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: SMA
Sponsor: Novartis Gene Therapies

Protocol Number:  AVXS-101-CL-302 
 
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:  NCT03461289 
 
Document Date:  25-Jun-2020 

 
 
SIGNATURE PAGE
TITLE CL-302 Clinical Protocol ID: PRO-747
User
Role
Job Title
Version
Decision
Date Signed
Final Approvers
Senior Director, U.S. Regulatory
Affairs
7.0
Approve
03 Jul 2020 06:41 PM
CEST
Final Approvers
Executive Medical Director
7.0
Approve
03 Jul 2020 08:03 PM
CEST
Final Approvers
Associate Director, Therapeutic
Lead
7.0
Approve
03 Jul 2020 05:27 PM
CEST
Final Approvers
Sr Dir. Clinical Development
(EMEA)
7.0
Approve
03 Jul 2020 06:36 PM
CEST
Final Approvers
Vice President
7.0
Approve
03 Jul 2020 06:50 PM
CEST
Final Approvers
Senior Director, Biostatistics
7.0
Approve
03 Jul 2020 06:48 PM
CEST
 
 
This is a copy generated on 22 Sep 2020 08:42 PM CEST.   Please refer to ACE for
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AVXS-101 
AVXS-101-CL-302 
 
IND Number: 
15699 
EudraCT Numbers: 
2017-000266-29 
 
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: 
AveXis, Inc. 
2275 Half Day Road, Suite 200 
Bannockburn, IL 60015 
Protocol Version/Date: 
7.0/Amendment 6/25 Jun 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 
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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. 
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Investigational Product: AVXS-101 
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1. 
ADMINISTRATIVE INFORMATION 
1.1. 
Approval 
Representatives from AveXis: 
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, 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): 
 
 
  
Vice President, Clinical Development & Analytics 
AveXis, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
 
 
 
Senior Director, Clinical Development 
AveXis, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
 
 
  
Senior Director, Regulatory Affairs 
AveXis, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
 
 
 
Associate Director, Therapeutic Lead 
AveXis, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
 
 
 
Senior Director, Biostatistics 
AveXis, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
 
 
 
Vice President & Head, Global Patient Safety 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
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1.2. 
Investigator’s Agreement 
I have received and read the Investigator’s Brochure for AVXS-101.  I have read the 
AVXS-101-CL-302 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 laws and regulations, including, without limitation, data privacy laws 
and regulations including but not limited to Clinical Trials Directive 2001/20/EC and 
Regulation (European Union) No 536/2014 of the European Parliament and of the 
Council of 16 April 2014 on clinical trials of medicinal products for human use 
• 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 
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AVXS-101-CL-302 
Investigational Product: AVXS-101 
Protocol Version 7.0/Amendment 6/25 Jun 2020 
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________________________________________________ 
Date (ddMmmyyyy) 
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Protocol Version 7.0/Amendment 6/25 Jun 2020 
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1.3. 
Key Contact Information 
Role in Study 
Contact Information 
Responsible Physician 
 Senior Director, Clinical Development 
  
Serious Adverse Event 
Reporting 
E-mail:
 
Fax: 
 
 
Additional study contact information is provided in the Study Contact List. 
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2. 
SYNOPSIS 
Name of Sponsor/Company:  AveXis, 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:  12−16 European Investigative Sites 
located in the following countries: Belgium, France, Germany, Italy, Netherlands, Spain, United 
Kingdom, Sweden 
Investigators:  Multicenter Trial - Investigator Information on File at AveXis 
Studied Period (years): 
Estimated date first patient enrolled: Q2 2018  
Estimated date last patient completed: Q3 2020 
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 WHO Motor Developmental 
Milestone. 
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 
• 
Determine efficacy by demonstrating achievement of developmental milestone of 
ability to hold head erect without support as defined by Bayley Scales of Infant and 
Toddler Development© Version 3 (BSIDv03) Gross Motor Subtest Item #4. 
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AVXS-101-CL-302 
Investigational Product: AVXS-101 
Protocol Version 7.0/Amendment 6/25 Jun 2020 
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• 
Determine efficacy by demonstrating achievement of developmental milestone of 
ability to roll over as defined by BSIDv03 Gross Motor Subtest Item #20. 
• 
Determine the efficacy by demonstrating achievement of developmental milestone of 
functional independent sitting for at least 30 seconds as defined by BSIDv03 Gross Motor 
Subtest Item #26.  
• 
Determine efficacy by demonstrating achievement of developmental milestone of ability to 
stand with assistance for at least 2 seconds as defined by BSIDv03 Gross Motor Subtest Item 
#33.  
• 
Determine efficacy by demonstrating achievement of developmental milestone of ability to 
crawl forwards on hands and knees for a distance of at least 5 feet as defined by BSIDv03 Gross 
Motor Subtest Item #34.  
• 
Determine efficacy by demonstrating achievement of developmental milestone of ability to 
pull to standing as defined by BSIDv03 Gross Motor Subtest Item #35. 
• 
Determine efficacy by demonstrating achievement of developmental milestone of ability to walk 
with assistance as defined by BSIDv03 Gross Motor Subtest Item #37.  
• 
Determine efficacy by demonstrating achievement of developmental milestone of ability to 
stand alone for at least 3 seconds as defined by BSIDv03 Gross Motor Subtest Item #40.  
• 
Determine efficacy by demonstrating achievement of developmental milestone of ability to walk 
at least 3 steps without support as defined by BSIDv03 Gross Motor Subtest Item #42.  
• 
Determine efficacy by demonstrating achievement of developmental milestone of ability to 
crawl as defined by WHO Motor Developmental Milestones. 
• 
Determine efficacy by demonstrating achievement of developmental milestone of 
ability to stand with assistance as defined by WHO Motor Developmental Milestones. 
• 
Determine efficacy by demonstrating achievement of developmental milestone of 
ability to stand alone as defined by WHO Motor Developmental Milestones. 
• Determine efficacy by demonstrating achievement of developmental milestone of 
ability to walk with assistance as defined by WHO Motor Developmental Milestones. 
• 
Determine efficacy by demonstrating achievement of developmental milestone of 
ability to walk alone as defined by WHO Motor Developmental Milestones. 
• 
Determine efficacy by demonstrating improvement of motor function as determined by 
improvement in the fine and gross motor domain components of the Bayley Scales of Infant 
and Toddler Development© (Version 3). 
• 
Determine efficacy by demonstrating improvement of gross motor function as determined 
by improvement in Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders (CHOP INTEND) score. 
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Investigational Product: AVXS-101 
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• 
Determine the effect of AVXS-101 on the ability to remain independent of ventilator 
support, defined as requiring no daily ventilator support/usage at 18 months of age. 
• 
Determine effect on the ability to thrive defined as achieving all of the following: 
• 
Does not receive nutrition through mechanical support (i.e., feeding tube) 
• 
Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
• 
Maintains weight (> third percentile for age and gender). 
Safety 
• 
Evaluate the safety of AVXS-101 in patients with SMA Type 1. 
 
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 1 or 2 copies of 
survival motor neuron 2 gene (SMN2).  Thirty patients < 6 months (< 180 days) of age at the time of 
gene replacement therapy (Day 1) are planned to 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 1-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 study 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. 
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 [39]) 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 gamma glutamyl transferase 
(GGT), alanine aminotransferase (ALT) values, and aspartate aminotransferase (AST) values are below 
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Investigational Product: AVXS-101 
Protocol Version 7.0/Amendment 6/25 Jun 2020 
Confidential | Proprietary 
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the threshold of 2 × Upper Limit 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 AST or 
ALT values are > 2 × ULN, the dose of prednisolone will be maintained until the AST and ALT values 
decrease below threshold.  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 World Health Organization [WHO] Child Growth Standards at 
any point up to and including the 18 months of age trial visit, and survival at 14 months of age. 
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 and will also convene within approximately 48 hours should any patient experience an 
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.  This includes any patient death, important clinical laboratory finding, or any complication 
attributed to administration of gene replacement therapy.  In such instances, the DSMB/DMC will 
review the safety information and provide its recommendation.  Based upon the DSMB/DMC’s review, 
the DSMB/DMC can recommend continuing enrollment, halting enrollment, or early termination of the 
trial for safety reasons. 
Number of Patients (planned): Thirty patients are planned to enroll. Babies who are in screening and 
meet eligibility criteria for the study when the enrollment target is met may be enrolled upon 
approval of the sponsor.  
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 1 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 that include palivizumab prophylaxis (also known as 
Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended. 
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: 
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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 < 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 World Health Organization (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 or C 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 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, 
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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 (gamma-glutamyl transpeptidase [GGT], 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin > 2 × the 
upper limit of normal (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. 
Investigational Product, Dosage and Mode of Administration: 
Patients will receive a 1-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 1-time IV infusion over 60 minutes, dependent upon volume. 
Reference Therapy, Dosage and Mode of Administration: Not Applicable 
Endpoint: 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 
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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 World Health Organization Multicentre Growth 
Reference Trial (WHO MGRS), confirmed by video recording, as a patient who sits up straight 
with head erect for at least 10 seconds; child does not use arms or hands to balance body or 
support position. 
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 
• 
Proportion of patients that achieve the ability to hold head erect without support as defined by 
BSIDv03 Gross Motor Subtest Item #4. 
• 
Proportion of patients that achieve the ability to roll over as defined by BSIDv03 Gross Motor 
Subtest Item #20. 
• 
Proportion of patients that achieve functional independent sitting for at least 30 seconds as 
defined by BSIDv03 Gross Motor Subtest Item #26. 
• Proportion of patients that achieve the ability to stand with assistance for at least 2 seconds 
as defined by BSIDv03 Gross Motor Subtest Item #33. 
• Proportion of patients that achieve the ability to crawl forwards on hands and knees for a 
distance of at least 5 feet as defined by BSIDv03 Gross Motor Subtest Item #34.  
• Proportion of patients that achieve the ability to pull to standing as defined by BSIDv03 
Gross Motor Subtest Item #35. 
• Proportion of patients that achieve the ability to walk with assistance as defined by 
BSIDv03 Gross Motor Subtest Item #37. 
• Proportion of patients that achieve the ability to stand alone for at least 3 seconds as 
defined by BSIDv03 Gross Motor Subtest Item #40. 
• Proportion of patients that achieve the ability to walk at least 3 steps without support as 
defined by BSIDv03 Gross Motor Subtest Item #42.  
• 
Proportion of patients that achieve the ability to crawl as defined by WHO Motor 
Developmental Milestones. 
• 
Proportion of patients that achieve the ability to stand with assistance as defined by WHO 
Motor Developmental Milestones. 
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• 
Proportion of patients that achieve the ability to stand alone as defined by WHO 
Motor Developmental Milestones. 
• 
Proportion of patients that achieve the ability to walk with assistance as defined by WHO 
Motor Developmental Milestones. 
• 
Proportion of patients that achieve the ability to walk alone as defined by WHO 
Motor Developmental Milestones. 
• 
Improvement of raw score from baseline to the maximum using Bayley Scales of Infant and 
Toddler Development (Version 3), Fine and Gross Motor Function Subtests. 
• 
Maximum change from baseline of CHOP INTEND score. 
• 
Proportion of patients achieving CHOP INTEND score ≥ 40. 
• 
Proportion of patients achieving CHOP INTEND score ≥ 50. 
• 
Proportion of patients achieving CHOP INTEND score ≥ 58. 
• 
Proportion of patients with the ability to remain independent of ventilator support, 
defined as requiring no daily ventilator support/usage at 18 months of age. 
• 
Proportion of patients maintaining the ability to swallow and to maintain weight 
(> 3rd percentile based on WHO Child Growth Standards for age and gender) without need of 
gastrostomy or other mechanical or non-oral nutritional support. 
• 
Age at which (WHO MGRS) sitting without support (10 seconds) is first achieved. 
 
Endpoint 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 pivotal Phase 3 trial assessing the efficacy and safety of AVXS-101.  Details of all analysis 
will be contained within the Statistical Analysis Plan. 
The primary and secondary efficacy analyses will be performed amongst symptomatic patients with 
biallelic SMN1 deletions and 2 copies of SMN2 without the genetic modifier (c.859G>C).  While the 
study will enroll a small number of additional patients, the above will comprise the population for 
evaluation of the primary and secondary endpoints and will be referred to as the ITT population 
hereafter. 
Based upon widely cited natural history of the disease (Pediatric Neuromuscular Clinical 
Research Network [PNCR]), it is expected that no patients in this population would be expected 
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to attain the ability to sit without support or attain other developmental milestones (rolling over, 
standing, walking) assessed as part of the trial. 
Assuming that the true response rate for the primary endpoint is actually zero (or as low as 0.1%) in 
the population of interest of the historical control, the primary efficacy endpoint hypothesis is 
whether AVXS-101 treated patients achieve a response rate greater than 0.1%. 
Based upon preliminary results from the completed Phase 1 clinical trial AVXS-101-CL-101, at least 
50% of treated patients in the defined ITT population are expected to achieve the primary efficacy 
endpoint of sitting without support for at least 10 seconds at any post-procedure visit up to and 
including 18 months of age.  With this assumption for the true response rate of AVXS-101 being in 
the range of 20%−50%, a sample size of 25 patients would provide power of greater than 95% to 
detect a significant difference from 0.1% with α = 0.025 using a 1-sided exact test for a binomial 
proportion. 
The secondary efficacy endpoint of survival at 14 months of age will be comparing the results 
observed in the ITT population with the results from the age and gender-matched control patients 
selected from existing natural history data sets (PNCR).  It is anticipated that 75% of patients in the 
PNCR population would not survive beyond 13.6 months of age, and that these control patients will 
represent a 25% survival rate based upon the natural history of the disease.  Preliminary results from 
the completed Phase I clinical study, AVXS-101-CL-101, suggest that at least 80% of patients in the ITT 
population are expected to survive, as defined, through 14 months of age.  These assumptions 
suggest that a sample size of at least 25 patients would provide at least 95% power to detect a 
significant difference from the historical control with α = 0.05 using a 2-sided Fisher’s Exact test. 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
ADMINISTRATIVE INFORMATION .......................................................................3 
1.1. 
Approval .......................................................................................................................3 
1.2. 
Investigator’s Agreement ..............................................................................................4 
1.3. 
Key Contact Information ..............................................................................................6 
2. 
SYNOPSIS ...................................................................................................................7 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................21 
5. 
INTRODUCTION ......................................................................................................24 
5.1. 
Background .................................................................................................................24 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients ................................................25 
5.3. 
Nonclinical Studies .....................................................................................................27 
5.4. 
Clinical Studies ...........................................................................................................31 
5.5. 
Risks ...........................................................................................................................32 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................36 
6.1. 
Primary Objective .......................................................................................................36 
6.2. 
Secondary Objective ...................................................................................................36 
6.3. 
Exploratory Objectives ...............................................................................................36 
6.4. 
Safety Objective ..........................................................................................................37 
7. 
INVESTIGATIONAL PLAN .....................................................................................38 
7.1. 
Overall Trial Design ...................................................................................................38 
7.2. 
Number of Patients .....................................................................................................40 
7.3. 
Criteria for Trial Termination .....................................................................................40 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................41 
8.1. 
Patient Inclusion Criteria ............................................................................................41 
8.2. 
Patient Exclusion Criteria ...........................................................................................41 
8.3. 
Patient Withdrawal Criteria ........................................................................................43 
9. 
TREATMENT OF PATIENTS ..................................................................................44 
9.1. 
Description of Trial Product .......................................................................................44 
9.2. 
Prior and Concomitant Medications ...........................................................................44 
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9.2.1. 
Prophylactic Administration of Prednisolone .............................................................44 
9.2.2. 
Prohibited Medications ...............................................................................................45 
9.2.3. 
Vaccinations ...............................................................................................................45 
9.3. 
Treatment Compliance ................................................................................................46 
9.4. 
Randomization and Blinding ......................................................................................46 
10. 
TRIAL PRODUCT MATERIALS AND MANAGEMENT ......................................47 
10.1. 
Trial Product ...............................................................................................................47 
10.2. 
Trial Product Dose and Dose Justification ..................................................................47 
10.3. 
Trial Product Packaging and Labeling ........................................................................47 
10.4. 
Trial Product Storage and Destruction ........................................................................47 
10.5. 
Trial Product Preparation ............................................................................................48 
10.6. 
Trial Product Administration ......................................................................................48 
10.7. 
Dose Adjustment Criteria ...........................................................................................48 
10.8. 
Trial Product Accountability .......................................................................................48 
10.9. 
Trial Product Handling and Disposal ..........................................................................48 
11. 
ASSESSMENT OF EFFICACY .................................................................................50 
11.1. 
Developmental Milestones..........................................................................................50 
11.2. 
Motor Function Tests ..................................................................................................51 
11.2.1. 
World Health Organization Multicentre Growth Reference Milestones ....................51 
11.2.2. 
Bayley Scales for Infant and Toddler Development/Developmental 
Milestones ...................................................................................................................51 
11.2.3. 
CHOP INTEND ..........................................................................................................52 
11.3. 
Video Evidence ...........................................................................................................52 
12. 
ASSESSMENT OF SAFETY .....................................................................................54 
12.1. 
Safety Parameters .......................................................................................................54 
12.1.1. 
Demographic/Medical History ...................................................................................54 
12.1.2. 
Physical Examinations ................................................................................................54 
12.1.3. 
Vital Signs/Weight and Length ...................................................................................55 
12.1.4. 
Electrocardiogram .......................................................................................................55 
12.1.5. 
Echocardiogram ..........................................................................................................55 
12.1.6. 
Continuous ECG Recordings ......................................................................................56 
12.1.7. 
Pulmonary Examinations ............................................................................................56 
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12.1.8. 
Swallowing Test .........................................................................................................56 
12.1.9. 
Photographs of Infusion Site .......................................................................................56 
12.1.10. 
Laboratory Assessments .............................................................................................57 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................62 
13.1. 
Definition of Adverse Events ......................................................................................62 
13.1.1. 
Adverse Event .............................................................................................................62 
13.1.2. 
Serious Adverse Event ................................................................................................62 
13.1.3. 
Adverse Events of Special Interest .............................................................................63 
13.2. 
Relationship to Trial Drug ..........................................................................................63 
13.3. 
Recording Adverse Events ..........................................................................................63 
13.4. 
Reporting Adverse Events ..........................................................................................64 
13.5. 
Expedited Safety Reporting to Regulatory Authorities ..............................................64 
14. 
STATISTICS ..............................................................................................................65 
14.1. 
Data Analysis ..............................................................................................................65 
14.1.1. 
Trial Endpoints and Populations .................................................................................65 
14.2. 
Sample Size Calculation .............................................................................................68 
14.3. 
Efficacy Analysis ........................................................................................................70 
14.3.1. 
General Considerations ...............................................................................................70 
14.3.2. 
Primary and Secondary Efficacy Analysis .................................................................70 
14.4. 
Safety Analysis ...........................................................................................................71 
14.4.1. 
Hy’s Law Criteria .......................................................................................................71 
15. 
DATA SAFETY MONITORING BOARD/DATA MONITORING 
COMMITTEE .............................................................................................................72 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................73 
16.1. 
Trial Monitoring .........................................................................................................73 
16.2. 
Audits and Inspections ................................................................................................73 
16.3. 
Institutional Biosafety Committee ..............................................................................74 
16.4. 
Institutional Review Board/Independent Ethics Committee .......................................74 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE ..........................................75 
18. 
ETHICS ......................................................................................................................76 
18.1. 
Ethics Review .............................................................................................................76 
18.2. 
Ethical Conduct of the Trial ........................................................................................76 
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18.3. 
Written Informed Consent ..........................................................................................76 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................78 
19.1. 
Electronic Case Report Forms ....................................................................................78 
19.2. 
Inspection of Records .................................................................................................78 
19.3. 
Retention of Records ..................................................................................................78 
20. 
PUBLICATION POLICY ..........................................................................................79 
21. 
LIST OF REFERENCES ............................................................................................80 
22. 
APPENDICES ............................................................................................................84 
APPENDIX 1. SCHEDULE OF ASSESSMENTS .....................................................................84 
APPENDIX 2. POST-MORTEM TISSUE AND ORGAN COLLECTION PLAN ...................88 
APPENDIX 3. BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) .............................................................................................................90 
APPENDIX 4. PERFORMANCE CRITERIA FOR BAYLEY SCALES INFANT 
AND TODDLER DEVELOPMENT (VERSION 3) DEVELOPMENTAL 
MILESTONES .........................................................................................................115 
APPENDIX 5. PERFORMANCE CRITERIA FOR WORLD HEALTH 
ORGANIZATION (WHO) DEVELOPMENTAL MILESTONES .........................116 
APPENDIX 6. CHOP INTEND ................................................................................................117 
APPENDIX 7. DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS ...............................120 
APPENDIX 8. SUMMARY OF CHANGES ...........................................................................126 
 
LIST OF TABLES 
Table 1: 
Spinal Muscular Atrophy Classification .....................................................................25 
Table 2: 
Investigational Product ...............................................................................................44 
Table 3: 
Total Blood Volume ...................................................................................................57 
Table 4: 
Common Terminology Criteria for Adverse Events ..................................................62 
Table 5: 
Tissue Sample for Analysis ........................................................................................88 
 
LIST OF FIGURES 
Figure 1: 
Kaplan-Meier Survival Curves and Survival Probabilities for SMA  Types 1, 
2, and 3 ........................................................................................................................26 
Figure 2: 
Trial Results, Including Staining of Transduced Spinal Motor Neurons, SMN 
Expression Levels, Righting Ability, and Weight and Survival Curves .....................28 
Figure 3: 
Body Mass of Treated and Control Mice Showed No Difference ..............................29 
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Figure 4: 
Trial Design ................................................................................................................39 
 
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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 event of special interest 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
ASO 
Antisense oligonucleotide 
AST 
Aspartate aminotransferase 
BSIDv03 
Bayley Scales of Infant and Toddler Development, version 3 
BUN 
Blood urea nitrogen 
CB 
Chicken-β-actin-hybrid 
cGMP 
Current Good Manufacturing Practice 
CHOP INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders 
CK 
Creatine kinase 
CK-MB 
Creatinine kinase-muscle/brain 
CMV 
Cytomegalovirus 
CTCAE 
Common Terminology Criteria for Adverse Events 
ddPCR 
Droplet digital polymerase chain reaction 
DMC 
Data Monitoring Committee 
DRG 
Dorsal root ganglia 
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 
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Abbreviation or Specialist Term 
Explanation 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunospot 
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 
HIV 
Human immunodeficiency virus 
ICD-10 code 
International Statistical Classification of Diseases and Related Health 
Problems 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITR 
Inverted terminal repeat 
ITT 
Intent-to-treat 
IV 
Intravenous 
LFE 
Liver function enzymes 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGRS 
Multicenter Growth Reference Study 
NHP 
Non-human primates 
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Abbreviation or Specialist Term 
Explanation 
NOAEL 
No observable adverse effect level 
PBMC 
Peripheral blood mononuclear cells 
PICU 
Pediatric intensive care unit 
PNCR 
Pediatric Neuromuscular Clinical Research Network 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
Sc 
Self-complementary 
scAAV 
Self-complementary adeno-associated virus 
scAAV9.CB.SMN 
Self-complementary adeno-associated virus serotype 9 chicken-β-actin- 
hybrid survival motor neuron 
SMA 
Spinal muscular atrophy 
SMN 
Survival motor neuron 
SMN1 
Survival motor neuron 1 gene 
SMN2 
Survival motor neuron 2 gene 
SoA 
Schedule of Assessments 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin 
ULN 
Upper limits 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-302 is a pivotal Phase 3 clinical gene therapy trial investigating the efficacy 
and safety of a single intravenous (IV) infusion of AVXS-101 in 30 patients with Type 1 spinal 
muscular atrophy (SMA) with 1 or 2 copies of survival motor neuron 2 gene (SMN2).  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 1 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 [1].  
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 
[2,3,4].  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 [5,6]; however, clinical studies 
employing several of these agents, most notably phenylbutyrate, valproic acid, and hydroxyurea, 
have not resulted in clinical benefit [7,8].  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.  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 
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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 up to 30 Type 1 patients with 1 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 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 [9]. 
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 2011[10] 
SMN2 = survival motor neuron 2 gene 
bold = predominant SMN2 copy number that defines the SMA Type, the other copy numbers represent a small percentage of 
the designated SMA Type. 
 
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 [11].  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 [11,12,13].  Although 
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SMN2 cannot completely compensate for the loss of the SMN1 gene, patients with milder forms 
of SMA generally have higher SMN2 copy numbers [14,15].  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 [16], 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.  As these percentages do not reflect the possible impact of modifier 
mutations such as that described by Prior et al 2009 [17], 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 1 SMN2 copy lived < 11 months, 88/94 with 2 SMN2 copies 
lived < 21 months, and 8/10 with 3 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. 
Figure 1: Kaplan-Meier Survival Curves and Survival Probabilities for SMA  
Types 1, 2, and 3 
 
n = number of patients Source: Farrar 2013 [18] 
 
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 [2,3,4]. 
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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.  Overexpression of SMN protein has 
been shown to be well tolerated in both mice and non-human primates, and 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 chicken β-
actin-hybrid (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 AAV vectors. 
Recent studies using self-complementary 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 1-
time delivery of vector [19].  Intravenous scAAV9 is able to transduce neurons, muscle and 
vascular endothelium, all of which have been proposed as target cells for SMA treatment. 
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 [20].  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 [19].  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.  SMN 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 
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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. 
Figure 2: Trial Results, Including Staining of Transduced Spinal Motor Neurons, SMN 
Expression Levels, Righting Ability, and Weight and Survival Curves 
 
Source: Foust 2010 [19] 
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 
Toxicology biodistribution studies were generated by the 
 [data on file].  In 
these non-Good Laboratory Practice (non-GLP) studies, 24 mice and 4 non-human primates 
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(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 vector genome per kilogram (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 [19].  
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 amino transferase [ALT], 
aspartate amino transferase [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 1 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 6 months until they were sacrificed 
at approximately 9 months of age.  No adverse effects were seen, and all clinical chemistries 
were normal.  T-cell immune response was tested using enzyme-linked immunospot (ELISpot) 
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in peripheral blood mononuclear cells (PBMCs), and all were negative at 6 months post-
injection. 
In these non-GLP studies, the 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 [19]. 
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 timepoints 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 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 an AAV9 
vectors in monkeys and minipigs (20, 21). 
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 effect 
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% reported by Finkel et 
al 2014 [23].  
• Based on independent video reviews, developmental milestones 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 Type 2 SMA children reported in the 
Pediatric Neuromuscular Clinical Research Network (PNCR) study [23].  
• Other clinically meaningful 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 
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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 
Investigator’s Brochure [25]. 
Patients could experience an allergic response to AVXS-101.  Patients could also develop an 
immune response to the AAV9 viral vector, which could prevent future use of gene transfers 
using this vector. 
Some mice affected with a form of SMA Type 1 that were treated with the study vector 
developed localized vascular necrosis around the ear called necrotic pinna.  This is believed to be 
unrelated to the vector, and likely related to an underlying defect that has been observed to occur 
in several SMA mouse models [26].  The relevance to humans with SMA is unknown. 
Respiratory tract infections in neonates are very common in the general pediatric population 
[27].  In one study, an estimated 338 million new episodes of respiratory syncytial virus (RSV) -
associated acute lower respiratory infections occurred worldwide in children younger than 5 
years, with at least 34 million episodes necessitating hospital admission [28].  RSV is the 
primary cause of hospitalization for respiratory tract infection in young children [29].  It would 
not be unexpected that infants enrolled in the AVXS-101 gene replacement therapy trials might 
have similar incidences of respiratory infections due to these pathogens. 
Patients must be clinically stable before AVXS-101 dosing.  Clinical signs or symptoms of 
infection should not be evident at the time of AVXS-101 administration.  Vaccinations, 
including palivizumab prophylaxis that can prevent RSV infections [30], are also recommended 
[31] and should be up to date.  Added caution is advised regarding the timing of AVXS-101 
administration in the presence of prodrome or resolving viral illness. In the event of a severe 
viral respiratory infection, the Investigator should be aware of the possibility of adrenal 
insufficiency in the presence of systemic immune response which may require longer 
glucocorticosteroid support at increasing doses to effectively manage the patient and prevent 
serious complications.   
Some mice affected with SMA Type 1 that were treated with AVXS-101 experienced liver 
findings comprised of hepatocellular hypertrophy, Kupffer cell activation, and scattered 
hepatocellular necrosis. 
Adverse events (AEs) of increased transaminases (ALT increased, AST increased, and 
transaminase increased) were reported as related to AVXS-101 in clinical studies. The 
underlying cause of the transaminase elevations is not known; though, may be related to an 
immune response to AAV9, as indicated by the response to prednisolone. Though these AEs can 
be serious, in most cases they were clinically asymptomatic, did not meet criteria for Hy's law 
(Section 14.4.1), did not exhibit clinically relevant increases in bilirubin, and generally resolved 
with prednisolone treatment. A case of acute liver failure (suspected unexpected serious adverse 
reaction [SUSAR]) was reported in the US Managed Access Program with AVXS-101.  A 6-
month-old male concurrently receiving nusinersen with elevations of AST and ALT of > 3 x the 
upper limit of normal (ULN) before treatment with AVXS-101 developed acute liver failure 
approximately 51 days post AVXS-101 dosing. The patient recovered with additional steroid 
therapy. 
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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.  
The available clinical cardiovascular safety data have not provided evidence for a cardiovascular 
safety problem in humans. As of the last update to the IB, there have been no cardiovascular AEs 
that have been judged to be related to AVXS-101 in the clinical studies. There have been no 
persistent clinically significant electrocardiogram (ECG) changes. In Study AVXS-101-CL-303, 
a Phase 3 open-label single-dose study in patients with one or two copies of SMN2, elevated 
CK-MB was reported for one patient, but this TEAE was determined by the Investigator to be 
unrelated to AVXS-101 administration. There have been no AEs reported for troponin-I. In 
Study AVXS-101-CL-101, there were minor transient increases in troponin-I at the proposed 
therapeutic dose in Cohort 2 with no associated clinical sequelae. None of the elevations in 
cardiac troponin-I observed during the study were considered clinically significant by the 
investigator. Small mean troponin elevations were minimally apparent during the first two 
months post-dose. Other troponin elevations appeared to be sporadic. By the end of the study all 
values had either returned to within the normal range or no longer met the pre-defined criterion 
for potential clinical significance. The autopsy report from Study AVXS-101-CL-303 patient, 
whose death was unrelated to AVXS-101, indicates that the heart was macroscopically and 
microscopically normal, with sections of the heart having no pathologic diagnosis. While the 
clinical significance of the transiently elevated troponin-I levels is unknown, it is recommended 
that troponin-I be monitored for the first 3 months following dosing. 
A transient decrease in platelet counts has been observed in Studies AVXS-101-CL-101, 
AVXS-101-CL-303, and AVXS-101-CL-102 typically at Day 7. The majority of values 
remained above the lower limit of normal. Decreases were clinically asymptomatic and transient.  
Preclinical data indicate that in most cases, DNA delivered by recombinant AAV vectors 
predominantly persists as extrachromosomal elements (episomes) rather than integrating into 
host cell genomes [32].  Although AVXS-101 is also not anticipated to integrate into the host 
cell genome as described above, the long-term consequences of administering AAV viral vectors 
to humans are not yet fully understood.  This is in contrast to wild-type AAV, also 
non-pathogenic, which has the ability to stably integrate into the host cell genome at a specific 
site (designated AAVS1) in the human chromosome 19 [33, 34].  Since the AVXS-101 product 
uses AAV9 with all of the wild-type DNA removed from the capsids, except for the Inverted 
Terminal Repeats, the potential risk of incorporation of AVXS-101 into the patient chromosomal 
DNA is thought to be significantly reduced. 
There are conflicting reports that integration of the wild-type AAV2 genome is associated with 
induction of hepatocellular carcinoma in a small subset of patients; however, there are several 
studies with evidence to contradict these claims including: a) AAV2 has infected approximately 
90% of the human population, b) AAV2 has been shown to possess anticancer activity, c) 
epidemiological evidence suggests that AAV2 infection plays a protective role against cervical 
carcinoma, and d) AAV serotypes including recombinant AAV2 and AAV9 have been or are 
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currently used in 162 clinical trials to date in which no cancer of any type has been observed or 
reported.  For a review of the topic, see Srivastava and Carter, 2017 [35].  Further support for the 
extremely low potential incorporation into host chromosomal DNA comes from pre-clinical 
studies, which to date have not shown the development of cancer in treated animals including 
mice and non-human primates exposed to AVXS-101. 
It is possible the AAV9 vector containing the SMN gene could interact with other viruses with 
which the patients come in contact, such as rhinoviruses, adenovirus, or herpes.  If this happens, 
the AAV9 vector could form a virus that causes infection if the patient and cells for rescue, 
replication, and packaging are also exposed to wild-type AAV2.  The rescue, replication, and 
packaging would stop; however, as the helper viruses, such as rhinoviruses, adenovirus, or 
herpes were cleared by the patient’s immune system.  This unlikely scenario has been studied.  In 
cell culture, the rAAV genome can be rescued and replicated by superinfection with wtAAV and 
a helper virus; however, in vivo rescue experiments have failed to show rescue and replication 
[36], except in 1 case in which very large doses of wtAAV and adenovirus were administered in 
a particular setting [37].  Therefore, AAV9 interaction with other viruses to cause infection 
appears to be a minimal risk for AVXS-101. 
Studies have shown that some vector can be excreted from the body for up to a few weeks after 
injection/infusion; this is called “viral shedding”.  Vector shedding can be found in the blood, 
urine, saliva, and stool for up to a few weeks following injection.  The risks associated with the 
shed vector are not known at this time; however, because the vector is non-pathogenic and 
cannot replicate, it is believed that shed vector is unlikely to result in clinically significant 
adverse effects.  Regardless, instructions should be provided to patient families and caregivers 
regarding use of protective gloves if/when coming into direct contact with patient bodily fluids 
and/or waste, as well as good hand-hygiene for a minimum of 4 weeks after the injection.  
Additionally, patients are prohibited from donating blood for 2 years following the vector 
injection. 
Viral shedding is dependent on a variety of factors including the route of administration of the 
product, the tropism of the virus or bacteria, and the natural route of transmission and shedding 
of the parent virus or bacterium from which the product is derived.  AveXis collected saliva, 
urine, and stool samples at weekly timepoints through Day 30 and then monthly timepoints 
through Month 18 after gene transfer during the AVXS-101-CL-101 clinical study from 5 
patients for viral shedding analysis.  This analysis detects the number of genome copies by 
ddPCR in the applicable shed samples. 
AVXS-101 is detectable in the shed samples from Day 1 post injection.  Clearance of AVXS-101 
is primarily via the feces and the majority of the dose is cleared within 30 days of dose 
administration.  While initially concentrated in stool, the amount of vector shed declines 
logarithmically.  In stool, levels 10% to 30% of the initial concentration in the body were 
detectable at Day 1 post infusion.  At Day 14 post-infusion one patient showed a peak 
concentration in stool of 280% of initial concentration in body.  In contrast, 3 patients for whom 
data were available showed a concentration of <1% of initial concentration in body at Day 14 
post infusion.  These concentrations declined approximately 4 logs over 30 days post dose, and 
all patients had levels of AVXS-101 in stool below the ddPCR limit of quantitation by 60 days 
post dose.  Concentrations of vector shed in saliva and urine are quite low and are below the 
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ddPCR limits of quantitation in the matrices within days post-dose.  AVXS-101 concentrations 
representing 0.1% to 0.01% of the initial dose (concentration) into the patient are found in urine 
and saliva at Day 1 post infusion, after which concentrations fell below the limit of quantitation 
of the assay [data on file].  Shed AAV vectors have been previously shown not to be infectious 
in urine and saliva excreta [36].  Together, these data demonstrate rapid decline of shed vector 
quantities well below initial concentrations in patients treated with AVXS-101.   
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.  No 
steroids were administered in the animal study (Section 5.3). 
A thorough review of the safety data from patients treated with AVXS-101 based on a data cut-
off of 31 December 2019 did not identify any adverse events related to sensory changes.  
Nevertheless, study participants will be closely monitored for any clinical manifestations of a 
potential DRG involvement. 
Finally, there are potential risks associated with intravenous dosing.  There may be a pain at the 
site of the infusion as well as bruising surrounding the infusion site.  Infections are also possible 
at the site of the infusion. 
These results also strongly support further clinical investigation of the efficacy and safety of 
AVXS-101 in patients with presymptomatic SMA.  Because SMA is a progressive 
neurodegenerative disease which involves the irreversible neurodegeneration and death of motor 
neurons beginning before the onset of clinical symptoms, administration of gene replacement 
therapy as early as possible is believed to be of substantial importance for preventing motor 
neuron loss, maximizing the opportunity for patients to experience meaningful benefits from this 
treatment.  This hypothesis is supported by data from the AVXS-101-CL-101 clinical study, 
which has included observations of substantial benefits in survival, motor function, and 
developmental milestone achievements relative to natural history, which were particularly 
striking for several patients treated at younger ages.  Based on the current available data, safety 
events that appear to be associated with AVXS-101 consist of transient liver enzyme elevations 
which have resolved following treatment with prednisolone.  Considering this favorable 
developing safety profile together with the potential for highly meaningful clinical benefits of 
early treatment, the risk-benefit relationship strongly supports further clinical investigation of 
AVXS-101 in infants with presymptomatic SMA. 
Taken together, results from the clinical and nonclinical studies support further clinical 
investigation of the efficacy and safety of AVXS-101 in patients with SMA.  
 
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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 for at least 10 seconds up to 18 months of age as assessed by World 
Health Organization (WHO) Motor Developmental Milestones (Appendix 5) [38]. 
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 
For the following exploratory efficacy endpoints, a Responder will be defined as a patient who 
demonstrates achievement of the endpoint at any post-procedure visit up to and including the 
18-month trial visit: 
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to hold head erect without support as defined by BSIDv03 Gross Motor Subtest Item #4 
(Appendix 3 and Appendix 4) [39] 
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to roll over as defined by BSIDv03 Gross Motor Subtest Item #20 (Appendix 3 and 
Appendix 4) [39] 
• Determine the efficacy by demonstrating achievement of developmental milestone of 
functional independent sitting for at least 30 seconds as defined by BSIDv03 item #26, 
(Appendix 3 and Appendix 4) [39] 
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to stand with assistance for at least 2 seconds as defined by BSIDv03 Gross Motor 
Subtest Item #33 (Appendix 3 and Appendix 4) [39] 
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to crawl forwards on hands and knees for a distance of at least 5 feet as defined by 
BSIDv03 Gross Motor Subtest Item #34 (Appendix 3 and Appendix 4) [39]  
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to pull to standing as defined by BSIDv03 Gross Motor Subtest Item #35 (Appendix 3 
and Appendix 4) [39] 
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• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to walk with assistance as defined by BSIDv03 Gross Motor Subtest Item #37 
(Appendix 3 and Appendix 4)[39] 
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to stand alone for at least 3 seconds as defined by BSIDv03 Gross Motor Subtest Item 
#40 (Appendix 3 and Appendix 4)[39]  
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to walk at least 3 steps without support as defined by BSIDv03 Gross Motor Subtest Item 
#42 (Appendix 3 and Appendix 4)[39]  
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to crawl as defined by WHO Motor Developmental Milestones (Appendix 5) [38] 
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to stand with assistance as defined by WHO Motor Developmental Milestones 
(Appendix 5) [38] 
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to stand alone as defined by WHO Motor Developmental Milestones (Appendix 5) [38] 
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to walk with assistance as defined by WHO Motor Developmental Milestones 
(Appendix 5) [38] 
• Determine efficacy by demonstrating achievement of developmental milestone of ability 
to walk alone as defined by WHO Motor Developmental Milestones (Appendix 5) [38] 
• Determine efficacy by demonstrating improvement of motor function as determined by 
improvement in the fine and gross motor domain components of the BSIDv03 
(Appendix 3) [39] 
• Determine efficacy by demonstrating improvement of gross motor function as determined 
by improvement in CHOP INTEND score (Appendix 6) 
• Determine the effect of AVXS-101 on the ability to remain independent of ventilator 
support, defined as requiring no daily ventilator support/usage at 18 months of age. 
• Determine effect on the ability to thrive defined as achieving all of the following: 
− Does not receive nutrition through mechanical support (i.e., feeding tube) 
− Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
− Maintains weight (> third percentile for age and gender) 
6.4. 
Safety Objective 
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 1 or 2 copies of SMN2.  Thirty patients < 6 months 
(< 180 days) of age at the time of gene replacement therapy (Day 1) are planned to be enrolled. 
Babies who are in screening and meet eligibility criteria for the study when the enrollment target 
is met may be enrolled upon approval of the sponsor. 
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 1-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, dependent upon required total volume, 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). 
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 conducted under a separate protocol.  Patients who 
discontinue prematurely will also be invited to participate in the long-term follow-up study. 
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 conducting 
study assessments may be implemented.  Phone calls, virtual contacts (e.g. teleconsult) or visits by site 
staff/home nursing service to the participant´s home depending on local regulations and capabilities, 
can replace on-site study visits, for the duration of the pandemic until it is safe for the participant to visit 
the site again. The process for obtaining remote informed consent must be followed in order to conduct 
these alternative study visits (Section 18.3). 
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. 
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Importantly, in instances in which the final scheduled study visit is not possible to be conducted at the 
study site or the scheduling of the final scheduled study visit is at risk of delay due to travel restrictions 
or other circumstances, the final scheduled study visit should be performed all or in part remotely within 
the protocol-defined visit window.  Critical data that pertain to the co-primary and co-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.   
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 (“dose”) 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”). 
In an attempt to dampen the host immune response to the 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 if, in the opinion of the investigator, 
prednisolone is not tolerated [41]) 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 gamma glutamyl transferase 
(GGT), ALT values, and AST values are below the threshold of 2 × ULN in accordance with the 
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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.   
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 month of age trial visit and 
survival at 14 months of age (as defined in Section 14.1.1.1.1).  Safety will be assessed through 
monitoring AEs, concomitant medication usage, physical examinations, vital sign assessments, 
cardiac assessments, and laboratory evaluations (Section 12).   
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 
Thirty patients are planned to enroll.  Patients who are in screening and meet eligibility criteria 
for the study when the enrollment target is met may be enrolled upon approval of the sponsor. 
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. 
SELECTION 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 1 or 2 copies 
of the SMN2 will be enrolled in this trial.  Patients may be of any racial, ethnic, or gender 
background. 
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 1 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 that include palivizumab prophylaxis (also known 
as Synagis) to prevent RSV infections are also recommended. 
5. 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 < 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 [42] 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 or C, or known Zika virus infection) 
6. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization 
within 2 weeks prior to screening 
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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 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 hypocalcuria 
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, and AST, or total 
bilirubin > 2 × ULN, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white 
blood cell > 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 
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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 
8.3. 
Patient Withdrawal Criteria 
Patients may be discontinued from the trial for the following reasons: 
• Death 
− 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) 
• 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 AAV9 containing the SMN gene under the control 
of the cytomegalovirus (CMV) enhancer/ CB.  One of the 2 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, colorless to faint white solution. 
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 completed 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 [41]) 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 
follow 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 tests should be 
checked prior to prednisolone discontinuation.  If the GGT, AST, or ALT values are ≥2 × ULN, 
then the present dose of prednisolone will be adjusted as needed until the GGT, AST, and ALT 
values decrease below threshold, at which point the taper may continue.  Liver function tests 
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. 
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 
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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 [43].  
Vaccinations that include palivizumab (also known as Synagis®) prophylaxis to prevent 
respiratory syncytial virus infections are also recommended (31, 44).  
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 1-time dose of AVXS-101 at 1.1 × 1014 vg/kg, equivalent to the dose 
received by Cohort 2 in the Phase 1 study via IV infusion administered in the completed Phase 1 
clinical study (AVXS-101-CL-101). 
Two doses were studied in the completed 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 preliminary 
data 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 batch/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. 
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 1-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, dependent upon volume required, utilizing an infusion set and 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 1-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 AveXis.  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. 
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. 
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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 14.1.1.1.1).  Efficacy assessments will be 
performed at the times specified in the SoA (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 co-
primary and co-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 co-primary or co-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 World Health Organization Multicentre Growth Reference Study (WHO MGRS) 
(Appendix 5) [24] and the BSIDv03 and will be analyzed to assess efficacy (Appendix 3 and 
Appendix 4).  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 videotapes (Section 11.3).  
Developmental milestones will be determined at each visit as shown in the SoA (Appendix 1) 
and as described in Section 11.2. 
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At the 18 months of age visit all developmental milestones (Appendix 4 and Appendix 5) 
should be assessed, documented, and video recorded, regardless of previous attainment. 
11.2. 
Motor Function Tests 
11.2.1. 
World Health Organization Multicentre Growth Reference Milestones 
The World Health Organization Multicentre Growth Reference Trial Group milestones defined 
for this study include 6 gross motor milestones (Appendix 5): 
• Sitting without support for 10 seconds, does not use arms or hands 
• Crawling on hands and knees, at least 3 consecutive movements 
• Standing with assistance at least 10 seconds 
• Walking with assistance at least 5 steps 
• Standing alone at least 10 seconds 
• Walking alone at least 5 steps 
These 6 gross 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 
5 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-302 
Physical Assessments Manual and may be submitted for review by a central reader 
(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.  The Bayley Scales will be administered by a qualified clinical evaluator 
in accordance with the Physical Assessments Manual.  The items from 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 
developmental milestone achievement in accordance with Appendix 3; this assessment must 
address all developmental 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 developmental milestone of functional independent sitting is defined by BSID GM#26, 
sitting for at least 30 seconds without external support from another person or object, however 
the child is allowed to use their upper extremities. This developmental milestone should be 
assessed, documented, and video recorded at every subsequent visit until attainment, 
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regardless of starting point on the scale.  It must be assessed at the 18 months of age visit 
regardless of previous attainment.  
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-302 Physical Assessments Manual, and videos containing developmental 
milestone evidence will be submitted for review by an independent central reviewer 
(Section 11.3). 
11.2.3. 
CHOP INTEND 
The CHOP INTEND is a motor function scale developed and validated for use specifically to 
monitor motor function status and decline amongst children with SMA Type 1, and will be 
administered by a qualified clinical evaluator [45, 46].  The CHOP INTEND scale (Appendix 6) 
examines several aspects of motor function, including head control, righting reactions, and trunk 
movements in supported sitting, supine, and prone positions.  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 3 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-302 
Physical Assessments Manual (Section 11.3). 
11.3. 
Video Evidence 
Clinic assessments (WHO Motor 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.  
AveXis, Inc. (AveXis) 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 AveXis requirements.  Any/all videos received at AveXis or 
the contracted vendor will be treated as confidential trial data and will be the sole property of 
AveXis.  AveXis 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. 
All videos of Developmental Milestones which meet WHO and BSID criteria will be provided to 
an independent, central reviewer for unbiased assessment of developmental milestone 
achievement.  The independent central reviewer will document whether the video displays 
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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. 
At the 18 month of age visit, the WHO Motor Developmental Milestone for sitting without 
support for at least 10 seconds (Appendix 5) and BSID GM #26 – Sits without support for 30 
seconds (Appendix 4) (functional independent sitting) will be submitted for central review, even 
if previously confirmed.  
New developmental milestones attained for the first time at 18 months of age will also be 
submitted for central review.  
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, every month or more frequently if needed) 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 monitors, 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 is 14 months of age, after which 
all visits will be 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 ventilator support, if any 
• Historical feeding support, if any. 
Patients are encouraged to follow all routinely scheduled immunizations, as recommended by the 
Local European Guideline throughout the trial.  Vaccinations that include palivizumab 
prophylaxis (also known as Synagis) to prevent RSV infections are also recommended. 
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: 
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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 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).   
For patients who were previously following the 6-monthly ECG schedule, a 12-lead ECG is to be 
performed at the study visit during which consent for additional ECGs is first obtained (ICF 
corresponding to protocol version 3.0 or later) and then in accordance with the SoA. 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 also 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).   
For patients who were previously following the 6-monthly echocardiogram schedule, an echocardiogram 
is to be performed at the study visit during which consent for additional echocardiograms is first 
obtained (ICF corresponding to protocol version 3.0 or later) and then in accordance with the SoA 
(Appendix 1).   
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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. 
12.1.6. 
Continuous ECG Recordings 
Twenty-four (24)-hour Holter monitoring will take place as specified in the SoA (Appendix 1).  
For patients not already undergoing Holter monitoring from 3 months of age, 24-hour Holter 
monitoring will be performed when consent for additional recording is first obtained (ICF 
corresponding to protocol version 3.0 or later version). 
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.  AveXis 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 ventilator support at the discretion of the pulmonologist 
(or appropriate individual as per standard institutional practice) and/or Investigator.  Non-
invasive ventilator support equipment will be provided by AveXis, Inc. through a third-party 
vendor if not covered by the patient’s insurance.  
Should the patient require non-invasive ventilator support at any time during the trial, the usage 
should be recorded in eCRF.   Patients requiring non-invasive ventilator support will be asked to 
bring the machine to each trial visit.  
12.1.8. 
Swallowing Test 
A standard bedside, non-barium (unless required per institutional policy), swallowing test will be 
performed as specified in the SoA (Appendix 1) to determine if the patient has signs of 
aspiration.  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.  AveXis 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 AveXis requirements.  
Any/all photographs received at AveXis or the contracted vendor will be treated as confidential 
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trial data and will be the sole property of AveXis.  AveXis 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. 
12.1.10. 
Laboratory Assessments 
Blood samples will be collected at each scheduled visit as specified in the SoA (Appendix 1) and 
in according with laboratory manuals provided for this study.  On Day -1, required blood 
samples will be collected locally prior to the start of gene replacement therapy infusion; 
duplicate samples will not be collected for shipment to the central laboratory.  Any clinically 
significant laboratory value will be repeated at the discretion of the Investigator. 
In most instances, blood samples will be collected and shipped to a central laboratory; however, 
at the discretion of the Investigator, samples may be processed locally for emergent safety 
monitoring or other logistical or technical reasons that warrant samples to be processed locally.  
Samples for laboratory tests required during the in-patient AVXS-101 infusion period prior to 
dosing will be collected and processed by the investigative site’s local laboratory to ensure 
receipt of results prior to dosing. 
Table 3: 
Total Blood Volume 
Visit 
Testsa 
Total Volume (mL)b 
Screening 
Hematology, chemistry/CK-MB or Troponin I, virus serology,  
ELISA immunology sample (AAV9/SMN Ab only), diagnostic 
genetic re-confirmation sample 
15.4 
Day 1 
Hematology, chemistry, capillary blood gas 
3.3 
Day 2 
Hematology, chemistry, capillary blood gas 
3.3 
Day 7 
Hematology, chemistry/CK-MB or Troponin I, immunology 
sample (ELISA) 
9.6 
Day 14 
Hematology, chemistry, immunology sample (ELISA only) 
3.3 
Day 21 
Hematology, chemistry, immunology sample (ELISA only) 
3.3 
Day 30 
Hematology, chemistry/CK-MB or Troponin I, immunology 
sample (ELISA) 
9.6 
Day 44 
Chemistry 
1.3a 
Day 60 
Hematology, Chemistry/CK-MB or Troponin I 
3.6 
Day 72 
Chemistry 
1.3 
Month 3/4/5/7/8/ 
10/11/13/14/16/1
7 
Hematology, chemistry 
26.6 
Month 6/9/12/15 
Hematology, chemistry/CK-MB or Troponin I 
14.4 
End of Trial/ET 
Hematology, chemistry/CK-MB or Troponin I 
3.6 
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Visit 
Testsa 
Total Volume (mL)b 
Maximum Total Volume for Trialc 
98.6 
CK-MB = creatinine kinase-muscle/brain; ET = early termination 
a Patients screened and dosed before IRB/EC approval of Protocol version 3.0 incorporating Amendment 2 will be 
tested for CK-MB throughout the study. Patients screened before IRB/EC approval of Protocol version 3.0 
incorporating Amendment 2 but dosed afterwards will be tested for CK-MB at screening but for Troponin 1 at 
baseline and thereafter. Patients screened after IRB/EC approval of Protocol version 3.0 incorporating 
Amendment 2 will be tested for Troponin 1 from screening onwards.  
b Troponin I requires 0.3 mL less blood than CK-MB, thus total blood volumes will be less for participants receiving 
troponin I testing. 
c 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. 
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 → creatinine kinase-muscle/brain (CK-MB) or 
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. 
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 shipped in accordance with the laboratory manual 
provided by the central laboratory.  Blood samples for hematology analysis will be collected as 
specified in the SoA (Appendix 1). 
Immediate/same-day hematology analyses required during in-patient dosing, as determined by 
Investigator, will be performed as per investigational site standard procedures at the local 
laboratory.  Investigators will receive hematology results from all trial visits from the central 
laboratory. 
12.1.10.2. Blood Chemistry 
Samples will be collected and shipped in accordance with the laboratory manual provided by the 
central laboratory.  Blood samples for chemistry analysis will be collected as specified in the 
SoA (Appendix 1). 
Immediate/same-day chemistry analyses required during in-patient dosing, as determined by 
Investigator, will be performed as per investigational site standard procedures at the local 
laboratory. 
Chemistry analysis will include the following at all trial visits: 
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• Serum GGT 
• AST/ALT 
• Serum total bilirubin 
• Direct bilirubin 
• Albumin 
• Glucose 
• Creatinine kinase 
• Creatinine 
• BUN 
• Electrolytes 
• Alkaline phosphatase 
CK-MB or Troponin I will be collected as specified in the SoA (Appendix 1) as applicable:   
• Patients screened and dosed before IRB/EC approval of Protocol version 3.0 
incorporating Amendment 2 will be tested for CK-MB throughout the study.  
• Patients screened before IRB/EC approval of Protocol version 3.0 incorporating 
Amendment 2 but dosed afterwards will be tested for CK-MB at screening but for 
Troponin 1 at baseline and thereafter.  
• Patients screened after IRB/EC approval of Protocol version 3.0 incorporating 
Amendment 2 will be tested for Troponin 1 from screening onwards. 
Investigators will receive chemistry results from all trial visits from the central laboratory. 
12.1.10.3. Urinalysis 
Urine samples will be collected in accordance with the laboratory manual provided by the central 
laboratory as specified in the SoA (Appendix 1).  Day -1 urinalysis will be processed locally in 
accord with local procedures.  Urinalysis will include the following parameters: 
• Color 
• Clarity/turbidity 
• pH 
• Specific gravity 
• Glucose 
• Ketones 
• Nitrites 
• Leukocyte esterase 
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• Bilirubin 
• 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 or C, 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 (Appendix 1) and 
shipped in accordance with the laboratory manual provided by the central laboratory. 
12.1.10.5. Capillary Blood Gas 
Capillary blood gas will be completed locally at Day –1 and Day 2 (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 Biological 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 biological mother of the patient to 
screen the biological mother for circulating antibodies to AAV9.  Once informed consent has 
been obtained, the biological mother will have her blood drawn from a peripheral vein at 
screening and shipped to the central laboratory for screening of anti-AAV9 antibodies.  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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If AAV9 antibodies are identified, the Investigator should discuss with the biological mother 
whether to continue or to stop breast feeding.  Patients consuming banked breast milk from 
donor sources that cannot be test 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 4 weeks 
after gene replacement therapy.  Additionally, patients are prohibited from donating blood for 2 
years following the vector infusion. 
Saliva, urine, and stool samples will be collected 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 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) [40] 
a 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 
A serious adverse event (SAE) is an AE occurring during any trial Phase (i.e., baseline, 
treatment, washout, or follow-up), and at any dose of the investigational product, or comparator 
that fulfils ≥ 1 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 not related) that occur after signing of the informed consent through 
30 days after the last trial visit will be collected and recorded on forms provided by AveXis 
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 
All AESIs (related and not related) that occur after signing of the informed consent through 
30 days after the last study visit, irrespective of grade, should be collected and recorded on forms 
provided by AveXis within 24 hours of the site becoming aware. 
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 not related) after signing of the 
informed consent form through the last study visit are to be collected.  Serious adverse event 
information will be collected after signing of the informed consent form through 30 days after 
the last study 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]), 
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intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused 
the patient to discontinue the trial. 
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 Adverse Events 
All SAEs (related and unrelated) will be recorded from signing of consent form through 30 days 
after 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 AveXis 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 AveXis 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 
AveXis 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. 
AveXis is responsible for notifying the relevant regulatory authorities of certain events.  It is the 
Principal Investigator’s responsibility to notify the IRB/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/IEC of these additional SAEs. 
13.5. 
Expedited Safety Reporting to Regulatory Authorities 
All suspected, unexpected serious adverse reactions (SUSARs) will be reported to regulatory 
authorities within the 15–day expedited timeline.  Fatal/life-threatening SUSARS will be 
reported immediately to French authorities and within the 7–day timeline to Eudravigilance 
according to EU regulation. 
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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, and the methods to be used 
to test the primary effectiveness hypothesis.  Additional details regarding methods for the final 
data analysis will be provided in a separate Statistical Analysis Plan (SAP).  The SAP will detail 
all analyses and data displays and will be executed according to Standard Operating Procedures 
in a controlled environment. 
14.1. 
Data Analysis 
14.1.1. 
Trial Endpoints and Populations 
14.1.1.1. Trial Endpoints 
The primary efficacy endpoint will be compared to the null.  The secondary efficacy variable 
will be evaluated relative to literature-based historical controls (such as the PNCR) [24].  This 
variable was selected on the basis of comparability to the target population and similarity to the 
investigational device. 
14.1.1.1.1. 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; child does not use arms or hands to balance body or 
support position. 
14.1.1.1.2. 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 ventilator 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 
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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 ventilator 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. 
• For a patient who develops an acute reversible illness and/or requires perioperative 
ventilator 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 ventilator support of ≥ 16 hours/day for 14 or 
more days). 
14.1.1.1.3. Exploratory Endpoints 
For the following exploratory efficacy endpoints, a Responder will be defined as a patient who 
demonstrates achievement of the endpoint at any post-procedure visit up to and including the 
18-month trial visit. 
1. Proportion of patients that achieve the ability to hold head erect without support as 
defined by BSIDv03 Gross Motor Subtest Item #4 (Appendix 3 and Appendix 4) [39]. 
2. Proportion of patients that achieve the ability to roll over as defined by BSIDv03 Gross 
Motor Subtest Item #20 (Appendix 3 and Appendix 4) [39]. 
3. Proportion of patients that achieve functional independent sitting for at least 30 seconds 
as defined by BSIDv03 Gross Motor Subtest Item  #26, (Appendix 3 and Appendix 4) 
[39]. 
4. Proportion of patients that achieve the ability to stand with assistance for at least 2 
seconds as defined by BSIDv03 Gross Motor Subtest Item #33 (Appendix 3 and 
Appendix 4) [39]. 
5. Proportion of patients that achieve the ability to crawl forwards on hands and knees for a 
distance of at least 5 feet as defined by BSIDv03 Gross Motor Subtest Item #34 
(Appendix 3 and Appendix 4) [39]. 
6. Proportion of patients that achieve the ability to pull to standing as defined by BSIDv03 
Gross Motor Subtest Item #35 (Appendix 3 and Appendix 4) [39]. 
7. Proportion of patients that achieve the ability to walk with assistance as defined by 
BSIDv03 Gross Motor Subtest Item #37 (Appendix 3 and Appendix 4) [39].  
8. Proportion of patients that achieve the ability to stand alone for at least 3 seconds as 
defined by BSIDv03 Gross Motor Subtest Item #40 (Appendix 3 and Appendix 4) [39].  
9. Proportion of patients that achieve the ability to walk at least 3 steps without support as 
defined by BSIDv03 Gross Motor Subtest Item #42 (Appendix 3 and Appendix 4) [39].  
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10. Proportion of patients that achieve the ability to crawl as defined by WHO Motor 
Developmental Milestones (Appendix 5) [38]. 
11. Proportion of patients that achieve the ability to stand with assistance as defined by WHO 
Motor Developmental Milestones (Appendix 5) [38]. 
12. Proportion of patients that achieve the ability to stand alone as defined by WHO Motor 
Developmental Milestones (Appendix 5) [38]. 
13. Proportion of patients that achieve the ability to walk with assistance as defined by WHO 
Motor Developmental Milestones (Appendix 5) [38]. 
14. Proportion of patients that achieve the ability to walk alone as defined by WHO Motor 
Developmental Milestones (Appendix 5) [38]. 
15. Improvement of raw score from baseline to the maximum using BSIDv03, Fine and 
Gross Motor Function Subtests (Appendix 3). 
16. Maximum change from baseline in CHOP INTEND score (Appendix 6). 
a. Proportion of patients achieving CHOP INTEND score ≥ 40 (Appendix 6). 
b. Proportion of patients achieving CHOP INTEND score ≥ 50 (Appendix 6). 
c. Proportion of patients achieving CHOP INTEND score ≥ 58 (Appendix 6). 
17. Proportion of patients with the ability to remain independent of ventilator support, 
defined as requiring no daily ventilator support/usage at 18 months of age. 
18. Proportion of patients maintaining the ability to swallow and to maintain weight (> third 
percentile based on WHO Child Growth Standards for age and gender [42]) without need 
of gastrostomy or other mechanical or non-oral nutritional support 
19. Age at which patient first achieves WHO MGRS sitting without support (10 seconds) 
(Appendix 5) 
14.1.1.1.4. Safety Endpoints 
Assessment of the safety and tolerability of AVXS-101 treatment, including evaluation of AEs, 
laboratory data, vital signs, and concomitant medications. 
14.1.1.2. Statistical Analysis Populations 
14.1.1.2.1. Intent-to-Treat Population 
The 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.  All primary and secondary efficacy analyses will be conducted on the ITT population. 
14.1.1.2.2. Ability to Thrive ITT Population 
The ability to thrive 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 
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infusion of AVXS-101 and have at least one post-baseline efficacy evaluation.  This population 
will be utilized to calculate the proportion of patients with the ability to thrive. 
14.1.1.3. Efficacy Completers Population 
The efficacy completers analysis population will consist of: 
• All treated patients who reach 14 months of age, OR 
• All treated patients who meet discontinuation criteria, discontinue the trial due to an AE 
or death 
14.1.1.4. All Enrolled Population 
The all enrolled population will consist all patients who receive an IV infusion of AVXS-101.  
Analyses of endpoints in this population are considered descriptive. 
14.1.1.5. Safety Population 
The safety analysis population will consist of all patients who receive an IV infusion of 
AVXS-101.  All safety analyses will be conducted on the safety analysis population. 
14.2. 
Sample Size Calculation 
The current trial will enroll 30 patients. (Babies who are in screening and meet eligibility criteria 
for the study at the time the enrollment target is met may be enrolled upon approval of the 
sponsor.)   At least 25 symptomatic patients, ITT population, will have biallelic deletion 
mutations of SMN1, 2 copies of SMN2 and without the genetic modifier (c.859G>C), ensuring a 
reasonably robust safety database at the time of the Marketing Authorization Application 
submission.  The trial power is based upon efficacy analysis of the ITT population. 
Based upon widely cited natural history of the disease (PNCR) [21], it is expected that no 
patients in this population would be expected to attain the ability to sit without support or 
accomplish other developmental milestones (rolling over, standing, walking) prior to reaching 
18 months of age.  Assuming that the true response rate for the primary endpoint is actually zero 
(or as low as 0.1%) in the population of interest of the historical control, the primary efficacy 
endpoint hypothesis is: 
𝐇𝟎: 𝑝AVXS −101 = 0.1% 
versus the alternative 
𝐇𝐚: 𝑝AVXS−101 > 0.1%, 
where 𝑝𝑝 is the proportion of sitting without support for at least 10 seconds up to and including 
the 18-month trial visit. 
Based upon preliminary results from the completed Phase 1 clinical trial AVXS-101-CL-101, at 
least 50% of treated symptomatic patients with 2 copies of SMN2 and without the genetic 
modifier (c.859G>C) are expected to achieve the primary efficacy endpoint of sitting without 
support for at least 10 seconds up to and including the 18-month trial visit.  With the assumption 
for the true response rate of AVXS-101 being in the range of 20% - 50%, a sample size of 25 
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patients would provide power of greater than 95% to detect a significant difference with 
α = 0.025 using a 1-sided exact test for a binomial proportion. 
 
 
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The secondary efficacy endpoint hypothesis: 
𝐇𝟎: 𝑝𝐴VXS−101 = 𝑝𝑃NCR 
versus the alternative 
𝐇𝐚: 𝑝𝐴VXS−101 ≠ 𝑝𝑃NCR 
where 𝑝𝑝 is the proportion patients of surviving at 14 months of age. 
Based upon preliminary results from the same completed Phase 1 clinical trial AVXS-101, at 
least 80% of treated symptomatic patients with 2 copies of SMN2 and without the genetic 
modifier (c.859G>C) are expected to achieve secondary efficacy endpoint of survival at or 
beyond 14 months of age (based upon the definition of survival outlined above).  It is anticipated 
that 75% of patients in the PNCR population would not survive beyond 13.6 months of age, and 
that these control patients will represent a 25% survival rate based upon the natural history of the 
disease.  Given this efficacy, a sample size of 25 patients would provide power of >90% to detect 
a significant difference with α = 0.05 using a 2-sided Fisher’s Exact test, as comparing to those 
control patients with age and gender-matched selected from existing natural history data sets 
[21], [45]. 
14.3. 
Efficacy Analysis 
14.3.1. 
General Considerations 
This trial will compare the activity of AVXS-101 administered IV versus the natural observational 
results from PNCR [24] in terms of sitting without support and survival rate. 
The analysis of the primary and secondary efficacy endpoints will be performed for the ITT 
population, and efficacy completers populations.  The analysis based on the ITT population will 
be considered as the primary analysis. 
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). 
14.3.2. 
Primary and Secondary Efficacy Analysis 
Primary and secondary efficacy analyses will be based on ITT population, those symptomatic 
patients with biallelic Exon 7/8 deletion mutations of SMN1, and 2 copies of SMN2 without the 
genetic modifier (c.859G>C).  These analyses are to test the superiority of AVXS-101 to the 
results from natural observation trial [24]. 
The primary efficacy hypothesis to be tested is: 
𝐇𝟎: 𝑝𝐴VXS−101 = 0.1% 
versus the alternative 
𝐇𝐚: 𝑝𝐴VXS−101 > 0.1%, 
where 𝑝𝑝 is the proportion of sitting without support for at least 10 seconds up to and including 
the 18 months of age visit, of the ITT population. 
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The secondary efficacy hypothesis to be tested is: 
𝐇𝟎: 𝑝𝐴VXS−101 = 𝑝𝑃NCR 
versus the alternative 
𝐇𝐚: 𝑝𝐴VXS−101 ≠ 𝑝𝑃NCR 
where 𝑝𝑝 is the proportion surviving at 14 months of age in ITT population. 
One-sided exact binomial tests (alpha level of 0.025) will be executed for the primary efficacy 
analysis in the ITT population.  For the secondary endpoint, a 2-sided Fisher’s Exact test will be 
used to compare the ITT population with patients from the PNCR natural history trial data-set. 
A sensitivity analysis will be conducted by repeating the primary efficacy analysis on the 
efficacy completers analysis population. 
14.4. 
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 analyses will be conducted on safety population. 
14.4.1. 
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 
key components:   
1.  Subjects showing ALT or AST elevations, greater than 3xULN, combined with serum TBL to ≥2xULN, 
without initial findings of cholestasis (elevated serum ALP);  
2. No other reason can be found to explain the combination of increased ALT or AST 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 [48].  
 
 
 
 
  
 
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15. 
DATA SAFETY MONITORING BOARD/DATA MONITORING 
COMMITTEE 
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 AveXis.  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 AveXis 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 AveXis 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 AveXis or its representatives.  This will be 
documented in a Clinical Trial Agreement between AveXis and the Investigator. 
 
During the trial, a monitor from AveXis 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 AveXis 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to AveXis 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 subjects. 
16.2. 
Audits and Inspections 
Authorized representatives of AveXis, a regulatory authority, an IRB/IEC may visit the site to 
perform audits or inspections, including source data verification.  The purpose of an AveXis 
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) 
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guidelines of the International Council for Harmonization (ICH), and any applicable regulatory 
requirements.  The Investigator should contact AveXis 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 
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.  AveXis 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, 
AveXis 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/IEC, as appropriate.  The 
Investigator must submit written approval to AveXis before he or she can enroll any patient into 
the trial. 
The Principal Investigator is responsible for informing the IRB/IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB/IEC must approve all 
advertising used to recruit patients for the trial.  The protocol must be re-approved by the 
IRB/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.  AveXis 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 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 
AveXis 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 < 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 
1. 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. 
2. 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. 
3. 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. 
4. Farrar MA, Vucic S, Johnston HM, Kiernan MC. Corticomotoneuronal integrity 
and adaptation in spinal muscular atrophy. Arch Neurol. 2012b;69(4):467-473. 
5. Riessland M, Ackermann B, Forster A, et al. SAHA ameliorates the SMA phenotype in 2 
mouse models for spinal muscular atrophy. Hum Mol Genet. 2010;19(8):1492-1506. 
6. 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. 
7. National Library of Medicine [Available from: www.ClinicalTrials.gov] 
8. 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. 
9. Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies 
and challenges. Lancet Neurol. 2012;11(5):443-452. 
10. Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011;68(8):979-
984. 
11. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification 
and characterization of a spinal muscular atrophy-determining gene. Cell. 
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12. 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. 
13. Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH 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. 
14. 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. 
15. 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. 
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16. 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. 
17. 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. 
18. 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. 
19. 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. 
20. 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. 
21. 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. 
22. 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. 
23. 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. 
24. 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):704-12. 
25. AVXS-101 Investigator’s Brochure version 6.0. 17 September 2019. AveXis, Inc., 
Bannockburn, IL. 
26. Narver HL, Kong L, Burnett BG, et al. Sustained improvement of spinal muscular atrophy 
mice treated with trichostatin A plus nutrition. Ann Neurol. 2008;64(4)465-470. 
27. Paes BA, Mitchell I, Banerji A, Lanctot KL, Langley JM. A decade of respiratory syncytial 
virus epidemiology and prophylaxis: translating evidence into everyday practice. Can 
Respir J. 2001;18(2): e10-9. 
28. Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections 
due to respiratory syncytial virus in young children: a systematic review and meta-analysis. 
Lancet, 2010; 375:1545–55. 
29. Hall CB. Respiratory syncytial virus and parainfluenza virus. New Engl J Med. 
2001;344:1917-1928. 
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30. Palivizumab SmPC. www.ema.europa.eu/en/documents/product-information/synagis-epar-
product-information_en.pdf. April 6, 2019. 
31. Finkel RS, Mercuri E, Meyer OH, et al. SMA Care group. Diagnosis and management of 
spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and 
immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207. 
32. McCarty DM, Young Jr SM, Samulski RJ. Integration of adeno-associated virus (AAV) and 
recombinant AAV vectors. Ann Rev Genet. 2004;38:819-845. 
33. Kotin RM, Siniscalco M, Samulski RJ, et al. Site-specific integration by adeno-associated 
virus. Proc Natl Acad Sci USA. 1990;87(6):2211-2215. 
34. Surosky RT, Urabe M, Godwin SG, et al. Adeno-associated virus Rep proteins target DNA 
sequences to a unique locus in the human genome. J Virol. 1997;71(10):7951-7959. 
35. Srivastava A and Carter BJ. AAV infection: protection from cancer. Hum Gene Ther. 
2017;28(4):323-327. 
36.  Favre D, Provost N, Blouin V, et al. “Immediate and long-term safety of recombinant 
adeno-associated virus injection into the nonhuman primate muscle.” Mol Ther. 
2001;4.6:559-566. 
37. Afione SA, Conrad CK, Kearns WG, et al. In vivo model of adeno-associated virus vector 
persistence and rescue. J Virol. 1996;70.5:3235-3241. 
38. Wijnhoven TMA, De Onis M, Oyango AW, Wang T, Bjoerneboe GA, Bhandari N, Lartey 
A, Al Rashidi B; WHO Multicentre Growth Reference Trial Group. Assessment of gross 
motor development in the WHO multicenter growth reference trial. Food Nutr Bull. 
2004;25(1 Suppl 1):S37S45. 
39. Albers CA, Grieve AJ. Test Review: Bayley, N. (2006). Bayley Scales of Infant and 
Toddler Development- Third Edition. San Antonio, TX: Harcourt Assessment. J 
Psychoeduc Assess. 2007;25(2):180-198. 
40. US Department of Health and Human Services. Common Terminology Criteria for 
Adverse Events (v4.03). Published May 2009 (Revised June 2010). 
41. Zoorob RJ, Cender D. A different look at corticosteroids. Am Fam Physician. 
1998;58(2):443-450. 
42. Onis M. WHO Child Growth Standards based on length/height, weight and age. Acta 
Paediatr. 2006;95.S450:76-85. 
43. Kroger A, Duchin J, Vazquez M. General Best Practice Guidelines for Immunization 
(ACIP). www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. 
Accessed on 2018.  
44. Palivizumab Summary of Product Characteristics.  
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information_en.pdf] 2018 
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45. 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. 
46. 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. 
47. Kolb S. Longitudinal results from the NeuroNEXT SMA infant biomarker trial. Presented 
at: 20th Annual International Spinal Muscular Atrophy Research Group Meeting; June 
2016; Anaheim, CA. 
48. 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.  
 
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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. 
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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  
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 
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.  
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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  
(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): Laboratory samples collected on Day -1 
to be processed locally, prior to dosing. 
(X)*: Liver function test (AST, ALT, total 
bilirubin, direct bilirubin, alkaline 
phosphatase, GGT) only. 
CK-MB or 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. 
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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  
AAV9 Ab Screen in 
Biological Mother 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 12.1.10.7. 
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 ALT values, 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; CK-MB = Creatinine kinase-muscle/brain;  
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 AveXis 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 
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Cervical level 
 
Inguinal lymph node 
 
Cerebrospinal fluid 
 
Gonads 
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APPENDIX 4. 
PERFORMANCE CRITERIA FOR BAYLEY SCALES INFANT AND 
TODDLER DEVELOPMENT (VERSION 3) DEVELOPMENTAL 
MILESTONES 
Developmental Milestone 
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 
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APPENDIX 5. 
PERFORMANCE CRITERIA FOR WORLD HEALTH 
ORGANIZATION (WHO) DEVELOPMENTAL MILESTONES 
Gross Motor Milestone 
Sitting without support 
Hands-and-knees crawling 
Standing with assistance 
Walking with assistance 
Standing alone 
Walking alone 
WHO = World Health Organization 
Source: World Health Organization Multicentre Growth Reference Trial Group [38] 
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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. 
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. 
2. 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 
3. 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.” 
4. 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. 
5. Medical progress is based on research that ultimately must include studies involving Human 
subjects. 
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6. 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. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
Human subjects and protect their health and rights. 
8. 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. 
9. 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. 
10. 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. 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
12. 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. 
13. Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
14. 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. 
15. Appropriate compensation and treatment for patients who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
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16. 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. 
17. 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. 
18. 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 
19. 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. 
20. 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. 
Scientific Requirements and Research Protocols 
21. 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. 
22. 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. 
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In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. 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 
24. Every precaution must be taken to protect the privacy of research patients and the 
confidentiality of their personal information. 
Informed Consent 
25. 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. 
26. 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. 
27. 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. 
28. 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. 
29. 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. 
30. 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. 
31. 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. 
32. 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 
33. 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: 
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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. 
Post-Trial Provisions 
34. 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 
35. Every research trial involving Human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. 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 
37. 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-302 
 
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 7.0, Amendment 6, 25 Jun 2020 
 
 
 
 
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This protocol amendment was required in order to: 
- 
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 
- 
clarify the schedule of assessments for some efficacy and safety parameters 
- 
address specific requests from Competent Authorities regarding Safety Reporting 
timelines and Hy’s Law Criteria 
- 
clarify and correct statistical analysis definitions 
- 
make administrative changes 
The following changes were made to the Protocol from Version 6.0 Amendment 5 dated 26 Nov 
2019 to Version 7.0 Amendment 6 dated 25 Jun 2020. 
SUMMARY OF CHANGES: 
The section below describes the changes incorporated into this version of the protocol.   
Protocol Version 7.0 Incorporating Amendment 6 includes the following changes: 
Description of Change 
Location(s) 
Rational for Change 
Updated protocol version, 
amendment number and date 
Cover page and header throughout 
Updated document 
Replaced 
 
 
 
 
. 
Corrected/updated 
 
s job titles 
Signature page 
To update per company 
administrative changes 
Updated study physician email 
address 
Replaced Serious Adverse Event 
Reporting email and fax number 
Key contact information 
Updated contact details 
Updated following migration 
to Novartis safety database 
and reporting process 
Addition of ADL (activities of 
daily living) 
Addition of AT 
(aminotransferase) and TBL 
(total bilirubin) 
Section 4: List of Abbreviations and 
Definitions of Terms 
As referenced in Section 
13.1.1 Adverse Event (Table 
4) and Section 14.4.1 Hy’s 
Law Criteria 
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 subject may be 
considered withdrawn due 
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 
In order 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 
PRO-747 Version7.0 Generated 22 Sep 2020 08:42 PM CEST | Effective Date: 03 Jul 2020 08:04 PM CEST

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Investigational Product: AVXS-101 
Protocol Version 7.0/Amendment 6/25 Jun 2020 
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Page 129 of 131 
Description of Change 
Location(s) 
Rational for Change 
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  
- 
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 
Addition of ‘developmental’ 
before ‘milestone’ where 
appropriate 
Throughout 
For consistency and 
clarification 
Definition of sitting 
developmental milestones: 
WHO – sitting without support 
BSID #26 – functional 
independent sitting 
Throughout 
For consistency and 
clarification 
Text for exploratory 
objectives/endpoints was revised 
to include BSIDv03 Gross 
Motor Subset Items 33, 34, 37, 
40, 42 
Synopsis: Objectives: Exploratory 
Synopsis: Endpoint: Exploratory  
Section 6.3: Exploratory Objectives 
Section 14.1.1.1.3: Exploratory 
Endpoints 
To align with Appendix 4 
Change to the date of the most 
recent data cut-off for safety 
data review from 08 March 
2019 to 31 December 2019 
Section 5.5: Risks 
 
Updated information 
Section 14.4.1 Hy’s Law 
Criteria and definition inserted, 
with a link in Section 5.5 
Section 5.5: Risks 
Section 14.4: Safety Analysis 
At the request of the 
Belgium FAMPH 
Text was added to state that at 
the 18 months of age visit all 
developmental milestones 
should be assessed, documented 
and video recorded regardless of 
previous attainment 
Section 11.1: Developmental 
Milestones 
For clarification 
Text was added to define the 
criteria required to attain each 
WHO milestones 
Section 11.2.1: World Health 
Organization Multicentre Growth 
Reference Milestones 
For clarification and to avoid 
confusion between WHO 
and BSIDv03 gross motor 
milestones 
Video Manual changed to 
Physical Assessments Manual 
Throughout 
The Physical Assessments 
Manual is the new reference 
document for Clinical 
Evaluators 
Text was added to clarify the 
BSID GM #26 milestone 
definition and requirement to 
assess at every visit, including at 
Section 11.2.2: Bayley Scales for 
Infant and Toddler 
Development/Developmental 
Milestones 
For clarification  
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Description of Change 
Location(s) 
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Month 18 regardless of previous 
attainment. 
Text added to clarify that 
Bayley Scales will be video 
recorded and videos containing 
developmental milestone 
evidence will be submitted for 
central review 
Text regarding the requirement 
to video record the Bayley 
Scales was deleted as this 
information is captured in 11.1 
and 11.3 
Section 11.2.2: Bayley Scales for 
Infant and Toddler 
Development/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 
Removal of text stating that 
each CHOP-INTEND exam will 
be submitted for review by 
central reviewer 
Section 11.2.3: CHOP-INTEND 
It was never the intention for 
CHOP-INTEND videos to 
be centrally reviewed 
Text added to clarify that all 
videos of Developmental 
Milestones which meet WHO 
and BSID criteria will be 
provided to an independent 
central reviewer 
Section 11.3: Video Evidence 
For clarification 
Text added to clarify that at the 
18 month of age visit, the WHO 
Motor Developmental Milestone 
for sitting without support for at 
least 10 seconds and the BSID 
GM #26 sitting milestones will 
be submitted for central review, 
even if previously confirmed. 
Section 11.3: Video Evidence 
Only the WHO sitting 
milestone (primary 
endpoint) and BSID GM #26 
sitting milestone 
(exploratory endpoint), and 
new developmental 
milestones attained for the 
first time, will be centrally 
PRO-747 Version7.0 Generated 22 Sep 2020 08:42 PM CEST | Effective Date: 03 Jul 2020 08:04 PM CEST

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Investigational Product: AVXS-101 
Protocol Version 7.0/Amendment 6/25 Jun 2020 
Confidential/Proprietary 
Page 131 of 131 
Description of Change 
Location(s) 
Rational for Change 
New developmental milestones 
attained for the first time at 18 
months of age will also be 
submitted for central review  
reviewed at the 18 months of 
age visit 
Changed the form provided 
from ‘by the Contract Research 
Organization’ to ‘by AveXis’ 
Section 13.1.2: Serious Adverse 
Event 
Section 13.1.3: Adverse Events of 
Special Interest 
SAE forms are now 
provided by AveXis using 
the Novartis template 
Text added to clarify the 
reporting timelines for fatal/life 
threatening SUSARs 
Section 13.5: Expedited Safety 
Reporting to Regulatory Authorities 
Per France ANSM request 
and EU reporting 
requirements 
Text ‘and subgroup analyses’ 
removed 
Text ‘and summarized by 
subgroup and overall’ removed 
Section 14.1.1.2.1: Intent-to-Treat 
Population 
Section 14.4: Safety Analysis 
There is no subgroup 
defined in the protocol; this 
will be defined in the 
Statistical Analysis Plan 
One-sided exact binomial tests 
alpha level changed from 0.05 to 
0.025 
Section 14.3.2: Primary and 
Secondary Efficacy Analysis 
Correction made to be 
consistent with power 
calculation 
Schedule of Assessments was 
updated with a new line to 
specify the schedule of 
BSIDv03 Gross and Fine Motor 
Subtests (with video) 
Appendix 1: Schedule of 
Assessments 
To align with Section 11.2.2 
Notes for 12-Lead ECG, 
Echocardiogram and 24-hour 
Holter Monitor – (X) to be 
completed every 3 months, 
starting at Month 3 until 12 
months post-dose. 
Appendix 1: Schedule of 
Assessments 
For clarification. Because of 
the age of some subjects 
when they are dosed, they 
may not have visits at 
Months 9 or 12. It is 
important that these tests are 
performed every 3 months 
from Month 3 until 12 
months post-dose, regardless 
of the visit/month number 
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 
Source reference in footer 
changed from (36) to (38) 
Appendix 5: Performance Criteria 
for World Health Organization 
(WHO) Developmental Milestones 
Correction 
Scoring sheet has been replaced 
with an updated version 
Appendix 6: CHOP-INTEND 
A new scoring sheet was 
provided by CHOP  
 
PRO-747 Version7.0 Generated 22 Sep 2020 08:42 PM CEST | Effective Date: 03 Jul 2020 08:04 PM CEST