.g., 
coughing or sputtering of food) within 4 weeks prior to screening 
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 (e.g., cyclosporine, tacrolimus, 
methotrexate, rituximab cyclophosphamide, IV immunoglobulin) 
8. Requiring invasive ventilation, tracheostomy or awake 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 
13. Hepatic dysfunction (i.e. aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), bilirubin, gamma-glutamyl transferase (GGT) or glutamate 
dehydrogenas (GLDH), >ULN 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 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. If previously treated with disease modifying therapy, participants are excluded if 
they received 
• 
less than 3 doses of nusinersen (Spinraza®) 
• 
nusinersen (Spinraza®) within 4 months prior to Screening 
• 
risdiplam (Evrysdi®) within 15 days prior to Screening (washout period of at 
least 5 half-lives before Screening) 

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17. Use of other investigational drugs within 5 half-lives of enrollment/initiation of 
study treatment (select as appropriate) within 30 days (e.g., small molecules) / or until 
the expected pharmacodynamic effect has returned to baseline (e.g., biologics), 
whichever is longer; or longer if required by local regulations. 
18. History of hypersensitivity to any of the study treatments or its excipients or to 
drugs of similar chemical classes. 
19. Documented any parental 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 definition obtained 
from the following: 
● WHO Multicentre Growth Reference Study (WHO-MGRS) and Bayley Scale of 
Infant and Toddler Development  (Bayley-III) 
● Hammersmith Functional Motor Scale - Expanded (HFMSE) 
● Revised Upper Limb Module (RULM), as appropriate according to participant age 
Key safety 
assessments 
Safety and tolerability of OAV101 treatment includes evaluation of adverse events 
(AEs), laboratory data, vital signs, and cardiac safety monitoring. 
Data analysis 
The primary endpoints include: 
1. Incidence and severity of treatment emergent AEs and severe adverse events 
(SAEs) 
2. Incidence of important identified and important potential risks 
3. Change from baseline in vital signs, clinical laboratory, and procedure (e.g. ECG, 
echocardiogram) results 
Incidence and severity for treatment emergent AEs and SAEs as well as important 
identified and important potential risks will be summarized by weight bracket and 
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 (e.g. 
ECG, echocardiogram) results will be summarized descriptively by weight bracket and 
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. 
No hypothesis testing will be performed. 
For secondary endpoints, changes from baseline in HFMSE and RULM will be 
summarized descriptively; the number and proportion of patients achieving each 
WHO-MGRS & Bayley Scale of Infant and Toddler Development developmental motor 
milestones will be presented. Summaries will be presented by weight bracket as well 
as overall. 
An interim analysis may be performed once the last participant reaches the 6-
month time point, and will include all available data up until that data cut-off. 
The size of approximately 24-30 participants is considered reasonable to provide 
descriptive safety information across 3 weight brackets ≥ 8.5 kg and ≤ 21 kg. 
A sample size of approximately 24-30 participants will provide 90% probability to 
observe at least one event if the underlying incidence of the event is 9%. 
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, 
“Nonsitters”, the majority of whom have SMA type 1, typically have 2 copies of SMN2 gene 
(approximate 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 
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 gene 
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 

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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 complimentary 
deoxiribonucleic acid (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). 
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 
potentially related to an innate and/or adaptive 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 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 IV 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 
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 

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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 (e.g., 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 IIIb open-label study 
will be conducted in SMA participants that weigh between 8.5 kg and 21 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 with SMA with bi-allelic mutations in the SMN1 gene weighing ≥ 
8.5 kg to ≤ 21 kg, during a 12-month 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) 
● The primary objective of this study is 
to assess the safety and tolerability of 
IV OAV101 over a 12-month period in 
participants with SMA weighing ≥8.5 kg 
to ≤ 21 kg. 
● 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 objective(s) 
Endpoint(s) for secondary objective(s) 
● Determine the efficacy of IV OAV101 
at 6 and 12 months post dose in 
participants with SMA weighing ≥ 8.5 kg 
to ≤ 21 kg, as measured by secondary 
endpoints. 
● Achievement of development motor milestones according to the 
World Health Organization-Multicentre Growth Reference Study 
(WHO-MGRS) and Bayley Scale of Infant and Toddler Development 
- Third Ed (Bayley-III) criteria (Section 16.1) 
 
● holds head erect for at least 3 seconds without support 
 
● sits with slight support 30 seconds 
 
 ● sitting without support 
 
● sits without support 30 seconds 
 
 ● hands-and-knees crawling 
 
● pulls to stand 
 
● standing with assistance 
 
● walking with assistance 
 
● standing alone 
 
● walking alone 
● Change from baseline in Hammersmith Functional Motor Scale - 
Expanded (HFMSE), as appropriate according to participant age. 
● Change from baseline in Revised Upper Limb Module (RULM), as 
appropriate according to participant age. 

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Objective(s) 
Endpoint(s) 
2.1 
Primary estimands 
The clinical question of interest: What is the safety of single administration of IV OAV101 
treatment in SMA participants WKDWZHLJK WR 21 kg? 
The primary estimand is described by the attributes listed below. 
The population of interest is participants with SMA WKDWZHLJKWR kg 
The primary variables include: 
1. Treatment emergent AEs and SAEs 
2. Important identified and important potential risks  
3. Change from baseline in vital signs, cardiac safety assessments, and clinical laboratory 
results 
The treatment of interest is IV OAV101. 
The remaining intercurrent events include receiving prohibited concomitant medications. Loss 
to follow-up due to reasons other than death will not impact 1 RUDERYHSULPDU\YDULDEOHVIRU
primary variable 3it 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. 
2.2 
Secondary estimands 
The secondary clinical question of interest: What is the efficacy of single administration of 
IV OAV101 treatment in SMA participants WKDWZHLJK WR 21 kg? 
The secondary estimand is described by the attributes listed below. 
The population of interest is patients with SMA WKDWZHLJK WR 21 kg. 
The secondary variables include: 
1. Change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE), as 
appropriate according to participant age. 
PPD

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2. Change from baseline in Revised Upper Limb Module (RULM), as appropriate according 
to participant age. 
3. Achievement of developmental motor milestones according to the World Health 
Organization-Multicentre Growth Reference Study (WHO-MGRS) and Bayley Scales of 
Infant and Toddler Development - Third Ed (Bayley-III) criteria. 
• holds head erect for at least 3 seconds without support 
• sits with slight support 30 seconds 
• sitting without support 
• sits without support 30 seconds 
• hands-and-knees crawling 
• pulls to stand 
• standing with assistance 
• walking with assistance 
• standing alone 
• walking alone 
The treatment of interest is IV OAV101. 
The remaining intercurrent events include receiving concomitant medications. Loss to 
follow-up due to reasons other than death will be handled by a hypothetical strategy for the 
change from baseline variables and by a composite strategy for milestones. 
The summary measures include mean for changes from baseline in HFMSE and RULM as well 
as incidence for developmental motor milestone achievement. 
3 
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 that weigh ≥ 8.5 
to ≤ 21 kg. Approximately 24-30 participants may be enrolled and distributed between 6 and 
10 participants per cohort in each of the three brackets in order to achieve an approximately 
even weight distribution (≥ 8.5-13kg, > 13-17kg, > 17‑21kg). 
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 12 months. The study will include a screening period of up 
to 45 days 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 
complete 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 and will undergo in-patient safety monitoring over the next 48 hours. Participants may 
be discharged 48 hours after the infusion, based on Investigator judgment. Section 6.7 outlines 
details regarding study drug preparation and administration. 

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Safety monitoring will be performed on an ongoing basis per protocol requirement and will be 
evaluated by the clinical and safety team as well as DMC. An interim analysis for safety and 
efficacy may 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 after 
12 months visits (EOS). 
After study completion eligible participants will be invited to enroll into Long Term follow-up 
study to collect additional safety and efficacy data. 
Figure 3-1 
Study design 
Remote procedures 
At the Investigator's direction and based on benefit-risk considerations of the participant's 
clinical condition,  qualifying  participants  may  be  offered  the  option  to  have  certain clinical 
trial procedures according to Table 8-1 Assessment schedule performed at a remote location.   
Procedures  will  be  performed  remotely  under  the  oversight  of  the  Investigator,  who  
retains accountability for the oversight and all efficacy and safety decisions with delegation of 
tasks to an off-site healthcare professional. 
The remote procedures will be offered in certain countries and sites as determined by Novartis 
based on national and local regulations. 
The off-site healthcare professionals update/add role as applicable in line with glossary will be 
provided by a third-party vendor sourced by Novartis. Where a site wishes to use off-site 
healthcare professionals update/add roles as applicable in line with glossary that are not 
provided by Novartis this must be agreed with Novartis before use. 
In addition to procedures performed by the off-site healthcare professional, the on-site staff will 
perform certain procedures remotely using tele-visits. 
4 
Rationale 
4.1 
Rationale for study design 
This Phase IIIb 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 
VDIHW\RI2$9LQFKLOGUHQNJDQGNJZLWKV\PSWRPDWLF60$ The open-label 
design is expected to facilitate enrollment 
 
  
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. The second screening visit will be used for weight eligibility 
PPD

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and dose calculation. The study will administer one-time OAV101 and monitor participants in 
an inpatient setting for a minimum of 48 hours after administration to carefully monitor the 
emergence of acute AEs. Participants will be followed up to 12 months, which is considered 
adequate to characterize safety given clinical experience (Section 4.6) and sufficient to evaluate 
efficacy. 
,QFOXVLRQRIFKLOGUHQNJDQGNJDOORZVIRUFDUHIXODVVHVVPHQWRIVDIHW\DQGFOLQLFDO
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 AAV9 immunity and thus 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 
planned before or after administration of OAV101. Please refer to Section 6.2 for more 
information. 
4.1.1 
Rationale for choice of background therapy 
7KH VWXG\ DOORZV IRU VWDQGDUG RI FDUH QRQဩGLVHDVH PRGLI\LQJ 60$ WKHUDS\ LQFOXGLQJ
respiratory and nutritional support, physical 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 and will undergo in-patient 
safety monitoring over the next 48 hours. Participants will receive a dose of 1.1e14 vg/kg. The 
total volume is determined by participant body weight. 
4.3 
Rationale for use of prednisolone 
An immune response to the AAV9 capsid may occur after administration of OAV101. This can 
lead to elevations in liver transaminases. 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 
PPD

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4.5 
Purpose and timing of interim analyses 
An interim analysis may be performed once the last participant reaches the 6-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. 
4.6 
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. 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 
• Dorsal root ganglia toxicity 
• Thrombotic microangiopathy 
Further details are outlined in the Investigator Brochure. 
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). 
The chronic use of corticosteroids may be associated with hypothalamic-pituitary-adrenal axis 
suppression, Cushing's syndrome and hyperglycemia which can be mitigated with adequate 

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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. Pharmacokinetic drug-drug interactions are 
not expected with OAV101. There might be pharmacodynamic drug-drug interactions with 
other therapeutic agents for the treatment of SMA, e.g., an additive effect on SMN protein levels 
and associated pharmacodynamic responses. 
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 survival 
motor neuron 2 (SMN2) gene copies or a clinical diagnosis of SMA.  
4.7 
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 24-30 participants with SMA with bi-allelic mutations in the SMN1 gene 
weighing ≥ 8.5 kg and ≤ 21 kg, at the time of Screening Visit 2, will be enrolled. 
5.1 
Inclusion criteria 
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. Weight ≥ 8.5 kg and ≤ 21 kg at the time of Screening Visit 2  
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 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 

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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 (e.g., coughing or 
sputtering of food) within 4 weeks prior to screening 
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 (e.g., cyclosporine, tacrolimus, methotrexate, rituximab cyclophosphamide, IV 
immunoglobulin) 
8. Requiring invasive ventilation, tracheostomy or awake 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 
13. Hepatic dysfunction (i.e. AST, ALT, bilirubin, GGT or GLDH, > ULN) 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 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. If previously treated with disease modifying therapy, participants are excluded if they 
received 
• less than 3 doses of nusinersen (Spinraza®) 
• nusinersen (Spinraza®) within 4 months prior to Screening 
• risdiplam (Evrysdi®) within 15 days prior to Screening (washout period of at least 5 
half-lives before Screening) 
17. Use of other investigational drugs within 5 half-lives of enrollment/initiation of study 
treatment (select as appropriate) within 30 days (e.g., small molecules) / or until the 
expected pharmacodynamic effect has returned to baseline (e.g., biologics), whichever is 
longer; or longer if required by local regulations. 
18. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes. 

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19. Documented any parental 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. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug is included in this trial. 
6.1.3 
Supply of study treatment 
US and non-EU countries where in-country depot is not required: IMP is manufactured and 
supplied by the Sponsor. The vials are packaged in a clinical carton (1 vial per carton) and 
shipped out of the Sponsor facility directly to 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. 
EU countries: IMP is manufactured by the Sponsor and supplied to EU Contract Manufacturing 
Organization. The vials are packaged in a clinical carton (1 vial per carton) and shipped out of 
the EU CMO facility 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.  
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. 

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6.1.4 
Treatment arms/group 
Single treatment arm OAV101 IV. 
6.1.5 
Treatment duration 
OAV101 will be administered as a one-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, elevations of 
Troponin I, or decreased platelet counts. Where feasible, the participant’s vaccination schedule 
should be adjusted to accommodate concomitant corticosteroid administration prior to and 
following OAV101, specifically 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  
Continue prednisolone 1 mg/kg/day until liver function tests return to baseline. For participants 
that require steroid dosing longer than 60 days total (including the weaning period) consider 
hepatology and infectious diseases specialty evaluation to address risk of opportunistic 
infections and 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. 

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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) 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 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 drug 
interactions expected. 
The Investigator should instruct the participant/caregiver to notify the study site about any new 
treatments 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. 
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, as a result of a screen failure. 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. 
The Investigator or designated staff will contact the IRT and provide the requested identifying 
information to register the participant. 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. 

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If the participant fails to be randomized or start treatment for any reason, the reason will be 
entered into the appropriate eCRF page and IRT should be notified as soon as possible.  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 
IRT will be used for this trial. This is an open-label trial and randomization numbers will not 
be used. At screening visit 1, the site will log into IRT and input the participant number from 
RAVE and participant’s weight. The site will log into IRT at Screening Visit 2 and enter 
participant’s weight. The depot will be notified of the participant's weight and quantity of kits 
will be selected to ship to site based on the participant's weight. Once kits are selected, IRT will 
be updated with medication numbers assigned for shipment. Once the site receives drug they 
will need to confirm shipment via IRT. Please see Pharmacy Manual for details regarding drug 
shipment confirmation. The Investigator or his/her delegate will contact the IRT after 
confirming that the participant fulfills all the inclusion/exclusion criteria. 
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 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 dose is not fully completed the site 
personnel will need to reflect total volume administered as well as the date and time of 
administration in the CRF page.  
6.6.2 
Recommended treatment of adverse events 
The Investigator will use his/her medical judgement in accordance with standard of care to treat 
adverse events. Medication and/or intervention used to medically manage AEs must be recorded 
on the appropriate CRF. 
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, 

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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 adverse 
events, 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 per 
Pharmacy manual and will be received ready for infusion at the bedside. 
OAV101 will arrive as outlined in the Pharmacy Manual. The total vector genome dose will be 
calculated based on the participant’s body weight; 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. The vessel will be delivered in accordance with the Pharmacy 
Manual. 
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 (e.g., 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 Pharmacy 
Manual. 
Following administration of 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. Participants 
should be maintained in an appropriate inpatient setting for 48 hours after the start of gene 
replacement therapy. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). 

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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 (e.g., pharmacists) in accordance with local regulations, 
policies, and procedures. Control of storage conditions, especially control of temperature (e.g., 
refrigerated/freezer storage) and information on in-use stability and instructions for handling 
prepared OAV101 should be managed in accordance with the Pharmacy Manual. 
OAV101 will be supplied to each site for each individual study subject after confirmation of 
weight at Screening Visit 2. Instructions for preparation of dose are detailed in the Pharmacy 
Manual. 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 (e.g., deficiency in condition, 
appearance, pertaining to documentation, labeling, expiration date, etc.) should be promptly 
reported to the Sponsor in accordance with procedures outlined in the Pharmacy Manual. 
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.  
Informed consent (video), and assent (7-11 years), if applicable, must be obtained before 
conducting any study-specific procedures (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent must be documented in the participant source 
documents. 
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 adverse events associated with study drug can be found in the IB. 
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 

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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: 
1. Global Model Parent Legal Guardian ICF 
x A subsection that requires a separate signature for the ‘Optional Consent for 
$GGLWLRQDO5HVHDUFK¶WRDOORZIXWXUHUHsearch on coded data collected during this 
study 
x $VXEVHFWLRQWKDWUHTXLUHVDVHSDUDWHVLJQDWXUHIRUWKHµ2SWLRQDO&RQVHQWIRU$XWRSV\¶
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 
x 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) 
x A subsectLRQIRUµ2SWLRQDO9LGHR5HFRUGLQJ¶WRFRQILUP'HYHORSPHQWDO0RWRU
Milestones 
2. Global Model Child Assent Form  
 
 
 
 
 
 

 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.  
The study includes the option for the participant to have certain study procedures performed 
offsite by an off-site healthcare professional instead of at the study site, for which a separate 
signature is required if the participant agrees. It is required as part of this protocol that the 
Investigator presents this option to the participant, as permitted by national and local governing 
regulations. The process for obtaining consent should be exactly the same as described above 
for the main informed consent. 
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 (e.g. telephone, videoconference) if 
allowable by a local Health Authority. 
PPD
PPD
PPD

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Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. 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 CRF. 
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 (e.g., 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 
Follow up Visits 
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 
13 
Week 
26 
Week 
39 
Week 
52 / 
EOS1 
Days 
-45 
-0 +5 
-15 
±2 
-1 
1 
2 to 2 3 to 3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±5 
57 
±5 
71 
±5 
92 
±14 
183 
±14 
274 
±14 
365 
±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 
X 
Vital Signs 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination2 
S 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Neurological 
Examination 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMA Medical 
History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology3 
X 
  
X 
  
 X4 
  
X 
X 
X 
 X5 
X 
X 
 X5 
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 
  
X 
  
  
  
  
X 
  
  
X 
  
X 
  
X 
X 
  
X 
Virus Serology6 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
Period 
Screening 
Baseline 
Treatment 
Follow up Visits 
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 
13 
Week 
26 
Week 
39 
Week 
52 / 
EOS1 
Days 
-45 
-0 +5 
-15 
±2 
-1 
1 
2 to 2 3 to 3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±5 
57 
±5 
71 
±5 
92 
±14 
183 
±14 
274 
±14 
365 
±21 
DNA 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urinalysis 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
Electrocardiogram 
(ECG) 
X 
  
X 
  
  
  
X 
  
  
X 
  
X 
  
X 
X 
  
X 
Echocardiogram 
X 
  
  
  
  
  
X 
  
  
X 
  
X 
  
X 
X 
  
X 
Prophylactic 
Prednisolone 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
OAV101 Infusion 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT contact 
X 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
HFMSE9,10 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
X 
RULM9,10 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
X 
Bayley Scales 
(Bayley-III) and 
WHO-MGRS 
Developmental 
Milestone 
Checklist10  
  
X 
  
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
X 
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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
Period 
Screening 
Baseline 
Treatment 
Follow up Visits 
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 
13 
Week 
26 
Week 
39 
Week 
52 / 
EOS1 
Days 
-45 
-0 +5 
-15 
±2 
-1 
1 
2 to 2 3 to 3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±5 
57 
±5 
71 
±5 
92 
±14 
183 
±14 
274 
±14 
365 
±21 
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 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 If discontinuation, all efforts should be made to complete the EOS assessments prior to study discontinuation. 
2 S = assessment to be recorded in source documentation only 
3 complete white blood count with differential 
4 Hematology assessment at Day 2 should be performed locally before discharge of the patients; further, platelets should be closely monitored following the first week 
after infusion. 
5 Hematology assessments at Week 4 and Week 10 are only applicable for Germany 
6 HIV antibody, Hepatitis C antibody, Hepatitis B surface antigen (HBsAG) 
 
 
 
 
 
9 HFMSE and RULM will not be administered until patient reaches 24 months of age 
10 physical assessments may occur over the span of more than 1 day within the visit window, but must not exceed 4 days 
 
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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
8.1 
Screening 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and 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 following eCRF pages must also be completed for screen failure 
participants if applicable and available: 
• Informed consent 
• Demography 
• Inclusion/Exclusion Criteria 
• Diagnosis_SMA 
• Assessments 
• Withdrawal of consent  
• Rescreen 
• Anti-AAV9 Antibody Testing (Blood) 
• 5q SMA Genetic Testing (SMN1 and SMN2)  
• AE page if seriousness criteria is Death 
 
In addition, anti-AAV9 Antibody testing results and 5q SMA Genetic Testing (SMN1 and 
SMN2) will be entered into the appropriate Novartis database. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening phase (see SAE 
section for reporting details, Section 10.1.2) or protocol-related adverse event. 
The Screening assessments will be performed from the time of the ICF signature. 
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. 
For participants who fail eligibility during the screening process for a temporary condition (e.g. 
viral illness, concomitant medication, or laboratory values, etc.) respective eligibility 
assessments can be repeated within the screening window up to two times; however, each case 
must be discussed and agreed with the Sponsor. Repeated assessments must be documented and 
eCRFs need to be completed for any additional visit. 
Participants who fail eligibility for a temporary condition exceeding the screening window may 
be re-screened once. Re-screened participants will need to be re-consented and a new 
Participant number will be assigned. Re-screening tests should be repeated as per 
inclusion/exclusion requirements and re-screening should be documented in medical records. 
Participants who fail upper weight eligibility at Screening Visit 2 cannot be re-tested or 
re-screened. 

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Protocol No. COAV101A12306 
 
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 SMN2 gene copies (if 
available), will be recorded in the eCRF.  
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. 
Further clinical evaluation of sensory abnormalities will include nerve conduction studies per 
local standard of care including but not limited to sural sensory nerve action potential (SNAP). 
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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
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, 
adminisWUDWLRQ RI WKH $$9 YHFWRU PD\ UHSUHVHQW DQ XQUHDVRQDEOH ULVN WKHUHIRUH QHJDWLYH
serology testing must be confirmed at screening, prior to treatment. These samples will be 
collected in accordance with the Table 8-1 and shipped in accordance with the laboratory 
manual provided by the central laboratory. 
8.3 
Efficacy 
The efficacy assessments described below have been selected in order to evaluate the effect of 
OAV101 on SMA.  
8.3.1 
Hammersmith Functional Motor Scale-Expanded (HFMSE) 
See Section 8.5.1.1 for details. 
8.3.2 
Revised Upper Limb Module (RULM) 
See Section 8.5.1.2 for details. 
8.3.3 
Developmental milestone checklist 
See Section 8.5.1.3 for details. 
8.3.4 
Video evidence 
Video evidence is optional. Parent(s)/legal guardian(s) may provide home videos at any time 
during the study that demonstrate achievement or maintenance of Developmental Motor 
Milestone in an effort to confirm compelling, demonstrable, documented evidence of efficacy. 
Completion of the Developmental Milestone Checklist for home videos uploaded is required to 
document achievement of developmental motor milestones between visits. The Developmental 
Milestone Checklist will contain the date of home video recording. 
Novartis will provide a secure process to upload, transfer and store videos through a contracted 
third-party vendor that will compile as per the sponsor requirements. A secure, encrypted 
transfer and storage solution will be provided to properly protect the identities of the patient 
and caregivers on the videos, which may be shared with regulatory agencies, the medical 
community, and/or in appropriate venues to discuss the results of this clinical trial. Any videos 
received will be treated as confidential data and will be either the sole property of Novartis or 
will be permanently licensed to Novartis to use and disclose. 
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Protocol No. COAV101A12306 
 
8.3.6 
Appropriateness of efficacy assessments 
Efficacy assessments for developmental milestones and motor assessments are 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. 
If participants cannot visit the site for safety lab assessments through central labs, local lab 
collection may be used and results will be entered in the eCRF. 
8.4.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to Investigators in the laboratory manual. 
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Clinical Trial Protocol (Clean Version No. 01) 
 
Protocol No. COAV101A12306 
 
Safety samples that can be collected remotely will be collected and analyzed in line with the 
study laboratory manual. Where samples are collected and analyzed at a local laboratory instead 
of the central laboratory, Novartis will ensure the results reported are equivalent to central 
laboratory collection and analysis.  
If participants cannot visit the site for safety lab assessments conducted through central labs, 
local lab collection may be used 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.  
If participants cannot visit the site for protocol specified safety lab assessments, an alternative 
lab (local) collection site may be used. 
8.4.1.1 
Hematology 
Hematology analysis will include a complete blood count with differential and platelet count. 
Samples will be collected and shipped in accordance with the laboratory manual provided by 
the central 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) 
To monitor platelet counts, 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. Investigators will receive 
hematology results from all other study visits from the central laboratory. Further, platelet 
counts should be closely monitored in the week following infusion and on a regular basis 
afterwards. 
In the event that clinically significant and/or moderate or severe thrombocytopenia and anemia 
are noted, further evaluation to diagnose Thrombotic Microangiopathy (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 
Coagulation panel 
Coagulation testing including prothrombin time (PT) and International Normalized Ratio 
(INR), and activated partial thromboplastin time (aPTT) will be performed prior to OAV101 
dosing (Table 8-1). 

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8.4.1.3 
Blood chemistry 
Samples will be collected and shipped in accordance with the laboratory manual provided by 
the central 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. 
Investigators will receive chemistry results from all trial visits from the central laboratory. 
If liver aminotransferase elevations occur, the process outlined in Section 10.2.1 should be 
followed. 
8.4.1.4 
Urinalysis 
Urine samples will be collected in accordance with the laboratory manual provided by the 
central laboratory at study visits in accord with the Schedule of Assessments (Table 8-1).  
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. 

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In the case of a series of assessments, ECG should be 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. 
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 number, date and 
time, and filed in the study site source documents. Investigator should document clinical 
evaluation in source. 
The ECG will be interpreted locally by a pediatric cardiologist or designee for immediate safety 
evaluation. The ECG tracings or ECG machine data will also be collected for centralized 
review. In the event that a clinically significant ECG abnormality is identified at the site (e.g., 
severe arrhythmia, conduction abnormality of QTcF > 500 ms), a copy of the assessment is sent 
to the central ECG laboratory for expedited review and the ECG is repeated to confirm the 
diagnosis. 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. All ECGs, including unscheduled safety ECGs 
with clinically relevant findings collected during the study need to be transmitted to the central 
ECG laboratory for review. 
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 ECHOs will also be collected for centralized review by a 
cardiologist. The Novartis physician or designee will be notified of any safety concerns from 
the centralized review. 

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Clinical Trial Protocol (Clean Version No. 01) 
 
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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 monitored during and after the infusion. 
Height and weight will be measured (supine or standing) at each study visit (Table 8-1). 
Screening weight shall be obtained at screening visit 2. On Day 1, weight and height will be 
measured pre-dose. 
8.4.4 
Other safety evaluations 
Sural sensory nerve action potential (sural SNAP) is a conduction study commonly used to 
evaluate suspected peripheral neuropathies and will be performed in case sensory abnormalities, 
to complement neurologic examination (Section 8.2.4). Results will be read locally and must 
be captured in eCRF and as adverse event when criteria met per Section 8.2.4. Central review 
to ensure consistent implementation and quality control of the neurophysiology data will be 
performed by an external expert. For details on SNAP assessments and quality checks, the 
sensory nerve conduction studies manual should be consulted. 
8.4.5 
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 (e.g., neuromuscular module and multi-dimensional fatigue scale) may be collected 
remotely (e.g., web portal, telephone interviews) depending on local regulations, technical 
capabilities, and following any applicable training in the required process. 
8.5.1.1 
Hammersmith Functional Motor Scale-Expanded (HFMSE) 
HFMSE was devised for use in children with SMA Type 2 and Type 3 to give objective 
information on motor ability and clinical progression (Glanzman et al 2011). 
The HFMSE (2019 edition) assessment will be administered by the qualified site clinical 
evaluator (e.g., licensed physical or occupational therapist, or national equivalent) in 
accordance with the Schedule of Assessments (Table 8-1) for all participants ≥ 24 months of 
age. Participants < 24 months of age at time of visit will begin having HFMSE assessments as 
such time that 24 months of age is reached. The HFMSE is a short SMA-specific 33-item 
questionnaire that is easily administered by trained clinical evaluators. It requires minimal 
equipment, and is designed to factor in patient fatigue. Each motor skill item is scored on a 
3-point Likert scale from 0 (no response) to 2 (full response), with a total score range of 0 to 
66. A higher score indicates a higher level of ability. 

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8.5.1.2 
Revised Upper Limb Module (RULM) 
RULM is a validated, SMA specific assessment that measures motor performance in the upper 
limbs from childhood through adulthood in ambulatory and non-ambulatory individuals with 
SMA, and weaker individuals who have a floor effect or very low score on the Hammersmith 
Functional Motor Scale (HFMS) (Mazzone et al 2017). The RULM has a total of 19 scorable 
items:18 items scored on a 0 (unable) to 2 (full achievement) scale, and one item that is scored 
from 0 (unable) to 1 (able).  These item scores are summed to give a total score ranging from 
0 to 37 points with lower scores reflecting poorer ability. The test is performed unilaterally 
using the limb preferred by the participant. The RULM will be administered by a site trained 
clinical evaluator (eg, licensed physical or occupational therapist, or national equivalent) in 
accordance with the Schedule of Assessments for all participants ≥ 24 months of age. 
Participants < 24 months of age at time of visit will begin having RULM assessments as such 
time that 24 months of age is reached. 
For participants between 24-30 months of age the following two test items will not be 
administered and a Can Not Test (CNT) will be entered due to developmental limitations: (C)- 
tracing a path and (H)- tearing a paper. These items will be added into the assessment at ≥30 
months of age. 
8.5.1.3 
Developmental milestone checklist 
Developmental motor milestones will be assessed using relevant definition obtained from the 
World Health Organization Multicentre Growth Reference Study (WHO-MGRS) and Bayley 
Scales of Infant and Toddler Development - Third Ed (Bayley-III). 
The Developmental Milestone Checklist will be completed by the qualified and trained site 
clinical evaluator (e.g., licensed physical or occupational therapist, or national equivalent) for 
all participants according to the Schedule of Assessments (Table 8-1). 
Table 8-2 
Developmental Milestone Checklist and Performance Criteria 
Current Status Achieved 
Developmental Motor Milestones: Bayley Scales of Infant and Toddler 
Development® Third edition (Bayley 2006) / WHO MGRS (2006) 
YES/NO 
Holds head erect for at least 3 seconds without support (Bayley GM #4) 
YES/NO 
Sits with slight support: 30 seconds (Bayley GM #19) ) 
YES/NO 
Sitting without support (WHO MGRS) 
YES/NO 
Sits without support: 30 seconds (Bayley GM #26) 
YES/NO 
Hands-and-knees crawling (WHO MGRS) 
YES/NO 
Pulls to stand (Bayley GM #35) 
YES/NO 
Standing with assistance (WHO MGRS) 
YES/NO 
Walking with assistance (WHO MGRS) 
YES/NO 
Standing alone (WHO MGRS) 
YES/NO 
Walking alone (WHO MGRS) 
Developmental Milestone 
Performance Criteria 
Head control (Bayley, Gross 
Motor Item #4) 
Child holds head erect for at least 3 seconds without support. 
Sits with support (Bayley, 
Gross Motor Item #19) 
Child sits with slight support for at least 30 seconds. Child may lose 
balance once or twice but is able to self-right (with your slight support). 
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. 

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Sits without support: 30 
seconds (Bayley, Gross Motor 
Item #26) 
Child sits alone without support for at least 30 seconds. Child may lose 
balance once or twice but is able to self-right (does not fall over). 
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. 
Pulls to Stand (Bayley, Gross 
Motor Item #35) 
Child raises self to standing position using chair or other convenient object 
for support. 
Standing with assistance 
(WHO MGRS) 
Child stands in upright position on both feet, holding onto a stable object 
(e.g., 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 
(e.g., 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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8.5.5 
Pharmacokinetics 
Not applicable. 
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DNA samples for genetic confirmation of SMA (mandatory) 
The study includes a mandatory genetic research component. 
Although participants are selected based on diagnostic testing results, it is possible that the 
diagnostic testing results needs to be confirmed during study process. The DNA sample 
collected may be used for genetic confirmation of SMA diagnosis and also be used for exon 7 
modifier testing (current planned SMA genetic testing may not be able to detect SMN1 point 
mutation).  
The focus of the analysis is open and not pre-defined. 
 
Laboratory manuals will be provided with detailed information on sample collection, handling, 
and shipment.  
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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 Week 52/EOS assessments indicated in the Assessment Schedule (Table 8-1). If 
they fail to return for these assessments for unknown reasons, every effort (e.g., 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: 
x New / concomitant treatments/medications 
x AEs, including SAEs 
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: 
x Does not want to participate in the study anymore, 
and 
x Does not want any further visits or assessments 
and 
x Does not want any further study related contacts 
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In this situation, the Investigator should make a reasonable effort (e.g., 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. 
Study treatment must be discontinued and no further assessments 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. 
9.1.3 
Further details on withdrawal of consent or the exercise of 
participants' data privacy rights are included in the corresponding 
informed consent form.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, e.g. 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 
• 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. 

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10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. 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 adverse events. 
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 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 adverse events 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. 

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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 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events 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. 
On the basis of 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 
• Dorsal root ganglia toxicity 
• Thrombotic microangiopathy 
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 
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 

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• 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, e.g. 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 safety immediately, without undue 
delay, but under no circumstances later than within 24 hours obtaining knowledge of events 
(Note: If more stringent, local regulations regarding reporting timelines prevail). Detailed 
instructions regarding the submission process and requirements are to be found in the 
Investigator folder provided to each site. Information about all SAEs is collected and recorded 
on the electronic SAE form with paper backup; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. 
SAEs occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis. 
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 
immediately without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). 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 Investigator’s Brochure 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 

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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 EU Clinical Trial 
Regulation 536/2014 (if submitted under EU CTR or) Guidance 2011/C 172/01 or as per 
national regulatory requirements in participating countries. Any SAEs experienced after the 30 
day period after the last study visit should only be reported to Novartis Safety if the investigator 
suspects a causal relationship to study treatment, unless otherwise specified by local 
law/regulations. 
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 elevated, repeated liver chemistry tests (i.e. ALT, AST, TBIL, Fractionated BIL, INR, and 
GLDH) will be performed within 48-72 hours to confirm elevation. If results will not be 
available from the central laboratory, then repeated testing should be performed at a local 
laboratory to monitor the safety of the participant. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should have 
results recorded on the appropriate eCRF page. If liver function tests are elevated, follow-up 
requirements include (refer to Table 16-2 and Table 16-3): 
• Hospitalization of the participant, if appropriate 
• Causality assessment of the liver event 
• Thorough investigation and follow-up of the liver event, which may include, based on 
Investigator’s discretion: serology tests, laboratory tests for other causes of hepatitis, 
including viral hepatitis, imaging such as ultrasound/Fibroscan, and pathology 
assessments. 
• Obtaining a more detailed history of signs and symptoms and prior or concurrent diseases. 
• Obtaining a history of concomitant drug use, including nonprescription medications (e.g. 
acetaminophen); and herbal and dietary supplement preparations 
• Exclusion of underlying liver disease 
• Considering pediatric gastroenterology or hepatology consultation 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.  

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10.2.2 
Post-mortem data collection 
In the event of a fatal outcome, and if parental consent is obtained, 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. Autopsy 
should be performed per local standard of care and local regulations, and with particular 
attention to CNS (e.g., DRG), liver, and cardiac examination. 
Declining 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. 

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Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the ATC classification system. Medical 
history/current medical conditions and adverse events will be coded using the MedDRA 
terminology. 
Dates of screenings, screen failures, treatment and study completion, as well as drug 
confirmation will be tracked using an IRT. The system will be supplied by a vendor, who will 
also 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. electronic CRFs 
(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 
12.1 
Analysis sets 
The FAS and Safety Set both comprises all participants that received any study drug.  

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12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by weight bracket (≥ 8.5-13 kg, > 13-17 kg, > 17-21 kg) and overall 
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.  
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term by weight bracket and overall. 
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 duration of administration in minutes will be summarized by means of descriptive statistics 
using the safety set. 
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 of the primary endpoint(s)/estimand(s) 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoints include: 
1. Incidence and severity of treatment emergent AEs and SAEs 
2. Incidence of important identified and important potential risks  
3. Change from baseline in vital signs, clinical laboratory, and procedure (e.g. ECG, 
echocardiogram) results 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Incidence and severity for treatment emergent AEs and SAEs as well as important identified 
and important potential risks will be summarized by weight bracket and overall in the safety 
set. The number and proportion of participants reporting a treatment emergent AE or SAE 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 results will be summarized 
descriptively by weight bracket and 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. 
No hypothesis testing will be performed. 

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12.4.3 
Sensitivity analyses for primary endpoint/estimand 
Given the descriptive nature of the summary of primary safety endpoints, no sensitivity analysis 
is planned. 
12.4.4 
Supplementary analysis 
No supplementary analysis is planned. 
12.4.5 
Supportive analyses 
No supportive analysis is planned as the analysis by weight bracket is already included in the 
primary analysis. 
12.5 
Analysis of secondary endpoints/estimands 
The secondary endpoints include: 
1. Changes from baseline in HFMSE and RULM 
2. Percent of participants achieving development motor milestones according to the 
WHO-Multicentre Growth Reference Study (WHO-MGRS) and Bayley Scale of Infant and 
Toddler Development - Third Ed (Bayley-III) criteria 
These endpoints will be presented by weight bracket and overall. 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
For secondary endpoints, changes from baseline in HFMSE and RULM will be summarized 
GHVFULSWLYHO\ in addition, mixed models with repeated measurement will be fitted that 
include the change from baseline as the dependent variable, and fixed effects of weight bracket, 
visit, and their interaction. The least squares (LS) means and 95% 2-sided confidence intervals 
will be reported for each scheduled visit. The number and proportion of participants achieving 
each WHO-MGRS & Bayley Scale of Infant and Toddler Development developmental motor 
milestone will be presented. Summaries will be presented by weight bracket as well as overall. 
12.5.2 
Safety endpoints 
Summary of adverse events, vital signs, and clinical laboratory results are described in 
Section 12.4. ECG and echocardiogram results will be summarized descriptively by weight 
bracket and overall. 
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12.7 
Interim analyses 
An interim analysis may be performed once the last participant reaches the 6-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. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The size of approximately 24 participants is considered reasonable to provide descriptive safety 
LQIRUPDWLRQDFURVVZHLJKWEUDFNHWVNJDQGNJ$ sample size of approximately 
24-30 participants will provide 90% probability to observe at least one event if the underlying 
incidence of the event is 9%. 
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 
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(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 (e.g., advertisements) and any other written information to 
be provided to participants. Prior to study start, the Investigator is required to sign a protocol 
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 (e.g., 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, 

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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. 
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 
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Arnold WD, Kassar D, Kissel JT (2015) Spinal muscular atrophy: diagnosis and management 
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Awano T, Kim JK, Monani UR (2014) Spinal muscular atrophy: journeying from bench to 
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Bayley N (2006) The Bayley-III is a revision of the Bayley Scales of Infant Development - 
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Hirschmann J, Sedlmayr B, Zierk J, et al (2017) Evaluation of an Interactive Visualization 
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care. Neuromuscul Disord p. 103-15. 
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Genomics Hum Genet p. 231-61. 

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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 Bayley scales infant and toddler development (version III) 
developmental milestones 
Appendix 4. Performance criteria for World Health Organization (WHO) developmental 
milestones 
16.1.1 
Clinically notable laboratory values and vital signs 
Potentially 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 (Flynn et al 2017, Fleming et al 2011). 
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: 
  

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ALT 
TBL 
Liver Symptoms 
Action 
ALT > 3 x ULN 
Normal 
For participants with Gilbert’s 
syndrome: No change in 
baseline TBL 
None 
● Review compliance with 
immunomodulatory therapy 
(Protocol Section 6.2) 
● Measure ALT, AST, 
TBIL,Fractionated 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 
immunomodulatory therapy 
(ProtocolSection 6.2) 
● Measure ALT, AST, TBIL, 
Fractionated BIL, INR, albumin, CK, 
and GLDH in 48-72 hours. 
● Follow-up for symptoms. 
● Initiate close monitoring 
(hospitalization when appropriate) 
and workup for competing 
etiologiesa 
● Exclude underlying liver disease 
● Detailed history of concomitant 
medications (e.g acetaminophen) 
● Consult pediatric 
Gastroenterologistb 
 
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 
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) 

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Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
  
  
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 Bayley scales infant and toddler 
developmental motor milestones (Bayley-III) 
Developmental Milestone 
Performance Criteria 
Head Control – Gross Motor Subtest Item #4 
Child holds head erect for at least 3 seconds without 
support 
Rolls from Back to Sides – Gross Motor Subtest Item 
#20 
Child turns from back to both right and left sides 
Sits Without Support – Gross Motor Subtest Item #26 
Child sits alone without support for at least 
30 seconds  
Stands With Assistance – Gross Motor Subtest Item 
#33 
Child supports own weight for at least 2 seconds 
Crawls – Gross Motor Subtest Item #34 
Child makes forward progress of at least 5 feet by 
crawling on hands and knees 
Pulls to Stand – Gross Motor Subtest Item #35 
Child raises self to standing position using chair or 
other convenient object for support 
Walks With Assistance – Gross Motor Subtest Item 
#37 
Child walks by making coordinated, alternated 
stepping movements 
Stands Alone – Gross Motor Subtest Item #40 
Child stands alone for at least 3 seconds after you 
release his or her hands 
Walks Alone – Gross Motor Subtest Item #42 
Child takes at least 3 steps without support, even if 
gait is stiff-legged and wobbly 
16.1.4 
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. 
Standing with 
assistance 
Child stands in upright position on both feet, holding onto a stable object (e.g., 
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. 

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Walking with assistance 
Child is in upright position with the back straight. 
Child makes sideways or forward steps by holding onto a stable object (e.g., 
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)