A Randomized, Sham-controlled, Double-blind Study to Evaluate the Efficacy and Safety of Intrathecal OAV101 in Type 2 Spinal Muscular Atrophy (SMA) Patients Who Are ≥ 2 to < 18 Years of Age, Treatment Naive, Sitting, and Never Ambulatory
Phase: PHASE3
Conditions: Type 2 Spinal Muscular Atrophy
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
OAV101/onasemnogene abeparvovec 
Clinical Trial Protocol/ NCT05089656
A randomized, sham-controlled, double-blind study to 
evaluate the efficacy and safety of intrathecal (IT) OAV101 
in patients with later onset Type 2 spinal muscular atrophy 
(SMA) who are ≥ 2 to < 18 years of age, treatment naive, 
sitting, and never ambulatory 
Document type: 
Amended protocol version  
EUDRACT number: 
2021-003474-31 
PIP number:  
EMEA-002168-PIP01-M06 
Version number: 
04 (Clean) 
Clinical Trial Phase: 
III 
Release date: 
17 May 2024 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 4 (17-May-2024) ........................................................................................... 13 
Amendment 3 (02-Jun-2023) ............................................................................................ 14 
Amendment 2 (08-Aug-2022) ........................................................................................... 22 
Amendment 1 (11-Mar-2022) ........................................................................................... 27 
Protocol summary .............................................................................................................. 60 
1 
Introduction ....................................................................................................................... 64 
1.1 
Background ............................................................................................................ 64 
1.2 
Purpose .................................................................................................................. 67 
2 
Objectives, endpoints and estimands ................................................................................. 67 
2.1 
Primary estimands ................................................................................................. 69 
2.2 
Secondary estimands ............................................................................................. 70 
3 
Study design ...................................................................................................................... 71 
4 
Rationale ............................................................................................................................ 77 
4.1 
Rationale for study design ..................................................................................... 77 
4.1.1 
Rationale for choice of background therapy ......................................... 80 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 80 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 81 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 81 
4.5 
Risks and benefits .................................................................................................. 82 
4.5.1 
Potential benefits to participants ........................................................... 82 
4.5.2 
Ethical considerations ........................................................................... 82 
4.5.3 
OAV101 risks........................................................................................ 83 
4.5.4 
OAV101-drug interactions .................................................................... 88 
4.5.5 
Teratogenicity and associated risks ....................................................... 88 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 88 
5 
Study Population ............................................................................................................... 88 
5.1 
Inclusion criteria .................................................................................................... 89 
5.2 
Exclusion criteria ................................................................................................... 90 
6 
Treatment ........................................................................................................................... 92 
6.1 
Study treatment ...................................................................................................... 92 

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6.1.1 
Investigational and control drugs .......................................................... 92 
6.1.2 
Additional study treatments .................................................................. 93 
6.1.3 
Treatment arms/group ........................................................................... 93 
6.1.4 
Supply of study treatment ..................................................................... 93 
6.1.5 
Treatment duration ................................................................................ 93 
6.2 
Other treatment(s) .................................................................................................. 94 
6.2.1 
Concomitant therapy ............................................................................. 95 
6.2.2 
Prohibited medication ........................................................................... 96 
6.3 
Preparation and dispensation ................................................................................. 96 
6.3.1 
Handling of study treatment and other treatment .................................. 99 
6.4 
Participant numbering, treatment assignment, randomization ............................ 100 
6.4.1 
Participant numbering ......................................................................... 100 
6.4.2 
Treatment assignment, randomization ................................................ 100 
6.5 
Treatment blinding ............................................................................................... 101 
6.6 
Dose escalation and dose modification ................................................................ 104 
6.7 
Additional treatment guidance ............................................................................. 104 
6.7.1 
Treatment compliance ......................................................................... 104 
6.7.2 
Recommended treatment of adverse events ........................................ 104 
6.7.3 
Emergency breaking of assigned treatment code ................................ 104 
7 
Informed consent procedures .......................................................................................... 105 
8 
Visit schedule and assessments ....................................................................................... 106 
8.1 
Screening ............................................................................................................. 118 
8.1.1 
Inclusion and exclusion criteria .......................................................... 118 
8.1.2 
Information to be collected on screening failures ............................... 118 
8.1.3 
Prior medications ................................................................................ 119 
8.1.4 
Medical history and current medical conditions ................................. 119 
8.1.5 
Screening laboratory testing ................................................................ 119 
8.1.6 
Virus serology ..................................................................................... 119 
8.1.7 
Ventilatory support .............................................................................. 120 
8.1.8 
Radiological evaluations ..................................................................... 120 
8.1.9 
Independent sitting assessment ........................................................... 120 
8.2 
Participant demographics/other baseline characteristics ..................................... 120 
8.3 
Efficacy ................................................................................................................ 121 
8.3.1 
Primary and secondary efficacy assessments ...................................... 121 
8.3.2 
Appropriateness of efficacy assessments ............................................ 124 
8.3.3 
Exploratory assessments ..................................................................... 124 

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8.4 
Safety ................................................................................................................... 127 
8.4.1 
Laboratory evaluations ........................................................................ 127 
8.4.2 
Pregnancy testing ................................................................................ 129 
8.4.3 
Clinical safety evaluations .................................................................. 130 
8.4.4 
Vital signs............................................................................................ 130 
8.4.5 
Electrophysiology ............................................................................... 130 
8.4.6 
Anthropometry .................................................................................... 132 
8.4.7 
Echocardiogram .................................................................................. 133 
8.4.8 
Electrocardiogram ............................................................................... 133 
8.4.9 
Appropriateness of safety measurements ............................................ 134 
8.5 
Additional assessments ........................................................................................ 134 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................. 134 
8.5.2 
 .......................................................................................... 135 
8.5.3 
 ................................................................... 136 
8.5.4 
 .................................................................................. 137 
9 
Discontinuation and completion ...................................................................................... 137 
9.1 
Discontinuation from study treatment and from study ........................................ 137 
9.1.1 
Discontinuation from study treatment ................................................. 137 
9.1.2 
Discontinuation from study ................................................................. 138 
9.1.3 
Lost to follow-up ................................................................................. 138 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ..... 138 
9.3 
Study completion and post-study treatment ........................................................ 139 
9.4 
Early study termination by the sponsor ............................................................... 139 
10 Safety monitoring, reporting and committees ................................................................. 140 
10.1 
Definition of adverse events and reporting requirements .................................... 140 
10.1.1 
Adverse events .................................................................................... 140 
10.1.2 
Adverse events of special interest ....................................................... 141 
10.2 
Data collection ..................................................................................................... 142 
10.2.1 
Serious adverse events ........................................................................ 142 
10.2.2 
SAE reporting...................................................................................... 143 
10.2.3 
Pregnancy reporting ............................................................................ 144 
10.2.4 
Reporting of study treatment errors including misuse/abuse .............. 145 
10.3 
Additional Safety Monitoring .............................................................................. 145 
10.3.1 
Liver safety monitoring ....................................................................... 145 
10.3.2 
 ...................................................... 146 
10.3.3 
Post-mortem data collection ................................................................ 146 
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10.3.4 
 ............................................ 147 
10.4 
Committees .......................................................................................................... 147 
10.4.1 
Data Monitoring Committee ............................................................... 147 
11 Data Collection and Database management .................................................................... 147 
11.1 
Database management and quality control .......................................................... 147 
11.2 
Site monitoring .................................................................................................... 148 
12 Data analysis and statistical methods .............................................................................. 148 
12.1 
Analysis sets ........................................................................................................ 148 
12.2 
Participant demographics and other baseline characteristics ............................... 149 
12.3 
Treatments ........................................................................................................... 149 
12.4 
Analysis supporting primary objectives .............................................................. 149 
12.4.1 
Definition of primary endpoint(s) ....................................................... 150 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 150 
12.4.3 
Handling of intercurrent events of primary estimand ......................... 151 
12.4.4 
Handling of missing values not related to intercurrent event ............. 151 
12.4.5 
Sensitivity analyses ............................................................................. 151 
12.4.6 
Supplementary analysis ....................................................................... 151 
12.5 
Analysis supporting secondary objectives ........................................................... 152 
12.5.1 
Efficacy and/or pharmacodynamic endpoint(s) .................................. 152 
12.5.2 
Safety endpoints .................................................................................. 153 
12.6 
Analysis of exploratory endpoints ....................................................................... 155 
12.6.1 
 .................................................................................................... 155 
12.6.2 
.......................................................................................... 155 
12.6.3 
 ................................................................... 155 
12.7 
Interim analyses ................................................................................................... 155 
12.8 
Sample size calculation ........................................................................................ 156 
12.8.1 
 ............................................................................. 156 
12.8.2 
Secondary endpoint(s) ......................................................................... 156 
13 Ethical considerations and administrative procedures .................................................... 157 
13.1 
Regulatory and ethical compliance ...................................................................... 157 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 157 
13.3 
Publication of study protocol and results............................................................. 157 
13.4 
Quality Control and Quality Assurance ............................................................... 157 
13.5 
Participant engagement ........................................................................................ 158 
14 Protocol adherence .......................................................................................................... 158 
14.1 
Protocol amendments ........................................................................................... 158 
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15 References ....................................................................................................................... 159 
16 Appendices ...................................................................................................................... 165 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ....................... 165 
16.2 
Appendix 2: Liver laboratory triggers & follow-up monitoring requirements.... 166 
16.2.1 
Liver laboratory triggers ..................................................................... 166 
16.2.2 
Follow up requirements for liver laboratory triggers – ALT and 
AST, with and without TBL................................................................ 166 
16.2.3 
Follow up requirements for liver laboratory triggers - isolated 
hyperbilirubinemia .............................................................................. 167 
16.2.4 
Prednisolone dosing ............................................................................ 167 
 
List of tables 
Table 1-1 
Spinal Muscular Atrophy Classification ............................................... 65 
Table 2-1 
Objectives and related endpoints .......................................................... 67 
Table 4-1 
Rationale for study design ..................................................................... 77 
Table 6-1 
Investigational drug ............................................................................... 92 
Table 6-2 
Prednisolone Prophylaxis and Placebo Administration ........................ 94 
Table 6-3 
Additional study treatment .................................................................... 94 
Table 6-4 
Blinding and unblinding plan .............................................................. 103 
Table 8-1 
Assessment Schedule .......................................................................... 107 
Table 16-1 
Follow-up requirements for liver laboratory triggers – ALT and 
AST, with and without TBL................................................................ 166 
Table 16-2 
Follow-up requirements for liver laboratory triggers - isolated 
hyperbilirubinemia .............................................................................. 167 
 
List of figures 
Figure 1-1 
Clinical Classification of SMA subtypes according to onset, 
milestones achieved, and clinical presentation. Typically associated 
SMN2 copy numbers are displayed. ...................................................... 66 
Figure 1-2 
OAV101 Vector Construct .................................................................... 66 
Figure 3-1 
Study design .......................................................................................... 71 
Figure 3-2 
Summary of Screening Period to end of Follow-up Period 1 ............... 72 
Figure 3-3 
Summary of Period 2 eligibility assessment, Treatment and 
Follow-up Period 2 ................................................................................ 76 
Figure 8-1 
Timing of study procedures ................................................................ 134 
Figure 12-1 
Testing sequence ................................................................................. 153 

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List of abbreviations 
AAV 
adeno-associated virus 
AAV2 
adeno-associated virus serotype 2 
AAV9 
adeno-associated virus serotype 9 
aPTT 
Activated partial thromboplastin clotting time 
 
 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ASMA 
Anti-smooth muscle antibody 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
Beta-hCG 
Blood beta-human chorionic gonadotropin 
BiPAP 
Bi-Level Positive Airway Pressure 
BMI 
Body Mass Index 
CB 
Chicken-β-Actin-Hybrid 
CDC 
Centers for Disease Control and Prevention 
cDNA 
Complementary Deoxyribonucleic Acid 
CFR 
Code of Federal Regulations 
 
 
 
 
 
 
CI 
Confidence interval 
CK 
Creatine Kinase 
 
 
ClinRO 
Clinician Reported Outcomes 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CNT 
Cannot Test 
COA 
Clinical Outcome Assessment 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSF 
Cerebrospinal fluid 
CSR 
Clinical study report 
 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTR 
Clinical trial registration 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DRG 
Dorsal Root Ganglia 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
eCOA 
Electronic Clinical Outcome Assessment 
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EDC 
Electronic Data Capture 
EOS 
End of Study 
eSource 
Electronic Source 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
GMFM 
Gross Motor Function Measure 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HEV 
Hepatitis E 
HFMSE 
Hammersmith Functional Motor Scale Expanded 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IT 
Intrathecal 
ITR 
Inverted terminal repeats 
ITT 
Intent-to-treat 
IV 
intravenous 
kg 
Kilogram(s) 
LFT 
Liver function test 
LPLV 
Last participant last visit 
LSMs 
Least square means 
LVEF 
Left ventricular ejection fraction 
LVFS 
Left ventricular fractional shortening 
MAP 
Meta-analytic-predictive  
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MMRM 
Mixed model with repeated measurements 
 
 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PNCR 
Pediatric Neuromuscular Clinical Research 
 
 
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PT 
prothrombin time 
QMS 
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
 
 
RNA 
Ribonucleic acid 
RSV 
Respiratory Syncytial Virus 
RULM 
Revised Upper Limb Module 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-
CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
SMA 
Spinal muscular atrophy 
SMN1 
Survival of Motor Neuron 1 
SMN2 
Survival of Motor Neuron 2 
SNAP 
Sensory nerve action potential 
TBL 
Total bilirubin 
TMA 
Thrombotic Microangiopathy 
ULN 
upper limit of normal 
US 
United States 
vg 
vector genome 
WHO 
World Health Organization 
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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) 
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 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all 
clinical trial activities. Examples of team members include the Study Lead, 
Medical Monitor, Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center team by 
replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over 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 
Discontinuation from study 
Point/time when the participant permanently stops receiving the study treatment 
and further protocol required assessments or follow-up, for any reason. No 
specific request is made to stop the use of their samples or data. 
Discontinuation from study 
treatment 
Point/time when the participant permanently stops receiving the study treatment 
for any reason (prior to the planned completion of study drug administration, if 
any). Participant agrees to the other protocol required assessments including 
follow-up. No specific request is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g., 100 mg 
once a day, 75 mg twice a day) 
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 source data/documents used at the point of care 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant 
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained. The action of enrolling one or more participants 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, allowing 
for the real time collection of clinical trial information to sponsors and other 
oversight authorities, as appropriate 

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Estimand 
As defined in the ICH E9(R1) addendum, estimand is 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 
participants 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 
Investigational Product/ 
Investigational Medicinal 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used 
as a reference ( such as an active comparator) in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an 
approved use. 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized participants 
Mis-randomized participants are those who were not qualified for randomization 
and who did not take study treatment, but have been inadvertently randomized 
into the study or the participant allocated to an invalid stratification factor 
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" 
terminology is used in the protocol whereas term "Subject" is used in data 
collection 
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. 
 
 
 
 
 
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. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization number 
A unique identifier assigned to each randomized participant 
Rescreening 
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited twice for a new Screening visit after medical judgment 
and as specified by the protocol 
Remote 
Describes any trial activities performed at a location that is not the investigative 
site where the investigator will conduct the trial, but is for example a home or 
another appropriate location 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
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Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant 
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. 
Tele-visit 
Procedures or communications conducted using technology such as telephone 
or video-conference, whereby the participant is not at the investigative site 
where the investigator will conduct the trial. 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations 
of interventions administered concurrently, e.g., as add-on to standard of care, 
or might consist of an overall regimen involving a complex sequence of 
interventions. This is the treatment of interest used in describing the related 
clinical question of interest, which might or might not be the same as the study 
treatment. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of study consent 
(WoC) / Opposition to use of 
data /biological samples 
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and biological samples (opposition to use 
data and biological samples) AND no longer wishes to receive study treatment, 
AND does not agree to further protocol required assessments. This request 
should be in writing (depending on local regulations) and recorded in the source 
documentation. 
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different legal reason 
than consent. 
 

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Amendment 4 (17-May-2024) 
The main purpose of this amendment is to enhance the consultation between the Principal 
Investigator and Sponsor for patients retesting of abnormal laboratory that could be transient or 
measurement error for Period 2 eligibility.   
The inclusion of Hy’s Law reporting text was added to Section 10.2.2: SAE reporting to ensure 
compliance with FDA request for expedited reporting of potential Hy’s Law cases. 
Key changes to the protocol and the rationale for changes are summarized in the following table. 
Changes to specific sections of the protocol are shown using strike through red font for deletions 
and red text for insertions. Editorial changes for clarity are not included in the summary of 
changes table.  
 
 
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Amendment 3 (02-Jun-2023) 
The main purpose of this protocol amendment is to revise several exclusion criteria so that they 
are now anchored to the Day 1 visit (day of OAV101 administration or the sham procedure). 
Secondly, the number of participants listed in the five strata has been removed. 
  
 
  
Finally, a theoretical risk of tumorigenicity due to vector DNA integration has been added to 
the OAV101 risks Section 4.5.3. The risk language has been revised to include the theoretical 
risk of tumorigenicity due to the very low potential incorporation of AAV vector DNA into 
chromosomal DNA that has been noted based on published literature for AAV-based therapies. 
Summary of changes  
Key changes to the protocol and the rationale for changes are summarized in the following table. 
Changes to specific sections of the protocol are shown using strike through red font for deletions 
and red text for insertions. Editorial changes for clarity as well as changes to align with an 
updated Novartis Clinical Trial Protocol Template are not included in the summary of changes 
table.  
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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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Amendment 2 (08-Aug-2022) 
The main purpose of this protocol amendment is to remove the use of the Central Treatment 
Site (hybrid model), which has not been utilized and is therefore not applicable for study 
execution.  
Secondly, adaptations have been made to clarify that the threshold used for anti-AAV9 antibody 
titer is one that is reported to be elevated. The anti-AAV9 antibody titer testing lab may be 
changed to a new lab that is able to meet the documentation and procedures necessary for an 
investigational device exemption (IDE) by the FDA. Due to the nature of the immunoassay used 
to evaluate anti-AAV9 antibody titer, the reported titer value as elevated may be different. 
In addition, further adaptations have been made for clarity including, mirroring exclusion 
criteria in treatment period 2 from treatment period 1 for safety considerations, and updating 
Section 4.5.3 on OAV101 risks. The risks of inaccurate anti-AAV9 antibody testing results was 
added because the test that’s currently being used to assess eligibility has not been approved by 
regulatory authorities for this purpose. As of June 2022, in the post-marketing setting, acute 
liver failure cases have been reported, including 2 cases with fatal outcomes. Therefore, this 
update was included to the OAV101 risks section.  
The visit schedule for troponin I collection was modified to better align with timepoints for 
electrocardiogram and echocardiogram assessments. Troponin I is a non-specific biomarker, 
which will likely provide limited value based on data from prior OAV101 studies. To date, all 
observed troponin I elevations have been isolated lab value elevations without associated signs 
or symptoms. ECG and ECHO, which are already incorporated into the study, will be used for 
cardiac safety monitoring. The revised visit schedule for troponin I now aligns with ECG and 
ECHO, as well as with other ongoing OAV101 studies. 
Finally, sensory nerve action potential (SNAP) evaluation on asymptomatic participants is no 
longer applicable and therefore was removed for clarity. All patients will undergo a neurological 
exam and SNAP at screening, and those with clinically significant sensory abnormalities in the 
neurological examination or those who are unable to obtain SNAP, will not be eligible. Post-
treatment, SNAP will ONLY be performed if there are sensory abnormalities in the neurological 
examination. Therefore, there will be no cases of asymptomatic participants for SNAP 
evaluation. 
Editorial changes have been made throughout for clarity and are not included in the Summary 
of key changes table. 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 underline for 
insertions. 
Summary of changes  
Key changes to the protocol and the rationale for changes are summarized in the following table. 
Changes to specific sections of the protocol are shown using strike through red font for deletions 
and red text for insertions.  

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Amendment 1 (11-Mar-2022) 
 
 
 
 The data analysis and statistical methods section were revised to include the 
following two secondary endpoints: 
• Achievement of at least a 3-point improvement from baseline in HFMSE total score at the 
end of Follow-up Period 1 in the overall study population 
• Achievement of at least a 3-point improvement from baseline in HFMSE total score at the 
end of Follow-up Period 1 in the ≥ 2 to < 5 years age group 
In addition, the schedule of sensory nerve action potential (SNAP) assessments has been 
modified in view of ethical consideration and clinical best practice to ensure evaluation and 
monitoring of potential neurotoxicity SNAPs will be evaluated in all patients at screening as 
described in the previous protocol version. However SNAP evaluation at five post-treatment 
visits has been adjusted. The neurological examination, which is already incorporated in the 
protocol at every post-treatment visit, will be used to primarily evaluate potential sensory 
abnormalities in patients. Upon detection of a potential sensory abnormality, a SNAP 
assessment will then be performed as a secondary evaluation. The core rationale for the change 
is as follows: 
• Standard clinical practice is to begin with a neurological exam, which is expected to be 
more sensitive than SNAP in detecting sensory abnormalities 
• Given the range of expertise in electrophysiology across clinical sites for this global study, 
the SNAP data are expected to be variable (as confirmed by our clinical expert on SNAP) 
• The SNAP procedure is not benign and can be quite painful to a child and may pose 
discomfort to patients across multiple study visits 
Finally, edits were made to the inclusion and exclusion criteria to provide additional clarity. 
Inclusion criterion #2 related to 
 
 
 is not critical to defining the study population of 
Type 2 SMA. The study population can be defined by genetic confirmation of 5q SMA along 
with clinical symptoms of being able to sit independently but never having walked 
independently (inclusion criterion #7). Due to feedback from investigators at sites, several of 
the exclusion criteria were revised to provide more clarity, such as adding specific timeframes. 
In addition, several exclusion criteria were added with rationale provided in the Summary of 
key changes table. 
Editorial changes as well as changes to align with Novartis’ Clinical Trial Protocol Template 
Version 5.0 (14-Jan-2022) have been made throughout for clarity and are not included in the 
Summary of key changes table. 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 
underline for insertions. 
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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 approval prior to implementation. 
Summary of changes  
Key changes to the protocol and the rationale for changes are summarized in the following table. 
Changes to specific sections of the protocol are shown using strike through red font for deletions 
and red text for insertions.  
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Protocol summary 
Protocol number 
COAV101B12301 
Full Title 
A randomized, sham-controlled, double-blind study to evaluate 
the efficacy and safety of intrathecal (IT) OAV101 in patients with 
later onset Type 2 spinal muscular atrophy (SMA) who are ≥ 2 to 
< 18 years of age, treatment naive, sitting, and never ambulatory 
Brief title 
Randomized, sham-controlled, double-blind trial to evaluate the 
efficacy and safety of intrathecal (IT) OAV101 in patients with 
later onset Type 2 spinal muscular atrophy (SMA). 
Sponsor and 
Clinical Phase 
Novartis 
Phase III 
Investigation type 
Biological 
Study type 
Interventional 
Purpose 
The purpose of this phase III multi-center, single dose (1.2 x 1014 
vector genomes), randomized, sham-controlled, double-blind trial 
is to investigate the safety, tolerability, and efficacy of intrathecal 
(IT) OAV101 in treatment naive, sitting and never ambulatory 
Type 2 SMA patients ≥ 2 to < 18 years. 
Primary Objective 
The primary objective of this study is to compare the efficacy of 
OAV101 IT vs. sham control as measured by the change from 
baseline in Hammersmith Functional Motor Scale-
Expanded (HFMSE) total score. 
The primary question of interest is: What is the effect of OAV101 
treatment versus the sham procedure on change from baseline in 
HFMSE total score after treatment in sitting but never ambulatory 
patients aged ≥ 2 to < 18 years with Type 2 SMA, regardless of 
study discontinuation or receipt of prohibited concomitant 
medications not for the intent to treat SMA? 
Secondary Objectives 
To compare the efficacy of OAV101 IT vs. sham control in two 
patient age groups: ≥ 2 to < 5 years (HFMSE, Revised Upper 
Limb Module (RULM)); ≥ 2 to < 18 years (RULM) 
To evaluate the safety and tolerability of OAV101 IT vs. sham 
control in patients ≥ 2 to < 18 years 
Study design 
This is a randomized, double-blind, sham-controlled study to 
evaluate the clinical efficacy, safety, and tolerability over 52 
weeks of a single, nominal dose (1.2 x 1014 vector genomes) of 
intrathecal OAV101 in patients with Type 2 SMA who are ≥ 2 to 
< 18 years of age, able to sit, but have never walked. 
Approximately 125 patients aged ≥2 to <18 years will be recruited 
consisting of ∼65 patients between the ages of ≥ 2 to < 5 years 
and ∼60 patients between the ages of ≥ 5 to < 18 years. 
Participants will be randomized in a 3:2 ratio to receive OAV101 
(1.2 x 1014 vector genomes) by lumbar intrathecal injection 
(n=~75) or to receive a sham procedure (n=~50). 
Rationale 
Safety and clinically meaningful efficacy with IT delivery of 
OAV101 was observed in the open label CL-102 study 
[Investigator's Brochure]. Hence, OAV101 IT may provide a safe, 
one time treatment option leading to clinically meaningful benefit 
in patients with SMA Type 2 age 2 to < 18 years. 

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Study population 
Study population attributes are described below. The population 
attribute will be represented by the entire study population. 
Genotype 
· 5q SMA as defined by biallelic SMN1 pathogenic variants  
Age range, randomization, and number of participants 
· Approximately 125 participants who are ≥ 2 to < 18 years will be 
recruited for the COAV101B12301 trial 
· This study population will consist of ∼65 patients between the 
ages of ≥ 2 to < 5 years and ∼60 patients between the ages of ≥ 
5 to < 18 years (Screening Visit 1 must occur before the patient's 
18th birthday) 
· Randomization is 3:2 ratio (treated:control) to receive OAV101 
(1.2 x 1014 vector genomes) by lumbar intrathecal injection 
(n=~75) or to receive a sham procedure (n=~50) 
 
 
 
 
 
 
 
 
 
 
 
Key Inclusion criteria 
· Diagnostic confirmation during screening period of 5q SMA  
· The patient must be treatment naive (historical or current use) 
for all SMN-targeting therapies (e.g., risdiplam (Evrysdi) and 
nusinersen (Spinraza)) 
· ≥ 2 years and < 18 years of age at screening visit 1 
· Onset of clinical signs and symptoms at ≥ 6 months of age 
· Patient must have a complete HFMSE assessment, with an 
available total score, as administered by qualified clinical 
evaluator during the screening period for trial eligibility 
· Able to sit independently at screening, but has never had the 
ability to walk independently 
- Definition of sitting independently: Child sits up straight with 
the head erect for at least 10 seconds without using arms or 
hands to balance body or support position 
(Wijnhoven et al 2004) 
- Definition of walking independently: The child is able to 
balance the body and control forward stepping movements 
without assistance (Wijnhoven et al 2004) 
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Key Exclusion criteria 
· Anti-adeno-associated virus serotype 9 (AAV9) antibody titer 
reported as elevated (reference to > 1:50 or a validated result 
consistent with being elevated) at screening as determined 
 
 
· Presence of any of the following: 
· An active infectious process requiring systemic 
therapy intended to eliminate the infection within 30 days prior 
to dosing of OAV101 or the sham procedure 
· An active but untreated viral or bacterial infectious process 
within 30 days prior to dosing of OAV101 or the sham 
procedure 
· Febrile illness within 30 days prior to OAV101 treatment or 
sham procedure 
· Hepatic dysfunction (i.e., alanine aminotransferase (ALT), total 
bilirubin (TBL), gamma-glutamyl transferase (GGT) or glutamate 
dehydrogenase (GLDH), > upper limit of normal (ULN) (i.e., 
Common Terminology Criteria for Adverse Events (CTCAE) 
grade1 or greater) at Screening Visit 1. NOTE: In the absence of 
other liver laboratory abnormalities, isolated AST elevation is not 
considered exclusionary 
· Requiring invasive ventilation, awake noninvasive ventilation 
for > 6 hours during a 24-hour period, noninvasive ventilation 
for > 12 hours during a 24-hour period, or requiring tracheostomy 
at screening and up to Day 1 
· Complications at screening that would interfere with motor 
efficacy assessments including but not limited to: 
· Presence of severe contractures (e.g., hip flexion 
contracture) which limits the participant’s ability to be 
positioned in prone for HFMSE item administration 
·Scoliosis with a Cobb angle > 40 degrees evident on x-ray 
examination at Screening 
· Surgery for scoliosis or hip fixation in the 12 months prior to 
Screening or planned within the next 64 weeks 
Study treatment 
OAV101 or sham procedure 
Treatment of interest 
OAV101 is a single administration of a nominal dose of 1.2 x 
1014 vector genomes as part of a randomized, double blind, sham 
procedure controlled clinical trial (COAV101B12301). 
Key efficacy assessments 
· HFMSE 
· RULM 
Key safety assessments 
· Adverse event monitoring 
· Vital Signs 
· Age-appropriate neurological examinations 
 
· Chemistries including Troponin I and hepatic enzymes 
· Hematology  
· Urinalysis 
· Anthropometry 
· Electrocardiogram (ECG) 
· Echocardiogram (ECHO) 
· Neurological examination 
· Neurophysiology for sensory neuronopathy (Dorsal root ganglia 
(DRG) toxicity) monitoring: Sensory Nerve Action Potential 
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(SNAP), if applicable based on abnormalities in neurological 
examination 
Other assessments  
 
 
 
 
 
 
 
 
 
Data analysis 
Mixed Effect Model with Repeated Measures (MMRM) for 
continuous primary and secondary endpoints; Generalized 
Linear Mixed Effects Model for dichotomous secondary 
endpoints (Section 12.4 and Section 12.5) 
Between-group differences in the change from Baseline in 
HFMSE or RULM total score at the end of Follow-up Period 1 will 
be evaluated using a Mixed Model with Repeated Measurements 
(MMRM). The model will include the observed change from 
Baseline in HFMSE or RULM total score at all post-Baseline visits 
(through the end of Follow-up Period 1) as the dependent 
variable. The fixed effects will include treatment, scheduled visit, 
the treatment by visit interaction, strata, and pre-treatment 
HFMSE or RULM total score as covariates. An unstructured 
covariance matrix will be used. Least square means (LSMs) for 
each treatment group, standard errors, associated 95% CIs, 
difference of LSMs compared to the sham procedure group, the 
associated 95% CIs for the difference, as well as the two-sided p-
values will be tabulated by visit and treatment. Between-group 
differences for the dichotomous endpoint of proportion of 
participants who achieve at least a 3-point improvement from 
baseline in HFMSE total score at the end of Follow-up Period 1 
will be analyzed using a Generalized Linear Mixed Effects Model 
with fixed effects including treatment, 
 
 
 
 
 
 NOTE: In order to account for variability in 
the completion of motor assessments (HFMSE or RULM) 
occurring at the Week 52 visit that could impact the MMRM 
assessment, the motor assessment score at Week 48 and Week 
52 will be averaged for the purposes of creating the end of 
Follow-up Period 1 time point.  
Key words 
Type 2 SMA, Late onset SMA, Phase III, double blind, 
randomized trial, HFMSE, RULM, gene therapy, recombinant 
AAV9, SMN, survival motor neuron, OAV101 
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1 
Introduction 
1.1 
Background 
Clinical description: SMA is a neurogenetic disorder caused by a loss or mutation in the 
survival motor neuron 1 gene (SMN1) on chromosome 5q13, which leads to reduced SMN 
protein levels and a selective dysfunction of motor neurons. SMA is an autosomal recessive, 
early childhood disease with an incidence of approximately 1:10,000 live births 
(Sugarman et al 2012). SMA is the leading cause of infant mortality due to genetic diseases. 
Disease severity and clinical prognosis depends on the number of copies of SMN2. In its most 
common and severe form (Type 1), hypotonia and progressive weakness are recognized in the 
first few months of life, leading to diagnosis by 6 months of age and then death due to 
respiratory failure by age 2 years. Motor neuron loss in SMA Type 1 is profound in the early 
postnatal period (or may even start in the pre-natal period), whereas motor neurons in Type 2 
and 3 SMA patients adapt and compensate during development and persist into adult life. The 
findings from various neurophysiological and animal studies have shown an early loss of motor 
neurons 
in 
the 
embryonic 
and 
early 
postnatal 
periods 
(Swoboda et al 2005, 
Le et al 2011, Farrar et al 2013). 
SMN protein depletion is the root cause across all SMA patient phenotypes and the disease 
pathogenesis, regardless of age. SMA is caused by abnormally low levels of the ubiquitously 
expressed SMN protein, resulting from a combination of homozygous deletions or mutations of 
the telomeric copy of the SMN gene (SMN1) on chromosome 5q and the presence of 1 or more 
copies of SMN2 (Lefebvre et al 1995), an almost identical but only partially functional 
centromeric copy which is unique to humans (Rochette et al 2001). The relevant difference 
between these two genes, a single nucleotide transition at exon 7, affects a splice site enhancer 
such that the majority of transcripts of SMN2 lack exon 7 (SMNΔ7), resulting in greatly reduced 
levels of functional, full-length SMN protein (Monani et al 1999). When the SMN1 gene is 
unable to supply SMN protein to the motor neurons, the only source of SMN protein is the 
SMN2 gene. The amount of neuronal SMN protein determines patient phenotype primarily by 
the number of SMN2 genes. 
In support of the hypothesis that gene copy numbers of SMN2 primarily drive phenotypic 
presentation of SMA, a large review examined the association between SMN2 copy number and 
SMA phenotype (Calucho et al 2018). The authors showed that 79% of patients with two copies 
of SMN2 developed SMA Type I, 16% developed SMA Type 2 and 5% developed SMA Type 
3; 54% of patients with three copies of SMN2 developed SMA Type 2, 31% developed SMA 
Type 3 and 16% developed SMA Type 1; and among patients with four copies of SMN2, most 
had mild SMA variants with only 1% developed SMA Type 1 and 11% developed SMA Type 
2. In keeping with the importance of SMN production by SMN2, few individuals with SMN1 
mutations and ≥6 copies of SMN2 develop symptoms and those who are affected develop only 
mild forms of SMA (Bernal et al 2010, Riessland et al 2017). SMN is part of the machinery 
which assembles spliceosomal components (Pellizzoni et al 1998). Ventral spinal cord motor 
neurons are specifically sensitive to SMN deficiency and are affected in all types of SMA 
(Burghes and Beattie 2009). 

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Irrespective of phenotypic classification, expert consensus is that all patients with biallelic 
pathogenic SMN1 variants and up to 4 SMN2 copies should receive SMN dependent therapy 
(Glascock et al 2018, Glascock et al 2020). Therapeutically increasing SMN levels leads to the 
most striking results in patients with SMA Type 1 (Pechmann et al 2018, Mercuri et al 2018a, 
Pane et al 2019, Aragon-Gawinska et al 2020). These results are thought to be mainly due to 
early intervention, preventing neurodegeneration and the associated progressive deterioration 
that is seen in all Type 1 SMA infants. These patients now experience improvement in their 
functional abilities and attain developmental milestones that had never previously been 
achieved in this population (Pechmann et al 2018, Mercuri et al 2018a, Pane et al 2019, 
Aragon-Gawinska et al 2020. A proportion of these infants acquire the ability to sit 
independently, and treatment can enable them to stand (usually with support), depending on 
how soon treatment is initiated after onset of symptoms. In children with SMA Type 2, 
treatment also clearly reduces progression of the disease compared with the natural history. For 
patients with mild SMA Type 2, developing the ability to walk is a possibility. 
SMA 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 spinal muscular atrophy (Kolb and Kissel 2011, Mercuri et al 2012). The 
classification of SMA is shown below (Table 1-1). SMA Type 1 patients present with 
symptoms within the first 6 months of life and by definition never attain independent sitting. 
SMA Type 1 is the leading genetic cause of infant death. In contrast, SMA Type 2 manifests 
within the first 18 months of life and follows a slower disease progression as compared to 
SMA Type 1. Children with SMA Type 2 are able to maintain sitting unassisted but never walk 
independently and have a life expectancy of 20-40 years of age. SMA Type 3 patients attain the 
ability to walk unaided (Type 3a have onset < 3 years of age; Type 3b have onset > 3 years of 
age). SMA Type 4 is an adult onset form of the disease. Table 1-1 summarizes SMA subtypes 
and associated clinical features as well as the relationship of the SMA subtypes to SMN2 copy 
numbers (Schorling et al 2020). 
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: < 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, 5 
SMN2 = survival motor neuron 2 gene 
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 

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Figure 1-1 
Clinical Classification of SMA subtypes according to onset, 
milestones achieved, and clinical presentation. Typically associated 
SMN2 copy numbers are displayed. 
 
Source: Schorling et al 2020 
OAV101 gene therapy mechanism of action: OAV101 is an in vivo gene therapy intended 
for a single treatment with 5q SMA. OAV101 is a non-replicating recombinant adeno-
associated virus serotype 9 (AAV9) containing the human SMN complementary 
deoxyribonucleic acid (cDNA) under the control of the cytomegalovirus (CMV) 
enhancer/chicken-β-actin-hybrid (CB) promoter (Figure 1-2). One of the two adeno-associated 
virus (AAV) inverted terminal repeats has been modified to promote intramolecular annealing 
of the transgene, thus forming a double-stranded transgene ready for transcription. 
Figure 1-2 
OAV101 Vector Construct 
 
The mechanism of action of OAV101 is the delivery of a functional copy of the gene encoding 
for the SMN protein into target cells, the loss of which is the root cause of all forms of (5q) 
SMA. The goal is to increase SMN protein levels in motor neurons prior to the development of 
irreversible injury and motor neuron loss, thereby modifying the patient’s SMA phenotype to a 
milder course with improved quality of life and prolonged survival. 
Recombinant AAVs are not known to actively integrate into the host genome, but rather persist 
episomally within the target cells. Thus, its expression is eventually lost in a dividing cell 
population (Hudry and Vandenberghe 2019). OAV101 is specifically designed to form a 
circular concatemeric transgene that harbors even lower potential for deoxyribonucleic acid 
(DNA) integration or alteration. Moreover, AAVs cannot replicate within the host cell in 

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absence of a helper virus, such as adenovirus, herpes simplex virus, human papillomavirus or 
vaccinia virus for productive infection. 
1.2 
Purpose 
The purpose of this phase III multi-center, single dose (1.2 x 1014 vector genomes), randomized, 
sham-controlled, double-blind trial is to investigate the safety, tolerability, and efficacy of 
intrathecal (IT) OAV101 in treatment naive, sitting and never ambulatory Type 2 SMA patients 
≥ 2 years to < 18 years (Screening Visit 1 must occur before the patient's 18th birthday). 
2 
Objectives, endpoints and estimands 
Objectives and related endpoints are described in Table 2-1. 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
EFFICACY: To compare the efficacy of 
OAV101 IT vs. sham control as measured by 
the change from baseline in HFMSE total 
score 
• 
Change from baseline in HFMSE total score at the end of 
Follow-up Period 1 (defined in Section 12.4.1)  in the overall 
study population (≥ 2 to < 18 years age group) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To compare the efficacy of OAV101 IT vs. 
sham control in two patient age groups: ≥ 2 to 
< 5 years (HFMSE, RULM); ≥ 2 to < 18 years 
(RULM) 
• 
Change from baseline in HFMSE total score at the end 
of Follow-up Period 1 in the ≥ 2 to < 5 years age group 
• 
Achievement of at least a 3-point improvement from 
baseline in HFMSE total score at the end of Follow-up Period 
1 in the overall study population 
• 
Achievement of at least a 3-point improvement from 
baseline in HFMSE total score at the end of Follow-up Period 
1 in the ≥ 2 to < 5 years age group 
• 
Change from baseline in RULM at the end of Follow-up 
Period 1 in the ≥ 2 to < 18 years age group 
• 
Change from baseline in the RULM at the end of Follow-
up Period 1 in the ≥ 2 to < 5 years age group 
• 
SAFETY: To evaluate the safety and 
tolerability of OAV101 IT vs. sham control in 
patients ≥ 2 to < 18 years 
• 
Incidence of treatment emergent adverse events (TEAEs) 
and serious (SAEs)  
• 
Number of participants with adverse events of special 
interest (AESIs) 
• 
Evaluation of changes from baseline in vital signs, 
physical/neurological examinations, laboratories (chemistry, 
hematology, liver functions tests), echocardiogram, ECG, 
anthropometry, and 
   
• 
Number (and percentage) of patients with intracardiac 
thrombi  
• 
Number (and percentage) of patients with low cardiac 
function 
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Objective(s) 
Endpoint(s) 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
• 
To assess the changes in motor function 
from baseline over 52 weeks in treated 
patients compared to sham controls and 
natural history data in the overall study 
population (≥ 2 to < 18 years) 
 
 
 
 
 
• To assess the changes in motor function 
from baseline over 52 weeks in treated 
patients compared to sham controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To assess changes in 
 
from baseline over 52 weeks in treated 
patients compared to sham controls in ≥ 2 to < 
5 years and in the ≥ 5 to < 18 years age 
groups 
• 
Change in 
 
 
 
• 
To assess changes in 
 from 
baseline over 52 weeks in treated patients 
compared to sham controls in each of three 
age groups: ≥ 2 to < 18 years, ≥ 2 to < 5 
years, ≥ 5 to < 18 years 
• 
Change in 
 over 
52 weeks in each of three age groups: ≥ 2 to < 18 years, ≥ 2 
to < 5 years, ≥ 5 to < 18 years 
• 
To assess the 
 of SMA 
over 52 weeks in treated patients compared to 
the sham controls in each of three age 
groups: ≥ 2 to < 18 years, ≥ 2 to < 5 years, ≥ 5 
to < 18 years 
 
 
 
 
 
• 
To assess the 
 
over 52 weeks in 
treated patients compared to the study sham 
controls in each of three age groups: ≥ 2 to 18 
years, ≥ 2 to < 5 years, ≥ 5 to < 18 years 
• 
Change in 
 
 over 52 weeks in each of three age 
groups: ≥ 2 to < 18 years, ≥ 2 to < 5 years, ≥ 5 to < 18 years  
 
• 
To assess for 
 
 in treated patients 
compared to sham controls in each of three 
age groups: ≥ 2 to < 18 years, ≥ 2 to < 5 
years, ≥ 5 to < 18 years 
• 
To assess 
 
 
 
 in each of three age 
groups: ≥ 2 to < 18 years, ≥ 2 to < 5 years, ≥ 5 to < 18 years. 
• 
To assess for changes 
 
 
 in treated patients compared to 
sham controls 
• 
Change from baseline over 52 weeks for 
 
 
  
• 
To assess 
 post OAV101 
• 
Evaluation of 
 in treated patients 
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2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g., premature discontinuation of treatment). 
The primary clinical question of interest is: What is the effect of OAV101 treatment versus the 
sham procedure on change from baseline in HFMSE total score after treatment in sitting but 
never ambulatory patients aged ≥ 2 to < 18 years with Type 2 SMA, regardless of study 
discontinuation or receipt of prohibited concomitant medications not for the intent to treat 
SMA? 
The justification for the primary estimand is that it will capture both the effect of OAV101 and 
the effect of additional medications not for the intent to treat SMA, mirroring the conditions in 
clinical practice. Further details can be found in Section 12. 
The primary estimand is described by the following attributes: 
1. Population: Sitting but never ambulatory patients aged ≥ 2 to < 18 years with Type 2 
SMA. Further details about the population are provided in Section 5. 
2. Endpoint: Change from baseline to the end of Follow-up Period 1 in HFMSE total score. 
• 
 
 
 
 
 
 
3. Summary measure: difference between treatment groups in least squares mean change 
from baseline in HFMSE total score up to the end of Follow-up Period 1 
4. Treatment of interest: The randomized treatment (OAV101 or sham procedure) with or 
without the use of prohibited concomitant medications not for the intent to treat SMA. 
Further details about the investigational treatment and control are provided in Section 6. 
Handling of intercurrent events: 
1. Study discontinuation due to reasons other than death: It is assumed that participants 
discontinuing the study prior to Week 52 would follow the same trend as participants who 
continued and remained in the study for the full 52 weeks. Data collected up to the point 
of discontinuation will be included in the Mixed Model for Repeated Measurements 
(MMRM) (Hypothetical strategy). 
2. Use of prohibited concomitant medications not for the intent to treat SMA: Assessments 
collected while/after receiving prohibited concomitant medications will be included in the 
analyses (Treatment policy strategy). 
3. Use of prohibited concomitant medications for the intent to treat SMA (i.e., nusinersen, 
risdiplam): Assessments collected while/after receiving prohibited concomitant 
medications will not be included in the analyses. Only data collected up to the point of 
initiating a prohibited medication for the intent to treat SMA will be included in the 
MMRM and the data collected after the initiation of prohibited medication for the intent to 
treat SMA will be considered as missing (Hypothetical strategy).  
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4. Study discontinuation due to death: The worst score for HFMSE will be imputed for 
participants who discontinue the study due to death, and this imputed score will be utilized 
in the analysis. The “worst score” refers to the worst (lowest) HFMSE score collected 
for the participant who had the death event throughout the trial (considering both 
the baseline and post-baseline period). It is anticipated that this intercurrent event is 
unlikely to occur during this study. 
2.2 
Secondary estimands 
The secondary estimand for the continuous secondary efficacy endpoints is defined similarly to 
the primary estimand. 
The secondary estimand for the dichotomous secondary efficacy endpoint (i.e., achievement of 
at least a 3-point improvement from baseline in HFMSE total score at the end of Follow-up 
Period 1) is described by the attributes listed below. 
1. Population of interest: Sitting but never ambulatory patients aged ≥ 2 to < 18 years with 
Type 2 SMA  
2. Endpoint: Proportion of participants achieving at least a 3-point improvement from 
baseline in HFMSE total score at the end of Follow-up Period 1.  
• 
 
 
 
 
 
3. Summary measure: odds ratio between treatment groups for the proportion of participants 
achieving at least a 3-point improvement from baseline in HFMSE total score at the end of 
Follow-up Period 1. 
4. Treatment of interest: The randomized treatment (OAV101 or sham procedure) with or 
without the use of prohibited concomitant medications not for the intent to treat SMA.  
Handling of intercurrent events: 
1. Study discontinuation due to reasons other than death: It is assumed that participants 
discontinuing the study prior to Week 52 would follow the same trend as participants who 
continued and remained in the study for the full 52 weeks. Data collected up to the point 
of discontinuation will be included in the Generalized Linear Mixed Effects Model 
(Hypothetical strategy). 
2. Use of prohibited concomitant medications not for the intent to treat SMA: Assessments 
collected while/after receiving prohibited concomitant medications will be included in the 
analyses (Treatment policy strategy). 
3. Use of prohibited concomitant medications for the intent to treat SMA (i.e., nusinersen, 
risdiplam): Assessments collected while/after receiving prohibited concomitant 
medications will not be included in the analyses. Only data collected up to the point of 
initiating a prohibited medication for the intent to treat SMA will be included in the 
Generalized Linear Mixed Effects Model and the data collected after the initiation of 
prohibited medication for the intent to treat SMA will be considered as missing 
(Hypothetical strategy). 
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4. Study discontinuation due to death: The worst score for HFMSE will be imputed for 
participants who discontinue the study due to death, and this imputed score will be utilized 
in the analysis. The “worst score” refers to the worst (lowest) HFMSE score collected 
for the participant who had the death event throughout the trial (considering both 
the baseline and post-baseline period). It is anticipated that this intercurrent event is 
unlikely to occur during this study. 
3 
Study design 
The study consists of a Screening and Baseline Period followed by two Treatment and 
follow-up Periods. 
Treatment Period 1 consists of OAV101/sham administration with in-patient hospitalization on 
Study Day 1, Day 2 and Day 3 (optional). Treatment Period 1 is followed by a 52-week 
out-patient follow-up period (Follow-up Period 1; Week 1-52) for safety and efficacy 
assessments (Figure 3-1; Figure 3-2). 
At the point each participant completes Follow-up Period 1, those who are eligible (see 
Treatment Period 2 eligibility criteria below) will subsequently enter into Treatment Period 2. 
Entry into Treatment Period 2 will occur in a rolling, seamless fashion as participants complete 
Follow-up Period 1. In Treatment Period 2, eligible participants who received a sham procedure 
on Study Day 1 of Treatment Period 1 will be hospitalized to receive OAV101 and participants 
who received OAV101 on Study Day 1 of Treatment Period 1 will be hospitalized to receive a 
sham procedure on the Week 52 +1 Day visit. In-patient observation will continue on Week 52 
+2 Days and Week 52 +3 Days (optional). Treatment Period 2 is followed by a 12-week follow-
up period (Follow-up Period 2; Week 53-64) for safety and efficacy assessments (Figure 3-1; 
Figure 3-3). The total duration of the study is 64 weeks. At the end of study all participants who 
received OAV101 will be eligible to enroll in a long-term follow-up study (15 years) to monitor 
long-term safety and efficacy. 
Figure 3-1 
Study design 
 
This is a phase III multi-center, single dose (1.2 x 1014 vector genomes), randomized, 
sham-controlled, double-blind trial that investigates the safety, tolerability, and efficacy of 
OAV101 IT in treatment naive, sitting and never ambulatory Type 2 SMA patients ≥ 2 to < 18 
years. Approximately 125 patients aged ≥ 2 to < 18 years will be recruited. Approximately 65 
recruited patients will be between ≥ 2 and < 5 years and approximately 60 patients will be 

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between ≥ 5 and < 18 years. Participants will be randomized in a 3:2 ratio to receive OAV101 
(1.2 x 1014 vector genomes) by lumbar intrathecal injection (n=~75) or to receive a sham 
procedure (n=~50). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3-2 
Summary of Screening Period to end of Follow-up Period 1 
 
Description of study periods 
Screening and Baseline periods, Treatment and Follow-up Period 1 
• Screening period (Day -60 to Day -14): After obtaining Informed 
Consent, participants will undergo a screening evaluation (Table 8-1). 
• Screening Visit 1 (Day -60): Clinical and laboratory data, including coagulation 
testing, is obtained for eligibility assessment.  
• Screening Visit 2 (Day -21): At this time, inclusion and exclusion criteria are 
reviewed and motor assessments are performed as well. 
• Screening Visit 3 (Day -14): If the participant is determined to be eligible for the trial, 
randomization will occur, and the double-blind period of the trial will begin 
• Screening period motor assessments: For each participant, an assessment of the 
HFMSE and RULM is performed (Section 8.3.1.1 and Section 8.3.1.2). In order to 
meet eligibility requirements for the trial, the participant must have a complete 
HFMSE administration with total score during the screening period (Section 5.1), thus 
assuring that at least one complete pre-treatment HFMSE assessment is available to 
assess OAV101 efficacy. If the HFMSE is unable to be completed to allow for a total 
score, a repeat of the assessment is required during the Screening period 
(Section 8.1). See Section 8.3.1.1and Section 8.3.1.2 for completion of HFMSE and 
RULM motor assessments. 
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• Baseline Period (Day -1): The Baseline Period occurs 1 day prior to intrathecal OAV101 
or the sham procedure. All eligible participants will undergo pre-dosing evaluations 
(Table 8-1). 
• Baseline Day -1 visit motor assessments: A HFMSE and RULM assessment is 
performed at the Baseline Day -1 visit. If either the HFMSE or RULM is unable to be 
completed providing a total score, no repeat of the assessment is required 
(Section 8.3.1.1 and Section 8.3.1.2). 
• Baseline Day -1 Prophylactic Prednisolone and placebo administration: In an 
attempt to dampen the host immune response to the adeno-associated virus (AAV) 
derived therapy, participants randomized to the treatment arm will receive oral 
prophylactic prednisolone 
 
 Participants randomized to the sham procedure arm will receive a matching 
placebo. Treatment or placebo will continue for 
 
 
• Treatment Period 1 
• OAV101 treatment or sham procedure (Day 1, Day 2, optional Day 3): Participants 
will be admitted to the study center on Day 1 (or on Day -1 as per local standard of 
care). Participants randomized to the treatment cohort will receive intrathecal 
OAV101. Participants randomized to the control group will receive a sham procedure 
that consists of only a needle prick. 
 
 in 
accordance with the Assessment Schedule (Table 8-1). Lumbar puncture and 
OAV101 administration should be performed using an atraumatic spinal needle (e.g. 
Whitacre, 22 or 25 gauge) which significantly lowers the incidence of blood patch 
treatment (Hatfield et al 2008). Following the OAV101 administration/sham 
procedure on Study Day 1, participants will remain at the study center for 24 to 48 
hours for post-procedure for safety monitoring. 
• Follow-up Period 1 
• Visit Week 1 to Visit Week 12: Assessments proceed as outlined in Table 8-1.  
• Visit Week 16 to Visit Week 48: Assessments proceed as outlined in Table 8-1. 
• End of Follow-up Period 1 (Week 52): Participants complete End of Follow-up Period 
1 (Week 52) when each participant returns to the treatment center for final follow-up 
evaluations as per the Assessment Schedule (Table 8-1). 
• Blinding will be maintained through the end of study (Week 64). When all 
participants complete the Week 52 visit, all data collected through Week 52 will be 
analyzed (Primary analysis). Data will be reported in a Registration Clinical Study 
Report (CSR) for health authority data submission. See Treatment Period 2 
description for further discussion of implications of elevated anti-AAV9 antibodies for 
trial blinding. 
• To minimize the time that the control group is untreated (Section 4.2), participants 
will be assessed for eligibility to enter Treatment Period 2 at the Follow-up Period 1 
Week 48 visit. Eligible participants will begin Treatment Period 2 (Week 52 +1 day 
visit) immediately after completion of Follow-up Period 1.  
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• Data collected at Week 48 (e.g., laboratory analyses and medical status) is used to 
assess patient eligibility for Treatment Period 2. 
• 
 
 
• 
 
 for eligibility for treatment with 
OAV101 in Period 2. 
 
 
 
 
 
• A small number of control patients (estimated as ≤ 5 participants) may not receive 
OAV101 treatment at Week 52+1 day Visit due to elevated anti-AAV9 antibodies and 
would be unblinded. No further follow-up in the trial will be needed for these 
participants. 
• Prednisolone or placebo prednisolone will be administered 
 
 Week 52 + 1 day Visit and will continue as per Section 6.2. 
Participants who complete the double-blind Follow-up Period 1 of the trial are assessed for 
eligibility for Treatment Period 2. Treatment Period 2 will consist of eligibility assessment 
(described below), administration of a single dose OAV101 or sham treatment, and a 12-week 
follow-up period (Figure 3-3). Blinding is maintained for all patients during Treatment Period 
2. Anti-AAV9 antibody results 
 will 
be supplied to designated unblinded Novartis personnel (Table 6-3). Designated unblinded 
Novartis personnel will communicate to the site physician when a participant (who received 
sham procedure in Period 1) has an anti-AAV9 antibody titer reported as elevated. These 
patients will be unblinded and no further follow-up will be required after the Week 52 Visit. 
Global Clinical Supply will ship OAV101 for participants in the sham group in Period 1 only 
if anti-AAV9 antibody titer is not reported as elevated (reference to > 1:50 or a validated results 
consistent with being elevated). 
Treatment and Follow-up Period 2 
Eligibility 
Participants meeting any of the following exclusion criteria at conclusion of Follow-up Period 
1 (Week 52) are not eligible for inclusion in the Treatment Period 2. Retesting of abnormal 
laboratory and other clinical parameters that could be transient or measurement error may be 
allowed  based on judgement of the Principal Investigator and approval by the Sponsor Medical 
Monitor. 
1.  Any medical condition considered clinically significant, that in the opinion of the 
Principal Investigator, would interfere with the overall interpretation of safety 
2. Anti-AAV9 antibody titer reported as elevated (reference to > 1:50 or a validated result 
consistent with being elevated) 
 
 This criterion does not apply to the OAV101 group from Period 1 as 
their anti-AAV9 antibody titers will be elevated after OAV101 treatment. 
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3. Clinically significant abnormalities in laboratory test results as determined by the 
Principal Investigator at week 48. 
4. Presence of any of the following:  
• An active infectious process requiring systemic therapy intended to eliminate the 
infection  within 30 days prior to the OAV101 administration or sham procedure 
• An active but untreated viral or bacterial infectious process within 30 days prior to the 
OAV101 administration or sham procedure  
• Febrile illness within  30 days prior to the OAV101 administration or sham procedure 
5. Clinical or radiological signs of aspiration within 30 days prior to the OAV101 
treatment/sham procedure 
6. Hepatic dysfunction (i.e., ALT, TBL, GGT or GLDH, > ULN (i.e., CTCAE grade 1 or 
greater)) at week 48 
NOTE: In the absence of other liver laboratory abnormalities, isolated AST elevation 
is not considered exclusionary 
7. Contraindications for lumbar puncture procedure (including but not limited to cutaneous 
infection at the treatment site and signs or symptoms of increased intracranial pressure), 
active administration of any intrathecal therapy, presence of an implanted shunt for the 
drainage of CSF, presence of an implanted central nervous system (CNS) catheter, or any 
impediment to CSF access 
8. Requiring ventilation for > 16 hours during a 24-hour period or requiring tracheostomy 
within 30 days prior to OAV101 treatment/sham procedure 
9. Awake hypoxemia (defined as O2 saturation < 95% in room air) within 30 days prior to 
the OAV101 treatment/sham procedure, that is clinically significant, as per investigator 
judgement 
NOTE: For altitudes > 1000 m, awake hypoxemia is defined as O2 saturation < 92% in 
room air 
NOTE: For altitudes > 2500m, awake hypoxemia is defined as O2 saturation < 90% in 
room air 
10. BMI < 3rd percentile, if considered clinically significant by the Investigator 
NOTE: BMI is based on the WHO Child Growth Standards (WHO 2022a) and WHO 
Growth reference data for 5-19 years (WHO 2022b). 
11. Positive for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C, including 
latent infections that may be susceptible to reactivation due to corticosteroids. 
Note: Other pathogens that may be endemic to specific regions/countries (e.g., human T-
lymphotropic virus or mycobacterium tuberculosis) may be tested, as per investigator 
discretion and discussion with Sponsor. 
12. Platelet count < lower limit of normal (LLN) at Week 48  
13. Platelet transfusion within 60 days prior to the OAV101 treatment/sham procedure 
14. Clinically significant sensory abnormalities in the neurological examination at Week 48 
15. Use of prohibited SMN-targeting therapy during Period 1 
16. Does not meet age-appropriate institutional criteria for use of anesthesia/sedation as 
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17. Female participants who are sexually active or have reached menarche have a positive 
pregnancy test at Week 48 
18. Administration of vaccines within 2 weeks prior to injection of OAV101 or sham 
procedure  
19. Concomitant use of any of the following medication categories within 90 days prior to 
study treatment (Week 52 + 1 Day):  
• Ongoing systemic immunosuppressive therapy (e.g., corticosteroids (except for 
prophylactic use for OAV101 dosing), cyclosporine, tacrolimus, methotrexate, 
cyclophosphamide, intravenous immunoglobulin, rituximab), plasmapheresis, 
immunomodulators (e.g., adalimumab)  
20. Inability to tolerate corticosteroids administered by mouth or gastrostomy tube 
21. Any medication deemed by Principal Investigator to pose an unacceptable safety risk for 
gene therapy administration 
Figure 3-3 
Summary of Period 2 eligibility assessment, Treatment and Follow-up 
Period 2 
Eligibility, Treatment and Follow-up Period 2 
Eligibility 
assessment 
 
OAV101 or Sham 
Administration 
Week 52 + 1 Day 
Week 53 to 64 data collection 
Maintain blinding (except for control patients ineligible for treatment 
Description 
Treatment Period 2 
• OAV101 treatment or sham procedure (Week 52 + 1 Day visit, Week 52 + 2 Day visit; 
Week 52 + optional 3rd Day visit): Participants will be admitted to the study center at the  
Week 52 + Day 1 visit (or on Week 52 as per local standard of care). Participants 
previously treated with OAV101 will receive only a needle prick and previously untreated 
participants who meet eligibility requirements will receive intrathecal OAV101. If study 
treatment visit at the Week 52 + 1 visit is not possible due to a national emergency or 
other unforeseen reason, extensions to the visit window may be discussed with the 
Sponsor.  
• Prophylactic Prednisolone and placebo: Prednisolone or placebo will be administered 
daily 
 
 
Follow-up Period 2 
• Visit Week 53 to Visit Week 64: All participants will be monitored for safety and efficacy 
until Week 64. Participants who prematurely discontinue the trial during the Treatment 
Period 2 will be offered enrollment in a separate Long Term Follow-Up study. Data 
collected during Treatment Period 2 will not be used for any endpoint analyses. Safety and 
efficacy data collected during Follow-up Period 2 will be presented using descriptive 
statistics in tables and listings and will be reported as a final CSR report. 
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• Visit Week 64 End of Study: The end of study is last participant; last visit. Novartis, 
parents/caregivers, and key study site personnel will be blinded to the participant's 
treatment assignment excluding any patients unblinded during the trial (e.g., controls 
ineligible for OAV101 treatment discussed above). 
Following end of study, participants will be invited to enroll in a Novartis-sponsored long-term 
follow-up study to monitor long-term safety and efficacy. 
4 
Rationale 
Safety and clinically meaningful efficacy with IT delivery of OAV101 was observed in the open 
label AVXS-101 CL-102 study (see Investigator's Brochure). Hence, OAV101 IT may provide 
a safe, one-time treatment option leading to prolonged, clinically meaningful benefit in older 
and heavier SMA patients. 
4.1 
Rationale for study design 
Table 4-1 
Rationale for study design 
Overall 
This is a randomized, sham-controlled, double-blind study to evaluate 
the efficacy, safety, and tolerability of OAV101 in sitting but never 
ambulatory participants aged ≥ 2 to < 18 years with Type 2 SMA. 
The primary efficacy endpoint is the change from baseline in HFMSE 
total score at the end of Follow-up Period 1 in the ≥ 2 to < 18 years 
age group. Secondary efficacy endpoints will evaluate the change 
from baseline HFMSE total score at the end of Follow-up Period 1 in 
the ≥ 2 to < 5 year age group, the achievement of at least a 3-point 
improvement in HFMSE total score at the end of Follow-up Period 1 in 
both the ≥ 2 to < 18 year age group and the ≥ 2 to < 5 year age group, 
and the change from baseline in RULM total score at the end of 
Follow-up Period 1 in both the ≥ 2 to < 18 year age group and the ≥ 2 
to < 5 year age group. 
Rationale using HFMSE and RULM motor scales for primary and 
secondary endpoints: 
HFMSE: The HFMSE is an SMA-specific 33-item questionnaire that is 
easily administered by clinical evaluators in a short period of time, 
requires minimal equipment, and is not fatiguing to individuals 
(Krosschell et al 2006, Krosschell et al 2011). The scale was originally 
developed with 20 scored activities devised for use in children with 
SMA Types II and III with limited ambulation to give objective 
information on motor ability and clinical progression (Main et al 2003). 
The expanded scale includes an additional module of 13 selected 
items from the Gross Motor Function Measure (GMFM) to allow for 
motor function evaluation in ambulatory children with SMA 
(O'Hagen et al 2007) 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 (Main et al 2003). Evaluation of inter-rater reliability 
and test-retest reliability demonstrated that these functional 
assessments could be performed reliably in a multicenter clinical trial 
with rigorous initial, annual, and periodic retraining and support to 
ensure standardization (Mercuri et al 2006). A Phase 1 study of 
nusinersen reaffirmed that the HFMSE is sensitive to change, with a 3-
point change in score considered clinically meaningful and indicates 
that a child improved on at least 2 HFMSE motor skills 
(Mercuri et al 2018b). The HFMSE has well-established psychometric 
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reliability and correlation with the GMFM and GMFM-75 
(Ramsey et al 2017). The HFMSE was used in the AveXis open label 
CL-102 trial of intrathecal OAV101 administration which allowed 
determination of efficacy response parameters in the 2 to 5 years age 
group important for COAV101B12301 trial. In addition to use with 
SMN-targeting therapies for SMA, the HFMSE is correlated with 
various aspects of SMA disease severity with positive associations 
found with SMN2 copy number, compound muscle action potential 
(CMAP), forced vital capacity (FVC) and muscle strength, making it 
clearly a disease-specific outcome measure of choice for clinical trials 
(Glanzman et al 2011, Kaufmann et al 2012, Farrar et al 2013). 
RULM: The RULM is a validated SMA-specific outcome measure that 
assesses upper limb functional abilities in individuals with SMA, 
including young children and non-ambulatory young children and 
weaker individuals who have a floor effect or very low score on the 
HFMS (Pera et al 2019). The original test consists of 9 items, but the 
revised version of the test consists of 19 scorable items: 18 items 
scored on a 0 (unable) to 2 (full achievement) scale, as with the 
HFMSE, 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 (Pera et al 2019). The 
RULM consists of upper limb performance items that are reflective of 
reachable space and activities of daily living (i.e., raise a can to mouth 
as if drinking, take a coin and place it in a box, and remove the lid of a 
container) (Pera et al 2019). The RULM is quickly administered, well 
tolerated by children of 30 months of age to adults, suitable for use in 
multicenter settings, and has been evaluated in clinical trials 
assessing the efficacy of SMN--targeting therapy 
(Mercuri et al 2018b). Since the RULM is being administered in a 
blinded fashion to treated participants and controls across the 2 to 18 
years age range, all patients will be scored. 
Randomization 
(strata, allocation ratio) 
Approximately 125 participants will be randomized 3:2 to receive 
OAV101 (N= ~75) or a sham procedure (N= ~50). The unequal 
randomization ratio limits the number of participants allocated to the 
sham-procedure arm. It is anticipated that approximately 65 
randomized participants will be aged ≥ 2 to < 5 years and 
approximately 60 randomized participants will be aged ≥ 5 to < 18 
years. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 to assess if OAV101 is 
efficacious, safe, and well-tolerated in this population. 
 
 
 
 thereby maximizing statistical power for detecting 
differences in each age group. . 
 rationale: The primary endpoint for the trial is the 
change in HFMSE over 52 weeks in the ≥ 2 to < 18 years age group. 
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Natural history assessment of late onset SMA patients 
demonstrates 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 rationale: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant and investigator 
blinding 
Blinding of participants, physical/occupational therapist (or national 
equivalent) who performs HFMSE and RULM, and the investigator 
controls for bias during study endpoint assessment.  
Duration of study 
A clinical study duration of 52 weeks optimizes the probability of 
clearly demonstrating the potential clinical efficacy of OAV101 for 
IT administration while limiting the time SMA participants randomized 
to the sham procedure arm are required to remain on a non-active-
treatment regimen. The data for assessment of endpoints is based on 
a 52-week follow-up period. 
Sham procedure comparator 
The use of a sham procedure as a comparator will provide a 
comparison group for an unbiased collection and assessment of 
efficacy, safety and tolerability. The sham procedure will consist of a 
small needle prick on the lower back at the location where the lumbar 
puncture injection is normally made. The needle will break the skin but 
no needle insertion for lumbar puncture will occur. Lumbar puncture 
and OAV101 administration should be performed using an atraumatic 
spinal needle (e.g., Whitacre, 22 or 25 gauge) which significantly 
lowers the incidence of blood patch treatment (Hatfield et al 2008). 
Observation period 
Review of data from the previous AVXS-101-CL-102 study confirmed 
the importance of following participants for 52 weeks to evaluate the 
statistical significance and clinical meaningfulness of the observed 
changes. Data analysis at time points before 52 weeks may not have 
sufficient power to adequately evaluate therapeutic efficacy. Although 
blinding is maintained at 52 weeks when a second blinded OAV101 
treatment of control patients and sham procedure with needle prick is 
performed on treated participants, the data for assessment of 
endpoints is based on a 52-week follow-up period. 
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4.1.1 
Rationale for choice of background therapy 
The study allows for standard of care, non‑disease modifying SMA therapy, including 
respiratory and nutritional support, physical therapy, and prevention of infection therapies in 
accordance to treatment guidelines and local practice.  
Participants are expected to have access to respiratory equipment (e.g., cough assist machine) 
in the event they are required during the course of the study (e.g., develop a respiratory illness). 
Sites should have a plan in place to provide respiratory equipment (including for inside and 
outside hospital settings), if required, to those who do not have access. This will further mitigate 
safety and efficacy confounders. 
Physiotherapy, occupational therapy and other forms of supportive therapies are allowed but 
the frequency should remain the same throughout the duration of the clinical study, if possible. 
The use of concomitant therapies or procedures must be documented on the appropriate Case 
Report Form (CRF) (Section 6.2.1). 
4.2 
Rationale for dose/regimen and duration of treatment 
OAV101 will be administered in this trial as a single intrathecal injection as a nominal dose of 
1.2 x 1014 vector genomes (vg). 
The primary, secondary and exploratory evaluation will be conducted over a 52-week follow-up 
period. A clinical study duration of 52 weeks optimizes the probability of clearly determining 
the potential clinical efficacy of OAV101 for IT administration while limiting the time SMA 
participants randomized to the sham OAV101 administration-control arm are required to remain 
on a non-active-treatment regimen. This conclusion is based on the clinically meaningful and 
statistically significant motor improvements over 52 weeks observed in the ≥ 2 to < 5 year age 
group from AVXS-101-CL-102 and from the late onset SMA natural history data which 
carefully investigates the ≥ 2 to < 18 year old age group over 52 weeks (Coratti et al 2020b, 
Coratti et al 2020a). 
a. AVXS-101-CL-102 in the ≥ 2 to < 5 year age group supports a trial duration of 52 weeks. 
Efficacy assessment in participants from the AVXS-101-CL-102 study who received IT 
OAV101, indicate that a 52-week follow-up period for the primary endpoint is appropriate for 
the COAV101B12301 clinical trial (see Investigator's Brochure). Based on a mixed model with 
repeated measurement analysis of change from baseline in HFMSE scores, participants aged 
2-5 years treated with OAV101 experienced a progressive improvement in motor skills over the 
12 month observation period (LS mean change from baseline at Month 12 6.0; 95% confidence 
interval 3.7 to 8.3) whereas the natural history controls (Pediatric Neuromuscular Clinical 
Research (PNCR) dataset) showed smaller change of motor skills (LS mean change from 
baseline at Month 12 0.5; 95% confidence interval -2.2 to 3.2 (see Investigator's Brochure). The 
estimated difference in LS means (95% confidence interval) relative to the PNCR dataset for 
the change in HFMSE from baseline to Month 12 was 5.5 (1.9, 9.0) points with a p-value of 
0.0027 (see Investigator's Brochure). 
The limited gross motor changes over 52 weeks observed in the CL-102 PNCR natural history 
cohort were recently confirmed in a large multi-national natural history study consisting of 267 
Type 2 SMA patients 30 months to 33.4 years of age (Coratti et al 2020b). Children from the 2 

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to 5 year old age group from this natural history study were able to sit but not walk at baseline 
which was similar to the clinical features of the CL-102 participants. The 12-month HFMSE 
change from baseline in this 2 to 5 year old natural history group demonstrated a mean ± 
standard deviation of 0.40 ± 4.09 (Coratti et al 2020b). 
Review of the LS mean at various points in the study confirmed the importance of following 
the participants for 52 weeks to evaluate the statistical significance and clinical meaningfulness 
of the observed changes. Data analysis at time points before 52 weeks may not have sufficient 
power to adequately evaluate therapeutic efficacy. 
b. Late onset SMA patient natural history supports a trial duration of 12 months for appropriate 
assessment of change from baseline in motor function (Coratti et al 2020a, Coratti et al 2020b). 
In the largest and most comprehensive natural history study to date in 267 Type 2 SMA patients 
(age range 30 months to 33.4 years), the detailed data based on 652 assessments allows 
delineation of age groups based on disease progression as well as patient motor abilities 
(Coratti et al 2020b, Coratti et al 2020a). Of the 652 assessments, 541 were from patients who 
could sit but were never ambulatory and all but one patient had 2 to 4 SMN2 copies. These key 
clinical features are aligned with the study population inclusion criteria for COAV101B12301. 
Although patient motor function declined with age in this natural history study, 12 months of 
assessment allowed clear characterization of changes across the age range, further supporting 
the 12-month trial duration chosen for the COAV101B12301 study population. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
The generally slow rate of decline observed in patients with late onset SMA combined with 
provision of treatment within 12 months for those in the sham control group, provides a strong 
rationale for the study design. Patients randomized to the sham control group will receive 
OAV101 after they complete Week 52. Additionally, to improve treatment access for 
participants during the study, randomization is set at 3:2 which limits the number of patients in 
whom treatment is delayed. 
Prednisolone prophylaxis and placebo: participants randomized to the treatment arm will 
receive prophylactic prednisolone 
 
, to dampen the host immune response. Prednisolone is continued 
 
, as indicated in Table 6-2. Participants randomized to the sham 
procedure arm will receive a placebo instead of prednisolone and follow the same 
administration protocol. The same administration protocol of prednisolone or placebo will be 
followed in Period 2. 
4.4 
Purpose and timing of interim analyses/design adaptations 
No formal interim analysis is planned for this trial. 
The data collected during this study will be reported two times. Once the last participant 
completes the Week 52 visit, formal cleaning procedures will be initiated and the database will 
be soft-locked in preparation for the primary analysis. Treatment assignments will be unblinded 
to designated sponsor personnel and a full analysis of all efficacy and safety data will be 
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conducted and reported to health authorities. This will constitute the first analysis of data. Once 
the last participant completes the Week 64 visit, formal cleaning procedures will be initiated 
and the database will be hard-locked in preparation for the final analysis. Efficacy data collected 
during Treatment Period 2 will be summarized descriptively in tables and listings. Safety data 
collected during Treatment Period 2 will be combined with safety data collected during 
Treatment Period 1 to provide a comprehensive safety analysis of data collected over the full 
64-week study duration. 
4.5 
Risks and benefits 
The ability of OAV101 to achieve sustained expression of SMN in motor neurons with one-time 
dosing is a clear unmet need in later onset SMA Type 2. Uninterruptable and constant 
SMN protein production within motor neurons positively impacts the clinical phenotype by 
allowing motor development which leads to stability in motor function. Clinical data strongly 
suggest OAV101 is safe and well tolerated with an acceptable benefit/risk profile when 
administered to patients with 5qSMA with 2 or 3 survival motor neuron 2 (SMN2) copies or a 
clinical diagnosis of SMA. Safety and clinically meaningful efficacy with IT delivery of 
OAV101 was observed in CL-102 (see Section 4.2). The risk to participants in this trial may be 
minimized by compliance with the eligibility criteria and study procedures, as well as close 
clinical monitoring. Refer to the Investigator's Brochure for a summary of OAV101 efficacy 
data. Categories of risks and benefits are discussed below. 
4.5.1 
Potential benefits to participants 
The ability of OAV101 to achieve sustained expression of SMN in motor neurons with one time 
dosing is a clear unmet need in later onset SMA patients. Uninterruptable and constant SMN 
protein production within motor neurons positively impacts the clinical phenotype by allowing 
motor development which leads to stability in motor function. Safety and clinically meaningful 
efficacy with IT delivery of OAV101 was observed in the open label CL-102 clinical trial (See 
Investigator's Brochure). Hence, OAV101 IT may provide a safe, one time treatment option 
leading to clinically meaningful benefit in patients with Type 2 SMA age 2 to < 18 years. 
4.5.2 
Ethical considerations 
The generally slow rate of decline observed in patients with late onset SMA combined with 
provision of treatment within 52 weeks of those in the sham procedure group provides a strong 
ethical rationale for the design of the COAV101B12301 clinical study. In the natural history 
study described above (Coratti et al 2020b), 62% of patients who could sit but not walk at 
baseline showed stability (12-month changes within ± 2 HFMSE points), 25% showed 
decreased function (12-month changes > 2 HFMSE points), and 13% of patients showed 
improvements (12-month changes > 2 HFMSE points). 
Ethical considerations for COAV101B12301 design include the following features. 
• All eligible individuals enrolled in study COAV101B12301 will be offered IT 
administration of OAV101. Participants randomized to the sham procedure cohort may 
receive OAV101 after they complete the 52-week clinical trial assessment period. 
Although it is possible that a very small number of individuals could have elevated 
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(Week 52 + 1 day), the risk of natural infection resulting in elevated neutralizing 
antibodies in the 2 to 18 year old age range appears to increase slowly with age 
(Mimuro et al 2014). It is estimated that ≤ 5 participants who received the sham procedure 
would be excluded from receiving OAV101 treatment as a result of contracting a natural 
infection during Period 1. 
• To improve treatment access during the study for participants, randomization is set at 3:2 
rather than 1:1, which limits the number of participants in whom treatment is delayed and 
improves the probability that a participant would be in the OAV101 treatment group. 
4.5.3 
OAV101 risks 
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 patients continue to exhibit 
the achievement of additional milestones. Data spans pre-symptomatic and symptomatic 
patients and includes SMA Type 1 and Type 2 patients. 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 external Data Monitoring Committee (DMC). The 
safety profile of OAV101 is described in the Investigator's Brochure. The risks and benefits are 
derived from the following categories of clinical safety and efficacy data for the intravenous 
(IV) and intrathecal administration of OAV101 plus non-clinical data. 
• Non-clinical toxicology and nonhuman primate studies 
• Numerous clinical studies for the intravenous treatment of symptomatic and 
pre-symptomatic patients with SMA who have 1, 2 or 3 copies of the SMN2 gene and 
bi-allelic SMN1 gene deletions. 
• Safety and clinically meaningful efficacy with intrathecal delivery of OAV101 was 
observed in the CL-102 clinical trial across an age range of 6 months to 5 years of age 
• Long term observational follow-up studies of patients who were administered intravenous 
OAV101 in clinical trials 
• United States (US) managed access program of patients treated with intravenous OAV101 
(Zolgensma) 
• Long-term registry of patients diagnosed with SMA, irrespective of type or treatment 
provided 
• Post-marketing safety monitoring 
A brief overview of the clinical data that defines the intravenous and intrathecal OAV101 risks 
are outlined below. 
Clinical data overview for intravenous and intrathecal administration: As of 11-Jun-2020, 
based on individual case safety reports from all sources, the most common adverse events (25 or 
more reports) were 
 
 
 On the basis of important identified and potential risks associated with 
OAV101, adverse events of special interest are summarized for the following categories. The 
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discussion of intrathecal OAV101 safety focuses on the 1.2 x 1014 vector genome dose selected 
for this clinical trial (COAV101B12301).  
Each of the following is an important identified or important potential risk associated with 
OAV101: 
• Hepatotoxicity 
• Transient thrombocytopenia 
• Cardiac adverse events 
• Dorsal root ganglia toxicity 
• Thrombotic microangiopathy 
• Theoretical risk of tumorigenicity due to vector integration 
Hepatotoxicity 
Intravenous administration overview: Elevation in liver transaminases is observed with AAV 
gene therapy in humans (Verdera et al 2020). In OAV101 clinical trials elevations in liver 
transaminases have been reported. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
As of June 2022, in the postmarketing setting, cases of acute liver failure have been reported, 
including 2 cases with a fatal outcome. In certain cases, patients required hospitalization, and 
exhibited signs and symptoms associated with liver dysfunction (e.g., jaundice, coagulopathy, 
elevated ammonia levels). 
Intrathecal administration overview: 
 
 
 With 
respect to the 1.2 x 1014 vector genome dose of intrathecal OAV101 selected for this clinical 
trial (COAV101B12301), the CL-102 open label trial included safety and efficacy evaluation 
of the 1.2 x 1014 vector genome dose of intrathecally administered OAV101 in 25 patients 
between 6 months and 5 years of age.
 
 
 
 
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Transient thrombocytopenia 
Intravenous administration overview: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intrathecal administration overview: 
 
 
 
 
 
 
 
 
 
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Cardiac adverse events 
Intravenous administration overview: Cardiac toxicity has been identified as an important 
potential risk based on non-clinical toxicology data. The translatability of the observed findings 
to humans has not been verified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intrathecal administration overview: 
 
 
 
 
 
 
 
 
 
Dorsal root ganglia toxicity 
 Following 
intrathecal administration of OAV101 
 
 
 
 
 
 findings in the nervous system 
 
 
 
 These findings were considered 
 
 
 
 
 
 
 
 nervous system findings 
 
 
 
 
 
 
 
 
 
 
Further details of the OAV101-related 
 
can be found in the Investigator’s Brochure. 
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Intravenous and intrathecal OAV101 administration: 
 
 
 
 
Thrombotic microangiopathy (TMA) 
Intravenous administration overview: Thrombotic microangiopathy (TMA) is characterized by 
arteriole and capillary endothelial pathology and microvascular thrombosis. TMA presents 
clinically as a syndrome of thrombocytopenia, hemolytic anemia, and acute kidney 
injury. 
 
 
 
 
Intrathecal administration overview: 
 
 
Theoretical risk of tumorigenicity due to vector integration 
There is a theoretical  risk of tumorigenicity due to integration of AAV vector DNA into the 
genome. OAV101 (onasemnogene abeparvovec) is composed of a non-replicating AAV9 
vector whose DNA persists largely in episomal form. Rare instances of random vector 
integration into human DNA are possible with recombinant AAV. The clinical relevance of 
individual integration events is unknown, but it is acknowledged that individual integration 
events could potentially contribute to a risk of tumorigenicity. 
Risk of immunosuppression 
All patients in the study will receive prophylaxis immunosuppression with prednisolone to 
mitigate safety risks associated with inflammation. 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 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 (Table 6-2). 
Risk of viral shedding 
OAV101 DNA can be found in the blood, urine, saliva, and stool for up to a few weeks 
following injection. The risks associated with the shed vector are not known at this time; 
however, because the vector is non-pathogenic and cannot replicate, it is believed that the shed 
vector is unlikely to result in clinically significant adverse effect. 
Risk of phlebotomy  
Pain or bruising at the injection site may occur. Infections at the injection site are also possible. 
The World Health Organization (WHO) Guidelines for Drawing Blood and Best practices in 
Phlebotomy in pediatric patients (WHO 2010) will be followed. 
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Risks of lumbar puncture 
Lumbar puncture risks can include headache, back pain, or bleeding near the puncture site that 
may need to be treated or may resolve on its own. Potential risks that are extremely rare include 
infection, nerve injury, and paralysis. 
The risks are minimal in the context of one-time gene therapy providing potentially overall 
efficacy. 
Risks of 
 
The test to measure 
 to determine 
 
 Thus, while the test can be utilized to 
measure 
 
Therefore, the accuracy of results from this test has not been fully established. Furthermore, the 
benefit-risk of OAV101 in participants with 
 has not been 
determined.  
4.5.4 
OAV101-drug interactions 
OAV101 is a gene replacement therapy product for one-time administration, which delivers a 
transgene construct expressing the SMN protein. Drug-drug interactions are not expected with 
OAV101. 
4.5.5 
Teratogenicity and associated risks 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the inclusion criteria. If there is any question that the participant will 
not reliably comply, they should not be entered or continue in the study. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a public health emergency as declared by local or regional authorities i.e., pandemic, 
epidemic, or natural disaster, mitigation procedures to ensure participant safety and trial 
integrity may be implemented. Notification of the public health emergency as declared by local 
or regional authorities should be discussed among investigators and  Novartis. All procedures 
adapted to the situation must be submitted, if required as per local regulations, through a 
protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures. 
5 
Study Population 
Inclusion and exclusion criteria should be assessed during the screening period to determine 
patient eligibility for the trial. This randomized, double-blind, sham-controlled study will test 
the clinical efficacy, safety, and tolerability over 52 weeks of a single, nominal dose (1.2 x 1014 
vector genomes) of intrathecal OAV101 in patients with 5q SMA who are ≥ 2 to < 18 years of 
age at the time of screening. The 5q SMA study population genotype is characterized as 
harboring biallelic SMN1 pathogenic variants. Approximately 125 patients aged ≥ 2 to < 18 
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years will be recruited consisting of ∼65 patients between the ages of ≥ 2 to < 5 years and of 
∼60 patients between the ages of ≥ 5 to < 18 years. The ~125 participants enrolled to the trial 
are randomized in a 3:2 ratio to receive OAV101 by intrathecal lumbar puncture (LP) injection 
(n=~75) or to receive the sham procedure (n=~50). 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria. 
1. Signed informed consent and assent (if applicable) must be obtained before any 
assessment is performed. 
2. Diagnostic confirmation during screening period of 5q SMA. 
3. The patient must be treatment naive (historical or current use) for all SMN-targeting 
therapies (e.g., risdiplam (Evrysdi) and nusinersen (Spinraza)). 
4. ≥ 2 years and < 18 years of age at screening visit 1. 
5. Onset of clinical signs and symptoms at ≥ 6 months of age. 
6. Patient must have a complete HFMSE assessment with an available total score, as 
administered by qualified clinical evaluator during the screening period for trial eligibility. 
7. Able to sit independently at screening, but has never had the ability to walk independently. 
• Definition of sitting independently: Child sits up straight with the head erect for at 
least 10 seconds without using arms or hands to balance body or support position 
(Wijnhoven et al 2004). 
• Definition of walking independently: The child is able to balance the body and control 
forward stepping movements without assistance (Wijnhoven et al 2004). 
8. Estimated life expectancy > 2 years from screening, in the opinion of the Investigator. 
9. Meets age-appropriate institutional criteria for use of anesthesia/sedation as assessed by 
the physician responsible for administering anesthesia/sedation. 
10. Female participants who are sexually active or have reached menarche must have a 
negative pregnancy test at Screening. Those females who are sexually active must also 
agree to use highly effective methods of contraception (implants, injectables, oral 
contraceptives [hormonal], IUDs, total abstinence) as well or limit sexual activity to 
surgically sterilized or contraception-practicing partners during the trial and for 24 months 
after the administration of the investigational product. Female patients must agree to 
refrain from egg freezing and egg donation until 24 months after dosing. 
Note: In case of use of oral contraceptives, females should have been stable on the same 
pill for a minimum of 3 months before taking the study treatment. If local regulations 
deviate from the contraception methods listed above to prevent pregnancy, local 
regulations apply and will be described in the informed consent form (ICF). 
11. Males capable of fathering a child must agree to use barrier contraception (combination of 
a condom and spermicide) or be abstinent for 6 months after each OAV101 
administration/sham procedure (i.e., Day 1 and Week 52 + 1 Day). In addition, male 
patients must agree to refrain from sperm donation during the trial and for 12 months after 
Treatment Period 2. 
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5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
Retesting of abnormal laboratory and other clinical parameters that could be transient or 
measurement error may be allowed up to two times based on judgement of the Principal 
Investigator in communication with the Sponsor Medical Monitor.  
1. Excluding SMA, any medical condition considered clinically significant by the 
Investigator, including cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine 
disorder including diabetes mellitus, gastrointestinal disorders, metabolic disorders, 
untreated B6 deficiency, 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. 
2. Anti-AAV9 antibody titer reported as elevated (reference to > 1:50 or a validated result 
consistent with being elevated) at Screening 
 
   
3. Clinically significant abnormalities in test results during screening period and/or during 
baseline period as determined by the investigator. 
4. Participants will be excluded from the trial for inpatient surgery hospitalization, 
hospitalization for a pulmonary event, or hospitalization for nutritional support within 2 
months prior to Screening and up to Day 1. In addition, patients will not be eligible for the 
trial if at Screening, inpatient major surgery is planned at any time during the 64-week 
study. Any other surgeries must not interfere with the ability of the patient to perform the 
study assessments. 
5. Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts the 
participant’s ability to perform any of the outcome measure testing required in the 
protocol and from which the participant has not fully recovered or achieved a stable 
baseline upon entry into screening period. 
6. Contraindications for lumbar puncture procedure, (including but not limited to cutaneous 
infection at the treatment site and signs or symptoms of increased intracranial pressure), 
active administration of any intrathecal therapy, presence of an implanted shunt for the 
drainage of CSF, presence of an implanted central nervous system (CNS) catheter, or any 
impediment to CSF access. 
7. Presence of any of the following: 
• An active infectious process requiring systemic therapy intended to eliminate the 
infection within 30 days prior to dosing of OAV101 or the sham procedure 
• An active but untreated viral or bacterial infectious process within 30 days prior to 
dosing of OAV101 or the sham procedure 
• Febrile illness within 30 days prior to OAV101 administration or sham procedure 
8. Administration of vaccines within 2 weeks prior to injection of OAV101 or sham 
procedure. 
9. Clinical or radiological signs of aspiration within 30 days prior to Day 1. 
10. Requiring invasive ventilation, awake noninvasive ventilation for > 6 hours during a 
24-hour period, noninvasive ventilation for > 12 hours during a 24-hour period or 
requiring tracheostomy within 30 days prior to Day 1. 
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11. Awake hypoxemia (defined as O2 saturation < 95% in room air) within 30 days prior to  
Day 1. 
NOTE: For altitudes > 1000 m, awake hypoxemia is defined as O2 saturation < 92% in 
room air 
NOTE: For altitudes > 2500 m, awake hypoxemia is defined as O2 saturation < 90% in 
room air 
12. Hepatic dysfunction (i.e., ALT, TBL, GGT or GLDH, > ULN (i.e., CTCAE grade 1 or 
greater)) at Screening Visit 1. 
NOTE: In the absence of other liver laboratory abnormalities, isolated AST elevation 
is not considered exclusionary 
13. Complications at screening that would interfere with motor efficacy assessments including 
but not limited to: 
• Presence of severe contractures (e.g., hip flexion contracture) which limits the 
participant’s ability to be positioned in prone for HFMSE item administration  
• Scoliosis with a Cobb angle > 40 degrees in a sitting position, evident on x-ray 
examination at Screening 
14. BMI < 3rd percentile if considered clinically significant by the investigator 
NOTE: BMI is based on the WHO Child Growth Standards (WHO 2022a) and WHO 
Growth reference data for 5-19 years (WHO 2022b). 
15. History of untreated or uncorrected vitamin deficiencies which can produce sensory 
neuropathies such as pyridoxine deficiency (B6). 
16. Concomitant use of any of the following medication categories within 90 days prior to 
study treatment (Day 1): 
• Ongoing systemic immunosuppressive therapy (e.g., corticosteroids (except for 
prophylactic use for OAV101 dosing), cyclosporine, tacrolimus, methotrexate, 
cyclophosphamide, intravenous immunoglobulin, rituximab), plasmapheresis, 
immunomodulators (e.g., adalimumab) 
17. Inability to tolerate corticosteroids administered by mouth or gastrostomy tube. 
18. Concurrent or previous participation in another investigational trial in which patient 
receives treatment within 30 days prior to screening, 5 half-lives of the drug, or until the 
expected pharmacodynamic effect has returned to baseline (e.g., biologics), whichever is 
longer. 
• NOTE: Participation in observational cohort studies or non-interventional studies in 
which the participant does not receive treatment or undergo procedures which may 
compromise this study data integrity may be allowed following Sponsor approval. 
19. History of gene therapy, hematopoietic transplantation, or solid organ transplantation. 
20. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes. 
21.  Deleted per Amendment #1 
22. Any medication deemed by Principal Investigator to pose an unacceptable safety risk for 
gene therapy administration. 
23. Surgery for scoliosis or hip fixation in the 12 months prior to Screening or planned within 
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24. Positive for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C, including 
latent infections that may be susceptible to reactivation due to corticosteroids 
Note: Other pathogens that may be endemic to specific regions/countries (e.g., human 
T-lymphotropic virus or mycobacterium tuberculosis) may be tested, as per investigator 
discretion and discussion with Sponsor.  
25. Platelet count < LLN at screening. 
26.  Platelet transfusion within 1 month prior to screening and up to Day 1. 
27. Clinically significant sensory abnormalities in the neurological examination at Screening. 
6 
Treatment 
The investigational drug, OAV101, will be prepared by Novartis and supplied to the unblinded 
study-site pharmacist or equivalent per local practice. The pharmacist (or equivalently trained 
individual per local practice) will prepare the appropriate dosage (detailed instructions will be 
provided in the Pharmacy Manual). An unblinded interventional radiologist or qualified 
specialist (e.g., neurologist) will administer OAV101 (as described in the Pharmacy Manual). 
Strict blinding will be maintained once the participant leaves the procedure room. 
6.1 
Study treatment 
For this study, the terms “investigational drug” or “study drug” refers to OAV101 administered 
as a single intrathecal dose of 1.2 x 1014 vector genomes. The term “study treatment” refers to 
OAV101 treatment or the sham procedure. The investigational drug OAV101 will be prepared 
and supplied by Novartis. See the Pharmacy Manual for OAV101 storage, preparation and 
administration procedures. 
6.1.1 
Investigational and control drugs 
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 inverted 
terminal repeats (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 
Treatment Title 
OAV101 (formerly AVXS-101) 
Treatment Description 
1.2 x 1014 vector genomes in  ml, one time 
Type 
biologic 
Dose Formulation 
solution 
Route of administration 
Intrathecal 
Sourcing 
Provided centrally by the sponsor or locally by 
designee 
Packaging and Labeling 
Study treatment will be provided in a single vial 
carton. Each vial carton will be labeled as required per 
country requirement.  
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6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and prednisolone/placebo (described in 
Section 6.2) are included in this trial. 
6.1.3 
Treatment arms/group 
Approximately 125 participants will be randomized to one of the following 2 treatment arms in 
a ratio of 3:2 (OAV101 : sham procedure): 
• Group 1: OAV101 (1.2 x 1014 vector genomes) 
• Group 2: sham procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.4 
Supply of study treatment 
US and non-European Union (EU) countries where in-country depot is not required: 
Investigational Medicinal Product (IMP) is manufactured by the Sponsor and supplied to US or 
EU Contract Manufacturing Organization. The vials are packaged in a clinical carton (1 vial 
per carton) and shipped out of the US Contract Manufacturing Organization facility directly to 
sites. 
 
 
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 Contract Manufacturing Organization facility directly to the clinical sites. 
 
 
 
Ex-US non-EU countries where in-country depot is required: IMP is manufactured by the 
Sponsor, shipped to US or EU Contract Manufacturing Organization and supplied to in-country 
depot as needed. 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. 
 
 
 
6.1.5 
Treatment duration 
OAV101 is a one-time, single dose treatment for SMA. See study design for OAV101 dosing 
schedule (Section 3). 
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6.2 
Other treatment(s) 
In accordance with this protocol, all study participants randomized to the OAV101 treatment 
arm will receive immunomodulatory therapy with prednisolone and all participants randomized 
to the sham procedure arm will receive matching placebo by the unblinded pharmacist (or 
equivalent). The prednisolone oral liquid will be supplied by 
 
 
 
 
 The matching placebo will be supplied by 
 
. If the above prednisolone and placebo are not 
available, an equivalent corticosteroid and placebo will be provided by other manufacturers. 
Immunomodulatory therapy is intended to mitigate safety risks associated with immune 
response to the AAV9 capsid that may occur after administration of OAV101. 
Immune responses may lead to elevations in liver transaminases or elevations of Troponin I. 
Prior to initiation of the immunomodulatory regimen and prior to administration of 
OAV101/sham procedure, the participant must be checked for symptoms of active infection of 
any nature. 
 
prednisolone/placebo dosing will be instituted according to the schedule below. 
Table 6-2 
Prednisolone Prophylaxis and Placebo Administration 
Period 
Dosing schedule 
Dose 
 
 
 
Prednisolone or placebo 
 
 
 
 
 
 
Prednisolone or placebo 
 
 
 
 
  
 
  
 
 
Table 6-3 
Additional study treatment 
Treatment Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Treatment 
Description 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
Dose 
Formulation 
 
 
 
 
Unit Dose 
Strength(s) 
 mg/ml  
 
 mg/ml 
 
Route of 
Administration 
 
 
 
 
Use 
Prophylactic 
therapy 
Matching 
placebo for 
prophylactic 
therapy 
Prophylactic 
therapy 
Matching 
placebo for 
prophylactic 
therapy 
Sourcing 
Provided centrally 
by the sponsor or 
locally by designee 
Provided centrally 
by the sponsor or 
locally by designee 
Provided centrally 
by the sponsor or 
locally by designee 
Provided centrally 
by the sponsor or 
locally by designee 
Packaging and 
Labeling 
Additional study 
treatment will be 
provided in a single 
bottle carton. Each 
bottle carton will be 
labeled as required 
per country 
requirement. 
Additional study 
treatment will be 
provided in a single 
bottle carton. Each 
bottle carton will be 
labeled as required 
per country 
requirement. 
Additional study 
treatment will be 
provided in a single 
bottle carton. Each 
bottle carton will be 
labeled as required 
per country 
requirement. 
Additional study 
treatment will be 
provided in a single 
bottle carton. Each 
bottle carton will be 
labeled as required 
per country 
requirement. 
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) 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 
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be started. If the participant is already enrolled, contact Novartis to determine if the participant 
should continue participation in the study. 
Participants are encouraged to follow all routinely scheduled immunizations, including 
vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as 
recommended by local health authorities and/or required by local site guidelines. 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 prior to OAV101 administration/sham procedure, and live vaccines should 
not be administered while receiving corticosteroids. 
Prior medications excluded according to the criteria in Section 5.2 will be recorded within 
90 days prior to Screening and all prior medications will be recorded on the eCRF at all visits 
prior to Baseline. 
6.2.2 
Prohibited medication 
Except for concomitant medication allowed per protocol (see Section 6.2.1) and/or any 
nonexcluded medications which may be required to treat AEs, no medication other than study 
treatment will be allowed from the date the informed consent 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 
• Plasmapheresis and immunomodulators 
• Use of intravenous immunoglobulins and vaccines 4 weeks after injection of OAV101 or 
sham procedure; unless required for treatment of Aes 
• Live vaccines are prohibited while receiving corticosteroids. Participants are advised to 
complete all age-appropriate inoculations with live vaccines prior to enrolling in the study 
if possible. 
• The use of immunosuppressive therapies, including but not limited to, cyclosporine, 
tacrolimus, methotrexate, cyclophosphamide, IVIG, rituximab, and adalimumab; unless 
required for treatment of Aes 
Given the nature and profile of the treatment, i.e., gene therapy, there are no pharmacokinetic 
(PK)/pharmacodynamic (PD) 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 
Preparation and dispensation 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, delivery of prednisolone directly to a participant’s home may be permitted (if allowed by 

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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. 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 
Study sites will be supplied with study drug in packaging as described under investigational and 
control drugs section. 
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 Interactive Response Technology (IRT) and obtaining the medication number(s). 
OAV101 will arrive as outlined in the Pharmacy Manual. A single administration of OAV101 
will be prepared by an appropriately trained unblinded pharmacist (or equivalent). 
Preparation of OAV101 will be done aseptically under sterile conditions at the site per 
Pharmacy Manual and will be received ready for injection at the bedside. 
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. The investigational delivery system will be used in accordance with the Pharmacy 
Manual. Instructions for Use will be included in the Pharmacy Manual. 
Study drug administration 
OAV101 
Participants will receive OAV101 injection under sterile conditions in an ICU patient room or 
other appropriate setting (e.g., interventional suite, operating room, dedicated procedure room) 
with immediate access to acute critical care management. Parents/caregivers must not be 
present in the procedure room to ensure blinding (See Section 6.5). Study drug will be 
administered in accordance with the Schedule of Assessments (Table 8-1). 
Sites are instructed to refer to the Pharmacy Manual in the use of atraumatic needles, which has 
been shown to considerably reduce damage to the dura and consequently decrease the risk for 
CSF leakage after lumbar puncture (Rochwerg et al 2018, Nath et al 2018). 
Sedation/anesthesia is required for all participants receiving OAV101 IT. Method and 
medications will be at the discretion of the local anesthesiologist but should incorporate a 
sufficient degree of sedation or anxiolysis to ensure analgesia and lack of movement for the 
procedure and post procedure Trendelenburg positioning placement. Participants will be placed 
in the Trendelenburg position, tilted head-down at 30° for 15 minutes following administration 
of OAV101 to enhance distribution to cervical and brain regions. 

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OAV101 will be administered under sterile conditions by an interventional radiologist or a 
qualified clinician in accordance with institutional guidelines. OAV101 will be delivered per 
standard of care for intrathecal delivery. In patients with medical complexities (e.g., scoliosis, 
spinal hardware, etc.) the use of image-guidance (e.g., fluoroscopy or ultrasound) is required to 
facilitate success of the procedure. For uncomplicated cases (e.g., a young child without 
scoliosis), the use of image- guidance is at the discretion of the proceduralist. Participants will 
be placed in the appropriate position and a spinal needle with stylet will be inserted by a lumbar 
puncture into the L3-L4 or L4-L5 (if needed, may be 1 segment above L3-L4 or 1 segment 
below L4-L5) interspinous space into the subarachnoid space, as detailed in the Pharmacy 
Manual. Subarachnoid cannulation will be confirmed with the flow of clear CSF from the 
needle hub. 
 
 
 
 
Dosing and administration of OAV101 is detailed 
in the Pharmacy Manual. 
Sham procedure 
The sham procedure will be performed in an ICU patient room or other appropriate setting (e.g., 
interventional suite, operating room, dedicated procedure room) with immediate access to acute 
critical care management. Parents/caregivers must not be present during the procedure to ensure 
blinding (See Section 6.5). The sham procedure will consist of a small needle prick on the lower 
back at the location where the LP injection is normally made. The needle will break the skin, 
but no needle insertion for lumbar puncture will occur. 
 
 A detailed description of the 
sham procedure is provided in the Pharmacy Manual. 
Post administration procedures 
Following administration of gene replacement therapy/sham procedure, participants should 
return to an appropriate designated setting to ensure close monitoring of vital signs and Aes. 
Vital signs will be monitored as described under Vital Signs (Section 8.4.4). Participants should 
be maintained in an appropriate inpatient setting for 24 to 48 hours after the start of gene 
replacement therapy/sham procedure. 
Participants will be kept in the ICU patient room or other appropriate setting (e.g., interventional 
suite, operating room, dedicated procedure room) with immediate access to acute critical care 
management for 24 to 48 hours for closer monitoring of mental status. During the inpatient stay, 
personnel are required to follow appropriate safety precautions as per institutional standards for 
infection control; standards may require personal protective equipment such as gowns, gloves, 
masks, glasses, and closed-toe shoes. Participants may be discharged from the hospital when 
the following criteria are met: 
• Afebrile 
• Absence of hypersensitivity reactions 
• Absence of meningism 
• Absence of abnormal laboratory values suggestive of possible CNS infection or 
complication 
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6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
Handling of study treatment 
Study treatment must be received by a designated unblinded person at the study site, handled 
and stored safely and properly and kept in a secured location to which only the designated site 
personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified in the Pharmacy Manual. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance. Please 
refer to procedures as outlined in the Pharmacy Manual. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The designated unblinded site personnel must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the designated 
site personnel will return a copy of the completed drug accountability log to the 
Novartis monitor or to the Novartis address provided in the investigator folder at each site. 
OAV101 will be stored in a locked, limited access room under the responsibility of the 
designated unblinded personnel (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. 
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. 
6.3.1.2 
Handling of other treatment 
The following non-study treatment has to be monitored specifically: 
The designated site personnel must maintain an accurate record of the shipment and dispensing 
of prednisolone/placebo treatment in a drug accountability log. Monitoring of drug 
accountability will be performed by monitors during site visits or remotely and at the 
completion of the trial. Participants/caregivers must be instructed to record the dose and date of 
prophylactic prednisolone/placebo taken/administered at home in the diary provided by 
Novartis and will be asked to return all unused study treatment and packaging at the end of the 
study or at the time of study discontinuation. 

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At the conclusion of the study, and as appropriate during the course of the study, the participant 
will return all unused prednisolone and matching placebo for accountability and reconciliation, 
which will be completed by designated site personnel and verified by the Novartis monitor. 
Upon completion of these tasks, drug can be destroyed at site according to institutional 
guidelines. 
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
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 rescreened. The Participant No. consists of the Site 
Number (Site 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 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 rescreened. The site should select the eCRF book with a matching Participant 
Number from the EDC system to enter data. If the participant fails to be treated for any reason, 
the IRT must be notified within 2 days that the participant was not treated. Rescreening is 
allowed for participants that were screen failures for a temporary reason. 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 rescreened participants. 
A new ICF will need to be signed if the investigator chooses to rescreen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
6.4.2 
Treatment assignment, randomization 
At Screening Visit 3, all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
IRT after confirming that the participant fulfills all inclusion/exclusion criteria. The IRT will 
assign a randomization number to the participant, which will be used to link the participant to 
a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by Novartis GCS using a validated system that 
automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis GCS using a validated system that automates the random assignment of medication 
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Randomization will 
 
 
 
 
 
 
 
 
 
 
 
 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
6.4.2.1 
Replacement policy 
No participant replacement will be done for this study. 
6.5 
Treatment blinding 
With the exception of designated unblinded site and Sponsor personnel, all other personnel, 
including participants, Investigator staff, clinical evaluators performing the assessments, and 
sponsor will remain blinded to the identity of the treatment from the time of randomization until 
database lock.  
Treatment Period 1 (Screening/Baseline through Week 52) 
Randomization: After eligibility for the trial has been determined and informed consent has 
been obtained, study participants will be randomly assigned using central randomization in a 
3:2 ratio (OAV101: sham procedure). Randomization data will be kept strictly confidential until 
the time of the primary analyses which will occur once the last participant completes Week 52, 
and will not be accessible by anyone else involved in the study with the following exceptions 
of unblinded study staff listed below. At this time, treatment assignments will be unblinded to 
designated sponsor personnel and a full analysis of all efficacy and safety data will be 
conducted. 
Parents and key study personnel (e.g, outcome assessors) must not be present during the 
procedure to ensure blinding.  
The following personnel will be unblinded to the identity of the treatment from the time of 
randomization: 
• IRT personnel who require access to unblinded data 
• For the purpose of DMC support, an independent analysis team (Unblinded Statistician/ 
Statistical Programmer/ Data Analyst) 
Sites: 
• Unblinded site pharmacist (or equivalent) 
• Designated site physician (e.g., Interventional Radiologist) whose role is to perform the 
sham procedure (i.e., needle prick) or to administer OAV101.  
• Designated Procedure Room staff required during the sham procedure or during OAV101 
administration 
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Sponsor: 
• Global Clinical Supply management 
• Designated Clinical Research Monitors (CRAs)  
• Novartis Scientific Monitor  
• Unblinded Medical Monitor 
• Other designated personnel 
Treatment and Follow-up Period 1 blinding 
Blinding of Treatment Allocation: The identity of ancillary study treatment (prednisolone and 
matching placebo) will be concealed by identical packaging, labeling, schedule of 
administration and appearance. 
Unblinding may occur in the event of participant emergencies. The Principal Investigator and 
Novartis will assess whether the participant whose treatment code has been broken should be 
withdrawn from the study prematurely (e.g., will not proceed into Treatment Period 2). 
If a participant has been randomized to OAV101 administration, the unblinded pharmacist (or 
equivalent) will prepare a single intrathecal dose of OAV101. The prepared dose will be 
delivered to the location of the procedure. Participants will be adequately sedated (following 
institutional guidelines) for lumbar puncture to avoid any awareness of the procedure. A 
qualified interventional radiologist or specialist (e.g., neurologist) who is unblinded to study 
treatment will perform the intrathecal administration of OAV101 or the sham procedure. Any 
study personnel involved with patient treatment or evaluation (e.g., Principal Investigator, study 
coordinator, 
site 
clinical 
evaluator) cannot 
be 
present 
at 
the 
time 
of 
the 
procedure. Parents/caregivers must not be present in the procedure room. Treatment assignment 
will remain blinded to all patients, site and Novartis personnel (unless otherwise specified), and 
will similarly be blinded to post-treatment anti-AAV9 antibody results. The pharmacist (or 
equivalent) and the clinician administering the procedure will be specifically instructed not to 
discuss any details regarding patient dosing with members of the study team (including 
the Principal Investigator, study coordinator, and site clinical evaluator) involved in the care or 
evaluation of the patients. 
Prednisolone and placebo prednisolone administration and blinding: Prednisolone 
administration is required at the time of OAV101 dosing to suppress the immune response. For 
those participants receiving OAV101, prednisolone will be given 
 
 
 
In order to mimic the prednisolone prophylaxis in the OAV101 treatment group 
and preserve blinding, the sham procedure group will receive a placebo formulation that is 
identical in packaging, labeling, schedule of administration, appearance, taste, and odor.  
Post-administration follow-up and blinding: The Principal Investigator, physical therapists and 
any other clinical evaluators will be blinded at all times. In order to limit any potential bias, the 
HFMSE and RULM assessors (i.e., physical therapists or equivalent) should not have access to 
any study-related data, other than the data for the assessment(s) which they will administer. 
Unblinded site personnel will be responsible for performing the OAV101 dosing/sham 
procedure and may also assess subject safety and AEs within the 2 to 3 days following the study 
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treatment administration (i.e., during the in-hospitalization period). The unblinded personnel 
must not be involved in any other aspect of the study, other than the responsibilities detailed in 
the Pharmacy Manual, and must not divulge the subject’s treatment assignment. The blinded 
personnel will be responsible for all other aspects of the study.  
Treatment and Follow-up Period 2 blinding 
Anti-AAV9 antibody results 
 will be supplied to 
designated unblinded Novartis personnel. Designated unblinded Novartis personnel will 
communicate to the investigator when a participant (who received sham procedure in Period 1) 
has an anti-AAV9 antibody titer reported as elevated (reference to > 1:50 or a validated result 
consistent with being elevated) (Table 6-4). Novartis GCS will issue OAV101 only if anti-
AAV9 antibody titer is not reported as elevated. 
At the Week 52 + 1 Day visit, all eligible participants who received the sham procedure in 
Treatment Period 1 (Day 1) will receive a lumbar puncture and the administration of OAV101 
1.2 and all eligible participants who received OAV101 in Period 1 will receive the sham 
procedure. Blinding will be maintained in the same manner described above for Treatment 
Period 1. Participants will be followed until Week 64 for efficacy and safety. A small number 
of control patients (estimated as ≤ 5) may not receive OAV101 treatment at Week 52 due to 
elevated AAV9 antibodies and would be unblinded. Sham-procedure participants who do not 
continue to Treatment Period 2 will be captured on the eCRF disposition page. 
The DMC responsible for assessments on the safety and overall risk to benefit ratio of the study 
conduct will have access to the results with aggregated treatment assignment (Section 10.4.1). 
An independent team of statisticians and programmers, not otherwise involved in the conduct 
of the study, will be responsible for the timely coordination and delivery of the data to the DMC 
on a regular basis and will have access to the aggregated treatment assignment and patient level 
data as requested. 
Table 6-4 
Blinding and unblinding plan 
Role 
Time or Event 
Randomization list 
generated 
Treatment 
allocation & 
dosing 
Safety event 
(single subject 
unblinded) 
Participants 
B 
B 
UI 
Site staff 
B 
B 
UI 
Unblinded site staff (see text for 
details)  
B 
UI 
UI 
Drug Supply and Randomization 
Office 
UI 
UI 
UI 
Unblinded sponsor staff (see text 
for details) 
B 
UI 
UI 
Statistician/statistical 
programmer/data analysts 
B 
B 
UI 
Independent committees used for 
assessing interim results 
B 
UI 
UI 
All other sponsor staff not 
identified above 
B 
B 
UI 
B Remains blinded 
UI Allowed to be unblinded on individual patient level 
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6.6 
Dose escalation and dose modification 
Not applicable. OAV101 is a recombinant AAV9 gene therapy which is administered once. 
6.7 
Additional treatment guidance 
Not applicable. 
6.7.1 
Treatment compliance 
OAV101 will be administered as a one-time intrathecal 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. The investigator must promote compliance with the administration 
of prednisolone or placebo by instructing the participant/caregiver to administer as prescribed 
and by stating that compliance is necessary for the participant’s safety and the validity of the 
study. The participant/caregiver must also be instructed to record the dose and date of 
prednisolone/placebo taken/administered at home in a diary provided by Novartis and to contact 
the investigator if he/she is unable for any reason to administer as prescribed. Compliance will 
be assessed by the investigator and/or study personnel using information provided by the 
participant/caregiver in the diary. This information should be captured in the source document 
at each visit. All prednisolone/placebo dispensed and returned must be recorded in the Drug 
Accountability Log. 
6.7.2 
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. At present there is insufficient information to provide specific 
recommendations regarding treatment of AEs other than prednisolone used to dampen the 
immune reaction directed against OAV101 (Table 6-2). 
6.7.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to treat the participant 
safely. Most often, knowledge of the possible treatment assignments are sufficient to treat a 
study participant who presents with an emergency condition. Emergency treatment code breaks 
are performed using the IRT. When the investigator contacts the system to break a treatment 
code for a participant, he/she must provide the requested participant identifying information and 
confirm the necessity to break the treatment code for the participant. The investigator will then 
receive details of the investigational drug treatment for the specified participant and a fax or 
email confirming this information. The system will automatically inform the Novartis monitor 
for the site and the study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The Investigator will provide: 
• protocol number 
• participant number 

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In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time. 
It is important to note that the decision to discontinue a treated participant from the study does 
not automatically preclude inclusion in the long-term follow-up study. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation) IRB/Independent Ethics Committee (IEC)-approved informed 
consent. 
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 level of understanding. 
Informed consent and assent, 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 
and assent forms that complies with the International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practice (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 side effects regarding the investigational treatment can be found in 
the Investigator’s Brochure. This information will be included in the participant informed 
consent and should be discussed with the caregiver(s)/parent(s)/legal guardian and/or 
participant upon obtaining consent and also during the study as needed. Any new information 
regarding the safety profile of the investigational drug that is identified between Investigator’s 
Brochure updates will be communicated as appropriate, for example, via an Investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the caregiver(s)/parent(s) and/or participant. 
The following informed consents are included in this study: 
• Global Model Informed Consent Form to be signed by the participant once he/she turns 
18 years of age (to the extent possible and in accordance with local IRB requirements). 
• Global Model Parent Legal Guardian ICF 
• Global Model Child Assent Form 
• Global Model Adolescent Assent Form 
• Global Pregnancy Follow-up Model ICF for Pregnant Participant 
• Global Pregnancy Follow-up Model ICF for Pregnant Partner of Male Participants 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 

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study and agree that in order to participate in the study they must adhere to the contraception 
requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
As per Section 4.6, 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, the Investigator 
may conduct the informed consent discussion remotely (e.g., telephone, videoconference) if 
allowable by a local Health Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (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 as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who discontinue from the study or 
withdraw their consent/oppose the use of their data/biological samples should be scheduled for 
a final evaluation visit if they agree 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 not previously reported must be recorded on the CRF. 
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database. 
As per Section 4.6, 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, national and local regulations 
and depending on operational capabilities, phone calls, virtual contacts (e.g., tele consultation) 
or visits by site staff/ off-site healthcare professional(s) staff to the participant´s home, can 
replace certain protocol assessments, for the duration of the disruption until it is safe for the 
participant to visit the site again. If the Investigator delegates tasks to an off-site healthcare 
professional, the Investigator must ensure the individual(s) is/are qualified and appropriately 
trained to perform assigned duties. The Investigator must oversee their conduct and remain 
responsible for the evaluation of the data collected. 

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Table 8-1 
Assessment Schedule 
Period 
Screening 
Baseline 
Treatment Period 1 
Follow-up Period 1 
Visit Name Visit 11 Visit 
2 
Visit 
3 
Baseline 
Visit2 
Day 
1 
Day 
2 
Optional 
Day 3 
WK 
1 
WK 
2 
WK 
3 
WK 
4 
WK 
6 
WK 
8 
WK 
10 
WK 
12 
WK 
16 
WK 
20 
WK 
24 
WK 
28 
WK 
32 
Days -60 +15 -21 
±7 
-14 
±7 
-1 
 
1 
2  
3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±2 
57 
±2 
71 
±2 
85 
±7 
113 
±7 
141 
±7 
169 
±7 
197 
±7 
225 
±7 
Inclusion / Exclusion 
criteria 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OAV101 IT 
administration/sham 
procedure 
 
 
 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT contact 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information to be 
collected on screening 
failures 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Independent Sitting 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
and therapies 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Head circumference for 
patients <= 3 years of 
age 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Head circumference for 
patients > 3 years of age 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Period 
Screening 
Baseline 
Treatment Period 1 
Follow-up Period 1 
Visit Name Visit 11 Visit 
2 
Visit 
3 
Baseline 
Visit2 
Day 
1 
Day 
2 
Optional 
Day 3 
WK 
1 
WK 
2 
WK 
3 
WK 
4 
WK 
6 
WK 
8 
WK 
10 
WK 
12 
WK 
16 
WK 
20 
WK 
24 
WK 
28 
WK 
32 
Days -60 +15 -21 
±7 
-14 
±7 
-1 
 
1 
2  
3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±2 
57 
±2 
71 
±2 
85 
±7 
113 
±7 
141 
±7 
169 
±7 
197 
±7 
225 
±7 
Vital Signs 
X 
X 
 
X 
X4 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMI 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Body Weight 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Body Height (Segmental 
by Tibial Length) 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Neurological Examination 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
S 
 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spinal X-Ray for Scoliosis 
Assessment 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prophylactic 
prednisolone/placebo 
 
 
 
X7 
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 
X 
X 
Hammersmith Functional 
Motor Scale Expanded 
(HFMSE) 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Revised Upper Limb 
Model (RULM) 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Ventilatory support 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Screening 
Baseline 
Treatment Period 1 
Follow-up Period 1 
Visit Name Visit 11 Visit 
2 
Visit 
3 
Baseline 
Visit2 
Day 
1 
Day 
2 
Optional 
Day 3 
WK 
1 
WK 
2 
WK 
3 
WK 
4 
WK 
6 
WK 
8 
WK 
10 
WK 
12 
WK 
16 
WK 
20 
WK 
24 
WK 
28 
WK 
32 
Days -60 +15 -21 
±7 
-14 
±7 
-1 
 
1 
2  
3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±2 
57 
±2 
71 
±2 
85 
±7 
113 
±7 
141 
±7 
169 
±7 
197 
±7 
225 
±7 
BLOOD: Serum beta-
human chorionic 
gonadotropin pregnancy 
test (Quantitative). 
Female participants 
only11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
URINE beta-human 
chorionic gonadotropin 
pregnancy test 
(Qualitative). Female 
participants only12 
S 
 
 
S 
 
 
 
 
 
 
S 
 
S 
 
S 
S 
S 
S 
S 
S 
Hepatitis Panel13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Screen 
(Antigen/Antibody) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
X 
 
X14 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Period 
Screening 
Baseline 
Treatment Period 1 
Follow-up Period 1 
Visit Name Visit 11 Visit 
2 
Visit 
3 
Baseline 
Visit2 
Day 
1 
Day 
2 
Optional 
Day 3 
WK 
1 
WK 
2 
WK 
3 
WK 
4 
WK 
6 
WK 
8 
WK 
10 
WK 
12 
WK 
16 
WK 
20 
WK 
24 
WK 
28 
WK 
32 
Days -60 +15 -21 
±7 
-14 
±7 
-1 
 
1 
2  
3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±2 
57 
±2 
71 
±2 
85 
±7 
113 
±7 
141 
±7 
169 
±7 
197 
±7 
225 
±7 
Troponin I 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Coagulation Panel 
X 
 
 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
5q SMA Genetic Testing 
(SMN1 and SMN2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Screening 
Baseline 
Treatment Period 1 
Follow-up Period 1 
Visit Name Visit 11 Visit 
2 
Visit 
3 
Baseline 
Visit2 
Day 
1 
Day 
2 
Optional 
Day 3 
WK 
1 
WK 
2 
WK 
3 
WK 
4 
WK 
6 
WK 
8 
WK 
10 
WK 
12 
WK 
16 
WK 
20 
WK 
24 
WK 
28 
WK 
32 
Days -60 +15 -21 
±7 
-14 
±7 
-1 
 
1 
2  
3 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±2 
57 
±2 
71 
±2 
85 
±7 
113 
±7 
141 
±7 
169 
±7 
197 
±7 
225 
±7 
Electrocardiogram (ECG) 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Sensory Nerve Action 
Potential 
(SNAP)/Electrophysiology 
X 
X20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study completion 
information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Period 
Follow-up Period 1 
Treatment Period 2 
Follow-up Period 2 
Visit Name WK 
36 
WK 
40 
WK 
44 
WK 
48 
WK 50 
WK 
522 
WK 
52+1 
Day 
WK 
52+2 
Days 
Optional 
WK 52+3 
Days 
WK 
53 
WK 
54 
WK 
55 
WK 
56 
WK 
58 
WK 
60 
WK 
62 
WK 
64/EOS21 
Days 253 
±7 
281 
±7 
309 
±7 
337 
±7 
351 
±2 
365 
±7 
366 
367 
368 
372 
±2 
379 
±2 
386 
±2 
393 
±2 
407 
±2 
421 
±2 
435 
±2 
449 
±3 
Inclusion / Exclusion criteria 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
OAV101 IT 
administration/sham 
procedure 
 
 
 
 
 
 
X22 
 
 
 
 
 
 
 
 
 
 
IRT contact 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
IRT randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Follow-up Period 1 
Treatment Period 2 
Follow-up Period 2 
Visit Name WK 
36 
WK 
40 
WK 
44 
WK 
48 
WK 50 
WK 
522 
WK 
52+1 
Day 
WK 
52+2 
Days 
Optional 
WK 52+3 
Days 
WK 
53 
WK 
54 
WK 
55 
WK 
56 
WK 
58 
WK 
60 
WK 
62 
WK 
64/EOS21 
Days 253 
±7 
281 
±7 
309 
±7 
337 
±7 
351 
±2 
365 
±7 
366 
367 
368 
372 
±2 
379 
±2 
386 
±2 
393 
±2 
407 
±2 
421 
±2 
435 
±2 
449 
±3 
Informed consent/assent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information to be collected 
on screening failures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/current 
medical conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Independent Sitting 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
and therapies 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Head circumference for 
patients <= 3 years of age 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Head circumference for 
patients > 3 years of age 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X23 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMI 
X 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Body Weight 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
Body Height (Segmental by 
Tibial Length) 
X 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Neurological Examination 
X 
X 
X 
X 
 
X23 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
S 
S 
S 
S 
 
S23 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Chest X-ray 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spinal X-Ray for Scoliosis 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Period 
Follow-up Period 1 
Treatment Period 2 
Follow-up Period 2 
Visit Name WK 
36 
WK 
40 
WK 
44 
WK 
48 
WK 50 
WK 
522 
WK 
52+1 
Day 
WK 
52+2 
Days 
Optional 
WK 52+3 
Days 
WK 
53 
WK 
54 
WK 
55 
WK 
56 
WK 
58 
WK 
60 
WK 
62 
WK 
64/EOS21 
Days 253 
±7 
281 
±7 
309 
±7 
337 
±7 
351 
±2 
365 
±7 
366 
367 
368 
372 
±2 
379 
±2 
386 
±2 
393 
±2 
407 
±2 
421 
±2 
435 
±2 
449 
±3 
Prophylactic 
prednisolone/placebo 
 
 
 
 
 
X7 
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 
Hammersmith Functional 
Motor Scale Expanded 
(HFMSE) 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Revised Upper Limb Model 
(RULM) 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Ventilatory support 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BLOOD: Serum beta-human 
chorionic gonadotropin 
pregnancy test 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Follow-up Period 1 
Treatment Period 2 
Follow-up Period 2 
Visit Name WK 
36 
WK 
40 
WK 
44 
WK 
48 
WK 50 
WK 
522 
WK 
52+1 
Day 
WK 
52+2 
Days 
Optional 
WK 52+3 
Days 
WK 
53 
WK 
54 
WK 
55 
WK 
56 
WK 
58 
WK 
60 
WK 
62 
WK 
64/EOS21 
Days 253 
±7 
281 
±7 
309 
±7 
337 
±7 
351 
±2 
365 
±7 
366 
367 
368 
372 
±2 
379 
±2 
386 
±2 
393 
±2 
407 
±2 
421 
±2 
435 
±2 
449 
±3 
(Quantitative). Female 
participants only11 
URINE beta-human 
chorionic gonadotropin 
pregnancy test (Qualitative). 
Female participants only12 
S 
S 
S 
 
 
S 
 
 
 
 
 
 
S 
 
S 
 
S 
Hepatitis Panel13 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Screen 
(Antigen/Antibody) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
 
X 
 
X14 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Troponin I 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Coagulation Panel 
 
 
 
X 
 
X14,23 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
5q SMA Genetic Testing 
(SMN1 and SMN2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Follow-up Period 1 
Treatment Period 2 
Follow-up Period 2 
Visit Name WK 
36 
WK 
40 
WK 
44 
WK 
48 
WK 50 
WK 
522 
WK 
52+1 
Day 
WK 
52+2 
Days 
Optional 
WK 52+3 
Days 
WK 
53 
WK 
54 
WK 
55 
WK 
56 
WK 
58 
WK 
60 
WK 
62 
WK 
64/EOS21 
Days 253 
±7 
281 
±7 
309 
±7 
337 
±7 
351 
±2 
365 
±7 
366 
367 
368 
372 
±2 
379 
±2 
386 
±2 
393 
±2 
407 
±2 
421 
±2 
435 
±2 
449 
±3 
Electrocardiogram (ECG) 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
Echocardiogram 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Sensory Nerve Action 
Potential 
(SNAP)/Electrophysiology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study completion 
information 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessments that are only in the participant’s source documentation and do not need to be recorded in the clinical database 
1 The assessments for Screening Visit 1 can be conducted over more than 1 visit, as close to the original visit date as possible 
2 Assessments for the Baseline Visit and Week 52 Visit can be conducted over more than 1 day, as close to the original visit date as possible. Clinical and laboratory 
results must be consistent with institutional guidelines for lumbar puncture before proceeding with OAV101 dosing/sham procedure.  
3 Patients will be hospitalized for inpatient OAV101administration/sham procedure on Day 1 (or on Day -1 as per local standard of care). In-patient observation will 
continue on Day 2 and Day 3 (optional), i.e., 24 to 48 hours post-study treatment If study treatment visit on Day 1 is not possible due to a national emergency or other 
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Protocol No. COAV101B12301 
 
 
Period 
Follow-up Period 1 
Treatment Period 2 
Follow-up Period 2 
Visit Name WK 
36 
WK 
40 
WK 
44 
WK 
48 
WK 50 
WK 
522 
WK 
52+1 
Day 
WK 
52+2 
Days 
Optional 
WK 52+3 
Days 
WK 
53 
WK 
54 
WK 
55 
WK 
56 
WK 
58 
WK 
60 
WK 
62 
WK 
64/EOS21 
Days 253 
±7 
281 
±7 
309 
±7 
337 
±7 
351 
±2 
365 
±7 
366 
367 
368 
372 
±2 
379 
±2 
386 
±2 
393 
±2 
407 
±2 
421 
±2 
435 
±2 
449 
±3 
unforeseen reason, extensions to the visit window may be discussed with the Sponsor. 
4 Vital signs, with the exception of blood pressure, will be recorded pre-study treatment (OAV101 dosing/sham procedure) and then monitored every 15 (± 5) minutes for 
the first 1 hour, every 30 (± 10) minutes until 2 hours, every 2 hours (± 15 minutes) until 8 hours, and every 4 hours (± 30 minutes) until 16 hours. Blood pressure will be 
recorded pre-study treatment and every 8 hours (± 2 hours) through 16 hours 
5 Vital signs should be performed 20-24 hours post OAV101 dosing/sham procedure 
6 Re-screening: Participants who screen failed and have study-specific spine films available, may use these spine films at re-screening with sponsor approval. The data 
from the study-specific spine films should be entered in the eCRF 
7 Prophylactic prednisolone/placebo must be administered 
 
8 
 
9 
 
 
10 
 
 
11 Female participants who are sexually active or have reached menarche must have a negative pregnancy test at Screening. A negative urine pregnancy test may be 
used for eligibility but should be confirmed with blood test prior to the Baseline visit.  
12 Female participants who are sexually active or have reached menarche. 
13 Hepatitis panel includes Hepatitis C antibody, Hepatitis B surface antigen (HbsAG), and Hepatitis B core antibody 
14 To be performed by local lab. For platelets, further close monitoring should be performed locally as needed, particularly in the first two weeks following infusion. 
15To be performed by Sponsor-designated lab 
16 
 
 
17 
 
 
18 
 
 
 
20 SNAP is not performed at Screening Visit 2 if a SNAP score was obtained at Screening Visit 1 
21 If discontinuation, all efforts should be made to complete the End of Study (EOS) assessments prior to study discontinuation. 
22 Patients will be hospitalized for inpatient OAV101administration/sham procedure on Week 52 +1 Day (or on Week 52 as per local standard of care). In-patient 
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Period 
Follow-up Period 1 
Treatment Period 2 
Follow-up Period 2 
Visit Name WK 
36 
WK 
40 
WK 
44 
WK 
48 
WK 50 
WK 
522 
WK 
52+1 
Day 
WK 
52+2 
Days 
Optional 
WK 52+3 
Days 
WK 
53 
WK 
54 
WK 
55 
WK 
56 
WK 
58 
WK 
60 
WK 
62 
WK 
64/EOS21 
Days 253 
±7 
281 
±7 
309 
±7 
337 
±7 
351 
±2 
365 
±7 
366 
367 
368 
372 
±2 
379 
±2 
386 
±2 
393 
±2 
407 
±2 
421 
±2 
435 
±2 
449 
±3 
observation will continue on Week 52 +2 Days and Week 52 +3 Days (optional), i.e., 24 to 48 hours post-study treatment. If study treatment visit on Week 52 + 1 Day is 
not possible due to a national emergency or other unforeseen reason, extensions to the visit window may be discussed with the Sponsor.  
23 Vital signs, neurological examination, physical examination, and coagulation will be performed within 2 days prior to the OAV101 dosing/sham procedure 
24 
 
25 
 
 
 
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8.1 
Screening 
Screening 
Written informed consent must be obtained prior to any screening procedures. Please refer to 
Section 7 for the Informed Consent procedures. After informed consent is collected, the 
participant must be registered in IRT, eligibility reviewed and, once eligible, study treatment 
pre-ordered. Assessments that confirm participant eligibility and randomization into the 
study will occur at Screening Visit 1 and 2 (Table 8-1).  
Given the potentially long duration of the study visits, sites may provide comfort items (e.g., 
playbooks, toys, teddy bears, and/or some form of media) that would not impact or interfere 
with study procedures and assessments, in order to promote compliance, and as per local 
guidelines and regulations.  
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 timely completion of the eligibility 
assessment. 
Re-screening: It is permissible to re-screen a potential participant if the participant fails the 
initial screening (screen failure); however, each case must be discussed and agreed with the 
Sponsor on a case-by-case basis. Re-screening should not be performed in order to avoid the 
eligibility criteria or for any reason that would place the participant at safety risk. 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 rescreening 
should be documented in medical records. 
8.1.1 
Inclusion and exclusion criteria 
The Investigator must ensure that all participants being considered for the study meet 
the inclusion and do not meet any exclusion criteria. No additional exclusions should be applied 
by the Investigator, in order that the study population will be representative of all eligible 
participants. Participant selection is to be established by checking through all 
inclusion/exclusion criteria at screening. A relevant record must be stored with the 
source documentation at the study site. Deviation from any entry criterion excludes a participant 
from enrollment into the study. The Investigator or his/her deputy must promote compliance to 
inclusion/exclusion criteria for the duration of the study. 
8.1.2 
 Information to be collected on screening failures 
Ineligible participants 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to enrollment will be considered as screen failures. The reason for screen failure should be 
entered on the applicable CRF. CRFs pertaining to demography, informed consent, withdraw 
of consent (if applicable), inclusion/exclusion criteria, SMA diagnosis, anti-AAV9 antibody, 
5q SMA genetic testing, and death (if applicable) should also be completed for screen failure 
participants. The anti-AAV9 antibody and 5q SMA genetic testing results will be collected in 
the appropriate Novartis database. No other data will be entered into the clinical database for 

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participants who are screen failures, unless the participant experienced a SAE during the 
screening period (see SAE section for reporting details) or protocol-related AE. Data and 
samples collected from participants prior to screen failure may still be analyzed. 
Failure due to temporary conditions 
Participants who fail eligibility during the screening process for a temporary or transient 
condition (e.g., viral illness, concomitant medication, or laboratory values, etc.) may be 
rescreened. When all inclusion and exclusion criteria will have to be reverified, a new 
participant number will be assigned. A participant initially excluded for a condition no longer 
exclusionary upon a protocol amendment may also be re-screened. 
8.1.3 
Prior medications 
Prior medications entered into the database will be coded using the WHO Drug Reference List, 
which employs the Anatomical Therapeutic Chemical (ATC) classification system. 
8.1.4 
Medical history and current medical conditions 
Relevant medical history, hospitalizations, and current medical conditions will be recorded on 
the eCRF until signature of the informed consent. Where possible, diagnoses and not symptoms 
will be recorded. Any event or change in the participant’s condition or health status 
occurring prior to informed consent will be reported in the Relevant medical history / Current 
medical conditions section of the eCRF. Medical history will be coded using the Medical 
dictionary for regulatory activities (MedDRA) and the number and percentage of participants 
with each history by preferred term presented, including the presence of scoliosis and presence 
of contractures. 
SMA HISTORY 
SMA history may include the following: 
• Type of SMN1 pathogenic variants on each allele (e.g., deletion, point mutation) 
• SMN2 gene copy number 
• Age at SMA symptom onset 
• Date at SMA diagnosis 
• Highest motor function achieved 
• Type and frequency of physical therapy 
• Number of hospitalizations for pneumonia with or without respiratory failure 
• Familial history of SMA, including parent carriers and affected sibling(s) 
8.1.5 
Screening laboratory testing 
Laboratory testing performed during the Screening/Baseline period is described in Table 8-1. 
8.1.6 
Virus serology 
The administration of an AAV vector has the risk of causing immune-mediated hepatotoxicity. 
For participants who have HIV or positive serology for hepatitis B or C, administration of the 
AAV vector may represent an unreasonable risk; therefore, negative serology testing must be 

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confirmed at screening, prior to treatment. These samples will be collected in accordance with 
Table 8-1 and shipped in accordance with the laboratory manual provided by the central 
laboratory. 
Other pathogens that may be endemic to specific regions/countries (e.g., human T-lymphotropic 
virus or mycobacterium tuberculosis) may also be tested, as per investigator discretion and 
discussion with sponsor. 
8.1.7 
Ventilatory support 
Ventilatory support assessment will be performed by a pulmonologist (or appropriate individual 
as per standard institutional practice) and conducted as specified in Table 8-1. Prior to study 
entry, the Investigator or designee will review and document ventilator usage during the 
2 weeks prior to screening 
8.1.8 
Radiological evaluations 
Radiological examinations are performed to assess participants for disease complications in 
accordance with Inclusion/Exclusion criteria (Section 5). 
8.1.8.1 
Chest X-Ray 
Standard posterior to anterior (PA) and lateral chest X-ray will be performed at Screening Visit 
1 and at Week 48. 
8.1.8.2 
Scoliosis assessment 
Spine films will be performed in two planes in a sitting position to assess scoliosis and pelvic 
obliquity. The following data is recorded for each participant (Fujak et al 2013). 
• Scoliosis shape (C-shape or S-Shape) 
• Levels involved (Cervical, Thoracic, and/or Lumbar) 
• Cobb angle 
• Pelvic obliquity, if available (Osebold et al 1982)  
Re-screening: Participants who screen failed and have study-specific spine films available, 
may use these spine films at re-screening with sponsor approval. The data from the study-
specific spine films should be entered in the eCRF.   
8.1.9 
Independent sitting assessment 
The ability to sit independently for at least 10 seconds will be assessed at Screening, in 
accordance with the inclusion criteria (Section 5.1). 
8.2 
Participant demographics/other baseline characteristics 
Demographics (including age, sex, race, and ethnicity)/medical history/current medical 
conditions (until date of signature of informed consent) will be captured in the eCRF. 
Participant race and ethnicity data are collected and analyzed to identify variations in safety or 
efficacy profile of the treatment due to these factors. In addition, these data are necessary to 
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regulations should be considered for the collection of demographic and baseline characteristics 
in alignment with CRF. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the protocol Section 6.2.1 Concomitant Therapy 
for further details on what information must be recorded on the appropriate page of the eCRF.  
8.3 
Efficacy 
The efficacy assessments described below have been selected in order to evaluate the effect of 
OAV101 on SMA. The primary and secondary efficacy assessments (HFMSE and RULM) are 
chosen based on their acceptability to health authorities, extensive validation and clinical use, 
Novartis study experience (AVXS-101-CL-102 open-label trial), and proof of utility for 
efficacy assessment in other trials (Mercuri et al 2018b). The assessments described for the 
exploratory endpoints (Section 8.3.3) are chosen to augment understanding of clinical 
meaningfulness of OAV101 treatment. 
8.3.1 
Primary and secondary efficacy assessments 
Primary and secondary endpoints rely on data collected by trained and qualified site clinical 
evaluators (physical therapist, occupational therapist, or national equivalent) using the HFMSE 
and the RULM over a 52-week period after OAV101 administration/sham procedure. Select 
HFMSE and RULM administrations may be observed during the assessment through 
videoconference (or recorded and reviewed) by an external trainer to provide initial and/or 
ongoing clinical evaluator feedback on assessment administration. Given the global nature of 
COAV101B12301, recordings for later review require compliance with local regulations and 
laws.  
8.3.1.1 
Hammersmith Functional Motor Scale Expanded (HFMSE) 
Background 
The 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 ) and has been used 
in a double blinded clinical trial of Type 2 SMA to demonstrate efficacy of SMN-targeting 
therapy (Mercuri et al 2018b). 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). The same clinical 
evaluator should administer the HFMSE for a given participant throughout the study (i.e., every 
visit). The HFMSE is a SMA-specific 33-item questionnaire that is easily administered by 
clinical evaluators in a short period of time, 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 ability level. A Phase 1 study of nusinersen reaffirmed that the HFMSE is sensitive to 
change, with a 3-point change in score considered clinically meaningful and indicates that a 
child improved on at least 2 HFMSE motor skills. The HFMSE has well-established 
psychometric properties. Evaluation of inter-rater reliability and test-retest reliability 
demonstrated that these functional assessments can be performed reliably in a multicenter 
clinical trial with rigorous initial, annual, and periodic retraining and support to ensure 
standardization. The HFMSE administration in OAV101B12301 will occur as follows. 

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Completion of Assessment 
• Obtaining a complete HFMSE assessment that is a true representation of the participant’s 
motor ability is critical in order to appropriately investigate OAV101 efficacy. The 
completeness of the HFMSE assessment has been considered in Type 2 SMA motor 
assessment analyses, thus allowing for fair and valid assessment of motor abilities 
(Mercuri et al 2019, Coratti et al 2020b). Every effort should be made to administer all 
scale items appropriately following scale criteria. In the event that an item is not able to be 
administered, a ‘Cannot Test’ (CNT) is marked for that item. To ensure the patient’s true 
motor ability is being represented, rescheduling of the assessment administration is 
warranted when any factor significantly impedes the participant’s ability to perform the 
motor assessment which includes behavior issues (e.g., tantrums, inconsolable), refusal to 
participate in testing, transient pain, fractures, intercurrent surgery, or recent pneumonia or 
other infections. 
 
 
 
 
 
 
 
 
 
 Study specific requirements around 
HFMSE administration requirements are outlined below. Based on prior experience in the 
open label AVXS-101-CL-102 clinical trial of intrathecal OAV101, very few incomplete 
assessments are anticipated. 
Contractures: It is important to note that contractures alone do not exclude participants from 
being scored on the HFMSE. The impact of contractures on some assessment items needs to be 
established, therefore the therapist should indicate “limited by contracture”. However, 
participants with severe contractures, which limit their ability to be positioned in prone during 
Screening, are not eligible (exclusion criterion 13).  
HFMSE at Screening  
• In order to assess trial eligibility, an HFMSE assessment with total score must be obtained 
during the Screening period (Section 5.1). 
• Two HFMSE assessments are performed during the screening period. Although two 
complete HFMSE assessments is preferred at Screening, a minimum of one assessment 
with total score must be obtained. 
• Rescheduling of the assessment administration within the screening window is required if 
an HFMSE assessment with a total score is unable to be obtained. 
HFMSE assessment at baseline and post-OAV101 administration/sham procedure to 
Week 64 (End of Study) 
• HFMSE is administered at each visit specified in the Schedule of Assessments 
(Table 8-1). 
HFMSE assessment 
 
 
 
 
 
 
 
 
 
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8.3.1.2 
Revised Upper Limb Model (RULM) 
Background 
RULM is a validated, SMA-specific assessment that measures motor performance in the upper 
limbs from childhood through adulthood in ambulatory and never 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 revised version of the test consists 
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 RULM consists of 
upper limb performance items that are reflective of reachable space and activities of daily living 
(i.e., raise a can to mouth as if drinking, take a coin and place it in a box, and remove the lid of 
a container). The test is performed unilaterally using the limb preferred by the patient. The 
RULM is quickly administered and suitable for use in multicenter settings. Evaluation of 
inter-rater reliability and test-retest reliability demonstrated that these functional assessments 
can be performed reliably in a multicenter clinical trial with rigorous initial, annual, and periodic 
retraining and support to ensure standardization. The RULM will be administered by a site 
clinical evaluator (e.g., licensed physical or occupational therapist, or national equivalent) in 
accordance with the Schedule of Assessments. 
The RULM was a critical motor assessment that contributed to risdiplam approval by the Food 
and Drug Administration (FDA) in the SUNFISH trial which included 2 to 25 year old Type 2 
and Type 3 SMA patients (EVRYSDI Prescribing Information 2020, Genentech 2021). The 
RULM was used in the CHERISH clinical trial of nusinersen which included Type 2 and 3 
SMA in 2 to 12 year olds (Mercuri et al 2018b). In the CHERISH study, the least squares mean 
analysis of the RULM data versus controls showed 3.7 point difference (95% CI = 2.3 – 
5.0). Since the RULM was a secondary endpoint in the CHERISH trial and a hierarchical end 
point analysis was performed, a p-value was not calculated since a prior endpoint did not reach 
statistical significance. Like the HFMSE, the RULM has been successfully implemented in 
clinical trials that assess efficacy of SMN-targeting therapies. RULM administration is 
recommended for assessment of patients > 2 years of age with the ability to sit by the 
SMArtCare-project (Pechmann et al 2019, Schorling et al 2020). 
Completion of Assessment 
Obtaining a complete RULM assessment at a visit that is a true representation of the 
participant’s motor ability is critical in order to appropriately investigate OAV101 efficacy. 
Every effort should be made to administer all scale items appropriately following scale criteria. 
In the event that an item is not able to be administered a ‘Cannot Test’ (CNT) is marked for that 
item. To ensure the patient’s true motor ability is being represented, rescheduling of the 
assessment administration is warranted when any factor significantly impedes the participant’s 
ability to perform the motor assessment which includes behavior issues (e.g., tantrums, 
inconsolable), refusal to participate in testing, transient pain, fractures, intercurrent surgery, or 
recent pneumonia or other infections. 
 
 
 Study specific requirements around RULM administration requirements 
are outlined below. Ensuring completeness of the assessment is an approach to ensure that data 
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representative of the participant’s motor function is used for analysis (Pera et al 2019). Of note, 
test participation refusals are uncommon among individuals performing the RULM, even in 
younger children (Mazzone et al 2017). 
RULM at Screening  
• Two RULM assessment are performed during the screening period.  Although two 
complete RULM assessments is preferred at Screening, a minimum of one assessment 
with total score should be obtained. 
RULM assessment at baseline and post-OAV101 administration/sham procedure to Week 
64 (End of Study), 
• RULM is administered at visits as specified in the Schedule of Assessments (Table 8-1). 
RULM assessment 
 
 
 
 
 
 
 
 
 
8.3.2 
Appropriateness of efficacy assessments 
Efficacy assessments in this study are standard for this indication and participant population. 
The rationale and support for HFMSE and RULM use for efficacy assessment are described in 
Section 4.1, Section 8.3.1.1, and Section 8.3.1.2. 
8.3.3 
Exploratory assessments 
8.3.3.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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8.3.3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.3.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.3.3.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.3.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.3.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
8.3.3.7 
 
 
 
 
 
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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 4.6, 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 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, home-nursing may be 
deployed using central lab kits or 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 unless otherwise 
specified. Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to Investigators in the Laboratory Manual. 
For countries where regulatory requirements do not permit Point of Care Testing for urinalysis 
(i.e., use of dipstick) the analysis will be performed at the central laboratory. 
8.4.1.1 
Urinalysis 
Dipstick measurements for protein, blood, and WBC/leukocytes will be performed. If dipstick 
measurement results are positive (abnormal), a urine sample will be sent to the central 
laboratory for microscopic evaluation in accordance with the Laboratory Manual. 
8.4.1.2 
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 at all trial visits: 
• Hematocrit 
• Hemoglobin 
• MCH 
• MCHC 
• MCV 
• Platelets 
• Red blood cells 
• White blood cells 
• Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands) 

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Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, 
were observed in OAV101 clinical studies with intravenous administration. In most cases, the 
lowest platelet value occurred the first week following OAV101 administration. Platelet counts 
should be obtained before OAV101/sham administration and should be closely monitored in 
the first two weeks following treatment on a regular basis afterwards as specified in Table 8-1, 
until any abnormal platelet counts return to baseline.  
Hematology analyses are required prior to discharge on Day 2 and Week 52+2 Days. These 
tests will be performed as per investigational site standard procedures at the local laboratory. 
As determined by the Investigator, further hematology tests should be done in the first two 
weeks following OAV101 administration as per investigational site standard procedures at the 
local laboratory. Local labs should be entered on the respective eCRF page.  
Investigators will receive hematology results from all other study visits from the central 
laboratory. 
8.4.1.3 
Coagulation panel 
Coagulation testing will include prothrombin time (PT), international normalized ratio (INR), 
and activated partial thromboplastin time (aPTT). Coagulation testing is required to be done 
locally to confirm that there are no clinically significant abnormal results prior to OAV101 
dosing/sham procedure (both Treatment Period 1 and 2). 
8.4.1.4 
Clinical 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 
Assessment Schedule (Table 8-1). Clinical chemistry may be evaluated in the non-fasted state.  
If immediate/same-day chemistry analyses are required during Treatment Period 1 or Treatment 
Period 2, as determined by Investigator, tests will be performed as per investigational site 
standard procedures at the local laboratory. If liver aminotransferase elevations occur post 
OAV101 administration/sham procedure, the process outlined in Section 10.3.1 should be 
followed. 
Chemistry analysis will include the following analytes: 
• Albumin 
• Alkaline phosphatase (ALP) 
• Alanine aminotransferase 
• Aspartate aminotransferase 
• GGT 
• Lactate Dehydrogenase (LDH) 
• Glutamate dehydrogenase 
• Bicarbonate 
• Calcium 
• Phosphorus 
• Chloride 

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• Sodium 
• Potassium 
• Creatinine 
• Creatine kinase 
• Total Bilirubin (NOTE: If the total bilirubin concentration is increased above 1.5 times the 
upper limit of normal, direct and indirect reacting bilirubin should be differentiated) 
• Direct Bilirubin 
• Indirect Bilirubin 
• Blood urea nitrogen 
• Glucose 
Troponin I will be collected as specified in the Schedule of Assessments (Table 8-1). 
 
 
8.4.1.5 
BLOOD: Serum beta-human chorionic gonadotropin pregnancy test 
(Quantitative). Female participants only 
Blood beta-human chorionic gonadotropin (beta-hCG) testing (Quantitative) will be performed 
at screening visit 2 and at the Week 48 visit. Serum beta-hCG testing will be performed on 
females of childbearing potential (See Section 8.4.2). 
8.4.1.6 
URINE beta-human chorionic gonadotropin pregnancy test 
(Qualitative). Female participants only 
All female participants who are sexually active or have reached menarche will have pregnancy 
testing. Additional pregnancy testing might be performed if requested by local 
requirements. The cultural differences as well as standard of care approaches across 
participating countries must be taken into account in order to appropriately manage 
contraception and pregnancy considerations. 
Urine human chorionic gonadotropin (hCG) dipstick testing will be performed on females of 
child-bearing potential. First-morning urine is the preferred specimen; however, any specimen 
is suitable for testing. 
8.4.2 
Pregnancy testing 
For female participants who are sexually active or have reached menarche, quantitative 
beta-human chorionic gonadotropin testing in blood for pregnancy is required at screening visit 
2 and at the Week 48 visit. For all female participants meeting this definition of child-bearing 
potential, qualitative beta-human chorionic gonadotropin in urine will be performed at monthly 
intervals during the trial. Note that a positive urine test should be confirmed with a serum 
pregnancy test. The cultural differences across participating countries need to be taken into 
account and it is acceptable to have both options simultaneously in the protocol to allow for 
cultural differences between participating countries. In case of a positive test, the participant 
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must contact the investigator immediately. In this fashion, the pregnancy discussion will 
become an additional point at each visit, serving to increase compliance with contraception. 
*Additional pregnancy testing may be performed if requested per local requirements. 
8.4.3 
Clinical safety evaluations 
8.4.3.1 
Neurological examination 
A complete neurological examination is performed at visits specified in Table 8-1, with 
attention to exam features and patient symptoms consistent with a sensory neuronopathy. The 
neurological exam should include detailed, age-appropriate sensory testing (such as 
examination of proprioceptive, vibratory, tactile and pain sensation) at each visit. An age-
appropriate sensory exam is important for sensory neuronopathy detection. 
Any clinically significant abnormal finding should be recorded as an AE. The neurological 
examination should only be recorded as abnormal if there are abnormalities in the sensory 
examination. 
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). 
8.4.3.2 
Physical examination 
Physical examinations will be conducted by the investigator or designee as specified in 
Table 8-1.  
A complete review of systems is performed at the time of each physical examination. Physical 
examinations will include each system: head, eyes, ears, nose and throat (HEENT), 
lungs/thorax, cardiovascular, abdomen, musculoskeletal, neurologic, dermatologic, lymphatic, 
and genitourinary. 
Physical examination data will be captured on source documentation. 
8.4.4 
Vital signs 
Vital sign parameters include blood pressure, respiratory rate, pulse, temperature, and pulse 
oximetry. 
Vital signs will be obtained as specified in the Table 8-1. On Day 1 and Week 52+1 Day 
(OAV101 administration or sham procedure), vital signs, with the exception of blood pressure, 
will be recorded pre-dose and then monitored every 15 (± 5) minutes for the first 1 hour, every 
30 (± 10) minutes until 2 hours, every 2 hours (± 15 minutes) until 8 hours, and every 4 hours 
(± 30 minutes) until 16 hours. Blood pressure will be recorded pre-dose and every 8 hours (± 2 
hours) through 16 hours.  
8.4.5 
Electrophysiology 
Electrophysiology assessments are performed in conjunction with patient history and 
neurological examination to monitor for sensory neuronopathy. 

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8.4.5.1 
Sensory nerve action potential (SNAP)/electrophysiology 
BACKGROUND 
The sensory nerve action potential (SNAP) provides information on the sensory nerve axon and 
its pathway from the distal receptors in the skin to the dorsal root ganglia. The SNAP represents 
the sum of single nerve fiber action potentials. 
PERFORMANCE 
Although electrophysiology (SNAP assessment) is performed at Screening and at post-
treatment visits when there are sensory abnormalities in the neurological examination detailed 
investigations for a sensory neuronopathy can be initiated based on the clinical judgement at 
any time during the study. 
Orthodromic or antidromic SNAPs are acceptable depending on the institutional 
protocol. Sensory nerve conduction studies to assess SNAPs will be performed for all study 
patients at Screening. The SNAP will be scored as “Present” or “Absent” or “Unable to obtain”. 
Pre-treatment: SNAP must be performed for all participants at Screening Visit 1. If the SNAP 
is scored as “Unable to obtain” at Screening Visit 1, then SNAP must be performed at Screening 
Visit 2. Bilateral radial and sural nerve SNAPs must be obtained at one of the two screening 
visits for trial eligibility. Rescheduling is warranted when any factor impedes the ability to 
obtain SNAP data. 
If the SNAP is scored as “Absent” at any one of the pre-treatment visits, the clinician must 
assess whether the absent SNAP is supported by any clinically significant sensory abnormal 
finding(s) in the neurological examination. 
Post-treatment: Post-treatment, SNAP is performed if there are sensory abnormalities in the 
neurological examination. A complete neurological examination is performed at visits specified 
in Table 8-1, with attention to exam features and patient symptoms consistent with a sensory 
neuronopathy (refer to Section 8.4.3.1).  
Any patient with new post-treatment sensory symptoms with or without loss of a SNAP will 
receive a comprehensive assessment of the differential diagnosis. The differential diagnosis 
should include a careful assessment for sensory neuronopathy (sensory ganglionopathy). CSF 
testing and MRI imaging of brain, spinal cord, and dorsal root ganglia is encouraged. Sensory 
ganglionopathies are usually associated with diffuse SNAP abnormalities but may be patchy 
early, with upper limb involved before lower limb. 
TECHNICAL REQUIREMENTS 
Performance of sensory nerve action potentials (SNAPs) should comply with professional 
society standards (Stålberg et al 2019, AANEM 2020). 
SNAP is a conduction study commonly used to evaluate suspected peripheral neuropathies.  
Nerve conduction study is a test commonly used to evaluate the function, especially the ability 
of electrical conduction by the motor and sensory nerves of human body. It is evaluated by 
performing sural SNAP. The sural SNAP is obtained by electrically stimulating sensory fibers. 
Results will be entered in the eCRF.   

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8.4.6 
Anthropometry 
Complications associated with SMA (e.g., scoliosis and contractures) are considered in the 
determination of height, weight, and BMI. 
8.4.6.1 
Body height (segmental by tibial length) 
Direct measurement of recumbent length or height may be challenging in children and 
adolescents with physical disabilities due to joint contractures, muscular weakness, scoliosis, 
or poor cooperation. Since patients in the trial are never ambulatory, use the tibial length for 
segmental height assessment in all participants (Preedy 2012, Samson-Fang and Bell 2013, 
Mokhy et al 2020). Tibial length measurement does not require specialized equipment, is not 
impacted on by knee and ankle contractures and the landmarks are relatively easy to palpate. 
• Use a flexible tape measure that does not stretch. 
• Tibial length is the distance from the superomedial edge of the tibia to the inferior edge of 
the medial malleolus. 
• The measurement should be conducted with the child in a seated position facing the 
observer with the left ankle or calf resting on the right knee so that the medial aspect of 
the tibia faces upwards. Measurements are recorded in centimeters (cm). 
Use the following equation for both males and females to estimate height in males and 
females who are ≥ 2 to ≤ 12 years of age (Stevenson Equation). 
• Height = (3.26 × TL) + 30.8 
• TL=Tibial length 
Use the following equations for males and females to estimate height in males and females 
who are > 12 years of age (Gauld Equation). 
• Males: Height = (2.758 × TL) + (1.717 × A) + 21.818 
• Females: Height = (2.771 × TL) + (1.457 × A) + 37.748 
• TL = Tibial length (cm) 
• A = age in years to one decimal place (e.g. 5.3 years) 
The height calculation is necessary to calculate BMI, an eligibility criterion that must be 
assessed at screening. The height calculation should be checked by an additional study staff to 
ensure accuracy. 
8.4.6.2 
Body weight 
The Centers for Disease Control and Prevention (CDC) procedure for weight measurement is 
recommended (CDC Anthropometry 2020). 
Weight measurement for all trial participants should be performed as follows: 
• Remove shoes and heavy clothes. Weights taken with shoes on will be considered invalid. 
A thin set of clothes or examination gown is permitted. 
• Disposable undergarments (e.g., diapers) should be dry. 
• All medical appliances must be removed (e.g., ankle foot orthosis; thoraco-lumbar-sacral 
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• Use appropriately calibrated digital scale as recommended by the 
CDC (CDC Anthropometry 2020). 
• Values are recorded in kilograms (kg) to two decimal places (e.g., 15.25 kg). 
• Participants who cannot stand alone on the scale will be weighed with the assistance of an 
adult (or per local standard of care). In order to obtain the patient weight, the adult weight 
is subtracted from the total weight of the patient+adult. 
8.4.6.3 
BMI 
BMI is a person’s weight in kilograms divided by the square of height in meters. The CDC BMI 
calculator for children and teens (age range 2 to 19 years) can be used to determine eligibility 
(CDC BMI Calculator 2020). 
Alternatively, the following equation may be used to calculate BMI: 
• BMI = W / H2 
• W = weight in kilograms (kg) to decimal places (e.g., 15.25 kg) 
• H = height in meters (m) to two decimal places (e.g., 0.92 m) (Section 8.4.6.1)  
8.4.6.4 
Head circumference for patients > 3 years of age 
Refer to CDC guidelines for head circumference measurement (CDC Anthropometry 2020). 
Serial measurements are not required on children > 3 years of age. 
8.4.6.5 
Head circumference for patients <= 3 years of age 
Refer to CDC guidelines for head circumference measurement (CDC Anthropometry 2020). 
Head circumference measurements will be taken in children ≤ 3 years of age in accordance with 
the Schedule of Assessments (Table 8-1). 
8.4.7 
Echocardiogram 
A standard transthoracic ECHO will be performed at times indicated in the Schedule of 
Assessments (Table 8-1) and interpreted locally by a cardiologist or a designee for immediate 
safety evaluation. The ECHOs will also be collected for centralized review by a cardiologist. 
8.4.8 
Electrocardiogram 
Full details of all procedures relating to the ECG collection and reporting will be contained in 
the technical manual which is provided to the site by the core laboratory. 
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 
core laboratory for expedited review if applicable, and the ECG is repeated to confirm the 
diagnosis. If the patient is hemodynamically compromised, the investigator or a medically 
qualified person must initiate appropriate safety procedures without delay (e.g., cardioversion). 
ECGs must be recorded (after 10 minutes rest in the supine position to ensure a stable baseline 
/ according to the ECG investigator manual). The preferred sequence of cardiovascular data 
collection during study visits is ECG collection first, followed by vital signs, and blood 

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sampling (Figure 8-1). The Fridericia QT correction formula (QTcF) must be used for clinical 
decisions, e.g., at the Screening and Baseline visits(s) to assess eligibility. The investigator must 
calculate QTcF if it is not auto-calculated by the ECG machine. Triplicate 12-lead ECGs are to 
be recorded approximately 2 minutes apart. The mean QTcF value for each visit will be 
calculated from the triplicate ECGs for each participant. For any ECGs with participant safety 
concerns, two additional ECGs must be performed to confirm the safety finding. ECG safety 
monitoring, or a review process, should be in place for clinically significant ECG findings, at 
Baseline, before administration of treatment and during the study. 
Additional unscheduled safety ECGs may be repeated at the discretion of the investigator at any 
time during the study as clinically indicated. 
Clinically significant abnormalities must be recorded on the relevant section of the CRFs as 
either medical history/current medical conditions or Aes as appropriate. 
Figure 8-1 
Timing of study procedures 
 
HFMSE and RULM are recommended to be performed first, prior to all other assessments, if 
possible. 
8.4.9 
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 
No additional tests will be performed on participants entered into this study. 
8.5.1 
Clinical Outcome Assessments (COAs) 
As per Section 4.6, 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 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. 
Clinician Reported Outcomes (ClinRO) 
The impact of OAV101 on ClinROs will be assessed by the following measures in order to 
understand clinically meaningful aspects of motor improvements. 
• Hammersmith Functional Motor Scale Expanded (2019 version) (Section 8.3.1.1) 

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• Revised Upper Limb Module (16-Dec-2014) (Section 8.3.1.2) 
 
 
 
 
 
 
Data will be captured through the use of an eCOA device, as provided to sites by selected 
third-party vendor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.5.2 
 
Collection and/or analysis of samples may not be performed in countries where it is not feasible 
(e.g., due to regulatory restrictions, not possible to export samples, and/or assay(s) not available 
in local countries). 
 
 
 These specimens will be used to identify and/or verify 
potential markers that may be predictive of disease activity, disease course and/or clinical 
response to treatment. 
 
 
 
 
 
While the goal of the 
 assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or not perform or 
discontinue an analysis 
 
 
 
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DNA samples (Required) 
Eligibility requires genetic testing confirmation of a molecular diagnosis of 5q SMA. 
 
 
 
8.5.2.1 
 
 
 
 
 
 
 
 
8.5.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.5.3.1 
 
 
 
 
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8.5.3.2 
Anti-AAV9 antibody testing (BLOOD) 
 
 
 
 
 
 
8.5.3.3 
 
 
 
8.5.4 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from study treatment 
Since this is a single dose trial of gene therapy, discontinuation of study treatment is not possible 
since the vector transduces patient cells resides as episomal concatemers in the host cell nucleus. 
Participants who decide they do not wish to participate in the study further should NOT be 
considered withdrawn from the study UNLESS they withdraw their consent (see ‘Withdrawal 
of Informed Consent’ section). Where possible, they should return for the assessments indicated 
in the Assessment Schedule. If 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 
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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 Visit should be completed (refer to Section 8). 
At a minimum, in abbreviated visits, the following data should be collected at clinic visits or 
via telephone/email contact: 
• New / concomitant treatments/medications 
• Aes, including SAEs 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study participation. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops any protocol-required 
assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
If a participant’s anti-AAV9 antibody titer test result is reported as elevated (reference to > 1:50 
 
discontinuation from the study will occur after the participant completes the End of follow-up 
Period 1 (Week 52). No further treatment or follow-up will occur (refer to Table 8-1 and 
Section 3). This does not apply to participants administered OAV101 in Period 1.  
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from the 
study or withdraw consent (or exercise other participants’ data privacy rights), 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. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment prior to OAV101 administration in Treatment 
Period 1 or Treatment Period 2 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
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This request should be as per local regulations (e.g., in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g., to respond to data queries) and potentially other country-specific restrictions. It is 
therefore very important to ensure accurate recording of withdrawal vs. discontinuation based 
on the protocol definition of these terms. 
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 their 
consent/exercise data/privacy rights and record this information. The investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
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. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data/privacy rights should be made as detailed in the assessment table (refer 
to Section 8). 
Further details on withdrawal of consent or the exercise of participants’ data privacy rights are 
included in the corresponding informed consent form. 
9.3 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their last study 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. 
9.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination (but not limited to): 
1. Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
2. Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
3. Discontinuation of study drug development 
4. 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 participant who discontinued from study treatment: 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. The 

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Principal Investigator or designee will contact the study participant and/or the caregiver and 
provide instructions for returning to the Independent Treatment Site, or the Local Study Site, as 
appropriate. Every effort will be made to complete all end of study visit assessments for all 
treated study participants in the case of early study termination by the sponsor. 
10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event 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. A treatment-emergent adverse event is defined as any event not 
present prior to the initiation of the treatment or any event already present that worsens in either 
intensity or frequency following exposure to the treatment.  
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): 
Adverse events will be assessed as follows: 
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 ongoing) 

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4. Whether it constitutes an SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment 
6. Its outcome (i.e., recovery status or whether it was fatal) 
All adverse events must be treated appropriately. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued through the end of study visit. If prednisolone 
treatment is required after the end of study visit (Week 64), AE monitoring will continue for 30 
days after the last dose of prednisolone. 
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 known adverse drug reactions for the investigational drug can be found in 
the Investigator'’s Brochure. 
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. Alert ranges for laboratory and other test abnormalities are included 
in Appendix 1. 
10.1.2 
Adverse events of special interest 
On the basis of important identified or potential risks associated with OAV101, AESIs are 
determined and categorized as follows. These will be summarized based using Standardized 
MedDRA terminology: 
• Hepatotoxicity 
• Transient thrombocytopenia 
• Thrombotic microangiopathy 
• Cardiac adverse events 
• Dorsal root ganglia toxicity 
• New malignancies 

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10.2 
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 
Code of Federal Regulations (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. 
10.2.1 
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 an 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 ICH-E2D Guidelines 2003). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient 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 an 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 

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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 
ICH-E2D Guidelines 2003). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. Any suspected transmission via a medicinal product of an 
infectious agent is also considered a serious adverse reaction. All reports of intentional misuse 
and abuse of the product are also considered serious adverse event irrespective if a clinical event 
has occurred. 
10.2.2 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit if there are 
post-treatment follow-up visits with no required procedures must be reported to Novartis safety 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
obtaining knowledge of the 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 
reporting. Novartis may need to issue an Investigator Notification (IN) 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 
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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. 
Treatment-emergent elevations in AST or ALT (>3x ULN) in combination with total 
bilirubin >2x ULN or jaundice in the absence of cholestasis (defined as ALP < 2 ULN) or other 
causes of hyperbilirubinemia can be an indicator of severe drug induced liver injury (Hy’s Law). 
For this reason, a potential Hy’s Law case requires expedited reporting, and will be handled as 
a serious unexpected adverse event (assessing it as medically significant in the absence of any 
other seriousness criteria). It must be reported as an SAE to the sponsor promptly (i.e., even 
before all other possible causes of liver injury have been excluded). Reporting should include 
all available information, especially that needed for evaluating the diagnosis, severity and 
likelihood that the study treatment caused the reaction. For patient monitoring and to better 
understand potential etiologies, the investigator must initiate a close follow-up until complete 
resolution of the problem and completion of all attempts to obtain supplementary data. 
10.2.3 
Pregnancy reporting 
If a female trial participant becomes pregnant, the pregnancy consent form should be presented 
to the trial participant. The participant must be given adequate time to read, review and sign the 
pregnancy consent form. This consent form is necessary to allow the investigator to collect and 
report information regarding the pregnancy. To ensure participant safety, each pregnancy 
occurring after signing the informed consent must be reported to Novartis within 24 hours of 
learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Risks 
to the fetus of recombinant AAV gene therapy to the fetus are unknown. Since there is a 
difference in risks between the treatment groups, all pregnancy cases must be unblinded. The 
investigator will break the study blind for that participant and inform the participant which 
treatment she was on. This applies also when pregnancy occurs in partners of male participants. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship of OAV101 to any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
NOTE: Payment for all aspects of obstetrical care, child or related care will be the participant’s 
responsibility. 

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10.2.4 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
• Misuse refers to situations where the medicinal product is intentionally and 
inappropriately used not in accordance with the protocol 
• Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE. Study treatment 
errors and uses outside of what is foreseen in the protocol, misuse or abuse will be collected 
and reported in the safety database irrespective of it being associated with an AE/SAE within 
24 hours of Investigator’s awareness. For more information on AE and SAE definition and 
reporting requirements, please see the respective sections. 
10.3 
Additional Safety Monitoring 
10.3.1 
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 Appendix 2, Section 16.2.1 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every hepatotoxicity event defined in Section 
16.2.1 should be followed up by the Investigator or designated personnel at the trial site, as 
summarized below. Additional details on actions required in case of liver events are outlined in 
Table 16-1 and Table 16-2. 
If elevated, repeat liver chemistry tests (i.e., ALT, AST, TBL, PT/INR, ALP, and G-GT) will 
be performed within 48-72 hours to confirm elevation. These liver chemistry repeats should be 
performed. At a local laboratory to monitor the safety of the participant. Any local liver 
chemistry tests should have results recorded on the appropriate CRF. 
If the initial elevation is confirmed,  follow-up requirements will be performed based on the 
liver laboratory trigger, and per Table 16-1 and Table 16-2: 
• 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 abdominal ultrasound/Fibroscan 
(i.e., elastography), and pathology assessments 
• Obtaining a more detailed history of signs and symptoms and prior or concurrent 
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• Obtaining a history of concomitant drug use, including nonprescription medications 
(e.g., acetaminophen); and herbal and dietary supplement preparations 
• Exclusion of underlying liver disease 
• Pediatric gastroenterology or hepatology consultations, if appropriate 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. 
10.3.2 
 
 
 
 
 will be administered by an individual 
who has received training and certification in its administration. 
 
 
 
 
 
 
 
 
 
 
 
 
In addition, all life-threatening events must be reported as SAEs. 
 
 
 
 
 
10.3.3 
Post-mortem data collection 
In the event of a fatal outcome, autopsy, where possible, an autopsy will be requested 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 with particular attention to CNS, dorsal root ganglia, 
liver, kidneys, heart, and skeletal muscle. Instructions to be followed for sample collection, 
processing and shipment are available in the Autopsy and Tissue/Organ Collection Manual. 
Declining autopsy will not prevent patients from participating in the trial. 
Final autopsy report will be stored in the eTMF. 
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10.3.4 
 
In the event a participant undergoes a 
 
 should be performed as per 
local standard of care and local regulations. 
 should be collected and sent 
 
 
These additionally obtained 
 
  
Participants/participants’ parents/guardians will be asked to provide additional consent 
 
 
 
10.4 
Committees 
10.4.1 
Data Monitoring Committee 
This study will include a data monitoring committee 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 
Database management and quality control 
Novartis personnel (or designated Contract Research Organisation (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment(s) dispensed to the participant 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. 
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Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.2 
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 Intent to Treat Analysis Set (ITT) comprises all randomized participants, regardless of 
whether they were dosed with study treatment (OAV101) or who underwent sham procedure 
during Treatment Period 1. Participants will be analyzed according to the treatment/procedure 
they have been assigned to.   

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The Full Analysis Set (FAS) comprises all randomized participants who were dosed with study 
treatment (OAV101) or who underwent sham procedure during Treatment Period 1. 
Participants will be analyzed according to the treatment/procedure they have been assigned to. 
As per the protocol, participant randomization occurs approximately 2 weeks prior to when 
treatment administration/sham procedure is planned to occur. There is a possibility that a 
participant is randomized but subsequently becomes ineligible for the trial during this time and 
ultimately would not be dosed with study treatment/undergo the sham procedure or contribute 
to the post-treatment study assessments. In order to account for this possibility, the FAS will 
exclude participants who were randomized but were not dosed with study treatment/did not 
undergo sham procedure. 
The Active Treatment Period 2 Set (ATP2) comprises all participants who were dosed with 
study treatment (OAV101) or who underwent sham procedure during Treatment Period 2. 
The Safety Set includes all participants who were dosed with study treatment (OAV101) or who 
underwent sham procedure. Participants will be analyzed according to the study 
treatment/procedure received. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group for the FAS and the Safety Set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles may also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group 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 details pertaining to the administration of study treatment will be summarized by means of 
descriptive statistics using the Safety Set. 
Concomitant medications and significant non-drug therapies prior to and after the 
administration of the study treatment will be summarized according to the ATC classification 
system, by treatment group. 
12.4 
Analysis supporting primary objectives 
The primary objective of the study is described in Table 2-1. Efficacy analyses will use the FAS 
unless otherwise specified. 
The primary analysis will be performed after all participants have completed Week 52 or 
discontinued prior to Week 52. A final analysis will be performed after all participants have 

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completed Week 64 (or discontinued prior to Week 64). Formal testing of the primary endpoint 
with full alpha level will be performed at the primary analysis time point. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint of the study is the change from Baseline in HFMSE total score at the end 
of Follow-up Period 1 in the overall study population (≥ 2 to < 18 year age group). 
 
 
 
 
 Refer to Section 8.3.1 for details pertaining to the completion of 
assessments. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The aim is to estimate the treatment effect of intrathecal OAV101 compared to the sham 
procedure, for the target population on the primary endpoint. The justification of the 
corresponding primary estimand are detailed in Section 2.1. 
The statistical hypothesis for the primary endpoint being tested is that there is no difference in 
the change from Baseline in HFMSE total score at the end of Follow-up Period 1 in the 
OAV101 treatment group compared to the sham procedure group. 
Let pj denote the change from Baseline in HFMSE total score at the end of Follow-up Period 1 
for treatments j, j = 0, 1 where: 
0 corresponds to sham procedure 
1 corresponds to OAV101 
In statistical terms, H0: p1 = p0, HA: p1 ≠ p0, i.e.,: 
H0: OAV101 is not different from sham procedure with respect to the change from Baseline in 
HFMSE total score at the end of Follow-up Period 1. 
HA: OAV101 is different from sham procedure with respect to the change from Baseline in 
HFMSE total score at the end of Follow-up Period 1. 
The primary efficacy endpoint variable will be analyzed using a mixed model with repeated 
measurements (MMRM) with the observed change from Baseline in HFMSE total score at all 
post-Baseline visits (through the end of Follow-up Period 1) as the dependent variable. The 
fixed effects will include treatment, scheduled visit, treatment by visit interaction, 
 
 An unstructured covariance matrix will be 
used. LSMs for each treatment group, standard errors, associated 95% confidence intervals 
(CIs), difference of LSMs compared to sham procedure group, the associated 95% CI for the 
difference, as well as the two-sided p-values will be tabulated by visit and treatment. The null 
hypothesis will be rejected if the two-sided p-value for the LSM difference between the 
OAV101 arm and the sham procedure arm at the end of Follow-up Period 1 is less than the 
alpha level dictated by the sequential testing procedure (Figure 12-1). 
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The detailed testing strategy including the primary efficacy endpoint is provided 
in Section 12.5. 
12.4.3 
Handling of intercurrent events of primary estimand 
The primary analyses will account for intercurrent events as explained in the following: 
• Study discontinuation due to reasons other than death: It is assumed that participants 
discontinuing the study prior to Week 52 would follow the same trend as participants who 
continued and remained in the study for the full 52 weeks. Data collected up to the point 
of discontinuation will be included in the MMRM (hypothetical strategy). 
• Use of prohibited concomitant medications not for the intent to treat SMA: 
Assessments collected while/after receiving prohibited concomitant medications will be 
included in the analyses (Treatment policy strategy). 
• Use of prohibited concomitant medications for the intent to treat SMA (i.e. 
nusinersen, risdiplam): Assessments collected while/after receiving prohibited 
concomitant medications will not be included in the analyses. Only data collected up to 
the point of initiating a prohibited medication for the intent to treat SMA will be included 
in the MMRM and the data collected after the initiation of prohibited medication for the 
intent to treat SMA will be considered as missing (Hypothetical strategy).  
• Study discontinuation due to death: The worst HFMSE score will be imputed for 
participants who discontinue the study due to death, and this imputed score will be utilized 
in the analysis. The “worst score” refers to the worst (lowest) HFMSE score collected 
for the participant who had the death event throughout the trial (considering both 
the baseline and post-baseline period).  It is anticipated that this intercurrent event is 
unlikely to occur during this study. 
12.4.4 
Handling of missing values not related to intercurrent event 
The primary analysis method, MMRM, implicitly imputes missing data under a missing at 
random assumption. 
12.4.5 
Sensitivity analyses 
In order to assess the potential impact of excluding participants from the primary analysis who 
are randomized into the study but did not receive treatment, the primary efficacy analysis will 
be repeated using the ITT Set. The same analysis methodology as described for the primary 
analysis of the primary efficacy endpoint (i.e. MMRM) will be applied for this sensitivity 
analysis. 
A sensitivity analysis using multiple imputation approach will also be performed for the primary 
estimand, to assess the robustness of the estimation in the presence of deviations from the 
assumptions specified in the primary analysis. Additional details will be provided in the 
statistical analysis plan (SAP). 
12.4.6 
Supplementary analysis 
No supplementary analysis is planned. 

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12.5 
Analysis supporting secondary objectives 
The secondary objectives are described in Table 2-1. Secondary efficacy analyses will use the 
FAS. 
12.5.1 
Efficacy and/or pharmacodynamic endpoint(s) 
The secondary endpoint analyses are as follows: 
1. Change from Baseline in HFMSE total score at the end of Follow-up Period 1 for 
participants aged ≥ 2 to < 5 years 
2. Achievement of at least a 3-point improvement from baseline in HFMSE total score at the 
end of Follow-up Period 1 (responders) for participants in the overall study population  
3. Achievement of at least a 3-point improvement from baseline in HFMSE total score at the 
end of Follow-up Period 1 in the ≥ 2 to < 5 years age group 
4. Change from Baseline in RULM total score at the end of Follow-up Period 1 for 
participants aged ≥ 2 to < 18 years 
5. Change from Baseline in RULM total score at the end of Follow-up Period 1 for 
participants aged ≥ 2 to < 5 years 
The continuous secondary endpoints of change from baseline in HFMSE and RULM scores in 
the younger age group or the whole study population will be analyzed in a similar manner to 
how the primary endpoint will be analyzed. 
The dichotomous endpoint (proportion of responders, defined as participants who achieve at 
least a 3-point improvement from baseline in HFMSE total score at the end of Follow-up Period 
1) will be analyzed by Generalized Linear Mixed Effects Model including treatment, 
 
 The model 
will include the link=logistic function. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Refer to Section 8.3.1 for details pertaining to the completion 
of assessments. 
Testing Procedure 
 
 
 
 
 
 
 
 
 
 
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Figure 12-1 
 
 
 
12.5.2 
Safety endpoints 
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) will include only data from the post-treatment period with 
the exception of baseline data, which will also be summarized where appropriate (e.g., change 
from baseline summaries). In addition, a separate summary for deaths occurring post-treatment 
will be provided. In particular, summary tables for adverse events (AEs) will summarize only 
on-treatment events, with a start date on or after the date of dose administration 
(treatmentemergent AEs). 
The on-treatment period lasts from the date of administration of study treatment to completion 
of the study at Week 64. 
Adverse events 
All information obtained on adverse events will be listed by treatment group and participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
with an onset after the dose of study medication or events which were present prior to start of 
double-blind treatment but increased in severity, changed from being not suspected to being 
suspected of study drug relationship, or developed into SAEs after the start of the treatment 
period) will be summarized in the following ways: 
• by treatment group, primary system organ class and preferred term. 
• by treatment group, primary system organ class, preferred term and maximum severity. 
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• by treatment group, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, deaths, 
serious adverse events, and other significant adverse events leading to discontinuation. 
The number (and proportion) of participants with AESIs will be summarized by treatment. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be summarized by treatment and visit/time. 
12-lead ECG 
All ECG data will be summarized by treatment and visit/time. 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study.  
Categorical analysis of QT/QTc interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from Baseline 
will be presented. 
Echocardiogram 
All echocardiogram data will be summarized by treatment and visit/time. Additionally, the 
following will be summarized: 
• 
Number and percentage of participants with intracardiac thrombi 
• 
Number and percentage of participants with low cardiac function 
These parameters are defined as follows:  
Intracardiac thrombi: Post-baseline ECHO result of thrombus present (response of Yes)  
Low cardiac function: Post-baseline ECHO results of LVEF < 56% or LVFS < 28% 
Clinical laboratory evaluations 
All laboratory data will be summarized by treatment and visit/time. Shift tables using the 
low/normal/high classification as well as CTCAE grades will be used to compare baseline to 
the worst on-treatment value. 
 
 
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12.6 
Analysis of exploratory endpoints 
The exploratory objectives are described in Table 2-1. 
The full list of exploratory endpoints to be included in the CSR and detailed analysis methods 
will be detailed in the study SAP. 
12.6.1 
 
 
 
 
 Additional data, 
from other clinical trials, are often needed to confirm associations. Alternatively, if the number 
of participants enrolled in the study is too small to complete proper statistical analyses, the data 
may be combined, as appropriate, with those from other studies to enlarge the dataset for 
analysis. 
Data generated on hypothesis-free platforms will be reported separately (e.g., CSR addendum). 
12.6.2 
 
, will be 
tabulated with descriptive statistics by visit and treatment. Additional exploratory analyses and 
their results, if applicable, will be included 
 
 
12.6.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.7 
Interim analyses 
No formal interim analysis is planned for this trial. 
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12.8 
Sample size calculation 
The sample size calculation is primarily based on the primary variable, change from Baseline 
in HFMSE total score. 
12.8.1 
 
 
 
 
 
 
 
 
Assuming a true treatment difference in the change from Baseline in HFMSE of 3 points and a 
standard deviation of 5 points, a sample size of 125 participants (75 in the OAV101 treatment 
group and 50 in the sham procedure group) provides approximately 90% power that the primary 
analysis will be statistically significant at the two-sided 5% alpha level assuming a minimal 
number of participants prematurely withdraw from the study prior to Week 52. In addition, 
assuming a larger treatment difference in the change from Baseline in HFMSE total score of 
5 points and the same standard deviation as anticipated in the overall study population (5 points) 
in the ≥ 2 to < 5 years old group, a sample size of 65 participants (39 in the OAV101 treatment 
group and 26 in the sham procedure group) could achieve > 95% power in this younger age 
group. 
12.8.2 
Secondary endpoint(s) 
Sample size considerations were primarily based on the primary endpoint. 
Because this is the first OAV101 clinical trial to include the RULM assessment, there are no 
historical data available upon which to base sample size calculations on.  
In the AVXS-101-CL-102-IT clinical trial, the HFMSE responder endpoint was defined as the 
achievement of improvement in HFMSE of ≥ 3 points at any post baseline time point (through 
Month 12): 11/12 (91.7%) patients treated with OAV101 achieved response, compared to 2/15 
(13.3%) patients in the PNCR group. For the current study, the responder endpoint is defined 
as the achievement of improvement in HFMSE of ≥ 3 points at the end of follow-up period 1 
(and will be based on the average of the HFMSE scores at Month 11 and Month 12). Applying 
this same definition to the AVXS-101-CL-102-IT data, 9/12 (75%) patients treated with 
OAV101 achieved response. For PNCR, HFMSE was assessed less frequently (the last 2 time 
points of relevance were Month 9 and Month 12). Considering just the PNCR patients with 
HFMSE data at Month 9 and/or Month 12, then based on the average of these 2 scores or based 
on the single available score, 2/15 (13%) achieved response. The power to detect a significant 
difference in the ≥ 2 to < 5 year age group in this study, assuming a response rate of 75% for 
OAV101 and 13% for sham and alpha=0.05, would be > 99% with the planned sample size of 
N=65 patients (39 in OAV101, 26 in sham). 
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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 Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (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. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 
Summary results of primary and secondary endpoints will be disclosed based upon global Last 
Participant Last Visit (LPLV) date, since multinational studies are locked and reported based 
upon the global LPLV. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 

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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. 
13.5 
Participant engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank you letter 
• Plain language trial summary–- after CSR publication 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
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 
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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
Clinically relevant laboratory abnormalities 
Age-appropriate, normal laboratory values and clinical measurements should be used in 
pediatric population. Laboratory tests are commonly interpreted in relation to established 
reference intervals. These limits serve to differentiate between normal and pathological 
findings, and to gauge the severity of any abnormal increases or decreases. As far as laboratory 
parameters are known to characteristically vary with age, pediatric test results are usually 
interpreted in relation to these physiological dynamics. Reference intervals for pediatric patients 
have been calculated by partitioning data from a healthy reference population into age groups, 
so that the corresponding subset-specific percentiles would form step functions of age 
(Hirschmann et al 2017). 
Vital signs 
Within vital signs data, height and weight are commonly collected along with heart rate, 
respiratory rate, and blood pressure. The exam and vital sign data can be interpreted only with 
a thorough understanding of normal values. In pediatrics, normal respiratory rate, heart rate, 
and blood pressure have age-specific norms (Fleming et al 2011, Flynn et al 2017). The full list 
of clinically relevant vital signs will be included in the CSR and detailed summary methods will 
be specified in the Statistical Analysis Plan. 

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16.2 
Appendix 2: Liver laboratory triggers & follow-up monitoring 
requirements 
16.2.1 
Liver laboratory triggers 
Liver laboratory triggers which require follow-up monitoring include: 
• ALT > 3 × ULN 
• TBL > 1.5 × ULN (in the absence of known Gilbert’s syndrome) 
• Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 × ULN 
[mainly conjugated (direct) fraction] without notable increase in ALP to > 2 × ULN) 
16.2.2 
Follow up requirements for liver laboratory triggers – ALT and AST, 
with and without TBL 
Table 16-1 
Follow-up requirements for liver laboratory triggers – ALT and AST, 
with and without TBL 
ALT 
TBL 
Liver Symptoms 
Actions/Follow-up Monitoring 
ALT > 3 x ULN 
· Normal 
· For participants with 
Gilbert’s syndrome: No 
change in baseline TBL 
None 
· Review compliance with 
immunomodulatory therapy 
(Section 6.2) 
· Measure ALT, AST, TBL, fractionated 
bilirubin (direct and indirect), INR, and 
GLDH within 48-72 hours 
· Follow-up for symptoms 
ALT > 5 x ULN 
 
· Normal 
· For participants with 
Gilbert’s syndrome: No 
change in baseline TBL 
With or without 
symptoms  
· Review compliance with 
immunomodulatory therapy 
(Section 6.2) 
· Measure ALT, AST, TBL, fractionated 
bilirubin (direct and indirect), INR, 
albumin, CK, and GLDH within 48 - 72 
hours  
· Follow-up for symptoms 
· Initiate close monitoring 
(hospitalization when appropriate) and 
workup for competing etiologiesa 
· Exclude underlying liver disease 
· Obtain detailed history of concomitant 
medications (e.g. acetaminophen) 
· Consult pediatric gastroenterologistb 
ALT or AST > 3 x 
ULN 
 
· TBL > 2 x ULN (or 
INR > 1.5) 
· For participants with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
With or without 
symptoms  
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
and/or 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, hepatitis B virus (HBV) DNA, hepatitis C virus (HCV) ribonucleic acid (RNA), anti-HCV, IgM & 
IgG, hepatitis E virus (HEV) RNA, anti-HEV, viral panel (CMV, EBV, HSV), autoimmune hepatitis (ANA, anti-
smooth muscle antibody (ASMA) titers) 
bConsider appropriate imaging and liver biopsy in consultation with a pediatric gastroenterologist 

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16.2.3 
Follow up requirements for liver laboratory triggers - isolated 
hyperbilirubinemia 
Table 16-2 
Follow-up requirements for liver laboratory triggers - isolated 
hyperbilirubinemia 
Criteria 
Total Bilirubin 
(isolated) 
Actions required 
Follow-up monitoring 
>1.5 – 3.0 x ULN 
· Repeat LFTs within 48-72 hours  
· Monitor LFTs weekly until resolution to ≤ 
Grade 1 or to baseline 
> 3 – 10 x ULN (in 
the absence of known 
Gilbert’s syndrome) 
· Repeat LFTs within 48-72 hours  
· Hospitalize if clinically appropriate 
· Establish causality 
· Record the AE and contributing factors 
(e.g. concomitant medications, medical 
history, labs) in the appropriate CRF 
· Monitor LFTs weekly until resolution to ≤ 
Grade 1 or to baseline (ALT, AST, TBL, 
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. concomitant medications, medical 
history, laboratory evaluations) in the 
appropriate CRF 
· ALT, AST, TBL, Alb, PT/INR, until 
resolution (frequency at investigator 
discretion) 
LFT(s) = liver function test 
Based on investigator’s discretion, investigation(s) for contributing factors for the liver event can include: 
Serology tests, imaging and pathology assessments, pediatric gastroenterologist's 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. 
16.2.4 
Prednisolone dosing 
Prednisolone dosing 
 
 
 
 
• 
 (as defined in Section 16.2.1), refer to the follow-
up requirements specified in Table 16-1 and Table 16-2.  
• 
Live vaccines are prohibited while receiving corticosteroids.  Participants are advised to 
complete all age-appropriate inoculations with live vaccines prior to enrolling in the 
study if possible. 
• 
 
 
 
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