Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion
Phase: PHASE3
Conditions: Spinal Muscular Atrophy Type I
Sponsor: Novartis Gene Therapies

Protocol Number:  AVXS-101-CL-306 
 
Official Title:  Phase 3, Open-Label, Single-Arm, Single-Dose Gene 
Replacement Therapy Clinical Trial for Patients with Spinal 
Muscular Atrophy Type 1 with One or Two SMN2 Copies 
Delivering AVXS-101 by Intravenous Infusion 
 
NCT Number: NCT03837184 
 
Document Date:  11-Nov-2020 

 
 
SIGNATURE PAGE
TITLE CL-306 Clinical Protocol ID: PRO-749
User
Role
Job Title
Version
Decision
Date Signed
Final Approvers
Executive Medical Director
6.0
Approve
12 Nov 2020 06:00 PM
CST
Final Approvers
Associate Director,
Therapeutic Lead
6.0
Approve
12 Nov 2020 04:14 PM
CST
Final Approvers
Senior Medical Director
6.0
Approve
12 Nov 2020 06:37 PM
CST
Final Approvers
Vice President
6.0
Approve
12 Nov 2020 04:12 PM
CST
Final Approvers
Vice President
6.0
Approve
13 Nov 2020 02:36 AM
CST
Final Approvers
Senior Director,
Biostatistics
6.0
Approve
12 Nov 2020 04:08 PM
CST
 
 
This is a copy generated on 13 Nov 2020 08:59 AM CST.   Please refer to ACE for
most recent effective version.  
PRO-749 Version6.0 Generated 13 Nov 2020 08:59 AM CST | Effective Date: 13 Nov 2020 08:54 AM CST

 
 
 
 
 
 
 
 
AVXS-101 
AVXS-101-CL-306 
 
 
Protocol Title: 
Phase 3, Open-Label, Single-Arm, Single-Dose Gene 
Replacement Therapy Clinical Trial for Patients with Spinal 
Muscular Atrophy Type 1 with One or Two SMN2 Copies 
Delivering AVXS-101 by Intravenous Infusion 
Indication Studied: 
Spinal Muscular Atrophy Type 1 
Sponsor Address: 
Novartis Gene Therapies, Inc. 
2275 Half Day Road, Suite 200 
Bannockburn, IL 60015 
Protocol Version/Date: 
6.0 Incorporating Amendment 5 / 11 Nov 2020 
The trial will be completed according to the guidelines of Good Clinical Practice.  Compliance with this 
standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, 
consistent with the principles that have their origin in the Declaration of Helsinki. 
 
Confidentiality Statement 
The information in this document contains trade and commercial information that is privileged or 
confidential and may not be disclosed unless such disclosure is required by federal or state law or 
regulations.  In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them.  These restrictions on 
disclosure will apply equally to all future information supplied to you which is indicated as privileged or 
confidential. 
PRO-749 Version6.0 Generated 13 Nov 2020 08:59 AM CST | Effective Date: 13 Nov 2020 08:54 AM CST

Novartis Gene Therapies, Inc. 
AVXS-101-CL-306 
Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
Confidential/Proprietary 
Page 2 of 106 
1. 
ADMINISTRATIVE INFORMATION 
1.1. 
Approval 
REPRESENTATIVES FROM Novartis Gene Therapies: 
This trial will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical trial protocol and also in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki 
• International Council for Harmonisation (ICH), Integrated Addendum to ICH E6 
(R1): Guideline for Good Clinical Practice E6 (R2) 
• All applicable laws and regulations, including, without limitation, data privacy laws 
and regulations 
SIGNATURES (may be applied electronically and will therefore be maintained in the electronic system): 
 
  
Senior Director, Clinical Development 
Novartis Gene Therapies, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
Vice President, Regulatory Affairs 
Novartis Gene Therapies, Inc. 
 
 
Date (ddMmmyyyy) 
 
  
Vice President, Clinical Development & Analytics 
Novartis Gene Therapies, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
Associate Director, Clinical Operations 
Novartis Gene Therapies, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
Senior Director, Biostatistics 
Novartis Gene Therapies, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
Vice President & Head, Global Patient Safety 
Novartis Gene Therapies, Inc. 
 
 
Date (ddMmmyyyy) 
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Novartis Gene Therapies, Inc. 
AVXS-101-CL-306 
Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
Confidential/Proprietary 
Page 3 of 106 
1.2. 
Investigator’s Agreement 
I have received and read the Investigator’s Brochure for AVXS-101.  I have read the 
AVXS-101-CL-306 protocol and agree to conduct the trial in accordance with the relevant 
current protocol. 
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol.  I agree to personally conduct or supervise the investigation(s).  I also agree to 
promptly report to the Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
all changes in the research activity and all unanticipated problems involving risks to human 
subjects or others.  Additionally, I will not make any changes in the research without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to human subjects.  I 
agree to protect the safety, rights, privacy, and well-being of trial participants.  I agree to comply 
with: 
• The ethical principles that have their origin in the Declaration of Helsinki 
• International Council for Harmonisation, Integrated Addendum to ICH E6 (R1): Guideline 
for Good Clinical Practice E6 (R2) 
• All applicable local and regional laws and regulations, including, without limitation, data 
privacy laws and regulations including but not limited to Medical Care Act, Pharmaceutical 
Affairs Act, regulations on human trials 2009, Human Subject Research Act 2011, regulations 
for Good Clinical Practice 2005, Human Biobank Management Act 2012, regulations for 
registration of medicinal products, regulation for drug samples or complementary drugs. 
• Terms outlined in the trial site agreement 
• Responsibilities of the Investigator (per regulatory guidelines and applicable regulations) 
• I further authorize that my personal information may be processed and transferred in 
accordance with the uses contemplated in this protocol. 
 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator or 
Consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee.  Your acceptance of this document constitutes agreement 
that you will not disclose the information contained herein to others without written 
authorization from the Sponsor. 
________________________________________________ 
Printed Name of Principal Investigator 
________________________________________________ 
Signature of Principal Investigator 
________________________________________________ 
Date (ddMmmyyyy) 
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Novartis Gene Therapies, Inc. 
AVXS-101-CL-306 
Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
Confidential/Proprietary 
Page 4 of 106 
1.3. 
Contact Information 
 
Role in Study 
Contact information 
Novartis Gene Therapies Medical Director 
 Senior Director, Clinical Development 
 
24-Hour Emergency Contact 
Please see Study Contact List in Investigator Site File 
 
Additional study contact information is provided in the Study Contact List. 
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Novartis Gene Therapies, Inc. 
AVXS-101-CL-306 
Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
Confidential/Proprietary 
Page 5 of 106 
2. 
SYNOPSIS 
Name of Sponsor/Company:  Novartis Gene Therapies, Inc. 
Name of Investigational Product:  AVXS-101 
Name of Active Ingredient:  Survival Motor Neuron Gene by Self‐Complementary 
Adeno-Associated Virus Serotype 9 (AAV9) 
Title of Trial:  Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy 
Clinical Trial for Patients with Spinal Muscular Atrophy Type 1 with One or Two SMN2 
Copies Delivering AVXS-101 by Intravenous Infusion 
Estimated number of Trial Center(s) and Countries or Regions:  Approximately 3 Asian 
Investigative Sites located in the following countries: Japan, South Korea, Taiwan. Japan is 
participating in this global study under a Japan-specific version of the AVXS-CL-101-306 
protocol. 
Investigators:  Multicenter Trial - Investigator Information on File at Novartis Gene 
Therapies, Inc. 
Studied Period (years): 
Estimated date first patient enrolled: Q3 2018 
Estimated date last patient completed: Q3 2021 
Phase of Development:  3 
Objectives: Primary 
• Determine efficacy by demonstrating achievement of developmental milestone of sitting 
without support for at least 10 seconds up to 18 months of age as defined by World Health 
Organization (WHO) Motor Developmental Milestones. 
Secondary 
• Determine efficacy based on survival at 14 months of age.  Survival is defined by the 
avoidance of combined endpoint of either (a) death or (b) permanent ventilation which is 
defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per 
day (via non-invasive ventilatory support) for ≥ 14 consecutive days in the absence of an 
acute reversible illness, excluding perioperative ventilation.  Permanent ventilation, so 
defined, is considered a surrogate for death. 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
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Novartis Gene Therapies, Inc. 
AVXS-101-CL-306 
Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
Confidential/Proprietary 
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Safety 
• Evaluate the safety of AVXS-101 in patients with SMA Type 1. 
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Novartis Gene Therapies, Inc. 
AVXS-101-CL-306 
Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
Confidential/Proprietary 
Page 7 of 106 
Methodology: 
Phase 3, open-label, single-arm, single-dose, trial of AVXS-101 (gene replacement therapy) in 
patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are 
genetically defined by a biallelic pathogenic mutation of the survival motor neuron 1 gene 
(SMN1) with one or 2 copies of survival motor neuron 2 gene (SMN2).  At least 6 patients 
< 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be 
enrolled. 
The trial includes a screening period, a gene replacement therapy period, and a follow-up 
period.  During the screening period (Days –30 to –2), patients whose parent(s)/legal 
guardian(s) provide informed consent will complete screening procedures to determine 
eligibility for trial enrollment.  Patients who meet the entry criteria will enter the in-patient 
gene replacement therapy period (Day –1 to Day 3).  On Day –1, patients will be admitted to 
the hospital for pre-treatment baseline procedures.  On Day 1, patients will receive a one-time 
intravenous (IV) infusion of AVXS-101 and will undergo in-patient safety monitoring over the 
next 48 hours.  Patients may be discharged 48 hours after the infusion, based on Investigator 
judgment.  During the outpatient follow-up period (Days 4 to End of Trial at 18 months of 
age), patients will return at regularly scheduled intervals for efficacy and safety assessments 
until the End of Trial when the patient reaches 18 months of age.  After the End of Trial visit, 
patients will be invited to participate in a long-term follow up trial conducted under a separate 
protocol. Patients who discontinue the trial prematurely will also be invited to participate in the 
long-term follow-up study.  
All post-treatment visits will be relative to the date on which gene replacement therapy is 
administered until the patient is 14 months of age, after which all visits will be relative to the 
patient’s date of birth.  All visits will be scheduled based on a 30-day month calendar. 
In an attempt to dampen the host immune response to the adeno-associated virus (AAV) 
derived therapy, all patients will receive prophylactic prednisolone at approximately 
2 mg/kg/day (or an equivalent dose of another glucocorticoid if prednisolone is unavailable or 
in the opinion of the investigator prednisolone is not tolerated) on Day -1, Day 1, and Day 2, 
and then 1 mg/kg/day starting on Day 3 and until at least 30 days post-AVXS-101 infusion.  
After 30 days post-AVXS-101 infusion, the dose of prednisolone (or, if needed, equivalent 
glucocorticoid) can be tapered for patients whose gamma glutamyl transferase (GGT), alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) values are below the threshold 
of 2 × Upper Limit of Normal (ULN) in accordance with the following treatment guideline: 
taper from 1 mg/kg/day to 0.5 mg/kg/day during Weeks 5 and 6 post-AVXS-101 infusion, then 
taper to 0.25 mg/kg/day during Weeks 7 and 8, and then discontinue prednisolone at Week 9.  
If the GGT, AST or ALT values are > 2× ULN, the dose of prednisolone should be maintained 
until the GGT, AST, and ALT values decrease below threshold at which point the taper may 
continue.  Variance from these recommendations will be at the discretion of the Investigator 
based on potential safety issues for each patient.  If another glucocorticoid is used in place of 
prednisolone by the investigator, similar considerations should be taken into account after 
30 days and tapered as appropriate and at the discretion of the investigator. 
Efficacy will be assessed by achievement of the key developmental milestone of sitting without 
support for at least 10 seconds based on WHO motor development milestones at any point up 
to and including the 18 months of age trial visit, and survival at 14 months of age. 
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Novartis Gene Therapies, Inc. 
AVXS-101-CL-306 
Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
Confidential/Proprietary 
Page 8 of 106 
Safety will be assessed through monitoring adverse events (AEs), concomitant medication 
usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory 
evaluations.  A Data Safety Monitoring Board (DSMB)/Data Monitoring Committee (DMC) 
will review safety data on a quarterly basis.  A detailed description of the DSMB/DMC, its role 
in this trial, and the timing and process of the scheduled reviews will be described in a 
DSMB/DMC Charter.   
Number of Patients (planned): At least 6 patients were planned to be enrolled as part of the 
combined analysis with Study AVXS-101-CL-302.  At the time of this protocol was amended 
(Protocol version 6.0 amendment 5 dated 11 Nov 2020), the enrollment was closed with 2 
active enrolled patients as the combined analysis is no longer to be performed.   
Diagnosis and Main Criteria for Inclusion: Inclusion Criteria: 
1. Patients with SMA Type 1 as determined by the diagnosis of SMA based on gene mutation 
analysis with biallelic SMN1 mutations (deletion or point mutations) and one or 2 copies of 
SMN2 [inclusive of the known SMN2 gene modifier mutation (c.859G>C)] 
2. Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion. 
3. Patients must have a swallowing evaluation test performed prior to administration of gene 
replacement therapy. 
4. Up-to-date on childhood vaccinations as per local health authorities.   
5. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and 
comply with trial procedures and visit schedule. 
Exclusion Criteria: 
1. Previous, planned or expected scoliosis repair surgery/procedure prior to 18 months of age. 
2. Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry 
< 95% saturation at screening 
a. Pulse oximetry saturation must not decrease ≥ 4 percentage points between screening 
and dosing with confirmatory oximetry reading 
b. Patients may be put on non-invasive ventilatory support for less than 12 hours per day 
at the discretion of their physician or trial staff. 
3. Use or requirement of non-invasive ventilatory support for ≥12 hours daily in the 2 weeks 
prior to dosing. 
4. Patient with signs of aspiration based on a swallowing test or whose weight-for-age falls 
below the 3rd percentile based on WHO Child Growth Standards and is unwilling to use an 
alternative method to oral feeding. 
5. Active viral infection (includes human immunodeficiency virus [HIV] or positive serology 
for hepatitis B, C, or E or known Zika virus infection). 
6. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization 
within 2 weeks prior to screening. 
7. Upper or lower respiratory infection requiring medical attention, medical intervention, or 
increase in supportive care of any manner within 4 weeks prior to screening. 
8. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in 
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Novartis Gene Therapies, Inc. 
AVXS-101-CL-306 
Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
Confidential/Proprietary 
Page 9 of 106 
the opinion of the Principal Investigator, creates unnecessary risks for gene replacement 
such as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalciuria 
e. Symptomatic cardiomyopathy. 
9. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients. 
10. Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, 
agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, 
plasmapheresis, immunomodulators such as adalimumab, or immunosuppressive therapy 
within 3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, 
tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab). 
11. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay 
(ELISA) binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 
antibody titer > 1:50, he or she may receive retesting within 30 days of the screening period 
and will be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50. 
12. Clinically significant abnormal laboratory values (GGT, ALT, AST, total bilirubin > 2× the 
ULN, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell 
[WBC] > 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated 
bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded. 
13. Participation in recent SMA treatment clinical trial (with the exception of observational 
cohort studies or non-interventional studies) or receipt of an investigational or commercial 
compound, product or therapy administered with the intent to treat SMA (e.g., nusinersen, 
valproic acid,) at any time prior to screening for this trial.  Oral β-agonists must be 
discontinued at least 30 days before gene therapy dosing.  Inhaled albuterol specifically 
prescribed for the purposes of respiratory (bronchodilator) management is acceptable and 
not a contraindication at any time prior to screening for this trial. 
14. Expectation of major surgical procedures during the trial assessment period (e.g., spinal 
surgery or tracheostomy). 
15. Parent(s)/legal guardian(s) unable or unwilling to comply with trial procedures or inability 
to travel for repeat visits. 
16. Parent(s)/legal guardian(s) unwilling to keep trial results/observations confidential or to 
refrain from posting confidential trial results/observations on social media sites. 
17. Parent(s)/legal guardian(s) refuses to sign consent form. 
18. Patient < 35 weeks gestational age at time of birth. 
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Novartis Gene Therapies, Inc. 
AVXS-101-CL-306 
Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
Confidential/Proprietary 
Page 10 of 106 
Investigational Product, Dosage and Mode of Administration: 
Patients will receive a one-time dose of AVXS-101 at 1.1 × 1014 vg/kg, a dose determined to 
be equivalent to the dose received by the Cohort 2 patients in the Phase 1 study 
(AVXS-101-CL-101) by direct testing using improved analytical methods. 
Duration of Treatment: 
AVXS-101 will be administered as a one-time IV infusion over approximately 60 minutes. 
Reference Therapy, Dosage and Mode of Administration: Not Applicable 
Criteria for Evaluation: Efficacy: 
Primary 
• Proportion of symptomatic SMA Type 1 patients who are homozygous negative for SMN1 
exon 7 and have 2 copies of SMN2 without the SMN2 genetic modifier that achieve the 
ability to sit without support for at least 10 seconds up to and including the 18 months of 
age trial visit.  Sitting without support is defined by the WHO Multicentre Growth 
Reference Study (WHO MGRS) confirmed by video recording, as a patient who sits up 
straight with head erect for at least 10 seconds; 
 
 
Secondary 
• Survival at 14 months of age amongst symptomatic SMA Type 1 patients who are 
homozygous negative for SMN1 exon 7 and have 2 copies of SMN2 without the SMN2 
genetic modifier.  Survival is defined by the avoidance of the combined endpoint of either 
(a) death or (b) permanent ventilation, which is defined by tracheostomy or by the 
requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive ventilatory 
support) for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding 
perioperative ventilation.  Permanent ventilation, so defined, is considered a surrogate for 
death. 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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Investigational Product: AVXS-101 
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Page 11 of 106 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
Assessment of the safety and tolerability of AVXS-101 treatment includes evaluation of AEs, 
laboratory data, vital signs, and concomitant medications. 
Statistical Methods: 
This is a Phase 3 trial assessing the efficacy and safety of AVXS-101.  Details of all analyses 
will be contained within the Statistical Analysis Plan. 
The Intent-to-Treat (ITT) population will consist of symptomatic patients with biallelic SMN1 
deletions and 2 copies of SMN2 without the genetic modifier (c.859G>C). 
Due to the small number of patients enrolled in this study, the primary, secondary, and 
exploratory efficacy endpoints as well as safety assessments will be provided in data listings 
only. 
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Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
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Page 12 of 106 
3. 
TABLE OF CONTENTS, LISTS OF TABLES AND FIGURES 
TABLE OF CONTENTS 
1. 
ADMINISTRATIVE INFORMATION .......................................................................2 
1.1. 
Approval .......................................................................................................................2 
1.2. 
Investigator’s Agreement ..............................................................................................3 
1.3. 
Contact Information ......................................................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LISTS OF TABLES AND FIGURES .............................12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................17 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Background .................................................................................................................20 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients ................................................21 
5.3. 
Nonclinical Studies .....................................................................................................24 
5.4. 
Clinical Studies ...........................................................................................................28 
5.5. 
Risks ...........................................................................................................................29 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................31 
6.1. 
Primary Objective .......................................................................................................31 
6.2. 
Secondary Objective ...................................................................................................31 
6.3. 
Exploratory Objectives ...............................................................................................31 
6.4. 
Safety Objectives ........................................................................................................32 
7. 
INVESTIGATIONAL PLAN .....................................................................................33 
7.1. 
Overall Trial Design ...................................................................................................33 
7.2. 
Number of Patients .....................................................................................................35 
7.3. 
Criteria for Trial Termination .....................................................................................35 
8. 
ELECTION AND WITHDRAWAL OF PATIENTS ................................................36 
8.1. 
Patient Inclusion Criteria ............................................................................................36 
8.2. 
Patient Exclusion Criteria ...........................................................................................36 
8.3. 
Patient Withdrawal Criteria ........................................................................................38 
9. 
TREATMENT OF PATIENTS ..................................................................................39 
9.1. 
Description of Trial Product .......................................................................................39 
9.2. 
Prior and Concomitant Medications ...........................................................................39 
9.2.1. 
Prophylactic Administration of Prednisolone .............................................................39 
9.2.2. 
Prohibited Medications ...............................................................................................40 
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Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
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9.2.3. 
Vaccinations ...............................................................................................................41 
9.3. 
Treatment Compliance ................................................................................................41 
9.4. 
Randomization and Blinding ......................................................................................41 
10. 
TRIAL PRODUCT MATERIALS AND MANAGEMENT ......................................42 
10.1. 
Trial Product ...............................................................................................................42 
10.2. 
Trial Product Dose and Dose Justification ..................................................................42 
10.3. 
Trial Product Packaging and Labeling ........................................................................42 
10.4. 
Trial Product Storage and Destruction ........................................................................42 
10.5. 
Trial Product Preparation ............................................................................................43 
10.6. 
Trial Product Administration ......................................................................................43 
10.7. 
Dose Adjustment Criteria ...........................................................................................43 
10.8. 
Trial Product Accountability .......................................................................................43 
10.9. 
Trial Product Handling and Disposal ..........................................................................44 
11. 
ASSESSMENT OF EFFICACY .................................................................................45 
11.1. 
Developmental Milestones..........................................................................................45 
11.2. 
Motor Function Tests ..................................................................................................46 
11.2.1. 
World Health Organization Multicentre Growth Reference Milestones ....................46 
11.2.2. 
Bayley Scales for Infant and Toddler Development/Developmental 
Milestones ...................................................................................................................46 
11.2.3. 
CHOP INTEND ..........................................................................................................47 
11.3. 
Video Evidence ...........................................................................................................47 
12. 
ASSESSMENT OF SAFETY .....................................................................................49 
12.1. 
Safety Parameters .......................................................................................................49 
12.1.1. 
Demographic/Medical History ...................................................................................49 
12.1.2. 
Physical Examinations ................................................................................................50 
12.1.3. 
Vital Signs/Weight and Length ...................................................................................50 
12.1.4. 
Electrocardiogram .......................................................................................................50 
12.1.5. 
Echocardiogram ..........................................................................................................50 
12.1.6. 
Continuous ECG Recording (24-Hour Holter Monitoring) ........................................51 
12.1.7. 
Pulmonary Examinations ............................................................................................51 
12.1.8. 
Swallowing Test .........................................................................................................51 
12.1.9. 
Photographs of Infusion Site .......................................................................................51 
12.1.10. 
Laboratory Assessments .............................................................................................52 
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Investigational Product: AVXS-101 
Protocol Version 6.0/Amendment 5/11 Nov 2020 
 
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12.1.10.1. Hematology .................................................................................................................53 
12.1.10.2. Blood Chemistry .........................................................................................................53 
12.1.10.3. Urinalysis ....................................................................................................................53 
12.1.10.4. Virus Serology ............................................................................................................54 
12.1.10.5. Capillary Blood Gas....................................................................................................54 
12.1.10.6. Immunology Testing (ELISA) ....................................................................................54 
12.1.10.7. AAV9 Antibody Screen in Mother .............................................................................54 
12.1.10.8. Blood for Diagnostic Confirmation Testing ...............................................................55 
12.1.10.9. Saliva, Urine, and Stool Collection ............................................................................55 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................56 
13.1. 
Definition of Adverse Events ......................................................................................56 
13.1.1. 
Adverse Event .............................................................................................................56 
13.1.2. 
Serious Adverse Event ................................................................................................56 
13.1.3. 
Adverse Events of Special Interest .............................................................................57 
13.2. 
Relationship to Trial Drug ..........................................................................................57 
13.3. 
Recording Adverse Events ..........................................................................................57 
13.4. 
Reporting Serious Adverse Events .............................................................................58 
13.5. 
Expedited Safety Reporting to Regulatory Authorities ..............................................58 
14. 
STATISTICS ..............................................................................................................59 
14.1. 
Study Endpoints ..........................................................................................................59 
14.1.1. 
Primary Efficacy Endpoint .........................................................................................59 
14.1.2. 
Secondary Efficacy Endpoint .....................................................................................59 
14.1.3. 
Exploratory Endpoints ................................................................................................60 
14.1.4. 
Safety Endpoints .........................................................................................................61 
14.2. 
Statistical Analysis Populations ..................................................................................61 
14.2.1. 
Intent-to-Treat Population ...........................................................................................61 
14.2.2. 
Ability to Thrive ITT Population ................................................................................61 
14.2.3. 
All Enrolled Population ..............................................................................................61 
14.2.4. 
Safety Population ........................................................................................................61 
14.3. 
Sample Size Calculation .............................................................................................61 
14.4. 
Efficacy Analysis ........................................................................................................62 
14.4.1. 
General Considerations ...............................................................................................62 
14.4.2. 
Primary and Secondary Efficacy Analysis .................................................................62 
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14.5. 
Safety Analysis ...........................................................................................................62 
14.5.1. 
Hy’s Law Criteria .......................................................................................................62 
15. 
DATA SAFETY MONITORING BOARD ................................................................63 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................64 
16.1. 
Trial Monitoring .........................................................................................................64 
16.2. 
Audits and Inspections ................................................................................................65 
16.3. 
Institutional Biosafety Committee ..............................................................................65 
16.4. 
Institutional Review Board/Independent Ethics Committee .......................................65 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE ..........................................66 
18. 
ETHICS ......................................................................................................................67 
18.1. 
Ethics Review .............................................................................................................67 
18.2. 
Ethical Conduct of the Trial ........................................................................................67 
18.3. 
Written Informed Consent ..........................................................................................67 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................69 
19.1. 
Electronic Case Report Forms ....................................................................................69 
19.2. 
Inspection of Records .................................................................................................69 
19.3. 
Retention of Records ..................................................................................................69 
20. 
PUBLICATION POLICY ..........................................................................................70 
21. 
LIST OF REFERENCES ............................................................................................71 
22. 
APPENDICES ............................................................................................................74 
APPENDIX 1. SCHEDULE OF ASSESSMENTS .....................................................................74 
APPENDIX 2. POST-MORTEM TISSUE AND ORGAN COLLECTION PLAN ...................77 
APPENDIX 3. BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) .............................................................................................................78 
APPENDIX 4. PERFORMANCE CRITERIA FOR BAYLEY SCALES INFANT 
AND TODDLER DEVELOPMENT (VERSION 3) DEVELOPMENTAL 
MILESTONES ...........................................................................................................94 
APPENDIX 5. PERFORMANCE CRITERIA FOR WORLD HEALTH 
ORGANIZATION (WHO) DEVELOPMENTAL MILESTONES ...........................95 
APPENDIX 6. CHOP INTEND ..................................................................................................96 
APPENDIX 7. DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS .................................98 
APPENDIX 8. SUMMARY OF CHANGES ...........................................................................103 
 
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LIST OF TABLES 
Table 1 - Spinal Muscular Atrophy Classification .........................................................................21 
Table 2 - Investigational Product ...................................................................................................39 
Table 3 - Total Blood Volume .......................................................................................................52 
Table 4 - Common Terminology Criteria for Adverse Events ......................................................56 
Table 5 - Tissue Sample for Analysis ............................................................................................77 
 
LIST OF FIGURES 
Figure 1 - Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 2, 
and 3 ............................................................................................................................23 
Figure 2 - Trial Results, Including Staining of Transduced Spinal Motor Neurons, SMN 
Expression Levels, Righting Ability, and Weight and Survival Curves .....................25 
Figure 3 - Body Mass of Treated and Control Mice Showed No Difference ................................26 
Figure 4 - Trial Design ...................................................................................................................34 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this trial protocol. 
Abbreviation or 
Specialist Term 
Explanation 
AAV 
Adeno-associated virus 
AAV9 
Adeno-associated virus serotype 9 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
ASO 
Antisense oligonucleotide 
AST 
Aspartate aminotransferase 
AT 
Aminotransferase 
BSIDv03 
Bayley Scales of Infant and Toddler Development, version 3 
BUN 
Blood urea nitrogen 
CB 
Chicken-β-actin-hybrid 
cDNA 
complimentary Deoxyribonucleic Acid 
cGMP 
Current Good Manufacturing Practice 
CHOP INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders 
CK 
Creatine kinase 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CTCAE 
Common Terminology Criteria for Adverse Events 
Day 1 
First 24-hour interval after the start of gene replacement therapy infusion 
Day –1 
24-hour interval prior to the start of gene replacement therapy infusion 
DMC 
Data Monitoring Committee 
DRG 
Dorsal root ganglia 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunospot 
ET 
Early termination 
FVB 
Friend Virus B-Type 
GCP 
Good Clinical Practice 
GFP 
Green fluorescent protein 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
HEENT 
Head, eyes, ears, nose, and throat 
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Abbreviation or 
Specialist Term 
Explanation 
HgB 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICD-10 code 
International Statistical Classification of Diseases and Related Health Problems 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon gamma 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
IT 
Intrathecal 
ITR 
Inverted terminal repeat 
ITT 
Intent-to-treat 
IV 
Intravenous 
LFE 
Liver function enzymes 
LFT 
Liver function test 
LV EF 
Left ventricular ejection fraction 
LV FS 
Left ventricular fractional shortening 
MAP 
Managed Access Program 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGRS 
Multicenter Growth Reference Study 
NCI 
National Cancer Institute 
NHP 
Non-human primates 
NOAEL 
No observable adverse effect level 
PBMC 
Peripheral blood mononuclear cells 
PICU 
Pediatric intensive care unit 
PNCR 
Pediatric Neuromuscular Clinical Research Network 
RNA 
Ribonucleic acid 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
Self-complementary 
scAAV 
Self-complimentary adeno-associated virus 
scAAV9.CB.SMN 
Self-complimentary adeno-associated virus serotype 9 chicken-β-actin- hybrid survival motor neuron 
SDA 
Source data verification 
SoA 
Schedule of Assessments 
SMA 
Spinal muscular atrophy 
SMN 
Survival motor neuron 
SMN1 
Survival motor neuron 1 gene 
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Abbreviation or 
Specialist Term 
Explanation 
SMN2 
Survival motor neuron 2 gene 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin 
TMA 
Thrombotic microangiopathy 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
US 
United States 
vg/kg 
Vector genome per kilogram 
WBC 
White blood cell 
WHO 
World Health Organization 
WT 
Wild type 
 
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5. 
INTRODUCTION 
Trial AVXS-101-CL-306 is a Phase 3 clinical gene therapy trial investigating the efficacy and 
safety of a single intravenous (IV) infusion of AVXS-101 in at least 6 patients with Type 1 
spinal muscular atrophy (SMA) with one or 2 copies of SMN2.  This trial is conducted by 
Novartis Gene Therapies, Inc. (formerly AveXis, Inc. with company’s name change). 
The survival motor neuron (SMN) gene will be transferred using self-complementary 
adeno-associated virus (scAAV) Type 9 under control of the chicken-β-actin hybrid promoter.  
Pre-clinical studies have demonstrated survival of the SMNΔ7 mouse model for SMA from a 
median of 15.5 days to over one year, following IV delivery to the peripheral vein.  Additionally, 
preliminary results from a completed Phase 1 clinical trial (AVXS-101-CL-101) of AVXS-101 
in SMA Type 1 patients demonstrates broad improvements in survival, motor function, 
pulmonary function, and nutritional function (Section 5.4). 
5.1. 
Background 
Spinal muscular atrophy 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.  Spinal muscular atrophy is an autosomal 
recessive, early childhood disease with an incidence of approximately 1:10,000 live births 
[Sugarman et al, 2012]  Spinal muscular atrophy is the leading cause of infant mortality due to 
genetic diseases.  Disease severity and clinical prognosis depends on the number of copies of 
survival motor neuron 2 gene (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 
before 6 months of age and early death due to respiratory failure before 2 years of age.  Motor 
neuron loss in SMA Type 1 is profound in the early post-natal period (or may even start in the 
prenatal period), whereas motor neurons in SMA Type 2 and Type 3 patients adapt and 
compensate during development and many will 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 post-natal periods [Swoboda et al, 2005; Le et al, 2011; Farrar et al, 2012].  
From a clinical perspective, these findings emphasize the importance of first targeting the SMA 
Type 1 group for gene transfer of SMN2 in hopes of rescuing neurons at this critical stage.  The 
goal in continuing the development plan for AVXS-101 is to modify the SMA Type 1 
phenotype, which will hopefully lead to a milder disease course and prolonged survival as seen 
in SMA Type 2 and Type 3 patients. 
Therapeutic efforts in SMA have focused on the potential for small molecules to increase SMN 
protein levels.  These include deacetylase inhibitors, such as valproic acid, sodium butyrate, 
phenylbutyrate, and trichostatin A.  These agents activate the SMN2 promoter, resulting in 
increased full-length SMN protein in SMA animal models [Riessland et al, 2010; 
Dayangac-Erden et al, 2011].  However, clinical studies employing several of these agents, most 
notably phenylbutyrate, valproic acid, and hydroxyurea, have not resulted in clinical benefit 
[Kissel et al, 2011; Swoboda et al, 2010; Mercuri et al, 2004; Chen et al, 2010; Darbar et al, 
2011].  In the United States, the Food and Drug Administration (FDA) recently approved 
nusinersen, an antisense oligonucleotide (ASO) drug designed to increase the production of the 
SMN protein by modulating the splicing of the SMN2 gene, thereby compensating for the 
underlying genetic defect.  Nusinersen has also received regulatory approvals in the European 
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Union and in other countries including Japan, South Korea, and Taiwan.  Clinical studies have 
shown some modest promise in improving motor function; however, the treatment must be 
administered indefinitely on a quarterly basis via intrathecal injection, requires a lengthy 
induction period prior to effectiveness, and has safety considerations that require clinical 
monitoring.  A single-dose IV administration trial of AVXS-101 will provide information on the 
potential that gene transfer has in treating SMA Type 1 patients and will hopefully show promise 
for success in modifying the disease prognosis. 
This is a single-dose trial that will include at least 6 Type 1 patients with one or 2 copies of 
SMN2.  The rationale for IV dosing is based upon the need for rapid, systemic impact given the 
severity of the disease in SMA Type 1 and its potential impact on systems outside of the central 
nervous system (CNS) such as the peripheral and autonomic nervous systems, heart, pancreas 
and gastrointestinal tract. 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients 
Patients with SMA Type 1 have been chosen as the target population for this gene therapy trial 
based on studies of the natural history of this disease.  The classification of SMA is shown below 
(Table 1) in which SMA Types 0 to 4 are described.  Spinal muscular atrophy is conventionally 
classified into 4 phenotypes on the basis of age at onset and highest motor function achieved, 
with an additional phenotype (Type 0) to describe the severe forms of antenatal-onset SMA 
[Mercuri et al, 2012]. 
 
Table 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: B-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 
Source: Adapted from [Kolb and Kissel, 2011] 
SMN2 = survival motor neuron 2 gene 
Bold underline = predominant SMN2 copy number that defines the SMA Type; the other copy numbers represent a small 
percentage of the designated SMA Type. 
 
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Spinal muscular atrophy Type 1 patients, by definition, never attain independent sitting and have 
hypotonia within the first 6 months of life.  Spinal muscular atrophy Type 1 is the leading 
genetic cause of infant death with an onset at ≤ 6 months of age (Table 1).  In contrast, SMA 
Type 2 manifests within the first 18 months, and children afflicted with this condition are able to 
maintain sitting unassisted but never walk independently.  Spinal muscular atrophy Type 3 
patients attain the ability to walk unaided (Type 3a have onset 18 months to 3 years of age; Type 
3b have onset > 3 years of age).  Spinal muscular atrophy Type 4 is an adult onset disease.  The 
genetic cause for SMA is well established and is intimately involved with one’s prognosis.  All 
forms of SMA are autosomal recessive in inheritance and are caused by deletions or mutations of 
the SMN1 gene. 
Humans also carry a second nearly identical copy of the SMN1 gene called SMN2 
[Lefebvre et al, 1995].  Both the SMN1 and SMN2 genes express SMN protein; however, the 
amount of functional full-length protein produced by SMN2 is only 10% to 15% of that produced 
by SMN1 [Lefebvre et al, 1995; Lorson et al, 1999; Monani et al, 1999].  Although SMN2 cannot 
completely compensate for the loss of the SMN1 gene, patients with milder forms of SMA 
generally have higher SMN2 copy numbers [Lefebvre et al, 1997; Park et al, 2010].  Quantitative 
analysis of SMN2 copies in 375 patients with Type 1, 2, or 3 SMA showed a significant 
correlation between SMN2 copy number and SMA Type, as well as, duration of survival.  In a 
large early trial by Feldkotter et al 2002, 2 copies of SMN2 was 97% predictive for developing 
SMA Type 1, 3 copies of SMN2 was 83% predictive for developing SMA Type 2, and 4 copies 
of SMN2 was 84% predictive of SMA Type 3 [Feldkotter et al, 2002].  As these percentages do 
not reflect the possible impact of modifier mutations such as that described by Prior et al 2009 
[Prior et al, 2009], they may understate the relationship between copy number (in the absence of 
a genetic modifier) and clinical phenotype.  Among 113 patients with Type 1 SMA, 9 with one 
SMN2 copy lived < 11 months, 88/94 with two SMN2 copies lived < 21 months, and 8/10 with 
three SMN2 copies lived 33 to 66 months.  Even more refined data describing this relationship 
has been generated and has also influenced our choice of the trial target group. 
The severity of SMA Type 1 is demonstrated by prognosis as illustrated in Kaplan-Meier 
survival curves shown in Figure 1. 
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Figure 1 - Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 2, 
and 3 
 
Source: [Farrar et al, 2013] 
n = number of patients  
 
In Figure 1, the relative stability of the clinical course of SMA Type 2 and Type 3 is dramatically 
illustrated.  Perhaps most importantly, these findings show that outcome differences are related 
to the number of SMN2 copies that enable motor neurons to adapt and compensate during the 
growth of the child and persist into adult life.  This contrasts with SMA Type 1 where motor 
neuron loss is profound in the early post-natal period (or may even start in the prenatal period, 
especially for SMA Type 1 patients presenting in first 3 months of life).  The findings in Figure 1 
confirm other pieces of evidence from neurophysiological studies and animal studies that also 
show early loss of motor neurons in the embryonic and early post-natal periods 
[Swoboda et al, 2005; Le et al, 2011; Farrar et al, 2012]. 
There is reason to believe that there are few safety issues to be concerned about when targeting 
the SMA Type 1 group in this gene therapy clinical trial. In humans, a high copy number of 
SMN2 poses no risk (as seen in Type 2, 3, and 4 patients who have high SMN2 copy number), 
allowing for use of robust, ubiquitous expression systems (like the CB-promoter) to ensure 
sustained, high-level SMN gene expression.  Additionally, it is important to point out that 
recombinant scAAV can be employed for this trial because of the small size of the SMN gene.  
This enables efficient packaging and allows for efficient gene transfer with lower viral titers (a 
safety consideration), compared with prototypical single-stranded adeno-associated virus vectors. 
Recent studies using self-complimentary adeno-associated virus serotype 9 
chicken-β-actin-hybrid survival motor neuron (scAAV9.CB.SMN) show a robust post-natal 
rescue of SMNΔ7 mice with correction of motor function, neuromuscular electrophysiology and 
survival after a one-time delivery of vector [Foust et al, 2010].  Intravenous scAAV9 is able to 
transduce neurons, muscle and vascular endothelium, all of which have been proposed as target 
cells for SMA treatment. 
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5.3. 
Nonclinical Studies 
A mouse model was developed by the 
 after a generation of 
evaluating various transgenic permutations.  It was found that the double transgenic, referred to 
as the SMNΔ7 mouse, provided the most suitable model to trial gene transfer 
[Butchbach et al, 2007].  Studies performed in the 
 have shown that injecting 
5 × 1011 viral genomes of scAAV9.CB.SMN into the facial vein on post-natal Day 1 rescues 
mice in the SMNΔ7 mouse model [Foust et al, 2010].  Figure 2 shows the results of these 
studies, including staining of transduced spinal motor neurons, SMN protein expression levels, 
righting ability, and weight and survival curves.  Approximately 42 ± 2% of lumbar spinal motor 
neurons were transduced in scAAV9.CB.GFP treated mice.  SMN transduction was shown by 
real time polymerase chain reaction (RT-PCR) in the mice.  Green fluorescent protein (GFP) 
transduction was observed by microscopy.  Both constructs were in adeno-associated virus 
serotype 9 (AAV9) and had transduction of motor neurons.  Survival motor neuron protein levels 
were increased as well, in brain, spinal cord, and muscle of scAAV9.CB.SMN-treated animals, 
compared to untreated SMNΔ7 mice (although lower than wild type [WT] controls).  SMNΔ7 
animals treated with either scAAV9.CB.SMN or scAAV9.CB.GFP on post-natal Day 1 (P1) 
were assessed for their righting ability and were compared to WT control mice and untreated 
mice.  Wild type controls could right themselves quickly, whereas the SMN- and GFP-treated 
SMA animals showed difficulty at P5.  However, by P13, 90% of SMN-treated animals could 
right themselves compared with 20% of GFP-treated controls and 0% of untreated SMA animals.  
At P18, SMN-treated animals were larger than GFP-treated animals, but smaller than WT 
controls.  Locomotive ability of the SMN-treated mice was nearly identical to WT controls, as 
assayed by open field testing and wheel running. 
Survival of SMN-treated SMNΔ7 animals compared with GFP-treated SMNΔ7 animals was 
significantly improved.  No GFP-treated control animals survived past P22 and had a median life 
span of 15.5 days.  The weights of GFP mice peaked at P10 and then precipitously declined until 
death, while SMN mice showed a steady weight gain until around P40 with it stabilizing at 17 g 
(about half the weight of WT controls).  The smaller size of corrected animals is likely related to 
the tropism and incomplete transduction of scAAV9, resulting in a ‘chimeric’ animal in which 
some cells were not transduced.  Additionally, the smaller size suggests an embryonic role for 
SMN protein.  Most remarkably, SMN-treated mice survived well past 250 days of age. 
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Figure 2 - Trial Results, Including Staining of Transduced Spinal Motor Neurons, SMN 
Expression Levels, Righting Ability, and Weight and Survival Curves 
 
Source: [Foust et al, 2010] 
CNS = central nervous system; GFP = green fluorescent protein; SMN = survival motor neuron; WT = wild type 
a. 
Shows transduced motor neurons in lumbar spinal cord 
b. 
Western Blots of SMN expression in CNS and muscle 
c. 
Improved righting ability of SMN-treated- similar to WT controls by post-natal Day 13 (P13) 
d. 
SMN-treated are larger than GFP-treated at P18 
e. 
Survival of SMN-treated markedly improved compared to GFP- treated 
f. 
Body weight increased in SMN-treated vs GFP 
 
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In non-Good Laboratory Practice (non-GLP) studies, 24 mice and 4 non-human primates (NHPs) 
were injected, by way of vascular delivery, with AVXS-101.  To assess toxicity and safety, 
AVXS-101 was injected into post-natal Day 1 (P1) wild type Friend Virus B-Type (FVB) mice 
with either vehicle (3 males/6 females) or 3.3 × 1014 vg/kg of AVXS-101 (previously known as 
scAAV9.CB.SMN (6 males/9 females) via the facial temporal vein.  This dose was previously 
shown to be most efficacious in the SMNΔ7 mouse model [Foust et al, 2010].  P1 mice were 
used in anticipation of simulating potential clinical studies in infants.  All mice survived the 
injection procedure and the initial 24-hour observation period without any signs of distress or 
weight loss.  Body mass was measured and hands-on observations were performed weekly for 
the remainder of the trial; neither revealed any difference between control and treated cohorts 
(Figure 3). 
Figure 3 - Body Mass of Treated and Control Mice Showed No Difference 
 
 
At 60, 90 and 180 days post-injection, blood from the mice was collected for hematology studies 
including complete blood counts with differentials.  At 90, 120 and 180 days post-injection, 
blood was collected for clinical chemistries assessment (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], alkaline phosphatase, creatinine, blood urea nitrogen [BUN], 
electrolytes, and creatine kinase [CK]).  For histopathology, 13 mice were necropsied at 
120 days post-injection and 8 mice at 180 days.  There were no clinically significant results 
observed during from the hematology, clinical chemistry, and histopathology portions of the trial 
and trends of both groups were comparable.  Of note, no significant lesions were present in any 
brain or spinal cord sections, although, the sections were frozen and thicker than 5 microns 
which may obscure subtle changes in cellular morphology. 
In the safety trial for the 4 male cynomolgus macaques, animals were injected at 90 days of age 
to closely mimic the likely age of administration of treatment in SMA Type 1 infants.  The 
AVXS-101 vector was administered one time by catheterization of the saphenous vein with a 
dose of 6.7 × 1013 vg/kg, which corresponds to the lowest dose tested for which SMNΔ7 mice 
showed a significant increase of survival.  Animals were followed for six months until they were 
sacrificed at approximately 9 months of age.  No adverse effects were seen, and all clinical 
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chemistries were normal.  T-cell immune response was tested using Enzyme-linked immunospot 
(ELISpot) in peripheral blood mononuclear cells (PBMCs), and all were negative at 6 months 
post-injection. 
In these non-GLP studies, serum chemistry and hematology data were unremarkable as was the 
histopathology assessment.  The NHPs mounted appropriate immune responses to capsid (but 
not to transgene), with very high transgene expression persisting at 6 months post-injection.  In 
conclusion, these studies provide strong evidence that systemically-delivered scAAV9.CB.SMN 
is safe and well tolerated, even at the high doses required for penetration of the blood-brain 
barrier [Foust et al, 2010]. 
When newborn FVB mice were given a single IV injection of AVXS-101 at levels up to 
3.3 × 1014 vg/kg on Day 1, there was neither test article-related mortality nor evidence of toxicity 
seen at time points up to 24 weeks after administration.  Treatment-related decreases in mean 
body weight and mean body weight gain, as well as lower activated partial thromboplastin time 
(APTT) values, were mild effects of treatment, but did not result in toxicity.  Activity of 
AVXS-101 was demonstrated by the biodistribution and the presence of a specific transgene 
ribonucleic acid (RNA) expression in brain and spinal cord, the main targeted therapeutic tissues.  
Low levels of antibodies to the AAV9 capsid were found after 12 and 24 weeks in males and 
females given 3.3 × 1014 vg/kg (Group 3).  No alteration was observed in clinical pathology and 
histopathology analyses.   
As part of the preclinical development of AVXS-101 for intrathecal delivery, an exploratory 
non-GLP biodistribution and safety study was performed in cynomolgus monkeys 
(Macaca fascicularis) to evaluate the transduction efficiency and safety of intrathecally 
administered AVXS-101 at a dose of 3 x 1013 vg/animal alone and in combination with 
2 iohexol-based contrast agents.  All 12 animals on study survived and were euthanized 2 weeks 
post-injection with no clinical evidence of toxicity.  However, inflammation of the dorsal root 
ganglia (DRG) was noted during histopathology evaluation of select tissues.  The inflammation 
was characterized by minimal to marked infiltration of mononuclear inflammatory cells, 
primarily lymphocytes, into the cervical, thoracic, lumbar, and sacral DRGs and associated 
nerves.  Minimal inflammation was associated with scattered infiltrates or small aggregates of 
mononuclear cells in the DRG, without evidence of neuronal necrosis.  With mild to marked 
inflammation, aggregates to sheets of mononuclear cells were present, along with neuronal 
satellitosis, neuronal necrosis, or neuronal loss with rare mineralization.  Inflammation was 
observed in ganglia from all examined levels, but incidence and severity were generally greater 
in the sacral DRG.  Moderate to marked inflammation was only observed in the sacral DRG of 
2 of the 12 animals on study.  The animals were not administered corticosteroids.   
The DRG was not identified as a target organ of toxicity in previous AVXS-101 studies 
conducted in mice (ICV route of administration) or cynomolgus monkeys (IV or IT routes of 
administration).  However, similar findings have been reported after administration of 
AAV9-vectors in monkeys and minipigs [Hinderer et al, 2018; Hordeaux et al, 2018]. 
In pivotal GLP compliant 3-month mouse toxicology studies, the main target organs of toxicity 
were the heart and liver.  Following IV infusion in the mouse, vector and transgene were widely 
distributed with the highest expression generally observed in heart and liver, and substantial 
expression in the brain and spinal cord.  AVXS-101-related findings in the ventricles of the heart 
were comprised of dose-related inflammation, edema and fibrosis, and in the atrium, 
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inflammation and thrombosis.  Liver findings were comprised on hepatocellular hypertrophy, 
Kupffer cell activation, and scattered hepatocellular necrosis.  A no observable adverse event 
level (NOAEL) was not identified for AVXS-101-related heart and liver findings in the mouse, 
and the Maximum Tolerated Dose was defined as 1.5 × 1014 vg/kg, providing a safety margin of 
approximately 1.4-fold relative to the recommended therapeutic dose of 1.1 × 1014 vg/kg.  The 
translatability of the observed findings in mice to primates is not known at this time. 
5.4. 
Clinical Studies 
First-in-human trial AVXS-101-CL-101 is a completed 2-year trial which evaluated the efficacy 
and safety of AVXS-101 in 15 SMA Type 1 patients with 2 copies of SMN2.  All patients have 
received a single IV dose of AVXS-101 in 2 cohorts: Cohort 1 (n = 3) received 6.7 × 1013 vg/kg 
and Cohort 2 (n = 12) received 2.0 × 1014 vg/kg (proposed therapeutic dose). After the End of 
Trial visit, patients were invited to participate in a long-term follow up study conducted under a 
separate protocol. 
Based on data obtained in Study AVXS 101-CL-101, the following conclusions can be made 
regarding the efficacy of AVXS-101: 
• AVXS-101 administration had a positive effect on survival.  Twenty-four months after 
dosing, all 15 patients were alive and free of permanent ventilation 24 months after dosing 
and all Cohort 2 patients had survived free of permanent ventilation, a statistically significant 
difference compared with the natural history rate of 8% [Finkel et al, 2014].  
• Developmental milestones, confirmed by independent video review, were achieved and 
maintained over time. 
o In Cohort 2, 11 patients (91.7%) could hold their head erect without support for 
≥ 3 seconds and sit with support, 9 patients (75.0%) were able to sit without support 
for ≥ 30 seconds, and 2 patients each (16.7% each) were able to stand with assistance, 
stand alone, walk with assistance, and walk alone. 
• The improvements in Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders (CHOP INTEND) scores from baseline in both cohorts were sustained over time. 
• Nearly all Cohort 2 patients (11/12, 91.7%) achieved a score ≥ 50 on the CHOP INTEND, 
approximating the range of scores for SMA Type 2 children reported in the Pediatric 
Neuromuscular Clinical Research Network (PNCR) study [Finkel et al, 2014]. 
• Other clinically meaningful developmental milestones were maintained 24 months after 
AVXS-101 infusion: 
o Of the 7 patients in Cohort 2 who did not require non-oral nutrition prior to 
AVXS-101 dosing, 5 (71.4%) maintained the ability to thrive. 
o Eleven Cohort 2 patients (91.7%) were still able to swallow effectively enough to 
feed orally. 
o Seven of 15 patients (46.7%) remained independent of ventilatory support. 
Additional ongoing and planned clinical studies of AVXS-101 are further described in the 
Investigator Brochure. 
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5.5. 
Risks 
A full understanding of all the risks associated with AVXS-101 is not known at this time. 
Potential risks of AVXS-101 are discussed below and further details are provided in the 
AVXS-101 Investigator’s Brochure.   
Important identified risks associated with AVXS-101 include hepatotoxicity, mainly elevations 
in serum transaminases.  Liver findings in mice were comprised of hepatocellular hypertrophy, 
Kupffer cell activation, and scattered hepatocellular necrosis, while in NHP the findings were 
limited to single cell necrosis of hepatocytes associated with slight mononuclear cell infiltrates.  
In both species, these microscopic findings may have correlated with increased liver enzyme 
activity.  In mice, the liver findings were minimal to slight in severity, and partially to fully 
reversible over 12 weeks.  Administration of AAV vector may result in hepatotoxicity as seen in 
pivotal GLP compliant 3-month mouse toxicology studies, in which the main target organs of 
toxicity were the heart and liver, consistent with an immune mediated mechanism for 
transaminase elevations.  Elevations in liver transaminases have been observed with AAV gene 
therapy in humans [Manno et al, 2006].  Adverse events within the hepatotoxicity category and 
clinical laboratory values showed elevations in liver transaminases and, in some cases, acute 
liver injury.  In clinical trials, these adverse events were clinically asymptomatic, resolved with 
prednisolone treatment, and no patient met clinical criteria for Hy’s Law (Section 14.5.1).  Of 
note, all patients received prophylactic prednisolone therapy. Although 2 patients in the United 
States Managed Access Program (US MAP) experienced liver function test (LFT) elevations that 
met the biochemical definition of Hy’s Law, these cases were confounded by one or more 
alternate etiologies, which include elevated LFTs at baseline, family history of elevated LFTs, 
and/or use of potentially hepatotoxic concomitant medications.  In both cases, liver injury 
resolved with prednisolone administration.  The post-marketing safety experience is consistent 
with that of the clinical trials and MAP/RESTORE.  
A transient decrease in platelet counts has been observed with both IV and less frequently with 
IT administration, typically at Day 7.  The majority of values remained above the lower limit of 
normal.  Decreases were clinically asymptomatic and transient.  This risk can be effectively 
managed through monitoring platelet counts for 1 month following dosing, and appropriate 
prednisolone treatment (or an equivalent corticosteroid in countries where prednisolone is not 
available) use. 
Nonclinical cardiovascular toxicity findings that could potentially be relevant to the clinical use 
of AVXS-101 have been reported in 2 mouse toxicology studies of AVXS-101.  Similar findings 
were reported in both studies.  Findings in the ventricles of the heart were comprised of 
inflammation, edema and fibrosis.  Primary findings in the atrium of the heart were thrombosis 
and inflammation.  The underlying mechanism of these findings and the translatability of the 
observed findings in mice to primates are not known at this time.  No intracardiac thrombi were 
observed. Echocardiogram findings did not show evidence of clinical pathology, as LV EF and 
LV FS indicated normal cardiac systolic function.  Troponin I data is limited, therefore no 
meaningful conclusion can be made.  However, no patterns suggestive of clinical toxicity 
associated with Troponin-I have been identified.  The available clinical cardiovascular safety 
data have not provided evidence for a cardiovascular safety problem in humans.   
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In an exploratory non-GLP study, inflammation of the DRG (characterized by infiltration of 
mononuclear inflammatory cells, along with neuronal satellitosis and neuronal necrosis or loss) 
was observed 14 days after cynomolgus monkeys were administered AVXS-101 intrathecally.  
Although the inflammation was observed in ganglia from all examined levels (cervical, thoracic, 
lumbar, and sacral), the incidence and severity were generally greater in the sacral DRG.  
Neuronal toxicity is therefore a potential risk following IT administration of AVXS-101; the risk 
after IV administration is not clear. 
A thorough review of the safety data from patients treated with AVXS-101 did not identify any 
adverse events related to sensory changes.  Therefore, given the acute nature (14 days) for the 
development of the DRG findings in cynomolgus monkeys relative to the duration (months to 
years) of the completed and ongoing clinical studies, there are no immediate clinical implications 
for patients who have been treated with AVXS-101 in ongoing trials.  Study participants will be 
closely monitored for any clinical manifestations of a potential DRG involvement.  
In the clinical trials with AVXS-101, patients were required to have an anti-AAV9 antibody titer 
of ≤ 1:50 prior to treatment with AVXS-101.  Thus, the safety of AVXS-101 in patients with anti 
AAV9 antibody titers >1:50 has not been studied.  All patients who had post-treatment AAV9 
assessments showed increases in anti-AAV9 titer, an expected response to the administration of 
AVXS-101 administration.  No patient developed antibodies to SMN protein.  Sporadic increases 
in T-cell responses to AAV9 peptide were observed; however, these were not persistent, and no 
trends were observed.  No T-cell response to SMN were observed. 
No cases of thrombotic microangiopathy (TMA) have been reported in the AVXS-101 clinical 
trials.  However, a search in the Novartis Argus Safety database that includes sources outside of 
clinical trials found 2 cases of TMA as of 11-Jun-2020, with a third case reported as of 
01-Jul-2020.  The 3 case reports were received within less than 1 year, with similar times to 
onset and consistent clinical presentations.  A causal association with AVXS-101 cannot be ruled 
out.  As such, this finding represents a new safety signal and Novartis Gene Therapies, Inc. 
(Novartis Gene Therapies, hereafter) has updated the Core Data Sheet and subsequent labeling 
accordingly.  TMA is added to the Investigator's brochure and informed consent to increase the 
level of awareness and timely management of this clinically treatable condition.  For detailed 
information on risks and benefits, see the current AVXS-101 Investigator’s Brochure. 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective is to: 
• Determine efficacy by demonstrating achievement of developmental milestone of sitting 
without support up for at least 10 seconds up to 18 months of age as assessed by WHO Motor 
Developmental Milestones (Appendix 5). 
6.2. 
Secondary Objective 
The secondary objective is to: 
• Determine efficacy based on survival at 14 months of age.  Survival is defined by the 
avoidance of combined endpoint of either (a) death or (b) permanent ventilation which is 
defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per 
day (via non-invasive ventilatory support) for ≥ 14 consecutive days in the absence of an 
acute reversible illness, excluding perioperative ventilation.  Permanent ventilation, so 
defined, is considered a surrogate for death.  
6.3. 
Exploratory Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.4. 
Safety Objectives 
The safety objective is to: 
• Evaluate the safety of AVXS-101 in patients with SMA Type 1. 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Trial Design 
This is a Phase 3, open-label, single-arm, single-dose trial of AVXS-101 (gene replacement 
therapy) in patients with SMA Type 1 with one or 2 copies of SMN2.  At least 6 patients 
< 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be 
enrolled. 
The trial includes 3 trial periods: screening, gene replacement therapy, and follow-up (Figure 4).  
During the screening period (Days –30 to –2), patients whose parent(s)/legal guardian(s) provide 
informed consent will undergo screening procedures to determine eligibility for trial enrollment.  
Patients who meet the entry criteria will enter the in-patient gene replacement therapy period 
(Day –1 to Day 3).  On Day –1, patients will be admitted to the hospital for pre-treatment 
baseline procedures.  On Day 1, patients will receive a one-time intravenous (IV) infusion of the 
equivalent of AVXS-101 cohort 2 dose received in the AVXS-101-CL-101 trial over 
approximately 60 minutes and will undergo in-patient safety monitoring over the next 48 hours.  
Patients may be discharged 48 hours after gene replacement therapy, based on Investigator 
judgment.  During the outpatient follow-up period (Days 4 to End of Trial at 18 months of age), 
patients will return at regularly scheduled intervals for efficacy and safety assessments until the 
patient reaches 18 months of age.  Any missed visit should be rescheduled as soon as possible, 
but within the visit windows shown in the Schedule of Assessments (SoA). All visits will be 
scheduled based on a 30-day month calendar. 
After dosing follow-up visits will be conducted according to the SoA (Appendix 1). All 
post-treatment visits will be relative to the date on which gene replacement therapy is 
administered until the patient is 14 months of age, after which all visits will be relative to the 
patient’s date of birth.  For the 14 and 18 months of age visits, the patient will return within 0 to 
14 days after the date on which the patient reaches 14 and 18 months of age, respectively.  The 
18 months of age visit will also serve as the End of Trial visit.  After the End of Trial visit, 
patients will be invited to participate in a long-term follow-up study under a separate protocol. 
Patients who discontinue prematurely will also be invited to participate in the long-term 
follow-up study. 
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Figure 4 - Trial Design 
 
Note: After the End of Trial visit at 18 months of age or at the time of early discontinuation patients will be invited to 
participate in a long- term follow-up study conducted under a separate protocol. 
a 
All post-treatment visits will be relative to the date on which gene replacement therapy is administered until the patient is 
14 months of age, after which all visits will be relative to the patient’s date of birth. Note: Depending on the patient’s age 
at dosing, the duration of participation at the end-of-trial visit can vary from approximately 12 months (baby dosed at 
approximately 6 months of age) to approximately 18 months (baby dosed near birth “0 months of age”).  All visits will be 
scheduled based on a 30-day month calendar. 
 
In an attempt to dampen the host immune response to the AAV-derived therapy, all patients will 
receive prophylactic prednisolone according to the regimen described in Section 9.2.1. 
Efficacy will be assessed by achievement of the key developmental milestone of sitting without 
support for at least 10 seconds at any time up to and including the 18 months of age trial visit, 
and survival at 14 months of age (as defined in Section 14.1.1).  Safety will be assessed through 
monitoring AEs, concomitant medication usage, physical examinations, vital sign assessments, 
cardiac assessments, and laboratory evaluations (Section 12).   
In the event that unforeseen catastrophic or other serious situations (such as the COVID-19 
pandemic) impact the ability to conduct the study on-site, alternative methods of continuing 
study assessments may be implemented.  Alternative visits include phone calls, virtual contacts 
through teleconsult or videoconference, or visits by site staff/home nursing providers to the 
patient’s home depending on local regulations, institutional policies, and capabilities of the 
investigative site.  Alternative visits may take place instead of on-site visits until such time that 
the patient can safely return to the site.  The process for obtaining remote informed consent must 
be followed if alternative study visits will be conducted (Section 18.3).  
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Throughout the study, the scheduling of study visits should adhere to the overall study schedule 
and visit windows defined in the protocol.  For each study visit, all study procedures and 
assessments should be performed or completed in accordance with the schedule of events.  Local 
institutions or other alternatives may be utilized. 
Importantly, in instances in which the final scheduled study visit is not possible to be conducted 
at the study site, the final scheduled study visit should be performed all or by an alternative visit 
within the protocol-defined visit window.  Critical data that pertain to the primary and secondary 
endpoints and other information such as adverse events, concomitant medications, use of feeding 
or ventilatory support, or other safety data that may be obtained remotely should be collected as 
part of the final study visit and within the protocol-defined visit window.   
Procedures such as laboratory and other safety assessments that cannot be performed or obtained 
as part of a remote visit may be performed separately and preferably within the protocol-defined 
visit window.   
Additionally, a Data Safety Monitoring Board/Data Monitoring Committee (DSMB/DMC) will 
review safety data on a quarterly basis.  A detailed description of the DSMB/DMC, its role in 
this trial, and the timing and process of the scheduled reviews will be described in a 
DSMB/DMC Charter.  
7.2. 
Number of Patients 
At least 6 patients was planned to be enrolled as part of the combined analysis with Study 
AVXS-101-CL-302.  At the time of this protocol was amended (Protocol version 6.0 
amendment 5 dated 11 Nov 2020), the enrollment was closed with 2 active enrolled patients as 
the combined analysis is no longer to be performed. 
7.3. 
Criteria for Trial Termination 
An independent DSMB/DMC will conduct quarterly and ad hoc reviews of the emerging safety 
data throughout the trial as described in Section 15. 
The trial may be terminated for the following reasons: 
• Development of unacceptable toxicity, defined as the occurrence of any unanticipated 
CTCAE Grade 3 or higher AE/toxicity that is possibly, probably, or definitely related to gene 
replacement therapy, and is associated with clinical symptoms and/or requires medical 
treatment.  
• DSMB/DMC can recommend early termination of the trial for safety reasons. 
• Trial is terminated by Sponsor. 
• Regulatory Authority recommendation. 
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8. 
ELECTION AND WITHDRAWAL OF PATIENTS 
Patients with SMA Type 1 who are < 6 months (< 180 days) of age at the time of gene 
replacement therapy (Day 1) with proven biallelic mutations of the SMN1 gene and one or 
2 copies of the SMN2 will be enrolled in this trial.   
8.1. 
Patient Inclusion Criteria 
Patients must meet all of the following inclusion criteria: 
1. Patients with SMA Type 1 as determined by diagnosis of SMA based on gene mutation 
analysis with biallelic SMN1 mutations (deletion or point mutations) and one or 2 copies of 
SMN2 [inclusive of the known SMN2 gene modifier mutation (c.859G>C)]  
2. Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion 
a. Patients must have a swallowing evaluation test performed prior to administration of 
gene replacement therapy 
b. Up-to-date on childhood vaccinations as per local health authorities.   
c. Parent(s)/legal guardian(s) willing and able to complete the informed consent process 
and comply with trial procedures and visit schedule 
8.2. 
Patient Exclusion Criteria 
Patients must not meet any of the following exclusion criteria: 
1. Previous, planned or expected scoliosis repair surgery/procedure prior to 18 months of age 
2. Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry 
< 95% saturation at screening 
a. Pulse oximetry saturation must not decrease ≥ 4 percentage points between screening 
and dosing with confirmatory oximetry reading 
b. Patients may be put on non-invasive ventilatory support for less than 12 hours per day 
at the discretion of their physician or trial staff 
3. Use or requirement of non-invasive ventilatory support for 12 or more hours daily in the 
two weeks prior to dosing 
4. Patient with signs of aspiration based on a swallowing test or whose weight-for-age falls 
below the 3rd percentile based on World Health Organization (WHO) Child Growth 
Standards [WHO 2006] and unwilling to use an alternative method to oral feeding 
5. Active viral infection (includes human immunodeficiency virus [HIV] or positive serology 
for hepatitis B, C, or E, or known Zika virus infection) 
6. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization 
within 2 weeks prior to screening 
7. Upper or lower respiratory infection requiring medical attention, medical intervention, or 
increase in supportive care of any manner within 4 weeks prior to screening 
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8. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in the 
opinion of the Principal Investigator, creates unnecessary risks for gene replacement such as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalciuria 
e. Symptomatic cardiomyopathy 
9. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients 
10. Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, 
agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, 
plasmapheresis, immunomodulators such as adalimumab, or immunosuppressive therapy 
within 3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, 
tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab) 
11. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay 
(ELISA) binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 antibody 
titer > 1:50, he or she may receive retesting within 30 days of the screening period and will 
be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 
12. Clinically significant abnormal laboratory values GGT, ALT, AST, total bilirubin >2x the 
ULN, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell 
[WBC] > 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated 
bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded. 
13. Participation in recent SMA treatment clinical trial (with the exception of observational 
cohort studies or non-interventional studies) or receipt of an investigational or commercial 
compound, product or therapy administered with the intent to treat SMA (e.g., nusinersen, 
valproic acid) at any time prior to screening for this trial.  Oral beta-agonists must be 
discontinued at least 30 days prior to dosing.  Inhaled albuterol specifically prescribed for the 
purposes of respiratory (bronchodilator) management is acceptable and not a contraindication 
at any time prior to screening for this trial 
14. Expectation of major surgical procedures during the trial assessment period (e.g., spinal 
surgery or tracheostomy) 
15. Parent(s)/legal guardian(s) unable or unwilling to comply with trial procedures or inability to 
travel for repeat visits 
16. Parent(s)/legal guardian(s) unwilling to keep trial results/observations confidential or to 
refrain from posting confidential trial results/observations on social media sites 
17. Parent(s)/legal guardian(s) refuses to sign consent form 
18. Patients < 35 weeks gestational age at time of birth 
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8.3. 
Patient Withdrawal Criteria 
Patients may be discontinued from the trial for the following reasons: 
• Death 
o An autopsy and/or post-mortem tissue/organ collection will be requested for any 
patient who expires following participation (see Post-Mortem Tissue and Organ 
Collection Plan in Appendix 2) as allowed per country/regional laws/regulations 
• Failure to comply with protocol-required visits or trial procedures for 3 or more consecutive 
visits that are not rescheduled, unless due to hospitalization 
• Parent(s)/legal guardian(s) withdraws consent 
• Investigator discretion 
End-of-trial procedures should be completed within 14 days for any patient who prematurely 
discontinues the trial for any reason, as indicated in Appendix 1.  Patients who terminate the 
study early for reasons other than death will be offered enrollment in a long-term follow-up 
study. 
In instances in which a patient withdraws from the study prior to the last scheduled visit, the 
investigator should differentiate between factors that are related to a catastrophe (such as the 
inability to travel, local ordinances or other restrictions, etc.) versus withdrawal of consent. 
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9. 
TREATMENT OF PATIENTS 
It is the responsibility of the Investigator to ensure the safe storage and administration of gene 
replacement therapy. 
9.1. 
Description of Trial Product 
AVXS-101 is a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) 
containing the human survival motor neuron (SMN) gene under the control of the 
cytomegalovirus (CMV) enhancer/chicken β-actin-hybrid promoter (CB).  One of the 
two adeno-associated vector (AAV) inverted terminal repeats (ITRs) has been modified to 
promote intramolecular annealing of the transgene, thus forming a double stranded transgene 
ready for transcription. 
Table 2 - Investigational Product 
 
Investigational Product 
Product Name 
AVXS-101 
Unit Dose 
1.1 × 1014 vg/kg; equivalent to the dose received by the Cohort 2 in the Phase 1 study 
(AVXS-101-CL-101) as determined by direct product testing with improved analytical methods. 
Route of Administration 
Intravenous infusion 
Physical Description 
AVXS-101 is a clear to slightly opaque, colorless to faint white solution, free of visible 
particulates 
 
9.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be captured in the electronic Case Report Form (eCRF) 
from 2 weeks prior to administration of gene replacement therapy through the last trial visit. 
9.2.1. 
Prophylactic Administration of Prednisolone 
An antigen specific T-cell response to the AAV vector was observed in the Phase 1 clinical trial 
(AVXS-101-CL-101) investigating AVXS-101 treatment via IV infusion [data on file].  This is 
an expected response between 2 to 4 weeks following gene replacement therapy.  One possible 
consequence to such antigen specific T-cell response is clearance of the transduced cells and loss 
of transgene expression. 
In an attempt to dampen the host immune response to the AAV-based therapy, all patients will 
receive prophylactic prednisolone at approximately 2 mg/kg/day (or an equivalent dose of 
another glucocorticoid if prednisolone is unavailable or in the opinion of the investigator 
prednisolone is not tolerated [Zoorob and Cender, 1998]) on Day -1, Day 1, and Day 2, and then 
1 mg/kg/day starting on Day 3 and until at least 30 days post-AVXS-101 infusion.  After 30 days 
post-AVXS-101 infusion, the dose of prednisolone can be tapered for patients whose GGT, ALT, 
and AST values are below the threshold of 2 × ULN.  To summarize, the overall course of 
prednisolone should proceed in accordance with the following treatment guideline: 
• Day -1, Day 1, and Day 2:  2 mg/kg/day  
• Day 3 until at least 30 days post AVXS-101 infusion: 1 mg/kg/day  
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• Weeks 5 and 6 post AVXS-101 infusion: 0.5 mg/kg/day 
• Weeks 7 and 8 post AVXS-101 infusion: 0.25 mg/kg/day 
• Week 9 post AVXS-101 infusion: prednisolone discontinued 
Liver function testing should guide each step of the taper, and liver function enzymes (LFEs) 
should be checked prior to prednisolone discontinuation.   If the GGT, AST or ALT values 
are > 2× ULN then the present dose of prednisolone should be adjusted as needed until the GGT, 
AST, and ALT values decrease below threshold, at which point the taper may continue.   LFTs 
should also be checked approximately 2 weeks after the taper has concluded and prednisolone 
has been discontinued to evaluate for rebound elevation of GGT, AST, or ALT levels.  Variance 
from these recommendations will be at the discretion of the Investigator based on potential safety 
issues for each patient.  If another glucocorticoid is used in place of prednisolone by the 
investigator, similar considerations should be taken into account after 30 days and tapered as 
appropriate and at the discretion of the investigator. 
9.2.2. 
Prohibited Medications 
Concomitant use of any of the following medications is prohibited: 
• Drugs for treatment of myopathy or neuropathy, or agents used to treat diabetes mellitus 
• Therapy received with the intent to treat SMA (e.g., nusinersen, valproic acid); oral 
β-agonists must be discontinued at least 30 days prior to gene therapy dosing.  Inhaled 
β-agonists may be used to treat respiratory complications of SMA provided such medications 
are dosed at clinically appropriate levels 
• Any investigational medication other than AVXS-101 is prohibited during the trial 
• Ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as 
adalimumab, or immunosuppressive therapy within 3 months prior to AVXS-101 dosing 
(e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV 
immunoglobulin, rituximab) 
Corticosteroid usage following completion of the prednisolone taper is permissible as part of 
routine clinical management.  The use of corticosteroids in such circumstances should be 
documented appropriately as a concomitant medication, and the event precipitating its usage 
should be appropriately documented as an adverse event. 
Should the use of corticosteroids (aside from inhaled corticosteroids for bronchospasm) be 
considered as part of care during the course of the prednisolone taper, this medical management 
should be discussed with the medical monitor. 
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9.2.3. 
Vaccinations 
Where feasible, the vaccination schedule should be adjusted appropriately to accommodate the 
prednisolone use. When avoiding vaccination while on steroids represents an undue delay or 
interruption of a vaccination schedule, vaccination should continue at the discretion and 
judgement of the treating physician given 1) the importance of maintaining childhood 
vaccination in this population and 2) the published literature that indicates that vaccination while 
on steroid doses 1 mg/kg/day or below is safe and effective [Pickering et al, 2012].  
Vaccinations that include palivizumab (also known as Synagis®) prophylaxis to prevent 
respiratory syncytial virus (RSV) infections are also recommended [Palivizumab Summary of 
Product Characteristics, 2018; American Academy of Pediatrics: Policy Statement, 2009]. 
9.3. 
Treatment Compliance 
AVXS-101 will be administered as a one-time IV injection. 
9.4. 
Randomization and Blinding 
This is an open-label trial. 
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10. 
TRIAL PRODUCT MATERIALS AND MANAGEMENT 
AVXS-101 is manufactured in accordance with current Good Manufacturing Practices (cGMP). 
10.1. 
Trial Product 
AVXS-101 
10.2. 
Trial Product Dose and Dose Justification 
Patients will receive a one-time dose of AVXS-101 at 1.1 × 1014 vg/kg via IV infusion, 
equivalent to the dose received by Cohort 2 in the Phase 1 trial (AVXS-101-CL-101). 
Two doses were studied in the Phase 1 clinical study (AVXS-101-CL-101); the higher dose 
(dose received by the Cohort 2 patients) was chosen for the present study as data have 
demonstrated both a dose response and significant clinical benefit, thus identifying it as the 
proposed therapeutic dose.  In the Phase 1 study, AVXS-101 demonstrated a dose response, with 
efficacy greater, as observed by motor milestone achievement and CHOP INTEND scores, at the 
higher dose (received by Cohort 2) than at the lower dose (received by Cohort 1).  Direct testing 
of the actual lot of Investigational Medicinal Product (IMP) used in the AVXS-101-CL-101 
study by an improved and more fully qualified analytical method has assigned a value of 
1.1 × 1014 vg/kg to the actual dose received by Cohort 2 in this Phase 1 study.  The same method 
has been used to establish an equivalent dose for the Phase 3 IMP.  This vg/kg value has been 
further verified in an improved and more fully qualified SMN∆7 Mouse Biopotency assay to 
support a similar extension of mouse lifetime in direct comparative assessment between the 
Phase 1 and Phase 3 IMP. 
10.3. 
Trial Product Packaging and Labeling 
AVXS-101 kits will be labeled with a specific kit number and lot number assigned at the cGMP 
facility.  The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
10.4. 
Trial Product Storage and Destruction 
AVXS-101 kits will be stored in a locked, limited access room under the responsibility of the 
Investigator or other authorized persons (e.g., pharmacists) in accordance with local regulations, 
policies, and procedures.  Control of storage conditions, especially control of temperature 
(e.g., refrigerated/freezer storage) and information on in-use stability and instructions for 
handling prepared AVXS-101 should be managed in accordance with the Pharmacy Manual. 
The vessel used for delivery of the vector should be resealed in the procedure room and 
processed for destruction in accordance with the Pharmacy Manual and applicable biohazardous 
waste guidelines for disposal. 
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10.5. 
Trial Product Preparation 
Preparation of AVXS-101 will be done aseptically under sterile conditions and will be received 
ready for infusion. 
AVXS-101 will arrive as outlined in the Pharmacy Manual.  The total vector genome dose will 
be calculated based on the patient’s body weight; sites will receive a patient-specific dose for 
each patient enrolled. 
The dose-delivery vessel will be delivered to the designated pediatric intensive care unit (PICU), 
patient room or other appropriate setting (e.g., interventional suite, operating room, dedicated 
procedure room) with immediate access to acute critical care management.  The vessel will be 
delivered in accordance with the Pharmacy Manual. 
10.6. 
Trial Product Administration 
AVXS-101 infusion will be administered under sterile conditions in a PICU or other appropriate 
setting (e.g., interventional suite, operating room, dedicated procedure room) with immediate 
access to acute critical care management.  AVXS-101 will be delivered one-time through a 
venous catheter inserted into a peripheral limb vein (arm or leg) at a dose equivalent to the 
cohort 2 dose administered in the AVXS-101-CL-101 trial.  AVXS-101 should be slowly infused 
over approximately 60 minutes, utilizing an infusion set and syringe pump in accordance with 
the Pharmacy Manual. 
Following administration of gene replacement therapy, patients should return to an appropriate 
designated setting to ensure close monitoring of vital signs and adverse events.  Vital signs will 
be continuously monitored throughout the gene replacement therapy infusion as described in 
Section 12.1.3.  Patients should be maintained in the PICU or other appropriate setting for 
48 hours after the start of gene replacement therapy. 
10.7. 
Dose Adjustment Criteria 
The trial investigates a one-time IV infusion of AVXS-101; no dose adjustments are possible. 
10.8. 
Trial Product Accountability 
The pharmacist or designee will maintain accurate records of the quantities of AVXS-101 
received, dispensed, destroyed, and/or returned to Novartis Gene Therapies.  The pharmacist or 
designee will document the date and time of delivery of the dose vessel to the dose procedure 
room as well as the time the used vessel was processed for destruction as per the Pharmacy 
Manual. 
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10.9. 
Trial Product Handling and Disposal 
All materials used for injection, including sterile drapes, needles, and syringes in contact with the 
vector must be sealed in leak-proof containers.  All waste must be sealed in bags bearing the 
biohazard symbol and disposed of in a biohazard waste container. 
All transfers must be done in spill-proof containers.  Individuals manipulating the vector will be 
required to wear personal protective equipment, such as gloves. 
Any quality issue noticed with the receipt or use of AVXS-101 (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 AVXS-101 to a third party, allow 
AVXS-101 to be used other than as directed by this clinical trial protocol, or dispose of 
AVXS-101 in any other manner. 
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11. 
ASSESSMENT OF EFFICACY 
Efficacy will be assessed by achievement of the key developmental milestone of sitting without 
support for at least 10 seconds at any time up to and including the 18 months of age trial visit and 
survival at 14 months of age (as defined in Section 14.1.1).  Efficacy assessments will be 
performed at the times specified in the Schedule of Assessments (Appendix 1) and should be the 
first assessments performed at any scheduled visit.  All post-treatment visits will be relative to 
the date on which gene replacement therapy is administered until the patient is 14 months of age, 
after which all visits will be relative to the patient’s date of birth. 
In the event of unforeseen catastrophe or other serious situation (such as the COVID-19 
pandemic) that occurs during the study, which limits or prevents on-site study visits, alternative 
methods of data collection pertaining to efficacy assessments may be considered.  Critical data 
that pertain to the primary and secondary endpoints should be collected according to the overall 
study schedule and within the protocol-defined visit window.  The maintenance of the overall 
visit schedule and visit windows is especially important for the final scheduled study visit, as this 
may impact the overall interpretation of the evaluation of efficacy.  As described in Section 7.1, 
allowances are made for the collection of data remotely, when necessary.  
Video recordings demonstrating the attainment of any new developmental milestones should be 
obtained within the protocol-defined visit window, including those that are required to be 
assessed as part of the final study visit or are related to primary or secondary endpoints 
(e.g, sitting without support).  This may include submission of recordings made by the family or 
others as described in Section 11.3.   
Alternative methods of data collection for efficacy assessments depending on local regulations, 
institutional polices, and capabilities may include:  
• developmental/motor efficacy assessments by a qualified clinical evaluator during a visit to 
the participant´s home 
• home videos or other recordings which demonstrate the achievement of developmental 
milestones that are specified in the protocol, including those to be assessed at the final 
scheduled study visit 
• use of ventilatory, cough or feeding support by the participant, evaluated during phone calls, 
virtual contacts (e.g., teleconsult) or visits by site staff/home nursing service to the 
participant´s home, or during visits by the participant to a local hospital. 
11.1. 
Developmental Milestones 
Developmental milestones will be assessed according to the 6 gross motor milestones definitions 
from the WHO MGRS (Appendix 5) and the BSIDv03 (Appendix 3 and Appendix 4), and will 
be analyzed to assess efficacy.  Achievement of each developmental milestone will be 
determined by the  qualified site clinical evaluator (physical or occupational therapist or national 
equivalent) and confirmed by the central reviewer based on an assessment of the submitted video 
(Section 11.3).  Developmental milestones will be determined at each monthly visit as shown in 
the SoA (Appendix 1). 
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At the 18 months of age visit all milestones (Appendix 4 and Appendix 5) should be assessed, 
documented, and video recorded regardless of previous attainment.  End of study developmental 
milestone may be submitted for review by an independent central reviewer. 
11.2. 
Motor Function Tests 
11.2.1. 
World Health Organization Multicentre Growth Reference Milestones 
The WHO Multicentre Growth Reference Study Group milestones defined for this study include 
six gross motor milestones (Appendix 5) [WHO 2006; Wijnhoven et al, 2004]: 
• Sitting without support 
• Crawling 
• Standing with assistance 
• Standing alone 
• Walking with assistance 
• Walking alone 
These six gross motor milestones will be assessed by a qualified clinical evaluator according to 
the SoA (Appendix 1).  If the Bayley Gross Motor Subtest Item 22 (Appendix 3), sits without 
support for five seconds, is achieved at a visit, then the WHO milestone for sitting without 
support for at least 10 seconds (Appendix 5) should be assessed at that visit and all subsequent 
visits.  Each developmental milestone assessment will be evaluated according to the WHO 
defined performance criteria and will be video recorded in accordance with the 
AVXS-101-CL-306 Physical Assessments Manual and may be submitted for review by a central 
reviewer (Section 11.3). 
11.2.2. 
Bayley Scales for Infant and Toddler Development/Developmental Milestones 
The BSIDv03 (Appendix 3) is a standardized, norm-referenced infant assessment of 
developmental functioning across 5 domains of cognitive, language, motor, social-emotional, 
and adaptive behavior [Albers and Grieve, 2007].  The Bayley Scales will be administered by a 
qualified clinical evaluator in accordance with the Physical Assessments Manual. The items from 
the BSIDv03 Gross Motor Subtest defined as developmental milestones for this protocol are 
specified in Appendix 4. 
During the Screening visit, the clinical evaluator will complete an assessment of baseline 
milestone achievement in accordance with Appendix 3; this assessment must address all 
milestones/items noted in Appendix 3, Gross Motor Subtest that are at or below the child’s 
baseline function, and be recorded on video.  The findings must be documented in the source.  
Items that are below the baseline level of assessment that are not successfully achieved during 
the baseline evaluation should be repeated at subsequent visits until successfully performed. 
The milestone of sitting independently (BSIDv03 Gross Motor Item #26) should be assessed, 
documented, and video recorded at every subsequent visit, until attainment of milestone, 
regardless of starting point on the scale.  This milestone must also be assessed at the 18 months 
of age visit, regardless of previous attainment.  
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As the Bayley Scales do not necessarily require the child to repeat previously attained 
milestones, it is essential that each attained milestone be captured on video. 
The gross and fine motor subtests of the motor domain will be administered according to the 
SoA (Appendix 1). 
Each Bayley Scales assessment will be video recorded in accordance with the 
AVXS-101-CL-306 Physical Assessments Manual and may be submitted for review by a central 
reviewer (Section 11.3). 
11.2.3. 
CHOP INTEND 
The CHOP INTEND (Appendix 6) is a motor function scale developed and validated for use 
specifically to monitor motor function status and decline amongst children with SMA Type 1 
[Glanzman et al, 2011; Glanzman et al, 2010] and will be administered by a qualified clinical 
evaluator.  The CHOP INTEND scale examines several aspects of motor function, including 
head control, righting reactions, and trunk movements in supported sitting, supine, and prone 
positions (Appendix 6).  Anti-gravity movements in assisted rolling, ventral suspension, and 
supported standing will also be measured.  Additional information on contractures will also be 
collected as described in the Physical Assessments Manual. 
The CHOP INTEND will be performed according to the SoA (Appendix 1).  For purposes of 
efficacy assessments, the CHOP INTEND assessment performed at Day -1 will be treated as the 
baseline assessment. 
Patients who achieve three consecutive CHOP INTEND scores ≥ 58 will not undergo any 
additional CHOP INTEND examinations. 
Each CHOP INTEND exam will be video recorded in accordance with the AVXS-101-CL-306 
Physical Assessments Manual and may be submitted for review by a central reviewer 
(Section 11.3). 
11.3. 
Video Evidence 
Clinic assessments (WHO Motor Developmental Milestones, Bayley Developmental Milestones, 
Bayley Scales and CHOP INTEND) required at each trial visit will be video recorded in an effort 
to produce compelling, demonstrable, documented evidence of efficacy, as determined by 
changes in functional abilities.  Novartis Gene Therapies will provide a secure and confidential 
upload process for transfer and storage of the videos from investigational sites to a contracted 
third-party vendor that will compile and arrange videos as per Novartis Gene Therapies 
requirements.  Any/all videos received at Novartis Gene Therapies or the contracted vendor will 
be treated as confidential trial data and will be either the sole property of Novartis Gene 
Therapies or permanently licensed to Novartis Gene Therapies to use and disclose as described 
in this protocol.  Novartis Gene Therapies and the contracted vendor will provide this secure, 
encrypted transfer and storage solution to properly protect the identities of patients/families on 
the videos, which may be shared with regulatory agencies, the medical community, and/or in 
appropriate venues to discuss the results of this clinical trial. 
Videos demonstrating Developmental Milestones which meet WHO and BSIDv03 criteria will 
be submitted to an independent, central reviewer for unbiased assessment of developmental 
milestone achievement.  The independent central reviewer will document whether the video 
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displays evidence of having achieved each developmental milestone.  The date of developmental 
milestone achievement will be computed as the earliest date on which video evidence 
demonstrates the achievement of the specified developmental milestone. 
Additionally, the parent(s)/legal guardian(s) may submit additional videos demonstrating 
achievement of developmental milestones at any time during the trial.  These videos will be 
handled in the same manner in which the trial-derived videos are handled. 
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12. 
ASSESSMENT OF SAFETY 
In the event of unforeseen catastrophe or other, serious situation (such as the COVID-19 
pandemic) that occurs during the study, which limits or prevents on-site study visits, regular 
phone or virtual video calls may occur (as per the Schedule of Assessments) for safety 
monitoring and discussion of the participant´s health status.  Visits by site staff/home nursing 
service to the participant´s home, or visits by the participant to a local hospital, laboratory, or 
imaging center, for performing certain safety assessments, depending on local regulations and 
capabilities, can replace on-site study visits, if necessary.  Analysis of laboratory samples 
(e.g., chemistry, hematology, urinalysis) may be performed at a local laboratory, if it is not 
possible to follow the central laboratory process.  Other safety assessments that cannot be 
conducted by telephone (such as vital signs, weight, length, cardiac testing etc.) may similarly be 
collected by the methods described above. 
12.1. 
Safety Parameters 
Safety parameters include physical examinations, pulmonary examinations, vital signs, capillary 
blood gas assessments, weight and length measurements, 12-lead ECGs, echocardiograms, 
24-hour Holter monitoring, swallowing tests, laboratory assessments, adverse event monitoring, 
and photographs of the infusion site.  In general, safety assessments will be performed at the 
times specified in the SoA (Appendix 1).  All post-treatment visits are relative to the date on 
which gene replacement therapy is administered until the patient reaches 14 months of age, after 
which all visits are relative to the patient’s date of birth. 
12.1.1. 
Demographic/Medical History 
Demographic/medical history information will be collected at screening and captured in the 
eCRF.  Information that will be collected includes: 
• Familial history of SMA including affected siblings or parent carriers 
• Gestational age at birth 
• Length/height/head circumference at birth 
• Hospitalization information from time of birth including number, duration, and reason for 
hospitalizations including International Statistical Classification of Diseases and Related 
Health Problems (ICD-10 codes), if available 
• Historical ventilatory support, if any 
• Historical feeding support, if any 
Patients are encouraged to follow all routinely scheduled immunizations, as recommended by the 
local health authority (e.g., the Japan Pediatric Society, Taiwan Immunization Schedule, or 
Korean Pediatric Society) throughout the trial.  Vaccinations that include palivizumab 
prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are 
also recommended. 
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12.1.2. 
Physical Examinations 
Physical examinations will be conducted by the Investigator or designee as specified in the SoA 
(Appendix 1).  The Day 1 physical examination will be performed prior to the start of gene 
replacement therapy infusion.  Physical examinations include a review of the following systems: 
head, eyes, ears, nose and throat (HEENT), lungs/thorax, cardiovascular, abdomen, 
musculoskeletal, dermatologic, lymphatic, neurologic, and genitourinary.  Specifically, the 
neurological exam should include detailed, age-appropriate sensory testing (such as examination 
of proprioceptive, vibratory, tactile and pain sensation) at each visit.  Any clinically significant 
abnormal finding should be recorded as an adverse event.  Further clinical evaluation should be 
considered as per judgment of the investigator. 
The head circumference shall be measured with each physical examination.  To measure head 
circumference, the examiner should securely wrap a flexible measuring tape around the 
circumference of the head, above the eyebrows over the broadest part of the forehead, above the 
ears, and over the most prominent part of the occiput.  The measurement should be taken 3 times, 
and the largest measurement should be recorded to an accuracy of 0.1 centimeters. 
12.1.3. 
Vital Signs/Weight and Length 
Vital sign parameters include blood pressure, respiratory rate, pulse, temperature, and pulse 
oximetry.  Vital signs will be obtained as specified in the SoA (Appendix 1).  On Day 1, vital 
signs will be continuously monitored throughout the gene replacement therapy infusion and 
recorded pre-dose and every 15 (± 5) minutes from the start of the infusion for the first 4 hours 
after the start of infusion, and then every hour (± 15 minutes) until 24 hours after the start of 
infusion.  Temperature will be recorded pre- and post-infusion. 
Weight and length will be measured at each trial visit as specified in the SoA (Appendix 1).  On 
Day 1, weight and length will be measured pre-dose. 
12.1.4. 
Electrocardiogram 
A 12-lead ECG will be performed as specified in the SoA (Appendix 1). 
Additional electrophysiological monitoring will be at the discretion of the Investigator as per 
local institutional guidelines. 
The ECG will be interpreted locally by a cardiologist or designee for immediate safety 
evaluation.  The ECG tracings or ECG machine data will be collected for centralized review and 
interpretation by a cardiologist. 
12.1.5. 
Echocardiogram 
A standard transthoracic echocardiogram will be performed as specified in the SoA 
(Appendix 1). The echocardiogram will be interpreted locally by a cardiologist or designee for 
immediate safety evaluation.  The echocardiograms will also be collected for centralized review 
and interpretation by a cardiologist. 
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12.1.6. 
Continuous ECG Recording (24-Hour Holter Monitoring) 
Twenty-four-hour Holter monitoring will take place as specified in the SoA (Appendix 1). 
Holter monitors will be provided to study sites along with a dedicated laptop for uploading the 
data from the memory cards for centralized review and analysis by a cardiologist or designee 
within 24 hours of data upload.  Novartis Gene Therapies will be notified of any safety concerns 
from the centralized review (Appendix 1). 
12.1.7. 
Pulmonary Examinations 
Pulmonary examinations will be performed by a pulmonologist (or appropriate individual as per 
standard institutional practice) as specified in the SoA (Appendix 1).  Prior to trial entry, a 
pulmonologist (or appropriate individual as per standard institutional practice) will review and 
document ventilator usage in the 2 weeks prior to screening. 
Patients may be fitted with non-invasive ventilatory support at the discretion of the 
pulmonologist (or appropriate individual as per standard institutional practice) and/or 
Investigator.  Non-invasive ventilatory support equipment will be provided by Novartis Gene 
Therapies through a third party vendor if not covered by the patient’s insurance. Should the 
patient require non-invasive ventilatory support at any time during the trial, the usage should be 
recorded in eCRF.  
Patients requiring non-invasive ventilatory support will be asked to bring the machine to each 
trial visit. 
12.1.8. 
Swallowing Test 
A standard bedside, non-barium (unless required by institutional policy) swallowing test will be 
performed as specified in the SoA (Appendix 1) to determine if the patient has signs of aspiration 
for consistencies tested during the assessment.  The swallowing test at Screening can be 
performed at the investigator site.  If the test is positive for aspiration, there may be a 
recommendation for the patient to use an alternate method to oral feeding for the duration of the 
trial at the determination of the Investigator and treating clinician. 
12.1.9. 
Photographs of Infusion Site 
Photographs will be taken of the infusion site as specified in the SoA (Appendix 1) to monitor 
healing of the infusion site.  The Day 1 infusion site photograph will be performed prior to the 
start of gene replacement therapy infusion.  Novartis Gene Therapies will provide a secure and 
confidential upload process for transfer and storage of the photographs from the investigative 
sites to a contracted third-party vendor that will compile and arrange photographs as per Novartis 
Gene Therapies requirements.  Any/all photographs received at Novartis Gene Therapies or the 
contracted vendor will be treated as confidential trial data and will be the sole property of 
Novartis Gene Therapies.  Novartis Gene Therapies and the contracted vendor will provide this 
secure, encrypted transfer and storage solution to properly protect the identities of 
patients/families in the photographs, which may be shared with regulatory agencies, the medical 
community, and/or in appropriate venues to discuss the results of this clinical trial. 
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12.1.10. 
Laboratory Assessments 
Blood samples will be collected at each scheduled visit as specified in the SoA (Appendix 1) and 
in accordance with the laboratory manual(s) provided for this study.  On Day -1, required blood 
samples will be collected locally prior to the start of gene replacement therapy infusion.  Any 
clinically significant laboratory value will be repeated at the discretion of the Investigator. 
 
Table 3 - Total Blood Volume 
Visit 
Tests 
Total Volume (mL)b 
Screening 
Hematology, chemistry, Troponin I, virus serology, ELISA immunology sample 
(AAV9/SMN Ab), diagnostic genetic re-confirmation sample 
15.4 b 
Day –1 
Hematology, chemistry, capillary blood gas 
3.3 b 
Day 2 
Hematology, chemistry, capillary blood gas 
3.3 b 
Day 7 
Hematology, chemistry, Troponin I, immunology sample 
9.6 b 
Day 14 
Hematology, chemistry, immunology sample 
3.3 b 
Day 21 
Hematology, chemistry, immunology sample 
3.3 b 
Day 30 
Hematology, chemistry, Troponin I, immunology sample 
9.6 b 
Day 44 
Chemistry 
1.3b 
Day 60 
Hematology, chemistry, Troponin I 
4.9 b 
Day 72 
Chemistry 
1.3b 
Month 3/4/5/7/8/ 
10/11/13/14/16/17 
Hematology, chemistry 
26.6 b 
Month 6/9/12/15 
Hematology, chemistry, Troponin I 
14.4 b 
End of Study/ET 
Hematology, chemistry, Troponin I 
3.6 b 
Maximum Total Volume for Triala 
99.9 b 
ET = early termination 
a Patients will have different numbers of monthly visits, depending on their age at dosing.  Maximum total volume based on a 
maximum of 16 monthly visits.  Additionally, lower blood volumes may be sufficient at some visits where testing can be 
combined. 
b Safety laboratory samples to be drawn by local laboratory; smaller volumes may be utilized. 
 
In a case where sufficient blood cannot be collected from a patient, blood will be used in the 
following priority order with the first having greatest priority and last having the least priority: 
1. Safety labs: chemistry → hematology → Troponin I 
2. Serum antibody to AAV9 and SMN 
3. Genetic reconfirmation testing 
If there is insufficient blood volume to include the genetic reconfirmation testing sample at the 
screening visit, patient must return before Visit 2.  All patients must have genetic reconfirmation 
testing completed. 
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12.1.10.1. Hematology 
Hematology analysis will include a complete blood count with differential and platelet count 
with smear.  Samples will be collected and processed by the sites’ local laboratories.  Blood 
samples for hematology analysis will be collected in accord with the SoA (Appendix 1). 
12.1.10.2. Blood Chemistry 
Samples will be collected and processed by the sites’ local laboratories.  Blood samples for 
chemistry analysis will be collected in accord with the SoA (Appendix 1). 
Chemistry analysis will include the following at all trial visits: 
• Serum GGT 
• AST/ALT 
• Serum total bilirubin 
• Direct bilirubin 
• Albumin 
• Glucose 
• Creatinine kinase 
• Creatinine 
• BUN 
• Electrolytes (potassium, chloride, CO2, calcium, inorganic phosphorus, sodium, magnesium) 
• Alkaline phosphatase 
Patients will have Troponin I collected on the visits specified in the SoA (Appendix 1). 
12.1.10.3. Urinalysis 
Urine samples will be collected and process by the sites’ local laboratories in accord with the 
SoA (Appendix 1).  Urinalysis will include the following parameters: 
• Color 
• Clarity/turbidity 
• pH 
• Specific gravity 
• Glucose 
• Ketones 
• Nitrites 
• Leukocyte esterase 
• Bilirubin 
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• Blood 
• Protein 
• Red Blood Cell 
• White Blood Cell 
• Squamous epithelial cells 
• Casts 
• Crystals 
• Bacteria 
• Yeast 
12.1.10.4. Virus Serology 
The administration of an AAV vector has the risk of causing immune-mediated hepatitis.  For 
patients who have HIV or positive serology for hepatitis B, C, or E, administration of AAV 
vector may represent an unreasonable risk; therefore, negative serology testing must be 
confirmed at screening, prior to treatment.  These samples will be collected at screening (SoA, 
Appendix 1) and processed by the sites’ local laboratories. 
12.1.10.5. Capillary Blood Gas 
Capillary blood gas (pCO2, pO2, total CO2) and pH will be measured locally at Day -1 and Day 2 
(SoA, Appendix 1).  A puncture or small incision will be made with a lancet or similar device 
into the cutaneous layer of the patient’s skin at a highly vascularized area (heel, finger, toe).  To 
accelerate blood flow and reduce the difference between the arterial and venous gas pressures, 
the area will be warmed prior to the puncture.  As the blood flows freely from the puncture site, 
the sample will be collected in a capillary tube. 
12.1.10.6. Immunology Testing (ELISA) 
Blood samples for immunology testing will be collected and shipped to the central laboratory in 
accordance with the laboratory manual to test for serum antibodies to AAV9 and SMN (ELISA).  
Blood samples will be collected as specified in the SoA (Appendix 1). 
12.1.10.7. AAV9 Antibody Screen in Mother 
There is potential that the biological mother of the patient may have pre-existing antibodies to 
AAV9 that may be transferred to the patient through breast milk or, theoretically, via placental 
transfer in utero.  Informed consent will be requested from the mother of the patient to screen the 
mother for circulating antibodies to AAV9.  Once informed consent has been obtained, the 
mother will have her blood drawn from a peripheral vein and shipped to the central laboratory 
for screening of anti-AAV9 antibodies.  If AAV9 antibodies are identified, the investigator 
should discuss with the biological mother whether to continue or stop breastfeeding. 
Patients whose biological mothers are involved with their care but do not consent to AAV9 
antibody screening are not eligible to participate. 
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Patients consuming banked breast milk from donor sources that cannot be tested for anti-AAV9 
antibodies must be transitioned to formula prior to participation. 
12.1.10.8. Blood for Diagnostic Confirmation Testing 
A blood sample will be collected during the screening visit and shipped to the central laboratory 
in accordance with the laboratory manual for reconfirmation of SMN1 deletions/mutations, 
SMN2 copy number, and absence or presence of exon 7 gene modifier mutation (c.859G>C). 
This will be done to ensure consistency in diagnostic testing practices. 
12.1.10.9. Saliva, Urine, and Stool Collection 
Studies have shown that some vector can be excreted from the body for a few weeks after 
injection; this is called “viral shedding.”  Vector shedding can be found in the blood, urine, 
saliva, and stool for up to a few weeks following infusion.  The risks associated with the shed 
vector are not known at this time; however, the risk is thought to be low as the vector cannot 
replicate.  Regardless, IRB/IEC- approved instructions should be provided to the patient’s family 
and care giver(s) regarding use of protective gloves if/when they come into direct contact with 
the patient’s bodily fluids and/or waste, as well as good hand-hygiene for a minimum of four 
weeks after gene replacement therapy.  Additionally, patients are prohibited from donating blood 
for two years following the vector infusion. 
Saliva, urine, and stool samples will be collected and shipped to the central laboratory for viral 
shedding studies as specified in the SoA (Appendix 1).  Samples will be collected, prepared, and 
shipped as per the laboratory manual.   
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13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
13.1. 
Definition of Adverse Events 
13.1.1. 
Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product.  In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including baseline or washout periods, 
even if no trial treatment has been administered. 
All AEs (related or not related) that occur after signing of the informed consent through the last 
trial visit will be collected and recorded in the eCRF. 
All AEs will be classified in accordance with the CTCAE version 4.03 (or later version, upon 
agreement of Novartis Gene Therapies) outlined in Table 4. 
 
Table 4 - Common Terminology Criteria for Adverse Events 
Grade 
Definition 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL.b 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
Source: Common Terminology Criteria for Adverse Events (version 4.03) [NCI, 2010] 
a 
ADL, Activities of daily living; Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
Additionally, a DSMB/DMC will review safety data on a quarterly basis.  A detailed description 
of the DSMB/DMC, its role in this trial, and the timing and process of the scheduled reviews will 
be described in a DSMB/DMC Charter.  
13.1.2. 
Serious Adverse Event 
An SAE is an AE occurring during any trial phase (e.g., screening, baseline, treatment, washout, 
or follow-up), and at any dose of the investigational product, or comparator that fulfils one or 
more of the following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
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• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
All SAEs (related and unrelated) that occur after signing of the informed consent through the last 
trial visit must be collected and recorded on forms provided by the Contract Research 
Organization within 24 hours of the site becoming aware. 
13.1.3. 
Adverse Events of Special Interest 
The following are considered AEs of special interest (AESIs): 
• Hepatotoxicity 
• Thrombocytopenia 
• Cardiac adverse events 
• Sensory abnormalities suggestive of ganglionopathy 
Grade 3 or higher elevated liver enzyme events related to AVXS-101 must be collected and 
recorded on the forms provided. These events should be reported within 24 hours of occurrence 
whether or not they are deemed to be an SAE. 
13.2. 
Relationship to Trial Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related, Probably Related, or 
Definitely Related).  The Investigator should decide whether, in his or her medical judgment, 
there is a reasonable possibility that the event may have been caused by the investigational 
product.  If no valid reason exists for suggesting a relationship, then the AE should be classified 
as “unrelated.”  If there is any valid reason, even if undetermined, for suspecting a possible 
cause-and-effect relationship between the investigational product and the occurrence of the AE, 
then the AE should be considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” then the event will be considered related to the investigational product 
for the purposes of expedited regulatory reporting. 
13.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient and/or in response to an open question 
from the trial personnel or revealed by observation will be recorded during the trial at the 
investigational site.  Information about AEs (related and unrelated) after signing of the informed 
consent form until the last study visit are to be collected.  Serious adverse event information will 
be collected from signing of the informed consent form through 30 days after the last trial visit.  
The AE term should be reported in standard medical terminology when possible.  For each AE, 
the Investigator will evaluate and report the onset (date and time [if start date during inpatient 
period]), resolution (date and time [if start date during inpatient period]), intensity, causality, 
action taken, serious outcome (if applicable), and whether or not it caused the patient to 
discontinue the trial. 
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It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 13.1.2.  An AE of severe intensity 
may not be considered serious. 
13.4. 
Reporting Serious Adverse Events 
All SAEs (related and unrelated) will be recorded after signing the informed consent through the 
last trial visit.  Any SAEs considered possibly, probably, or definitely related to the 
investigational product and discovered by the Investigator at any time after the trial should be 
reported.  All SAEs must be reported to Novartis Gene Therapies or designee within 24 hours of 
the first awareness of the event.  The Investigator must complete, sign and date the SAE pages, 
verify the accuracy of the information recorded on the SAE pages with the corresponding source 
documents, and send a copy by fax or e-mail to Novartis Gene Therapies or designee.  Note: 
elective procedures or minor surgeries where hospitalization is required should not be reported as 
SAEs. 
Additional follow-up information, if required or available, should all be faxed or e-mailed to 
Novartis Gene Therapies or designee within 24 hours of receipt and this should be completed on 
a follow-up SAE form and placed with the original SAE information and kept with the 
appropriate section of the eCRF and/or trial file. 
Novartis Gene Therapies is responsible for notifying the relevant regulatory authorities of certain 
events.  It is the Principal Investigator’s responsibility to notify the IRB or IEC of all SAEs that 
occur at his or her site.  Investigators will also be notified of all unexpected, serious, drug-related 
events (7/15 Day Safety Reports) that occur during the clinical trial.  Each site is responsible for 
notifying its IRB or IEC of these additional SAEs. 
13.5. 
Expedited Safety Reporting to Regulatory Authorities 
All serious, unexpected, suspected adverse reactions (SUSARs) will be reported to regulatory 
authorities within the 15-day expedited timeline. Unexpected fatal or life-threatening suspected 
adverse reactions will be reported according to the 7-day timeline. 
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14. 
STATISTICS 
This section summarizes key aspects of the analysis plan including definitions of primary, 
secondary, and exploratory efficacy endpoints and safety endpoints.  Additional details regarding 
methods for the final data presentation will be provided in a separate Statistical Analysis Plan 
(SAP).  The SAP will detail all data displays and will be executed according to Standard 
Operating Procedures in a controlled environment.   
14.1. 
Study Endpoints 
The following endpoints will not be analyzed formally but will be presented in data listings. 
14.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
Proportion of symptomatic SMA Type 1 patients who are homozygous negative for SMN1 
exon 7 and have 2 copies of SMN2 without the SMN2 genetic modifier that achieve the ability to 
sit without support for at least 10 seconds at any visit up to and including the 18 months of age 
visit.  It is defined by the WHO MGRS, confirmed by video recording, as a patient who sits up 
straight with head erect for at least 10 seconds; 
 
 
14.1.2. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is: 
Survival at 14 months of age amongst symptomatic SMA Type 1 patients who are homozygous 
negative for SMN1 exon 7 and have 2 copies of SMN2 without the SMN2 genetic modifier. 
Survival is defined by the avoidance of the combined endpoint of either (a) death or (b) 
permanent ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of 
respiratory assistance per day (via non-invasive ventilatory support) for ≥ 14 consecutive days in 
the absence of an acute reversible illness, excluding perioperative ventilation.  Permanent 
ventilation, so defined, is considered a surrogate for death. 
• An “acute reversible illness” is defined as any condition other than SMA that results in 
increased medical intervention (i.e., increased requirement for respiratory support; use of 
other concomitant medications as rescue) requirements and is expected to be reversible or 
improved following definitive intervention (i.e., surgery, antibiotics) or introduction of 
escalated supportive care, such as hospitalization (i.e., for upper respiratory infection, 
spontaneous fracture).  The specific duration of the condition antecedent intervention shall 
not be considered in the definition of “acute.”  The date of “definitive intervention” shall be 
defined as the date of provision of a procedure (i.e., surgery, etc.) or medication (i.e., 
antibiotics) intended to cure or substantially improve the condition.  For conditions such as 
viral respiratory infections for which supportive care is provided, the date of “definitive 
intervention” shall be considered the date of hospitalization or substantial escalation of care.  
• “Perioperative” use reflects any alteration of ventilatory use related to a surgical or other 
medical procedure of any nature for which the patient received medications that could impair 
or interfere with respiratory function. 
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• For a patient who develops an acute reversible illness and/or requires perioperative 
ventilatory support, a recovery period not to exceed 21 days following the date of definitive 
intervention will be instituted.  Following this recovery period, the condition will be 
considered subacute and the patient will become evaluable with regards to the surrogate 
survival endpoint (requirement of ventilatory support of ≥ 16 hours/day for 14 or more days). 
14.1.3. 
Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14.1.4. 
Safety Endpoints 
Assessment of the safety and tolerability of AVXS-101 treatment includes evaluation of AEs, 
laboratory data, vital signs, and concomitant medication. 
14.2. 
Statistical Analysis Populations 
14.2.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will consist of symptomatic patients with biallelic deletion 
mutations of SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the 
known gene modifier mutation (c.859G>C) who receive an IV infusion of AVXS-101 at less 
than 180 days of age.   
14.2.2. 
Ability to Thrive ITT Population 
The ability to thrive combined study ITT population will consist of symptomatic patients with 
biallelic deletion mutations of SMN1, 2 copies of SMN2 without the genetic modifier 
(c.859G>C), intact swallowing and receiving no enteral (mechanical) nutrition at baseline, who 
receive an IV infusion of AVXS-101 and have at least one post-baseline efficacy evaluation.   
14.2.3. 
All Enrolled Population 
The all enrolled population will consist of all patients who receive an IV infusion of AVXS-101.   
14.2.4. 
Safety Population 
The safety analysis population will consist of all patients who receive an IV infusion of 
AVXS-101.   
14.3. 
Sample Size Calculation 
The study was originally designed to have sufficient power, when combined with an identically 
designed study AVXS‐101‐CL‐302, to establish efficacy with regard to the primary and 
secondary endpoints.  Due to the change in data analysis and narrowed scope of 
AVXS-101-CL-306, no combined analysis or stand-alone analysis will be conducted.  
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14.4. 
Efficacy Analysis 
14.4.1. 
General Considerations 
This trial will assess the efficacy of AVXS-101 administered IV in terms of functional 
independent sitting and survival rate. 
Unless otherwise specified, the baseline measurement is defined as the last non-missing 
measurement collected prior to or on the day of gene replacement therapy infusion (i.e., on or 
before Day 1 visit). 
14.4.2. 
Primary and Secondary Efficacy Analysis 
Primary and secondary efficacy endpoints will be presented in data listings where patients will 
be identified as to the analysis set(s) to which they belong.  Endpoints defined as proportions will 
be presented as a dichotomous outcome for each patient. 
14.5. 
Safety Analysis 
Safety will be assessed through the incidence and severity of AEs, vital sign assessments, cardiac 
assessments, laboratory evaluations (chemistry, hematology, immunology, urinalysis), physical 
examinations, and use of concomitant medications.  Adverse events will be coded in accordance 
with the most current version of the MedDRA coding dictionary.  Safety assessment will be 
presented in data listings. 
14.5.1. 
Hy’s Law Criteria 
In order to assess hepatotoxicity, all elevations in liver transaminases are evaluated using 
Hy’s Law criteria as these help to determine the risk of drug-induced liver injury.  All elevations 
in liver transaminases will be assessed against these criteria.  Hy’s Law cases have the following 
three components:   
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug or 
placebo; 
2. Among trial patients showing such aminotransferase (AT) elevations, often with ATs much 
greater than 3×ULN, one or more patients also shows elevation of serum total bilirubin 
(TBL) to ≥2×ULN, without initial findings of cholestasis (elevated serum ALP);  
3. No other reason can be found to explain the combination of increased AT and TBL, such as 
viral hepatitis A, B, or C, pre-existing or acute liver disease, or another drug capable of 
causing the observed injury [FDA (2009)]. 
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15. 
DATA SAFETY MONITORING BOARD 
The DSMB/DMC is an independent multidisciplinary group consisting of clinicians and a 
biostatistician that, collectively, have experience in the management of patients with SMA Type 
1 and other diseases, and in the conduct and monitoring of randomized clinical studies with 
interim analyses.  The DSMB/DMC will be chartered to oversee the safety of patients during the 
conduct of the trial and will act in an advisory capacity to Novartis Gene Therapies.  A detailed 
description of the DSMB/DMC, its role in this trial, and the timing of the scheduled reviews will 
be described in a DSMB/DMC Charter. 
The DSMB/DMC will routinely convene on a quarterly basis to review emerging safety data 
from the trial.  Following each meeting, the DSMB/DMC will make a recommendation as to 
whether or not the accumulated safety data warrants a suspension or discontinuation of the trial, 
a modification to the trial, or any additional comments or recommendations related to safety.  
The DSMB/DMC will prepare and provide minutes of their meetings to Novartis Gene Therapies 
who will provide copies to the regulatory authorities as appropriate. 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Trial Monitoring 
Before an investigational site can enter a patient into the trial, a representative of Novartis Gene 
Therapies will visit the investigational trial site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Novartis Gene Therapies or its representatives.  
This will be documented in a Clinical Trial Agreement between Novartis Gene Therapies and 
the Investigator. 
During the trial, a monitor from Novartis Gene Therapies or representative will have regular 
contacts with the investigational site, for the following: 
• Provide information and support to the Investigator(s)  
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product accountability 
checks are being performed 
• Perform source data verification.  This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records relevant 
to the trial.  This will require direct access to all original records for each patient (e.g., clinic 
charts, electronic medical records) 
• Record and report any protocol deviations not previously sent to Novartis Gene Therapies 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any SAEs 
have been forwarded to Novartis Gene Therapies and those SAEs that met criteria for 
reporting have been forwarded to the IRB/IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
In the event of unforeseen catastrophe or other serious situation (such as the COVID-19 
pandemic) that occurs during the study, which limits or prevents on-site visits, remote site 
monitoring visits may be conducted.  This should not include remote source data verification 
(SDV), unless in exceptional circumstances, depending upon local regulations and prior 
informed consent having been obtained from participating patients. 
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16.2. 
Audits and Inspections 
Authorized representatives of Novartis Gene Therapies, a regulatory authority, an IEC or an IRB 
may visit the site to perform audits or inspections, including source data verification.  The 
purpose of a Novartis Gene Therapies audit or inspection is to systematically and independently 
examine all trial-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the protocol, 
Good Clinical Practice (GCP) guidelines of the International Council for Harmonization (ICH), 
and any applicable regulatory requirements.  The Investigator should contact Novartis Gene 
Therapies immediately if contacted by a regulatory agency about an inspection. 
16.3. 
Institutional Biosafety Committee 
As this trial involves gene therapy, the Principal Investigator must obtain approval/favorable 
opinion for the investigation from a designated institutional or independent biosafety committee 
(IBC) in accordance with institutional requirements and/or guidelines. 
16.4. 
Institutional Review Board/Independent Ethics Committee 
The Principal Investigator must obtain IRB/IEC approval for the investigation (see Section 18.1).  
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this trial including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Qualified individuals designated by the Sponsor will monitor all aspects of the study according 
to GCP, standard operating procedures (SOPs), and for compliance with applicable government 
regulations.  Please see Section 16.1 for more details regarding the quality control and 
monitoring process.  Novartis Gene Therapies may also conduct a quality assurance audit any 
time during or after the completion of the study.  Please see Section 16.2 for more details 
regarding the audit process. 
The Investigator agrees to allow these Sponsor representatives direct access to the clinical data 
and supplies, dispensing and storage areas and if requested, agrees to cooperate fully or assist the 
Sponsor representative.  The Investigator and staff are responsible for being present or available 
for consultation during routinely scheduled site visits conducted by the Sponsor or its designees. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
Investigator, site staff, or representatives of the Sponsor will lead to prompt action by the 
Sponsor to secure compliance.  Continued noncompliance may result in termination of the 
corresponding party’s involvement in the study.  The IRB/IEC and relevant regulatory authority 
will also be informed. 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Novartis Gene Therapies may conduct a quality assurance audit.  Please see Section 16.2 for 
more details regarding the audit process. 
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18. 
ETHICS 
18.1. 
Ethics Review 
The final trial protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC, as appropriate.  The 
Investigator must submit written approval to Novartis Gene Therapies before he or she can enroll 
any patient into the trial. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the trial.  The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other trial conducted with the investigational 
product.  Novartis Gene Therapies or designee will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this trial including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
18.2. 
Ethical Conduct of the Trial 
The trial will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (Appendix 7) and are consistent with ICH/GCP, applicable regulatory 
requirements. 
18.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the parent(s)/legal guardian(s) are 
given full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the trial.  The parent(s)/legal guardian(s) must also be notified that they are free to 
discontinue the patient from the trial at any time.  The parent(s)/legal guardian(s) should be given 
the opportunity to ask questions and allowed time to consider the information provided. 
The signed and dated informed consent must be obtained before conducting any trial procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the parent(s)/legal guardian(s). 
There will be 3 informed consent forms: 
• Parent(s)/legal guardian(s) informed consent form 
• Biological mother baseline AAV9 antibody screening informed consent form 
• Autopsy informed consent form (see Appendix 2; if the parent(s)/legal guardian(s) decline an 
autopsy, it will not prevent the patient from participating in the trial) 
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In the event of unforeseen catastrophe or other serious situation (such as the COVID-19 
pandemic) that occurs during the study, the ability to obtain a standard written informed consent 
may be challenged due to limits that prevent an on-site visit.  In this situation, the Investigator 
may conduct the informed consent discussion remotely (e.g., telephone, videoconference).  
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 
informed consent forms (ICFs) by trial participant and person obtaining informed consent; a 
video or other recording of the consent process and affirmation of consent may be considered to 
supplement the documentation of obtaining consent, if allowable by local regulations etc.). 
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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Electronic Case Report Forms 
Adequate and accurate case records will be maintained, and all relevant observations and data 
related to the trial will be recorded.  This will include medical history/ physical examination, 
hematology, clinical chemistry and serology results, a check list of inclusion and exclusion 
criteria, product administration, and a record of sample collection, hemodynamic measurements, 
clinical assessments, AEs, and final evaluation. 
Electronic CRFs will be used in this trial.  The eCRF will be electronically signed and dated by 
the Principal Investigator or his designee after his/her review.  After the completion of the trial, 
completed eCRFs will be retained in the archives. 
Completed eCRFs will be reviewed by the trial monitor against the source documentation for 
accuracy and completeness.  Once signed by the Investigator, the monitor will transmit the 
completed eCRFs to data management for data validation and database analysis. 
19.2. 
Inspection of Records 
Novartis Gene Therapies or designee will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the trial.  The Investigator agrees to allow 
the monitor to inspect the product storage area, trial product stocks, product accountability 
records, patient charts and trial source documents, and other records relative to trial conduct. 
19.3. 
Retention of Records 
All primary data that are a result of the original observations and activities of the trial and that 
are necessary for the reconstruction and evaluation of any trial report will be retained in a secure 
archive at the trial site for a period not less than 2 years after the last approval of a marketing 
application in an ICH region, and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least 2 years have lapsed since the formal 
discontinuation of the clinical development of the investigational product.  All country/region 
specific requirements that may be more stringent than the 2 years included in ICH shall be 
followed. 
The site will maintain essential documents as required by ICH-GCP.  The site must keep these 
documents available for review by the Sponsor, IRB/IEC, and/or regulatory bodies. 
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20. 
PUBLICATION POLICY 
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the trial.  During the trial, only the Sponsor may make trial information 
available to other trial Investigators or to regulatory agencies, except as required by law or 
regulation.  Except as otherwise allowable in the clinical trial site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or trial results, other 
than trial recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the trial (including data and information 
generated by the Investigator) without the consent of the Investigator.  Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document.  All publications and presentations must be prepared in accordance with 
this section and the Clinical Trial Site Agreement.  In the event of any discrepancy between the 
protocol and the Clinical Trial Site Agreement, the Clinical Trial Site Agreement will prevail. 
If the trial is being conducted as part of a multicenter clinical trial, data from all sites 
participating in the trial will be pooled and analyzed by the Sponsor or the Sponsor’s designee.  
The first publication of the trial results shall be made in conjunction with the results from other 
trial sites as a multicenter publication.  If a multicenter publication is not forthcoming within 
24 months of completion of the trial at all sites, the Investigator may publish or present the 
results generated at his or her site. 
The Investigator will provide the Sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days prior to such presentation or submission 
for publication.  The Sponsor shall inform the Investigator in writing of any changes or deletions 
in such presentation or publication required to protect the Sponsor’s confidential and proprietary 
technical information and to address inaccurate data or inappropriate interpretations in the 
context of any pooled multicenter results.  At the expiration of such 60-day period, the 
Investigator may proceed with the presentation or submission for publication unless the Sponsor 
has notified the institution or the Investigator in writing that such proposed publication or 
presentation discloses the Sponsor’s confidential and proprietary technical information.  Further, 
upon the request of the Sponsor, the Investigator will delay the publication or presentation for an 
additional 90 days to permit the Sponsor to take necessary actions to protect its intellectual 
property interests. 
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21. 
LIST OF REFERENCES 
Albers C, Grieve A. Test Review: Bayley, N. (2006). Bayley Scales of Infant and Toddler 
Development. Third ed. San Antonio, TX: Harcourt Assessment; 2007. 
American Academy of Pediatrics: Policy statements--Modified recommendations for use of 
palivizumab for prevention of respiratory syncytial virus infections. Committee on Infectious 
Diseases. Pediatrics. 2009 Dec;124(6):1694-701. 
AVXS-101 Investigator’s Brochure version 6.0. 17 September 2019 
Butchbach ME, Edwards JD, Burghes AH. Abnormal motor phenotype in the SMNDelta7 mouse 
model of spinal muscular atrophy. Neurobiol Dis. 2007;27(2):207-219. 
Chen TH, Chang JG, Yang YH, et al. Randomized, double-blind, placebo-controlled trial of 
hydroxyurea in spinal muscular atrophy. Neurology. 2010;75(24):2190-7. 
Darbar IA, Plaggert PG, Resende MB, Zanoteli E, Reed UC. Evaluation of muscle strength and 
motor abilities in children with Type II and III spinal muscle atrophy treated with valproic acid. 
BMC Neurol. 2011;11:36. 
Dayangac-Erden D, Bora-Tatar G, Dalkara S, Demir AS, Erdem-Yurter H. Carboxylic acid 
derivatives of histone deacetylase inhibitors induce full length SMN2 transcripts: a promising 
target for spinal muscular atrophy therapeutics. Arch Med Sci. 2011;7(2):230-234. 
Farrar MA, Vucic S, Johnston HM, et al. Pathophysiological insights derived by natural history 
and motor function of spinal muscular atrophy. J Pediatr. 2013;162(1):155-159. 
Farrar MA, Vucic S, Johnston HM, Kiernan MC. Corticomotoneuronal integrity and adaptation 
in spinal muscular atrophy. Arch Neurol. 2012;69(4):467-473. 
FDA (2009) U.S. Department of Health and Human Services, Center for Drug Evaluation and 
Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for 
Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation; 
https://www.fda.gov/downloads/guidances/UCM174090.pdf. 
Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and 
SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction 
of severity of spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358-368. 
Finkel RS, McDermott MP, Kaufmann P, et al. Observational trial of spinal muscular atrophy 
Type I and implications for clinical trials. Neurol. 2014;83(9):810-817. 
Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype in a 
mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010;28(3):271-274. 
Glanzman AM, Mazzone E, Main M, et al. The Children’s Hospital of Philadelphia Infant Test 
of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromusc 
Disord. 2010;20(3):155-161. 
Glanzman AM, McDermott MP, Montes J, et al. Validation of the Children's Hospital of 
Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther. 
2011;23(4):322-326. 
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Hinderer C, Katz N, Buza EL, et al. Severe toxicity in nonhuman primates and piglets following 
high-dose intravenous administration of an adeno-associated virus vector expressing human 
SMN. Hum Gene Ther. 2018 Mar;29(3):285-298 
Hordeaux J, Hinderer C, Goode T, et al. Toxicology study of intra-cisterna magna 
adeno-associated virus 9 expressing human alpha-L-iduronidase in rhesus macaques. 
Mol Ther Methods Clin Dev. 2018 Jul 14;10:79-88 
Kissel JT, Scott CB, Reyna SP, et al. SMA CARNI-VAL TRIAL PART II: A prospective, 
single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular 
atrophy. PLoS ONE. 2011;6(7):e21296. doi:10.1371/journal.pone.0021296. 
Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011;68(8):979-984. 
Le TT, McGovern VL, Alwine IE, et al. Temporal requirement for high SMN expression in 
SMA mice. Hum Mol Genet. 2011;20(18):3578-3591. 
Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular 
atrophy-determining gene. Cell. 1995;80(1):155-164. 
Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity & SMN protein level in spinal 
muscular atrophy. Nat Genet. 1997;16(3):264-269. 
Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates 
splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 
1999;96(11):6307-6311. 
Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, et al. Successful transduction 
of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. 
Nat Med. 2006;12(3):342-347 
Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and 
challenges. Lancet Neurol. 2012;11(5):443-452. 
Mercuri E1, Bertini E, Messina S, et al.  Pilot trial of phenylbutyrate in spinal muscular atrophy. 
Neuromuscul Disord. 2004;14(2):130-5. 
Monani UR, Lorson CL, Parsons DW, et al. A single nucleotide difference that alters splicing 
patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 
1999;8(7):1177-1183. 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events v4.0. NCI, 
NIH, DHHS. May 29, 2009 (v4.03: June 14, 2010). NIH publication #90-5410. 
Palivizumab Summary of Product Characteristics. 2018 
https://www.ema.europa.eu/en/documents/product-information/synagis-epar-product-
information_en.pdf. 
Park GH, Kariya S, Monani UR. Spinal muscular atrophy: new and emerging insights from 
model mice. Curr Neurol Neurosci Rep. 2010;10(2):108-117. 
Pickering L, Baker C, Kimberlin D, Long S, eds. Red Book: Report of the Committee on 
Infectious Diseases. 2012; 29th ed. Elk Grove Village, IL: American Academy of Pediatrics. 
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Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the SMN2 
gene. Am J Hum Genet. 2009;85:408-413. 
Riessland M, Ackermann B, Forster A, et al. SAHA ameliorates the SMA phenotype in 
two mouse models for spinal muscular atrophy. Hum Mol Genet. 2010;19(8):1492-1506. 
Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for 
spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 
2012;20(1):27-32. 
Swoboda KJ, Scott CB, Crawford TO, et al. SMA CARNI-VAL trial part I: double-blind, 
randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. 
PLoS ONE. 2010;5(8):e12140. doi:10.1371/journal.pone.0012140. 
Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to age, 
SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-712. 
WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on 
length/height, weight and age. Acta Paediatr Suppl. 2006;450:76-85. 
WHO Multicentre Growth Reference Study Group. WHO Motor Development Study: Windows 
of Achievement for Six Gross Motor Development Milestones. Acta Paediatr Suppl. 
2006;450:86-95. 
Wijnhoven TMA, de Onis M, Oyango AW, et al for the WHO Multicentre Growth Reference 
Study Group. Assessment of gross motor development in the WHO multicenter growth reference 
trial. Food Nutr Bull. 2004;25(1 Suppl 1):S37-45. 
Zoorob RJ, Cender D.  A different look at corticosteroids. Am Fam Physician. 1998;58:443-50. 
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22. 
APPENDICES 
APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Trial Period 
Screen-
ing 
Gene Replacement 
Therapy (In-patient) 
Follow-up (Outpatient) 
Notes 
Nominal Study Day  
(Visit Relative To Dose) –30 to –2 
-1 
1 
2 
3 
7 
14 21 30 
44 
60 (or 
Month 2) 72 
90 (or 
Month 3 
Month 
4,5,7,8,10,11,13 
Month 
6,9,12 
End of Trial 
(18 months 
of age or 
ET) 
Depending on the patient’s age at dosing, 
the duration of participation can vary from 
approximately 12 months (baby dosed at 
approximately 6 months of age) to 
approximately 18 months (baby dosed near 
birth, “0 months of age”). 
Visit According To 
Months of Age 
 
 
 
 
 
 
 
 
 
 
 
 
 
14,16,17 
15 
Window 
(No Window) 
± 2 days 
± 7 days 
(Except +0–14 days at 14 Months of Age) 
+0–14 days  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 18.3  
AVXS-101 Infusion 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 10.6. Day 1 assessments will 
be performed prior to the start of gene 
replacement therapy infusion. 
BSIDv03/WHO 
Developmental 
Milestones (with video) 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
See Sections 11.1, 11.2.1, 11.2.2, and 11.3. 
BSIDv03 Gross and Fine 
Motor Subtests (with 
video) 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
See Sections 11.1, 11.2.1, 11.2.2 and 11.3. 
CHOP INTEND (with 
video) 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
See Sections 11.2.3 and 11.3. Patients who 
achieve 3 consecutive CHOP-INTEND 
scores ≥ 58 will not continue CHOP-
INTEND assessments. 
Demographic/Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 12.1.1. 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
See Section 12.1.2 
Vital Signs/Weight & 
Length 
X 
X 
(X) 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
See Section 12.1.3. 
(X): Vital signs will be continuously 
monitored throughout the infusion of gene 
replacement therapy and recorded every 15 
minutes (+/- 5 minutes)  post dose for the 
first 4 hours after the start of infusion, then 
every hour (+/- 15 minutes) until 24 hours 
after the start of infusion.  Axillary 
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Trial Period 
Screen-
ing 
Gene Replacement 
Therapy (In-patient) 
Follow-up (Outpatient) 
Notes 
Nominal Study Day  
(Visit Relative To Dose) –30 to –2 
-1 
1 
2 
3 
7 
14 21 30 
44 
60 (or 
Month 2) 72 
90 (or 
Month 3 
Month 
4,5,7,8,10,11,13 
Month 
6,9,12 
End of Trial 
(18 months 
of age or 
ET) 
Depending on the patient’s age at dosing, 
the duration of participation can vary from 
approximately 12 months (baby dosed at 
approximately 6 months of age) to 
approximately 18 months (baby dosed near 
birth, “0 months of age”). 
Visit According To 
Months of Age 
 
 
 
 
 
 
 
 
 
 
 
 
 
14,16,17 
15 
Window 
(No Window) 
± 2 days 
± 7 days 
(Except +0–14 days at 14 Months of Age) 
+0–14 days  
temperature will be recorded pre- and post-
infusion. 
12-Lead ECG 
X 
 
 
X 
 
 
 
 
X 
 
 
 
(X) 
(X) 
(X) 
X 
See Sections 12.1.4, 12.1.5, and 12.1.6. 
(X): Completed every 3 months, starting at 
Month 3 until 12 months post-dose. 
Echocardiogram 
X 
 
 
 
 
 
 
 
X 
 
 
 
(X) 
(X) 
(X) 
X 
24-hour Holter Monitor 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
(X) 
(X) 
(X) 
X 
Pulmonary Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
See Section 12.1.7. 
Swallowing Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
See Section 12.1.8.  
(X): Completed every 6 months, starting at 
Month 6 through the End of Trial at 
18 months of age. 
Photograph of Infusion 
Site 
 
 
(X) 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
See Section 12.1.9. 
(X): Day 1 infusion site photograph will be 
performed prior to the start of gene 
replacement therapy infusion. 
Hematology/Chemistry 
/Urinalysis 
X 
X 
 
X 
 
X 
X 
X 
X (X)* 
X 
(X)* 
X 
X 
X 
X 
See Sections 12.1.10.1, 12.1.10.2 and 
12.1.10.3. 
 (X)*: Liver function test (AST, ALT, total 
bilirubin, direct bilirubin, alkaline 
phosphatase, GGT) only. 
Troponin I 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
See Section 12.1.10.2. 
Virus Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 12.1.10.4. 
Capillary Blood Gas 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 12.1.10.5. 
Immunological Testing: 
ELISA (anti-
AAV9/SMN Ab) 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
See Section 12.1.10.6. 
AAV9 Ab Screen in 
Biological Mother 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 12.1.10.7. 
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Trial Period 
Screen-
ing 
Gene Replacement 
Therapy (In-patient) 
Follow-up (Outpatient) 
Notes 
Nominal Study Day  
(Visit Relative To Dose) –30 to –2 
-1 
1 
2 
3 
7 
14 21 30 
44 
60 (or 
Month 2) 72 
90 (or 
Month 3 
Month 
4,5,7,8,10,11,13 
Month 
6,9,12 
End of Trial 
(18 months 
of age or 
ET) 
Depending on the patient’s age at dosing, 
the duration of participation can vary from 
approximately 12 months (baby dosed at 
approximately 6 months of age) to 
approximately 18 months (baby dosed near 
birth, “0 months of age”). 
Visit According To 
Months of Age 
 
 
 
 
 
 
 
 
 
 
 
 
 
14,16,17 
15 
Window 
(No Window) 
± 2 days 
± 7 days 
(Except +0–14 days at 14 Months of Age) 
+0–14 days  
Blood for Diagnostic 
Confirmation Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 12.1.10.8. 
Saliva, Urine, and Stool 
Samples (for viral 
shedding) 
X 
 
 
(X) (X) X 
X 
X 
X 
 
 
 
 
 
 
 
See Section 12.1.10.9. 
(X): Collected within 24 and 48 hours post 
dose. 
Prophylactic 
Prednisolone 
 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
(X) 
 
 
 
 
 
See Section 9.2.1.   
(X): After 30 days, prednisolone (or 
equivalent glucocorticoid) can be tapered 
for patients whose GGT, ALT, and AST 
values are below the threshold. 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 13. 
 
Prior and Concomitant 
Medications 
Collected from 2 weeks before gene replacement therapy until End of Trial visit 
 
Ab = antibody; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BSIDv03 = Bayley Scales of Infant and Toddler Development version 3; 
CBC = complete blood count; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; ECG = electrocardiogram; ELISA = 
enzyme-linked immunosorbent assay; ET = early termination; GGT = gamma glutamyl transferase; IRB = Institutional Review Board; LFT = liver function tests; WHO 
= World Health Organization 
 
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APPENDIX 2. 
POST-MORTEM TISSUE AND ORGAN COLLECTION 
PLAN 
Post-mortem tissue/organ collection and autopsy, where possible, will be requested for any 
patient who receives gene replacement therapy.  The autopsy and tissue collection will be 
performed by the clinical site local pathologist or a contracted vendor who may deploy a 
pathology assistant to the funeral home, hospital, or other applicable location to perform the 
tissue and organ collection.  Standard autopsy incisions will be used to perform the procedures. 
During the procedure, multiple tissues along with the entire spinal cord will be collected for 
research purposes, including up to 7 sections or pieces from each organ and each region of the 
spinal cord.  Upon collection, these tissue samples will be provided to Novartis Gene Therapies 
for analysis. 
Tissue analysis will be done to determine whether the vector transduced the expected motor 
neurons and if the SMN gene was expressed.  These results will demonstrate whether the vector 
delivered the therapeutic gene as expected.  Tissue samples collected will also be available for 
histology and immunohistochemistry, allowing the state of the motor neurons and muscles to be 
examined. 
Specifically, tissue samples from the spinal cord, muscles, and organs will be collected as 
indicated in Table 5.  Tissue samples will be frozen or fixed (e.g., 2% paraformaldehyde) for 
appropriate analysis. 
Families may be asked to consent to authorize tissue collection prior to any sign of moribund or 
death by the clinical team conducting the trial.  Declining the post-mortem tissue and organ 
collection will not prevent patients from participating in the trial. 
Table 5 - Tissue Sample for Analysis 
Brain 
Spinal Cord 
Muscles 
Organs 
Motor cortex 
Cervical spinal cord 
Diaphragm 
Spleen 
Layer 5 motor cortex 
Thoracic spinal cord 
#6/#7 Rib with intercostal muscle and nerve 
Kidney 
Brain stem 
Lumbar spinal cord 
Psoas muscle 
Small intestine 
 
Sacral spinal cord 
 
Large intestine 
 
Dorsal root 
 
Pancreas 
 
Cervical level 
 
Stomach 
 
Ventral root 
 
Lung 
 
Cervical level 
 
Heart 
 
DRG root 
 
Liver 
 
Cervical level 
 
Inguinal lymph node 
 
Cerebrospinal fluid 
 
Gonads 
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APPENDIX 3. 
BAYLEY SCALES OF INFANT AND TODDLER 
DEVELOPMENT (VERSION 3) 
 
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APPENDIX 4. 
PERFORMANCE CRITERIA FOR BAYLEY SCALES 
INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) DEVELOPMENTAL MILESTONES 
Developmental Milestone 
Performance Criteria 
Head Control – Gross Motor Subtest Item #4 
Rolls from Back to Sides – Gross Motor Subtest Item #20 
Sits Without Support – Gross Motor Subtest Item #26 
Stands With Assistance - Gross Motor Subtest Item #33 
Crawls – Gross Motor Subtest Item #34 
Pulls to Stand – Gross Motor Subtest Item #35 
Walks With Assistance – Gross Motor Subtest Item #37 
Stands Alone – Gross Motor Subtest Item #40 
Walks Alone – Gross Motor Subtest Item #42 
Source: Bayley, N. (2006). Bayley Scales of Infant and Toddler Development. Third ed. San Antonio, TX: Harcourt 
Assessment; 2007. 
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APPENDIX 5. 
PERFORMANCE CRITERIA FOR WORLD HEALTH 
ORGANIZATION (WHO) DEVELOPMENTAL 
MILESTONES 
Gross Motor Milestone 
Performance Criteria 
Sitting without support 
Hands-and-knees crawling 
Standing with assistance 
Walking with assistance 
Standing alone 
Walking alone 
WHO = World Health Organization 
Source: WHO Multicentre Growth Reference Study Group. WHO Motor Development Study: windows of achievement for six 
gross motor development milestones. Acta Paediatr Suppl. 2006;450:86-95 and Wijnhoven TMA, de Onis M, Onyango AW, et 
al. Assessment of gross motor development in the WHO Multicentre Growth Reference Study. Food Nutr Bull. 2004;25(1 
Suppl):S37-45 
 
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APPENDIX 6. 
CHOP INTEND 
 
 
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APPENDIX 7. 
DECLARATION OF HELSINKI: ETHICAL 
PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the:  
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd WMA 
General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 64th WMA General Assembly, 
Fortaleza, Brazil, October 2013 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving Human subjects, including research on identifiable 
human material and data. 
2. The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
3. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians.  The 
WMA encourages others who are involved in medical research involving Human subjects to adopt 
these principles. 
General Principles 
1. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
2. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research.  The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
3. Medical progress is based on research that ultimately must include studies involving Human subjects. 
4. The primary purpose of medical research involving Human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments).  Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
5. Medical research is subject to ethical standards that promote and ensure respect for all Human 
subjects and protect their health and rights. 
6. While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research patients. 
7. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
patients.  The responsibility for the protection of research patients must always rest with the physician 
or other health care professionals and never with the research patients, even though they have given 
consent. 
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8. Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
Human subjects in their own countries as well as applicable international norms and standards.  No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research patients set forth in this Declaration. 
9. Medical research should be conducted in a manner that minimizes possible harm to the environment. 
10. Medical research involving Human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications.  Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
11. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
12. Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research trial will not adversely 
affect the health of the patients who serve as research patients. 
13. Appropriate compensation and treatment for patients who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits 
1. In medical practice and in medical research, most interventions involve risks and burdens.  Medical 
research involving Human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research patients. 
2. All medical research involving Human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimize the risks must be implemented.  The risks must be continuously monitored, 
assessed and documented by the researcher. 
3. Physicians may not be involved in a research trial involving Human subjects unless they are confident 
that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
trial. 
Vulnerable Groups and Individuals 
1. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
2. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group.  In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
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Scientific Requirements and Research Protocols 
1. Medical research involving Human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation.  The welfare of animals used for 
research must be respected. 
2. The design and performance of each research trial involving Human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed.  The protocol should include information 
regarding funding, Sponsors, institutional affiliations, potential conflicts of interest, incentives for 
patients and information regarding provisions for treating and/or compensating patients who are 
harmed as a consequence of participation in the research trial. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
1. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the trial begins.  This committee must be transparent in 
its functioning, must be independent of the researcher, the Sponsor and any other undue influence and 
must be duly qualified.  It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
patients set forth in this Declaration. 
The committee must have the right to monitor ongoing studies.  The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events.  
No amendment to the protocol may be made without consideration and approval by the committee.  
After the end of the trial, the researchers must submit a final report to the committee containing a 
summary of the trial’s findings and conclusions. 
Privacy and Confidentiality 
1. Every precaution must be taken to protect the privacy of research patients and the confidentiality of 
their personal information. 
Informed Consent 
1. Participation by individuals capable of giving informed consent as patients in medical research must 
be voluntary.  Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research trial unless he or she 
freely agrees. 
2. In medical research involving Human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
trial and the discomfort it may entail, post-trial provisions and any other relevant aspects of the trial.  
The potential subject must be informed of the right to refuse to participate in the trial or to withdraw 
consent to participate at any time without reprisal.  Special attention should be given to the specific 
information needs of individual potential patients as well as to the methods used to deliver the 
information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing.  If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed. 
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All medical research patients should be given the option of being informed about the general outcome 
and results of the trial. 
3. When seeking informed consent for participation in a research trial the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent 
under duress.  In such situations the informed consent must be sought by an appropriately qualified 
individual who is completely independent of this relationship. 
4. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorized representative.  These individuals must not be included 
in a research trial that has no likelihood of benefit for them unless it is intended to promote the health 
of the group represented by the potential subject, the research cannot instead be performed with 
persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
5. When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative.  The potential subject’s dissent should be 
respected. 
6. Research involving patients who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research group.  In such circumstances the 
physician must seek informed consent from the legally authorized representative.  If no such 
representative is available and if the research cannot be delayed, the trial may proceed without 
informed consent provided that the specific reasons for involving patients with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the trial 
has been approved by a research ethics committee.  Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorized representative. 
7. The physician must fully inform the patient which aspects of their care are related to the research.  
The refusal of a patient to participate in a trial or the patient’s decision to withdraw from the trial 
must never adversely affect the patient-physician relationship. 
8. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse.  There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research.  In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
Use of Placebo 
1. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or where 
for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention and the patients who receive any intervention less effective than 
the best proven one, placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  Extreme care must be 
taken to avoid abuse of this option. 
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Post-Trial Provisions 
1. In advance of a clinical trial, Sponsors, researchers and host country governments should make 
provisions for post-trial access for all patients who still need an intervention identified as beneficial in 
the trial.  This information must also be disclosed to patients during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
1. Every research trial involving Human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
2. Researchers, authors, Sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research.  Researchers have a duty to make publicly 
available the results of their research on Human subjects and are accountable for the completeness 
and accuracy of their reports.  All parties should adhere to accepted guidelines for ethical reporting.  
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available.  Sources of funding, institutional affiliations and conflicts of interest must be declared in 
the publication.  Reports of research not in accordance with the principles of this Declaration should 
not be accepted for publication. 
Unproven Interventions in Clinical Practice 
1. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering.  
This intervention should subsequently be made the object of research, designed to evaluate its safety 
and efficacy.  In all cases, new information must be recorded and, where appropriate, made publicly 
available. 
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APPENDIX 8. 
SUMMARY OF CHANGES 
The section below describes the changes incorporated into this version of the protocol.   
 
 
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AVXS-101 
AVXS-101-CL-306 
 
Protocol Title: 
Phase 3, Open-Label, Single-Arm, Single-Dose Gene 
Replacement Therapy Clinical Trial for Patients with Spinal 
Muscular Atrophy Type 1 with One or Two SMN2 Copies 
Delivering AVXS-101 by Intravenous Infusion 
Summary of Changes: 
Protocol Version 6.0, Amendment 5, 11 Nov 2020 
SUMMARY AND JUSTIFICATION OF CHANGES 
This protocol amendment was required in order to: 
− Update to reflect current non-clinical, clinical, and risk information 
− adjust trial sample size 
− update statistical methods to align with the changes  
− address COVID-19 related impact on trial conduct 
− apply consistent definitions of the primary endpoint and exploratory endpoints 
− clarify the collection and central review of videos of efficacy parameters 
− update the schedule of assessments to align protocol changes for consistency 
− address specific requests from Competent Authorities regarding Safety Reporting 
timelines and Hy’s Law Criteria 
− make administrative changes 
− make minor changes and edits for error correction, clarification, and overall 
consistency. 
The following changes were made to the Protocol from Version 5.0 Amendment 4 dated 
26 Nov 2019 to Version 6.0 Amendment 5 dated 11 Nov 2020. 
 
 
 
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SUMMARY OF CHANGES: 
The section below describes the changes incorporated into this version of the protocol.   
Protocol Version 6.0 Incorporating Amendment 5 includes the following changes 
Description of Change 
Location(s) 
Rationale for Change 
Replaced AveXis with Novartis Gene Therapies 
Overall 
To update per company name change 
Replaced 
 with 
, 
 with 
. 
 
 with 
, and 
 
r with 
 
Signature page 
To update per company administrative 
changes 
Updated to reflect current nonclinical, clinical, 
and risk information 
Section 5: Introduction 
To include new information 
Modified language associated with enrollment as 
at least 6 patients was originally planned to be 
enrolled, the enrollment was closed with 2 
patients actually enrolled. 
Section 2: Synopsis 
Section 7.2: Number of 
Patients 
Section 14.3: Sample 
Size Calculation 
Enrollment is discontinued due to the 
changes in the scope of study and related 
data analysis. Combining analysis with 
Study AVXS-101-CL-302 data will no 
longer be performed. 
Text for exploratory objectives/endpoints was 
revised t
 
 
Synopsis: Exploratory 
Objectives 
Sections 6.3: Exploratory 
Objectives 
Section 14.1.3: 
Exploratory Endpoints 
To align with Appendix 4 
Updated text to include that safety monitoring 
for AESIs and all visits will be scheduled based 
on a 30-day month calendar 
Synopsis: Methodology, 
Statistical Methods 
Section 7.1: Overall Trial 
Design 
Figure 4 footnotes 
To align with Section 13.3 for consistency 
and for clarification  
Text added to allow changes in study conduct 
during the COVID-19 pandemic (or other similar 
catastrophic event): 
- 
change to the conduct of study visits  
- 
when a patient may be considered 
withdrawn due these factors, versus 
withdrawn consent 
- 
change to the manner in which efficacy and 
safety assessments are performed  
- 
change to the manner in which monitoring 
visits are performed 
- 
the process of obtaining remote informed 
consent  
Section 7.1: Overall Trial 
Design 
Section 8.3: Patient 
Withdrawal Criteria 
Section 11: Assessment 
of Efficacy 
Section 12: Assessment 
of Safety 
Section 16.1: Trial 
Monitoring 
Section 18.3: Written 
Informed Consent 
To address the impact of the COVID-19 
pandemic (or other similar catastrophic 
event) on: 
- 
a site’s ability to conduct on-site study 
visits and efficacy and safety 
assessments per protocol 
- 
a subject’s willingness or ability to 
continue participating in the study 
- 
a monitor’s ability to perform on-site 
monitoring visits 
- 
a site’s ability to follow the usual 
process of obtaining written informed 
consent 
Text was added to state that all developmental 
milestones should be assessed, documented and 
video recorded regardless of previous attainment 
Section 11.1: 
Developmental 
Milestones 
For clarification 
Text added to state that additional information 
on contractures will also be collected, as 
described in the Physical Assessments Manual 
Section 11.2.3: CHOP 
INTEND 
Collection of contractures data was included 
in the scoring sheet provided in Appendix 6 
of previous protocol versions, but is not 
included in the new scoring sheet provided 
by CHOP. The Physical Assessment Manual 
contains a supplemental CHOP-INTEND 
contractures data collection sheet for use by 
investigator sites, to ensure consistency in 
the data collected throughout the study 
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Description of Change 
Location(s) 
Rationale for Change 
Text added to include examples of electrolytes to 
be collected in the protocol 
Section 12.1.10.2: Blood 
Chemistry 
To provide clarity 
“30 days after last visit” was removed from SAE 
Reporting; language SAE Reporting was 
reverted back to protocol version 4.0/amendment 
3 
Section 13.1.2 Serious 
Adverse Event 
“30 days after last visit” is unnecessary for a 
single dose treatment of gene therapy. SAEs 
will be collected through the end of study 
visit. 
“Within 24 hour” was removed for AESI 
Reporting and the AESIs Reporting requirements 
was reverted back to language in protocol 
version 4.0 
Section 13.1.3 Adverse 
Events of Special Interest 
AESI reporting within 24 hour is not feasible 
as AESIs are coded after Investigator 
reporting of AEs and SAEs. Investigators are 
made aware of AESIs categories for 
increased surveillance of reporting. 
Revised statistical analysis methods to align with 
the adjustment of study: 
- 
Efficacy Analysis Population removed. 
- 
Removed text for sample size calculation 
Section 14: Statistics 
Section 14.2: 
Section 14.3: Sample 
Size Calculation 
- 
Study CL-306 will no longer be 
considered a secondary efficacy 
population with the European 
counterpart, AVXS-101-CL-302.  
- 
Data for Study CL-306 study will be 
presented as data listings descriptively. 
Sample size calculation based on 
hypothesis combined with Study CL-
302 study is no longer applicable for 
Study CL-306. 
Section 14.5.1 Hy’s Law Criteria and definition 
inserted, with a link in Section 5.5 
Section 14.5: Safety 
Analysis 
At the request of the Belgium FAMPH 
Video Manual changed to Physical Assessments 
Manual 
Throughout 
The Physical Assessments Manual is the new 
reference document for Clinical Evaluators 
Schedule of Assessments was updated with 
minor editing and to specify the schedule of 
BSIDv03 Gross and Fine Motor Subtests (with 
video), to include the cross-link sections 
Appendix 1: Schedule of 
Assessments 
To align with protocol changes and for 
clarification 
Addition of copyright information at the bottom 
of each page of the Bayley record 
Appendix 3: Bayley 
Scales of Infant and 
Toddler Development 
(Version 3) 
Per copyright requirements 
Scoring sheet has been replaced with an updated 
version 
Appendix 6: 
CHOP INTEND 
A new scoring sheet was provided by CHOP  
 
PRO-749 Version6.0 Generated 13 Nov 2020 08:59 AM CST | Effective Date: 13 Nov 2020 08:54 AM CST