A Global Study of a Single, One-Time Dose of AVXS-101 Delivered to Infants With Genetically Diagnosed and Pre-symptomatic Spinal Muscular Atrophy With Multiple Copies of SMN2
Phase: PHASE3
Conditions: Spinal Muscular Atrophy
Sponsor: Novartis Gene Therapies

Protocol Number:  AVXS-101-CL-304 
 
Official Title:  A Global Study of a Single, One-Time Dose of AVXS-101 
Delivered to Infants with Genetically Diagnosed and 
Pre-symptomatic Spinal Muscular Atrophy with Multiple Copies of 
SMN2 
 
NCT Number: NCT03505099 
 
Document Date:  28-Jul-2020 

 
 
SIGNATURE PAGE
TITLE CL-304 Clinical Protocol ID: PRO-639
User
Role
Job Title
Version
Decision
Date Signed
Final Approvers
Senior Medical Director
6.0
Approve
04 Aug 2020 01:31 PM CDT
Final Approvers
Executive Medical Director
6.0
Approve
04 Aug 2020 03:15 PM CDT
Final Approvers
Associate Director,
Therapeutic Lead
6.0
Approve
04 Aug 2020 01:59 PM CDT
Final Approvers
Vice President
6.0
Approve
04 Aug 2020 07:55 AM CDT
Final Approvers
Vice President
6.0
Approve
04 Aug 2020 07:55 AM CDT
Final Approvers
Senior Director, Biostatistics
6.0
Approve
04 Aug 2020 08:04 AM CDT
 
 
This is a copy generated on 05 Aug 2020 09:52 AM CDT.   Please refer to ACE for
most recent effective version.  
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AveXis, Inc. 
AVXS-101-CL-304 
Investigational Product: AVXS-101 
Protocol v6.0/Amendment 5/28 Jul 2020 
Confidential | Proprietary 
Page 1 of 128 
 
 
AVXS-101 
PROTOCOL AVXS-101-CL-304 
IND Number: 
15699 
EudraCT Number: 
2017-004087-35 
Protocol Title: 
A Global Study of a Single, One-Time Dose of AVXS-101 
Delivered to Infants with Genetically Diagnosed and 
Pre-symptomatic Spinal Muscular Atrophy with Multiple Copies of 
SMN2 
Indication Studied: 
Spinal Muscular Atrophy 
Sponsor Address: 
AveXis, Inc. 
2275 Half Day Road 
Bannockburn, IL 60015 
Protocol Version/Date: 6.0 /Amendment 5/ 28 Jul 2020 
 
The study 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 study subjects are protected, 
consistent with the principles that have their origin in the Declaration of Helsinki. 
 
Confidentiality Statement 
The information in this document contains trade and commercial information that is privileged or 
confidential and may not be disclosed unless such disclosure is required by federal or state law or 
regulations.  In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them.  These restrictions on 
disclosure will apply equally to all future information supplied to you which is indicated as privileged or 
confidential. 
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1. 
ADMINISTRATIVE INFORMATION 
1.1. 
Approval 
Representatives from AveXis: 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki 
• International Council for Harmonization, 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 Medical Director, Translational Medicine 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
 
Associate Director, Therapeutic Lead 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
 
Vice President, Regulatory Affairs, 
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-304 protocol and agree to conduct the study in accordance with the relevant 
current protocol(s).  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 study 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 Informed Consent 21 CFR Part 56, 
Institutional Review Board Review in 21 CFR Part 56, Adverse Event Reporting as 
defined in Section 13 and in 21 CFR 312.64, Adequate/accurate and accessible 
records in accordance with 21CFR 312.62 and 312.68. 
• Terms outlined in the study 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 Investigator 
 _________________________________________________ 
Signature of Investigator 
 _________________________________________________ 
Date (ddMmmyyyy) 
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1.3. 
Key Contact Information 
 
Role in Study 
Contact information 
Responsible Physician 
. Senior Medical Director, Translational 
Medicine, AveXis, Inc., 
 
24-Hour Emergency Contact 
Please see Study Contact List in ISF 
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 delivered by Self‐Complementary 
Adeno-Associated Virus Serotype 9 (AAV9) 
Title of Study:  A Global Study of a Single, One-Time Dose of AVXS-101 Delivered to Infants with 
Genetically Diagnosed and Pre-Symptomatic Spinal Muscular Atrophy with Multiple Copies of SMN2 
Study Center(s):  up to 32 global centers 
Japan is participating in this global study under a Japan-specific version of the AVXS-CL-101-304 
protocol. 
Studied Period (years): 
Estimated date first patient enrolled: 1Q 2018 
Estimated date last patient completed: SMN2 2 copies: 4Q 
2020; 3 copies: 3Q 2021 
Phase of Development: 3 
Objectives: 
Safety: 
• 
Evaluate the safety of AVXS-101 through incidence of adverse events (AEs) and/or serious 
adverse events (SAEs) 
• 
Evaluate the safety of AVXS-101 based on the change from baseline in clinical laboratory 
parameters 
Efficacy objectives will be assessed independently for each cohort. 
Efficacy for patients with bi-allelic SMN1 deletions and 2 copies of SMN2: 
Primary: 
• 
Assess the efficacy of AVXS-101 by demonstrating functional independent sitting 
 
 as defined by Bayley Scales of Infant and Toddler Development© Version 3 
(BSIDv03) Gross Motor Subset Item #26 at any visit up to 18 months of age  
Secondary: 
• 
Determine the efficacy of AVXS-101 based on survival, defined as avoidance of death or the 
requirement of permanent ventilation in the absence of acute illness or perioperatively as 
assessed at 14 months of age 
• 
Assess efficacy of AVXS-101 by demonstrating the ability to maintain weight at or above the 
third percentile without need for non-oral/mechanical feeding support at any visit up to 
18 months of age 
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Exploratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Efficacy for patients with bi-allelic SMN1 deletions and 3 copies of SMN2: 
Primary: 
• 
Assess the efficacy of AVXS-101 based on the proportion of patients achieving the ability to 
stand without support for at least 3 seconds as defined by BSIDv03 Gross Motor Subtest Item 
#40 at any visit up to 24 months of age  
Secondary: 
• 
Assess the efficacy of AVXS-101 by demonstrating the ability to walk alone 
 
, as defined 
by BSIDv03 Gross Motor Subtest Item #43, at any visit up to 24 months of age  
Exploratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Methodology: 
Phase 3, open-label, single-arm study of a single, one-time dose of AVXS-101 (gene replacement 
therapy) in patients with spinal muscular atrophy (SMA) who meet enrollment criteria and are 
genetically defined by bi-allelic deletion of survival motor neuron 1 gene (SMN1) with 2 or 3 copies of 
survival motor neuron 2 gene (SMN2).  Patients with SMN1 point mutations or the SMN2 gene modifier 
mutation (c.859G>C) may enroll but will not be included in the efficacy analysis sets. 
The study will enroll at least fourteen (14) patients with 2 copies of SMN2 that meet the Intent-to-Treat 
(ITT) criteria and at least twelve (12) patients with 3 copies of SMN2 that meet the ITT criteria.  Patients 
in both cohorts must be ≤6 Weeks of age at the time of gene replacement therapy (Day 1). 
The study 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 undergo screening procedures to determine eligibility for study enrollment.  
Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day -1 to 
Day 2).  On Day -1, patients will be admitted to the hospital for pre-treatment baseline procedures.  On 
Day 1, patients will receive a single, one-time intravenous (IV) infusion of AVXS-101 and will undergo 
in-patient safety monitoring for a minimum of 24 hours post infusion.  Patients may be discharged 
24 hours after the infusion, based on Investigator judgment.  During the outpatient follow-up period 
(Days 3 to EOS) at 18 or 24 months of age, dependent upon respective SMN2 copy number), patients 
will return at regularly scheduled intervals for efficacy and safety assessments until the EOS when the 
patient reaches 18 months of age (SMN2 = 2) or 24 months of age (SMN2 = 3).  After the EOS visit, 
patients will be monitored for safety for 30 days.  Additionally, patients will be invited to participate in 
a long-term follow up study conducted under a separate protocol. 
After dosing, follow-up visits will be conducted according to the Schedule of Assessments.  Visits prior 
to and including the Day 72 visit are timed based on the Day of AVXS-101 dose (Day 1).  Visits 
following Day 72 are based on patient’s date of birth.  The EOS visit for patients with 2 and 3 copies of 
SMN2 will be the 18 and 24 months old visits, respectively.  However, safety monitoring will continue 
for 30 days after EOS visit.  Any missed visit should be rescheduled as soon as possible within the 
window described in the Schedule of Assessments.  All visits will be scheduled based on a 
30-day month calendar. 
In an attempt to dampen the host immune response to the adeno-associated virus (AAV) derived 
therapy, all patients will receive prophylactic prednisolone at approximately 2 mg/kg/day (or an 
equivalent dose of another glucocorticoid if prednisolone is unavailable or in the opinion of the 
investigator prednisolone is not tolerated) on Day -1, Day 1, and Day 2, and then 1 mg/kg/day starting 
on Day 3 and until at least 30 days post-AVXS-101 infusion.  After 30 days post-AVXS-101 infusion, 
the dose of prednisolone can be tapered for patients whose gamma glutamyl transferase (GGT), alanine 
aminotransferase (ALT) values, and aspartate aminotransferase (AST) values are below 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. 
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Investigational Product: AVXS-101 
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If the GGT, AST, or ALT values are > 2 × ULN, the dose of prednisolone will be maintained until the 
GGT, AST, and ALT values decrease below threshold, at which point the taper may continue.  Variance 
from these recommendations will be at the discretion of the Investigator based on potential safety issues 
for each patient.  If another glucocorticoid is used in place of prednisolone by the Investigator, similar 
considerations should be taken into account after 30 days and tapered as appropriate and at the 
discretion of the Investigator. 
Efficacy will be assessed by achievement of the key developmental milestone of functional independent 
sitting 
 (SMN2 = 2) at any visit up to 18 months of age; and ability to stand 
without support for at least 3 seconds (SMN2 = 3) at any visit up to 24 months of age.  Additional 
developmental milestones will be assessed using the WHO-MGRS and BSIDv03.  Safety will be 
assessed through monitoring AEs, concomitant medication usage, physical examinations, vital sign 
assessments, cardiac assessments, and laboratory evaluations.  The primary efficacy analysis for each 
SMN2 copy number cohort will be completed separately at such time that enrollment in the respective 
cohort is complete and the last patient has completed the EOS visit at the respective age or has 
discontinued (SMN2 = 2, End of Study (EOS) = 18 months of age; SMN2 = 3, EOS = 24 months of age). 
Number of Patients (planned): A minimum of twenty-six (26) patients that meet ITT criteria  
Diagnosis and Main Criteria for Inclusion:  The study will enroll genetically diagnosed and 
pre-symptomatic spinal muscular atrophy patients with 2 or 3 copies of SMN2. 
Inclusion Criteria: 
All patients: 
1. Age ≤6 Weeks (≤42 days) at time of dose 
2. Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test  
3. Compound muscle action potential (CMAP) ≥2 mV at Baseline; centralized review of CMAP 
data will be conducted 
4. Gestational age of 35 to 42 weeks 
5. Up-to-date on childhood vaccinations that include palivizumab prophylaxis (also known as 
Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in 
accordance with the guidance of local health authorities. 
6. Able and willing to follow the Consensus Statement for Standard of Care in Spinal Muscular 
Atrophy. 
7. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and 
comply with study procedures and visit schedule 
8. Genetic diagnosis as described below, obtained from an acceptable newborn or pre-natal 
screening test method 
Patients with 2 copies of SMN2 (n ≥14) 
• 
Patients with pre-symptomatic SMA Type 1 as determined by the following features: 
o 2 copies of SMN2 
Patients with 3 copies of SMN2 (n ≥12) 
• 
Patients with pre-symptomatic SMA Type 2 as determined by the following features: 
o 3 copies of SMN2 
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Exclusion Criteria: 
1. Weight at screening visit <2 kg 
2. Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or 
respiratory support) at the screening visit or for altitudes >1000 m, oxygen saturation <92% 
awake or asleep without any supplemental oxygen or respiratory support at the screening visit 
3. Any clinical signs or symptoms at screening or immediately prior to dosing that are, in the 
opinion of the Investigator, strongly suggestive of SMA (e.g., tongue fasciculation, hypotonia, 
areflexia) 
4. Tracheostomy or current prophylactic use or requirement of non-invasive ventilatory support at 
any time and for any duration prior to screening or during the screening period 
5. Patients with signs of aspiration/inability to tolerate non-thickened liquids based on a formal 
swallowing test performed as part of screening or patients receiving any non-oral feeding 
method 
6. Clinically significant abnormal laboratory values (GGT, ALT, and AST, or total 
bilirubin > 2 × the ULN, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white 
blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy.  Patients with an 
elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be 
excluded. 
7. Patients with any other clinically significant abnormalities in hematology or clinical chemistry 
parameters as determined by the investigator or medical monitor 
8. Treatment with an investigational or commercial product, including nusinersen, given for the 
treatment of SMA.  This includes any history of gene therapy, prior antisense oligonucleotide 
treatment, or cell transplantation. 
9. Patients whose weight-for-age is below the third percentile based on World Health Organization 
(WHO) Child Growth Standards. 
10. Biological mother with active viral infection as determined by screening laboratory samples 
(includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C) 
a. Biological mothers with clinical suspicion of Zika virus that meet Centers for Disease 
Control and Prevention (CDC) Zika virus epidemiological criteria including history of 
residence in or travel to a geographic region with active Zika transmission at the time of 
travel will be tested for Zika virus ribonucleic acid (RNA); positive results warrant 
confirmed negative Zika virus RNA testing in the patient prior to enrollment 
11. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 
2 Weeks prior to screening 
12. Upper or lower respiratory infection requiring medical attention, medical intervention, or 
increase in supportive care of any manner within 4 Weeks prior to dosing 
13. 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 Investigator or Sponsor medical monitor, creates unnecessary risks for gene 
replacement therapy such as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalciuria 
e. Symptomatic cardiomyopathy 
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14. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients 
15. Previous, planned or expected major surgical procedure including scoliosis repair 
surgery/procedure during the study assessment period 
16. 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, immunosuppressive therapy within 4 Weeks prior to 
gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, 
cyclophosphamide, IV immunoglobulin, rituximab) 
17. Anti-AAV9 antibody titer >1:50 as determined by enzyme-linked immunosorbent assay 
(ELISA) binding immunoassay 
a. Should a potential patient demonstrate Anti-AAV9 antibody titer >1:50, he or she may 
receive retesting inside the 30-Day screening period and will be eligible to participate if 
the Anti-AAV9 antibody titer upon retesting is ≤1:50, provided patient is still 
<6 weeks of age at the time of dosing 
18. Biological mother involved with the care of the child refuses anti-AAV9 antibody testing prior 
to dosing 
19. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to 
travel for repeat visits 
20. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain 
from posting confidential study results/observations on social media sites 
21. Parent(s)/legal guardian(s) refuses to sign consent form 
Investigational Product, Dosage and Mode of Administration: 
Patients will receive a one-time dose of AVXS-101 at 1.1 × 1014 vg/kg. 
Duration of Treatment: 
AVXS-101 will be administered as a one-time IV infusion over approximately 60 minutes 
Reference Therapy, Dosage and Mode of Administration: Not Applicable 
Definition for Endpoints (alphabetically): 
Chronological development reference standard: Fine and Gross motor development will reference 
and be assessed using the BSIDv03 Gross and Fine Motor Subsets 
Functional independent sitting:  Sitting without support 
 (BSIDv03 – Gross Motor 
subset #26) 
Permanent Ventilation: Tracheostomy or 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. 
Respiratory Intervention: Use of ventilatory support (Bi-level Positive Airway Pressure (BiPAP) or 
other ventilator) for ≥14 consecutive days in the absence of an acute reversible illness, excluding 
perioperative ventilation 
Standard deviation: 7+ points on the scaled scoring for the gross and fine motor subsets of the 
BSIDv03. 
Standing alone: Stand without support for at least 3 seconds (BSIDv03 Gross Motor Subset #40) 
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Survival: Avoidance of death or the requirement of permanent ventilation (including non-invasive 
ventilatory support ≥ 16 hours per Day for ≥ 2 weeks) in the absence of acute reversible illness or 
perioperatively  
Walking alone:  
 
(BSIDv03 – Gross Motor Subset #43) 
Criteria for Evaluation: 
Safety: 
Primary: 
• 
Incidence of AEs and/or SAEs 
• 
Change from baseline in clinical laboratory parameters 
Efficacy objectives will be assessed independently for each cohort. 
Efficacy for patients with bi-allelic SMN1 deletions and 2 copies of SMN2: 
Primary: 
• 
Proportion of patients achieving the development milestone of functional independent sitting as 
defined by BSIDv03 Gross Motor Subtest Item #26 at any visit up to 18 months of age  
Secondary: 
• 
Proportion of patients that have survived and have not required permanent ventilation in the 
absence of acute reversible illness or perioperatively assessed at 14 months of age 
• 
Proportion of patients that have achieved the ability to maintain weight at or above the third 
percentile without need for non-oral/mechanical feeding support at any visit up to 18 months of 
age 
Exploratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Efficacy for patients with bi-allelic SMN1 deletions and 3 copies of SMN2: 
Primary: 
• 
Proportion of patients achieving the ability to stand without support for at least 3 seconds as 
defined by BSIDv03 Gross Motor Subtest Item #40 at any visit up to 24 months of age  
Secondary: 
• 
Proportion of patients demonstrating the ability to walk alone
 
 as defined by BSIDv03 
Gross Motor Subtest Item #43 at any visit up to 24 months of age  
Exploratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Methods: 
This is a Phase 3 study assessing the efficacy and safety of AVXS-101.  The primary efficacy analysis 
for each SMN2 copy number cohort will be completed separately at such time that enrollment in the 
respective cohort is complete and the last patient has completed the EOS visit at the respective age 
(SMN2 = 2, EOS = 18 months of age; SMN2 = 3, EOS = 24 months of age).  Safety monitoring will 
continue for 30 days after the EOS visit.  Details of all analyses will be contained within the Statistical 
Analysis Plan.  
The primary and secondary efficacy analyses will be performed on the populations of patients with 
bi-allelic SMN1 deletions and 2 or 3 copies of SMN2 without the SMN2 gene modifier mutation 
(c.859G>C).  While the study may 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 
Intent-To-Treat (ITT) populations hereafter.  Study power is based upon efficacy analysis of these 
subpopulations.  Patients with SMN1 point mutations or the SMN2 gene modifier mutation (c.859G>C) 
will be evaluated separately as part of additional subgroup analyses. 
At least fourteen (14) patients with 2 copies of SMN2 and at least twelve (12) patients with 3 copies of 
SMN2 will be enrolled.   
Patients with 2 copies of SMN2 
The primary efficacy endpoint for patients with 2 copies of SMN2 will be the proportion of patients who 
achieve the ability to sit without support 
 at any visit up to the 18 months of age 
study visit.  Based upon widely cited natural history of the disease (Pediatric Neuromuscular Clinical 
Research Network [PNCR]), it is expected that no patient meeting the ITT criteria (bi-allelic SMN1 
deletion, SMN2 copy number of 2 without the SMN2 gene modifier mutation (c.859G>C)) would be 
expected to attain the ability to sit without support.  Based upon data from the completed 
AVXS-101-CL-101 study, we expect at least 60% of treated patients with 2 copies of SMN2 to achieve 
the ability to sit without support for at least 30 seconds.  With this efficacy, a sample size of at least 
14 patients who meet the cohort ITT criteria would provide power of >90% to detect a significant 
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Page 15 of 128 
difference compared with a rate of 0.1% (in lieu of zero) with α = 0.025 using a 1-sided exact test for a 
binomial proportion. 
Patients with 3 copies of SMN2 
The primary efficacy endpoint for patients with 3 copies of SMN2 will be the proportion of patients who 
achieve the ability to stand without support for at least 3 seconds at any visit up to the 24 months of age 
study visit.  Based upon patient-level data available from the PNCR dataset, 23.5% of patients with 
SMN2=3 who meet the ITT criteria (bi-allelic SMN1 deletions, 3 copies of SMN2, absence of SMN2 
gene modifier mutation (c.859G>C)) achieved the ability to stand without support.  We expect 85% of 
treated patients with 3 copies of SMN2 to achieve the ability to stand without support.  With this 
efficacy, a sample size of at least 12 patients that meet the ITT criteria for this cohort would provide 
power of >90% to detect a significant difference compared with the matched control cohort with 
α = 0.05 using a 2-sample 2-sided superiority Fisher exact test. 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
ADMINISTRATIVE INFORMATION .......................................................................2 
1.1. 
Approval .......................................................................................................................2 
1.2. 
Investigator’s Agreement ..............................................................................................3 
1.3. 
Key Contact Information ..............................................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
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 Pre-Symptomatic SMA Patients ...............................25 
5.3. 
Nonclinical Studies .....................................................................................................28 
5.4. 
Clinical Studies ...........................................................................................................32 
5.5. 
Risks ...........................................................................................................................33 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................37 
6.1. 
Safety Objectives ........................................................................................................37 
6.1.1. 
Primary Objectives .....................................................................................................37 
6.2. 
Efficacy Objectives .....................................................................................................37 
6.2.1. 
Patients with bi-allelic SMN1 deletions and 2 copies of SMN2 ..................................37 
6.2.2. 
Patients with bi-allelic SMN1 deletions and 3 copies of SMN2 ..................................39 
7. 
INVESTIGATIONAL PLAN .....................................................................................41 
7.1. 
Overall Study Design ..................................................................................................41 
7.2. 
Number of Patients .....................................................................................................43 
7.3. 
Criteria for Study Termination ...................................................................................44 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................45 
8.1. 
Patient Inclusion Criteria ............................................................................................45 
8.2. 
Patient Exclusion Criteria ...........................................................................................46 
8.3. 
Patient Withdrawal Criteria ........................................................................................48 
9. 
TREATMENT OF PATIENTS ..................................................................................49 
9.1. 
Description of Product ................................................................................................49 
9.2. 
Prior and Concomitant Medications ...........................................................................49 
9.2.1. 
Prophylactic Administration of Prednisolone .............................................................49 
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9.2.2. 
Prohibited Medications ...............................................................................................50 
9.2.3. 
Vaccinations ...............................................................................................................51 
9.3. 
Treatment Compliance ................................................................................................51 
9.4. 
Randomization and Blinding ......................................................................................51 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT ....................................52 
10.1. 
Study Product..............................................................................................................52 
10.2. 
Study Product Dose and Dose Justification ................................................................52 
10.3. 
Study Product Packaging and Labeling ......................................................................52 
10.4. 
Study Product Storage and Destruction ......................................................................52 
10.5. 
Study Product Preparation ..........................................................................................53 
10.6. 
Study Product Administration ....................................................................................53 
10.7. 
Dose Adjustment Criteria ...........................................................................................53 
10.8. 
Study Product Accountability .....................................................................................53 
10.9. 
Study Product Handling and Disposal ........................................................................53 
11. 
ASSESSMENT OF EFFICACY ................................................................................54 
11.1. 
Developmental Milestones .........................................................................................55 
11.2. 
Motor Function Tests ..................................................................................................56 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental 
Milestones and World Health Organization Multicentre Growth Reference 
Milestones ...................................................................................................................56 
11.2.2. 
CHOP INTEND ..........................................................................................................57 
11.3. 
Video Evidence ...........................................................................................................57 
11.4. 
Compound Motor Action Potential ............................................................................58 
12. 
ASSESSMENT OF SAFETY .....................................................................................59 
12.1. 
Safety Parameters .......................................................................................................59 
12.1.1. 
Demographic/Medical History ...................................................................................59 
12.1.2. 
Physical Examinations ................................................................................................60 
12.1.3. 
Vital Signs/Weight and Length ..................................................................................60 
12.1.4. 
Electrocardiogram .......................................................................................................60 
12.1.5. 
Echocardiogram ..........................................................................................................60 
12.1.6. 
Twenty-Four Hour Holter Monitoring ........................................................................61 
12.1.7. 
Pulmonary Examinations ............................................................................................61 
12.1.8. 
Swallowing Test .........................................................................................................61 
12.1.9. 
Photographs of Infusion Site ......................................................................................61 
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12.1.10. 
Laboratory Assessments .............................................................................................62 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................66 
13.1. 
Definition of Adverse Events .....................................................................................66 
13.1.1. 
Adverse Event .............................................................................................................66 
13.1.2. 
Serious Adverse Event ................................................................................................66 
13.1.3. 
Adverse Events of Special Interest .............................................................................67 
13.2. 
Relationship to Study Product ....................................................................................67 
13.3. 
Recording Adverse Events .........................................................................................67 
13.4. 
Reporting Serious Adverse Events .............................................................................68 
13.4.1. 
Reporting to Regulatory Authorities ..........................................................................68 
14. 
STATISTICS ..............................................................................................................69 
14.1. 
Study Endpoints and Populations ...............................................................................69 
14.1.1. 
Study Endpoints ..........................................................................................................69 
14.1.2. 
Statistical Analysis Populations ..................................................................................72 
14.2. 
Sample Size Calculation .............................................................................................73 
14.2.1. 
Patients with bi-allelic SMN1 deletions and 2 copies of SMN2 ..................................73 
14.2.2. 
Patients with bi-allelic SMN1 deletions and 3 copies of SMN2 ..................................74 
14.3. 
Efficacy Analysis ........................................................................................................75 
14.3.1. 
General Considerations ...............................................................................................75 
14.3.2. 
Primary and Secondary Efficacy Analysis for patients with bi-allelic SMN1 
deletions and 2 copies of SMN2 ..................................................................................75 
14.3.3. 
Primary and Secondary Efficacy Analysis for patients with bi-allelic SMN1 
deletions and 3 copies of SMN2 .................................................................................76 
14.4. 
Safety Analysis ...........................................................................................................77 
14.4.1. 
Hy’s Law Criteria .......................................................................................................77 
15. 
DATA SAFETY MONITORING BOARD (DATA MONITORING 
COMMITTEE) ...........................................................................................................78 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................79 
16.1. 
Study Monitoring ........................................................................................................79 
16.2. 
Audits and Inspections ................................................................................................80 
16.3. 
Institutional Biosafety Committee/Genetically Modified Organisms (GMO) 
Committee/Competent Authority for Biosafety .........................................................80 
16.4. 
Institutional Review Board/Institutional Ethics Committee .......................................80 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................81 
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18. 
ETHICS ......................................................................................................................82 
18.1. 
Ethics Review .............................................................................................................82 
18.2. 
Ethical Conduct of the Study ......................................................................................82 
18.3. 
Written Informed Consent ..........................................................................................82 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................84 
19.1. 
Electronic Case Report Forms ....................................................................................84 
19.2. 
Inspection of Records .................................................................................................84 
19.3. 
Retention of Records ..................................................................................................84 
20. 
PUBLICATION POLICY ..........................................................................................85 
21. 
LIST OF REFERENCES ............................................................................................86 
22. 
APPENDICES ............................................................................................................90 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................91 
APPENDIX 2. POST-MORTEM PLAN ....................................................................................98 
APPENDIX 3. BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) .............................................................................................................99 
APPENDIX 4. PERFORMANCE CRITERIA FOR BAYLEY SCALES OF INFANT 
AND TODDLER DEVELOPMENT (VERSION 3) DEVELOPMENTAL 
MILESTONES .........................................................................................................115 
APPENDIX 5. PERFORMANCE CRITERIA FOR WORLD HEALTH 
ORGANIZATION (WHO) DEVELOPMENT MILESTONES ..............................116 
APPENDIX 6. CHOP INTEND................................................................................................117 
APPENDIX 7. DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS...............................119 
APPENDIX 8. SUMMARY OF CHANGES ...........................................................................125 
 
LIST OF TABLES 
Table 1 - Spinal Muscular Atrophy Classification ........................................................................25 
Table 2 - Investigational Product ...................................................................................................49 
Table 3 - Total Blood Volume: Patient ..........................................................................................62 
Table 4 - Total Blood Volume: Biological Mother .......................................................................63 
Table 5 - Common Terminology Criteria for Adverse Events ......................................................66 
Table 6 - Tissue Sample for Analysis ............................................................................................98 
LIST OF FIGURES 
Figure 1 - Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 2, 
and 3 ............................................................................................................................27 
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Figure 2 - Study Results, Including Staining of Transduced Spinal Motor Neurons, SMN 
Expression Levels, Righting Ability, and Weight and Survival Curves ....................29 
Figure 3 - Body Mass of Treated and Control Mice Showed No Difference ................................30 
Figure 4 - Study Design .................................................................................................................43 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study 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 
AST 
Aspartate aminotransferase 
AT 
Aminotransferase 
BSID 
Bayley Scales of Infant and Toddler Development 
BUN 
Blood urea nitrogen 
CB 
Chicken-β-actin-hybrid 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practice 
CHOP INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders 
Chronological development 
reference standard 
Fine and Gross motor development will reference and be assessed using the 
Bayley Scales of Infant and Toddler Development© V.3 Gross and Fine 
Motor Subsets 
CK 
Creatine kinase 
CK-MB 
Creatine kinase isoenzyme 
CMAP 
Compound motor action potential 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CTCAE 
Common Terminology Criteria for Adverse Events 
Day 1 
First 24-hour interval after the start of gene replacement therapy infusion 
Day –1 
24-hour interval prior to the start of gene replacement therapy infusion  
ddPCR 
Droplet digital polymerase chain reaction 
DMC 
Data Monitoring Committee 
DRG 
Dorsal root ganglia 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELISpot 
Enzyme-linked ImmunoSpot 
EOS 
End of Study 
ET 
Early Termination 
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Abbreviation or Specialist Term 
Explanation 
Functional independent sitting 
Sitting without support for ≥30 seconds (Bayley Scales of Infant and 
Toddler Development v.3 – Gross Motor subset #26) 
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 
HgB 
Hemoglobin 
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 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
ITR 
Inverted terminal repeat 
ITT 
Intent-to-treat 
IV 
Intravenous 
LFT 
Liver function test 
NHP 
Non-human primate 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHP 
Non-human primates 
NOAEL 
No Observable Adverse Effect Level 
OAE 
Other Adverse Event 
PBMC 
Peripheral blood mononuclear cells 
Permanent Ventilation 
Tracheostomy or 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. 
PICU 
Pediatric intensive care unit 
PNCR 
Pediatric Neuromuscular Clinical Research Network 
rAAV 
Recombinant Adeno-associated virus 
Respiratory intervention 
Use of ventilatory support (Bi-level Positive Airway Pressure (BiPAP) or 
other ventilator) for ≥14 consecutive days in the absence of an acute 
reversible illness, excluding perioperative ventilation 
RNA 
Ribonucleic acid 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
scAAV 
Self-complimentary adeno-associated virus 
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Abbreviation or Specialist Term 
Explanation 
scAAV9.CB.SMN 
Self-complimentary 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 
Standard deviation 
7+ points on the scaled scoring for the gross and fine motor subsets of the 
Bayley Scales of Infant and Toddler Development© V.3  
Standing alone 
Stand without support for at least 3 seconds (Bayley© Scales of Infant and 
Toddler Development – Gross Motor Subset #40) 
Survival 
Avoidance death or the requirement of permanent ventilation (including 
non-invasive ventilatory support ≥16 hours per Day for ≥2 weeks) in the 
absence of acute reversible illness or perioperatively 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin 
ULN 
Upper limit normal 
US 
United States 
vg/kg 
Vector genome per kilogram 
Walking alone 
 
(Bayley© Scales of Infant and Toddler Development – Gross Motor Subset 
#43) 
WBC 
White blood cell 
WHO 
World Health Organization 
WHO-MGRS 
World Health Organization Multcentre Growth Reference Milestones 
wtAAV 
Wild type Adeno-associated virus  
WT 
Wild type 
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5. 
INTRODUCTION 
Study AVXS-101-CL-304 is a Phase 3 clinical gene therapy study investigating the efficacy and 
safety of a single intravenous (IV) infusion of AVXS-101 in up to 26 patients with spinal 
muscular atrophy (SMA) having either 2 or 3 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 a facial vein.  Additionally, results 
from a completed Phase 1 clinical study (AVXS-101-CL-101) of AVXS-101 in SMA Type 1 
patients demonstrates broad improvements in motor function, pulmonary function, and 
nutritional function (Section 5.4) as well as survival beyond 20 months of age for 100% of 
treated patients. 
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 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 neuron loss in SMA 
Type 2 and Type 3 patients is less profound and a greater population of neurons is able to survive 
and compensate during development and persist into adult life.  The findings from various 
neurophysiological and animal studies have shown an early loss of motor neurons in the 
embryonic and early post-natal periods (2-4).  From a clinical perspective, these findings 
emphasize the importance of targeting pre-symptomatic SMA patients, regardless of their 
ultimate disease course, for gene transfer of SMN1 in hopes of rescuing neurons at this critical 
stage.  The goal in continuing the development plan for AVXS-101 is to modify the SMA 
phenotype, which will hopefully lead to a milder disease course, reduced morbidity and 
prolonged survival for all patients with SMA. 
Therapeutic efforts in SMA have focused on the potential for small molecules to increase SMN 
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).  FDA recently approved nusinersen, an antisense 
oligonucleotide 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 which require clinical 
monitoring.  A single-dose IV administration study of AVXS-101 in pre-symptomatic patients 
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will provide information on the potential gene transfer has in treating SMA patients early and 
will hopefully show promise for success in modifying the disease prognosis. 
This is a single-dose study that will include up to 26 patients with 2 or 3 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 and its potential impact on systems outside of the central nervous system 
(CNS) such as the peripheral and autonomic nervous systems, heart, pancreas and 
gastrointestinal tract. 
5.2. 
Rationale for Gene Transfer to Pre-Symptomatic SMA Patients 
Patients with pre-symptomatic genetically diagnosed SMA have been chosen as the target 
population for this gene therapy study 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. 
As discussed in Section 5.4: Clinical Studies, a robust clinical response was seen amongst 
symptomatic patients with 2 copies of SMN2 and early symptom onset consistent with SMA 
Type 1, with 9 of 12 patients treated at the proposed therapeutic dose achieving the ability to sit 
independently, and 11 of 12 surpassing a Children’s Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders (CHOP INTEND) score of 40 points, a threshold not achieved by any 
untreated type 1 patients older than 6 months of age.  There appears to be a relationship between 
baseline age and function and motor function achievement.  One patient treated at almost 
8 months of age with poor baseline function showed modest response to treatment; in contrast 
two patients treated within the first 2 months of life with relatively modest symptoms have 
showed a dramatic clinical response and are both walking independently.  This suggests that 
there is a critical window to treat before significant motor neuron loss has occurred to achieve 
the optimal response to intervention with AVXS-101.  Under this paradigm, treating patients in a 
pre-symptomatic setting represents the idealized approach to therapeutic intervention in this 
disease. 
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 
4-8 
Source: Adapted from Kolb 2011 (9) 
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. 
 
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Spinal muscular atrophy Type 1 patients, by definition, never attain independent sitting and have 
hypotonia within the first 6 months of life.  Spinal muscular atrophy Type 1 is the leading 
genetic cause of infant death with an onset at ≤6 months of age (Table 1).  In contrast, SMA 
Type 2 manifests within the first 18 months, and children afflicted with this condition are able to 
maintain sitting unassisted but never walk independently.  Spinal muscular atrophy Type 3 
patients attain the ability to walk unaided (Type 3a have onset before 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 (10).  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 (10-12).  Although 
SMN2 cannot completely compensate for the loss of the SMN1 gene, patients with milder forms 
of SMA generally have higher SMN2 copy numbers (13, 14).  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 study by 
Feldkotter et al 2002, 2 copies of SMN2 was 97% predictive for developing SMA Type 1, 
3 copies of SMN2 was 83% predictive for developing SMA Type 2, and 4 copies of SMN2 was 
84% predictive of SMA Type 3 (15).  As these percentages do not reflect the possible impact of 
modifier mutations such as that described by Prior et al 2009 (16), they may understate the 
relationship between copy number (in the absence of a genetic modifier) and clinical phenotype.  
Among 113 patients with Type 1 SMA, 9 with one SMN2 copy lived <11 months, 88/94 with 
two SMN2 copies lived <21 months, and 8/10 with three SMN2 copies lived 33 to 66 months.  
Even more refined data describing this relationship has been generated and has also influenced 
our choice of the study target group. 
The severity of SMA Type 1 is demonstrated by prognosis as illustrated in Kaplan-Meier 
survival curves shown in . 
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Figure 1 - Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 2, 
and 3 
 
n = number of patients 
Source: Farrar 2013 (17) 
 
In , 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  
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 (2-4). 
It is important to note that the classification system used in SMA is based upon best function 
(and expectation of best function extrapolated from clinician experience at the time of diagnosis) 
in a clinical landscape devoid of disease modifying therapies.  Given the close relationship 
between SMN2 copy number and expected clinical course, it makes more sense to approach the 
disease in a prospective manner from the perspective of SMN2 copy number rather than clinical 
symptoms that will no longer be fully manifested in effectively treated patients. 
There is reason to believe that there are few safety issues to be concerned about when targeting 
pre-symptomatic, genetically diagnosed SMA patients in this gene therapy clinical study.  
Overexpression of SMN has been shown to be well tolerated in both mice and non-human 
primates (NHPs), 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 expression.  Additionally, it is important to point out that recombinant scAAV 
can be employed for this study because of the small size of the SMN gene.  This enables efficient 
packaging and allows for efficient gene transfer with lower viral titers (a safety consideration), 
compared with prototypical single-stranded adeno-associated virus (AAV) vectors. 
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Recent studies using self-complimentary adeno-associated virus serotype 9 
chicken-β-actin-hybrid survival motor neuron (scAAV9.CB.SMN) show a robust post-natal 
rescue of SMNΔ7 mice with correction of motor function, neuromuscular electrophysiology and 
survival after a one-time delivery of the vector (18).  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 multiple 
variants.  It was found that the double transgenic, referred to as the SMNΔ7 mouse, provided the 
most suitable model to study gene transfer (19).  Studies performed in the 
 
have shown that injecting 5 × 1011 viral genomes of scAAV9.CB.SMN into the facial vein on 
Day 1 old mice rescues the SMNΔ7 mouse model (18).   shows the results of these studies, 
including staining of transduced spinal motor neurons, SMN 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 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 were assessed for their righting 
ability and were compared to WT control mice and untreated mice.  Wild type controls could 
right themselves quickly, whereas the SMN- and GFP-treated SMA animals showed difficulty at 
P5; however, by P13, 90% of SMN-treated animals could right themselves compared with 
20% of GFP-treated controls and 0% of untreated SMA animals.  At P18, SMN-treated animals 
were larger than GFP-treated animals, but smaller than WT controls.  Locomotive ability of the 
SMN-treated mice was nearly identical to WT controls, as assayed by open field testing and 
wheel running. 
Survival of SMN-treated SMNΔ7 animals compared with GFP-treated SMNΔ7 animals was 
significantly improved.  No GFP-treated control animals survived past P22 and had a median life 
span of 15.5 days.  The weights of GFP mice peaked at P10 and then precipitously declined until 
death, while SMN mice showed a steady weight gain until around P40 with it stabilizing at 17 g 
(about half the weight of WT controls).  The smaller size of corrected animals is likely related to 
the tropism and incomplete transduction of scAAV9, resulting in a ‘chimeric’ animal in which 
some cells were not transduced.  Additionally, the smaller size suggests an embryonic role for 
SMN.  Most remarkably, SMN-treated mice survived well past 250 days of age. 
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Figure 2 - Study Results, Including Staining of Transduced Spinal Motor Neurons, SMN 
Expression Levels, Righting Ability, and Weight and Survival Curves 
 
Source: Foust 2010 (18) 
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 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 (GLP) studies, 24 mice and 4 NHPs were injected, by way 
of vascular delivery, with AVXS-101.  To assess toxicity and safety, AVXS-101 was injected 
into P1 WT Friend Virus B-Type (FVB) mice with either vehicle (3 males/6 females) or 
3.3 × 1014 vg/kg of 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 (18).  P1 mice 
were used in anticipation of simulating potential clinical studies in infants.  All mice survived the 
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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 study; neither revealed any difference between control and treated cohorts 
(). 
Figure 3 - Body Mass of Treated and Control Mice Showed No Difference 
 
 
At 60, 90 and 180 days post-injection, blood from the mice was collected for hematology studies 
including complete blood counts with differentials.  At 90, 120 and 180 days post-injection, 
blood was collected for clinical chemistries assessment (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], alkaline phosphatase, creatinine, blood urea nitrogen [BUN], 
electrolytes, and creatine kinase [CK]).  For histopathology, 13 mice were necropsied at 
120 days post-injection and 8 mice at 180 days.  There were no clinically significant results 
observed during from the hematology, clinical chemistry, and histopathology portions of the 
study 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 made cellular morphology obscure and subtle changes may not have been identified. 
In the safety study for the 4 male cynomolgus macaques, animals were injected at 90 days of age 
to closely mimic the likely age of administration of treatment in SMA Type 1 infants.  The 
AVXS-101 vector was administered one time by catheterization of the saphenous vein with a 
dose of 6.7 × 1013 vg/kg, which corresponds to the lowest dose tested for which SMNΔ7 mice 
showed a significant increase of survival.  Animals were followed for six months until they were 
sacrificed at approximately 9 months of age.  No adverse effects were seen, and all clinical 
chemistries were normal.  T-cell immune response was tested using Enzyme-linked ImmunoSpot 
(ELISpot) in peripheral blood mononuclear cells (PBMCs), and all were negative at 6 months 
post-injection. 
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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 [data on file]. 
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 (RNA) expression in brain and spinal cord, the main targeted therapeutic tissues.  
Low levels of antibodies to the AAV9 capsid were found after 12 and 24 weeks in males and 
females given 3.3 × 1014 vg/kg (Group 3).  No alteration was observed in clinical pathology and 
histopathology analyses.   
As part of the preclinical development of AVXS-101 for intrathecal delivery, an exploratory 
non-GLP biodistribution and safety study was performed in cynomolgus monkeys 
(Macaca fascicularis) to evaluate the transduction efficiency and safety of intrathecally 
administered AVXS-101 at a dose of 3 × 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 
two of the twelve animals on study.  The animals were not administered corticosteroids.   
The DRG was not identified as a target organ of toxicity in previous AVXS-101 studies 
conducted in mice (ICV route of administration) or cynomolgus monkeys (IV or IT routes of 
administration).  However, similar findings have been reported after administration of 
AAV9 vectors in monkeys and minipigs (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, 
inflammation and thrombosis.  Liver findings were comprised on hepatocellular hypertrophy, 
Kupffer cell activation, and scattered hepatocellular necrosis.  A no observable adverse event 
level (NOAEL) was not identified for AVXS-101-related heart and liver findings in the mouse, 
and the maximum tolerated dose was defined as 1.5 × 1014 vg/kg, providing a safety margin of 
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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 study AVXS-101-CL-101 is a completed 2-year study 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 at all 3 time 
points 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, 2014 (22). 
• 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 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 
(22).  
• Other clinically meaningful developmental milestones were maintained 24 months 
after AVXS-101 infusion: 
o Of the 7 patients in Cohort 2 who did not require non-oral nutrition prior to 
AVXS-101 dosing, 5 (71.4%) maintained the ability to thrive 
o Eleven Cohort 2 patients (91.7%) were still able to swallow effectively enough to 
feed orally 
o Seven of 15 patients (46.7%) remained independent of ventilatory support 
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5.5. 
Risks 
A full understanding of all risks of 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 (23). 
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 (24).  The relevance to humans with SMA is unknown. 
Respiratory tract infections in neonates are very common in the general pediatric population 
(25).  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 (26).  RSV is the 
primary cause of hospitalization for respiratory tract infection in young children (27).  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 (28), are also recommended 
(29) 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 on 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 United States (US) Managed Access Program with 
AVXS-101.  A 6-month-old male concurrently receiving nusinersen with elevations of AST and 
ALT of > 3 x 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 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 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 101, 303, and 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 Adeno-associated 
virus (rAAV) vectors predominantly persists as extrachromosomal elements (episomes) rather 
than integrating into host cell genomes (30).  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 adeno-associated virus (wtAAV), 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 (31, 32).  Since the AVXS-101 product uses AAV9 with all of the WT DNA 
removed from the capsids, except for the Inverted Terminal Repeats (ITRs), 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 
currently used in 162 clinical trials to date in which no cancer of any type has been observed or 
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reported.  For a review of the topic, see Srivastava and Carter, 2017 (33).  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 NHPs 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 (34), except in one case in which very large doses of wtAAV and adenovirus were 
administered in a particular setting.  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 four weeks after the injection.  
Additionally, patients are prohibited from donating blood for two 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 
five patients for viral shedding analysis.  This analysis detects the number of genome copies by 
droplet digital polymerase chain reaction (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 
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 
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of the assay [data on file].  Shed AAV vectors have been previously shown not to be infectious 
in urine and saliva excreta (34).  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.  The 
clinical relevance of the DRG findings in cynomolgus monkeys is unknown at this time.  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 
cutoff of 31 December 2019, did not identify any AEs 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 IV 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 pre-symptomatic 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, 
and 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 pre-symptomatic 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. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Safety Objectives 
6.1.1. 
Primary Objectives 
The safety objectives are to: 
• Evaluate the safety of AVXS-101 through incidence of AEs and/or serious adverse 
events (SAEs) 
• Assess the safety of AVXS-101 based on the change from baseline in clinical 
laboratory parameters 
6.2. 
Efficacy Objectives 
Efficacy objectives will be assessed independently for each cohort. 
6.2.1. 
Patients with bi-allelic SMN1 deletions and 2 copies of SMN2 
6.2.1.1. 
Primary Objective (2 copy) 
Assess the efficacy of AVXS-101 by demonstrating functional independent sitting for 
 
 as defined by Bayley Scales of Infant and Toddler Development© Version 3 
(BSIDv03) Gross Motor Subtest Item #26 at any visit up to 18 months of age. 
6.2.1.2. 
Secondary Objective (2 copy) 
Secondary objectives include: 
• Assess the efficacy of AVXS-101 based on survival, defined as avoidance of death or 
the requirement of permanent ventilation in the absence of acute illness or 
perioperatively as assessed at 14 months of age  
• Assess efficacy of AVXS-101 by demonstrating the ability to maintain weight at or 
above the third percentile without need for non-oral/mechanical feeding support at 
any visit up to 18 months of age 
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6.2.1.3. 
Exploratory Objectives (2 copy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.2.2. 
Patients with bi-allelic SMN1 deletions and 3 copies of SMN2 
6.2.2.1. 
Primary Objectives (3 copy) 
Assess the efficacy of AVXS-101 based on the proportion of patients achieving the ability to 
stand without support for at least 3 seconds as defined by BSIDv03 Gross Motor Subtest 
Item #40 at any visit up to 24 months of age. 
6.2.2.2. 
Secondary Objectives (3 copy) 
Assess the efficacy of AVXS-101 by demonstrating the ability to walk alone defined as the 
 as defined by 
BSIDv03 Gross Motor Subtest Item #43 at any visit up to 24 months of age. 
6.2.2.3. 
Exploratory Objectives (3 copy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, open-label, single-arm study of a single, one-time dose of AVXS-101 
(gene replacement therapy) in patients with SMA who meet enrollment criteria and are 
genetically defined by bi-allelic deletion of SMN1 with 2 or 3 copies of SMN2.  Patients with 
SMN1 point mutations or the SMN2 gene modifier mutation (c.859G>C) may enroll but will not 
be included in the efficacy analysis sets. 
At least 14 patients with bi-allelic deletion of SMN1 and 2 copies of SMN2, and at least 
12 patients with bi-allelic deletion of SMN1 and 3 copies of SMN2 that are ≤6 Weeks of age 
at the time of gene replacement therapy (Day 1) will be enrolled. 
The study includes a screening period, an inpatient gene replacement therapy period, and an 
outpatient follow-up period.  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 study enrollment.  Patients who meet the entry criteria will enter the 
in-patient gene replacement therapy period (Day –1 to Day 2).  On Day –1, patients will be 
admitted to the hospital for pre-treatment baseline procedures.  On Day 1, patients will receive a 
single, one-time IV infusion of AVXS-101 and will undergo in-patient safety monitoring over 
the next 24 hours.  Patients may be discharged 24 hours after the infusion, based on Investigator 
judgment.  During the outpatient follow-up period (Days 3 to EOS at 18 or 24 months of age, 
dependent upon respective SMN2 copy number), patients will return at regularly scheduled 
intervals for efficacy and safety assessments until the EOS when the patient reaches 18 months 
of age (SMN2 = 2) or 24 months of age (SMN2 = 3).  After the EOS visit, patients will be 
monitored for safety for 30 days.  Additionally, eligible patients will be invited to participate in a 
long-term follow up study conducted under a separate protocol. 
After dosing, follow-up visits will be conducted according to the Schedule of Assessments (SoA) 
(Appendix 1).  Visits prior to and including the Day 72 visit are timed based on the Day of 
AVXS-101 dose (Day 1).  Visits following Day 72 are based on patient’s date of birth.  The EOS 
visit for patients with 2 and 3 copies of SMN2 will be the 18 and 24 months old visits, 
respectively.  However, safety monitoring will continue for 30 days after EOS visit.  Any missed 
visit should be rescheduled as soon as possible within the window described in the SoA.  All 
visits will be scheduled based on a 30-day month calender.  
In an attempt to dampen the host immune response to the AAV derived therapy, all patients will 
receive prophylactic prednisolone (or equivalent glucocorticoid) at approximately 2 mg/kg/day 
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 × 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.  
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If the GGT, AST, or ALT values are > 2 × ULN, the dose of prednisolone will be maintained 
until the GGT, 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 functional 
independent sitting for at least 30 seconds (SMN2 = 2) at any visit up to 18 months of age; and 
ability to stand without support for at least 3 seconds (SMN2 = 3) at any visit up to 24 months of 
age.  Additional developmental milestones will be assessed using the WHO-MGRS and 
BSIDv03.  Safety will be assessed through monitoring AEs, concomitant medication usage, 
physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluations.  
The primary efficacy analysis for each SMN2 copy number cohort will be completed separately 
at such time that enrollment in the respective cohort is complete and the last patient has 
discontinued or completed the EOS visit at the respective age (SMN2 = 2, EOS = 18 months of 
age; SMN2 = 3, EOS = 24 months of age). 
After the EOS 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 that unforeseen catastrophic or other serious situations (such as the COVID-19 
pandemic) impact the ability to conduct the study on-site, alternative methods of continuing 
study assessments may be implemented.  Alternative visits include phone calls, virtual contacts 
through teleconsult or videoconference, or visits by site staff/home nursing providers to the 
patient’s home depending on local regulations, institutional policies, and capabilities of the 
investigative site.  Alternative visits may take place instead of on-site visits until such time that 
the patientt can safely return to the site.  The process for obtaining remote informed consent must 
be followed if alternative study visits will be conducted (Section 18.3).  
Throughout the study, the scheduling of study visits should adhere to the overall study schedule 
and visit windows defined in the protocol.  For each study visit, all study procedures and 
assessments should be performed or completed in accordance with the schedule of events.  Local 
institutions or other alternatives may be utilized. 
Importantly, in instances in which the final scheduled study visit is not possible to be conducted 
at the study site, the final scheduled study visit should be performed all or by an alternative visit 
within the protocol-defined visit window.  Critical data that pertain to the primary and secondary 
endpoints and other information such as adverse events, concomitant medications, use of feeding 
or ventilatory support, or other safety data that may be obtained remotely should be collected as 
part of the final study visit and within the protocol-defined visit window.   
Procedures such as laboratory and other safety assessments that cannot be performed or obtained 
as part of a remote visit may be performed separately and preferably within the protocol-defined 
visit window.   
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Figure 4 - Study Design 
Patients with 2 copies of SMN2 
 
Note:  After the EOS visit at 18 months of age, patients will be monitored for safety for 30 days after the EOS visit.  
Additionally, patients will be invited to participate in a long-term follow-up study conducted under a separate protocol. 
EOS = End of Study; ET = early termination 
 
Patients with 3 copies of SMN2 
 
Note:  After the EOS visit at 24 months of age, patients will be monitored for safety for 30 days after the EOS visit.  
Additionally, patients will be will be invited to participate in a long-term follow-up study conducted under a separate protocol. 
EOS = End of Study; ET = early termination 
 
Additionally, a Data Safety Monitoring Board (DSMB)/Data Monitoring Committee (DMC) will 
review safety data on a quarterly basis.  A detailed description of the DSMB/DMC, its role in 
this trial, and the timing and process of the scheduled reviews will be described in a 
DSMB/DMC Charter.   
7.2. 
Number of Patients 
At least 26 patients meeting the ITT criteria will be enrolled.  Sponsor may cap enrollment in one 
geographic region to ensure appropriate regional patient distribution as necessary. 
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7.3. 
Criteria for Study Termination 
An independent DSMB/DMC will conduct quarterly and ad hoc reviews of the emerging safety 
data throughout the study as described in Section 15. 
The study 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 study for safety reasons.   
• Study is terminated by Sponsor 
• Regulatory Authority recommendation 
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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients with SMA who are ≤6 Weeks (≤42 days) of age at the time of gene replacement 
therapy (Day 1) with documented absence of the SMN1 gene and 2 or 3 copies of the SMN2 gene 
will be enrolled in this study.  Patients may be of any racial, ethnic, or gender background. 
The primary and secondary efficacy analyses will be performed on the population of patients 
with bi-allelic SMN1 deletions and 2 or 3 copies of SMN2 without the SMN2 gene modifier 
mutation (c.859G>C).  While the study may enroll a small number of patients that don’t meet 
these criteria, the above will comprise the population for evaluation of the primary and 
secondary endpoints and will be referred to as the Intent-To-Treat (ITT) population hereafter.  
Patients with SMN1 point mutations and patients with the SMN2 gene modifier mutation 
(c.859G>C) will be evaluated separately as part of additional subgroup analyses. 
8.1. 
Patient Inclusion Criteria 
Patients must meet all of the following inclusion criteria: 
All patients: 
1. Age ≤6 Weeks (≤42 days) at time of dose 
2. Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test 
3. Compound muscle action potential (CMAP) ≥2mV at Baseline; centralized review of 
CMAP data will be conducted 
4. Gestational age of 35 to 42 weeks 
5. Up-to-date on childhood vaccinations that include palivizumab prophylaxis (also known 
as Synagis) to prevent RSV infections are also recommended in accordance with the 
guidance of local health authorities. 
6. Able and willing to follow the Consensus Statement for Standard of Care in Spinal 
Muscular Atrophy (36) 
7. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and 
comply with study procedures and visit schedule 
8. Genetic diagnosis as described below, obtained from an acceptable newborn or pre-natal 
screening test method: 
Patients with 2 copies of SMN2 (n ≥14) 
• Patients with pre-symptomatic SMA Type 1 as determined by the following features: 
− 2 copies of SMN2 
Patients with 3 copies of SMN2 (n ≥12) 
• Patients with pre-symptomatic SMA Type 2 as determined by the following features: 
− 3 copies of SMN2 
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8.2. 
Patient Exclusion Criteria 
Patients must not meet any of the following exclusion criteria: 
1. Weight at screening visit <2 kg 
2. Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen 
or respiratory support) at the screening visit or for altitudes >1000 m, oxygen saturation 
<92% awake or asleep without any supplemental oxygen or respiratory support at the 
screening visit 
3. Any clinical signs or symptoms at screening or immediately prior to dosing that are, in 
the opinion of the Investigator, strongly suggestive of SMA (e.g., tongue fasciculation, 
hypotonia, areflexia) 
4. Tracheostomy or current prophylactic use or requirement of noninvasive ventilatory 
support at any time and for any duration prior to screening or during the screening period 
5. Patients with signs of aspiration/inability to tolerate nonthickened liquids based on a 
formal swallowing test performed as part of screening or patients receiving any non-oral 
feeding method 
6. Clinically significant abnormal laboratory values (GGT, ALT, and AST, or total 
bilirubin > 2 × the ULN, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; 
white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy.  Patients 
with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall 
not be excluded.  
7. Patients with any other clinically significant abnormalities in hematology or clinical 
chemistry parameters as determined by investigator or medical monitor 
8. Treatment with an investigational or commercial product, including nusinersen, given for 
the treatment of SMA.  This includes any history of gene therapy, prior antisense 
oligonucleotide treatment, or cell transplantation. 
9. Patients whose weight-for-age is below the third percentile based on World Health 
Organization (WHO) Child Growth Standards (37). 
10. Biological mother with active viral infection as determined by screening laboratory 
samples (includes human immunodeficiency virus [HIV] or positive serology for 
hepatitis B or C) 
a. Biological mothers with clinical suspicion of Zika virus that meet Centers for Disease 
Control and Prevention (CDC) Zika virus epidemiological criteria including history 
of residence in or travel to a geographic region with active Zika transmission at the 
time of travel will be tested for Zika virus RNA.  Positive results warrant confirmed 
negative Zika virus RNA testing in the patient prior to enrollment. 
11. Serious nonrespiratory tract illness requiring systemic treatment and/or hospitalization 
within 2 Weeks prior to screening 
12. Upper or lower respiratory infection requiring medical attention, medical intervention, or 
increase in supportive care of any manner within 4 Weeks prior to dosing 
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13. Severe nonpulmonary/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 Investigator or Sponsor medical monitor, creates unnecessary 
risks for gene replacement therapy such as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalciuria 
e. Symptomatic cardiomyopathy 
14. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients. 
15. Previous, planned or expected major surgical procedure including scoliosis repair 
surgery/procedure during the study assessment period 
16. 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, immunosuppressive therapy 
within 4 Weeks prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, 
tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab) 
17. AntiAAV9 antibody titer >1:50 as determined by Enzyme-linked Immunosorbent Assay 
(ELISA) binding immunoassay 
a. Should a potential patient demonstrate AntiAAV9 antibody titer >1:50, he or she may 
receive retesting inside the 30-Day screening period and will be eligible to participate 
if the AntiAAV9 antibody titer upon retesting is ≤1:50, provided the <6 Week age 
requirement at the time of dosing is still met 
18. Biological mother involved with the care of the child refuses anti-AAV9 antibody testing 
prior to dosing 
19. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or 
inability to travel for repeat visits 
20. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to 
refrain from posting confidential study results/observations on social media sites 
21. Parent(s)/legal guardian(s) refuses to sign consent form 
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8.3. 
Patient Withdrawal Criteria 
Patients may be discontinued from the study for the following reasons: 
• Death 
− Post-mortem tissue/sample collection will be requested for any patient who 
expires following treatment with AVXS-101 (see Post-mortem Plan in 
Appendix 2) 
• Parent(s)/legal guardian(s) withdraws consent 
• Investigator discretion 
End of study procedures should be completed within 14 days for any patient who prematurely 
discontinues the study 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 Product 
The biological product is a non-replicating recombinant AAV9 containing the complimentary 
deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus 
(CMV) enhancer/CB promoter.  The AAV ITR has been modified to promote intramolecular 
annealing of the transgene, thus forming a double-stranded transgene ready for transcription.  
This modified ITR, termed a “self-complementary” (sc) ITR, has been shown to significantly 
increase the speed of which the transgene is transcribed, and the resulting protein is produced.  
The biological product, called AVXS-101, expresses the human SMN protein in transduced 
cells. 
Table 2 - Investigational Product 
 
Investigational Product 
Product Name: 
AVXS-101 
Unit Dose 
1.1 × 1014 vg/kg 
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 study 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 study (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 (38)) 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 values, and AST 
values are below the threshold of 2 × ULN.  To summarize, the overall course of prednisolone 
should follow the following treatment guideline: 
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• 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 
• 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 (LFTs) 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 maintained until the GGT, AST, 
and ALT values decrease below threshold, at which time 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 diabetes, myopathy or neuropathy 
• 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 βagonists 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 study 
• Ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as 
adalimumab, or immunosuppressive therapy within 4 Weeks of starting the study 
(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 AE. 
Should the use of corticosteroids (aside from inhaled corticosteroids for bronchospasm) be 
considered as part of care during the course of the prednisolone taper, this medical management 
should be discussed with the medical monitor. 
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9.2.3. 
Vaccinations 
Where feasible, the vaccination schedule should be adjusted appropriately to accommodate the 
prednisolone use.  When avoiding vaccination while on steroids represents an undue delay or 
interruption of a vaccination schedule, vaccination should continue at the discretion and 
judgement of the treating physician given 1) the importance of maintaining childhood 
vaccination in this population and 2) the published literature that indicates that vaccination while 
on steroid doses 1 mg/kg/day or below is safe and effective (39, 40). 
Vaccinations that include palivizumab (also known as Synagis®) prophylaxis to prevent 
respiratory syncytial virus (RSV) infections are also recommended (40, 41). 
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 study. 
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10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT 
AVXS-101 is manufactured in accordance with current Good Manufacturing Practices (cGMP).   
10.1. 
Study Product 
AVXS-101 
10.2. 
Study Product Dose and Dose Justification 
Patients will receive a onetime dose of AVXS-101 at 1.1 × 1014 vg/kg; this dose is equivalent to 
the dose received by the second dosing cohort in the Phase 1 study via IV infusion administered 
in the 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 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 life time in direct comparative assessment between the 
Phase 1 and Phase 3 IMP. 
10.3. 
Study Product Packaging and Labeling 
AVXS-101 kits will be labeled with a specific kit number and lot number assigned at the cGMP 
facility.  The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
10.4. 
Study Product Storage and Destruction 
AVXS-101 kits will be stored in an appropriate, locked 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 and/or return to AveXis, Inc. (AveXis) in accordance with the 
Pharmacy manual and applicable biohazardous waste guidelines for disposal. 
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10.5. 
Study Product Preparation 
Preparation of AVXS-101 should be done under sterile conditions by a pharmacist and will 
arrive at the clinical site ready for infusion. 
The total vector genome dose will be calculated based on the patient’s body weight. 
The dose-delivery syringe will be delivered to the designated dosing location in accordance with 
the Pharmacy Manual. 
10.6. 
Study Product Administration 
AVXS-101 infusion will be administered under sterile conditions in a pediatric intensive care 
unit (PICU) or other appropriate setting (e.g., interventional suite, operating room, dedicated 
procedure room) with immediate access to acute critical care management.  AVXS-101 will be 
delivered one-time through a venous catheter inserted into a peripheral limb vein (arm or leg) at 
a dose of 1.1 × 1014 vg/kg.  AVXS-101 should be slowly infused over approximately 60 minutes 
utilizing an infusion set and syringe pump in accordance with the Pharmacy Manual.  Vital signs 
will be continuously monitored throughout the gene replacement therapy infusion as described in 
Section 12.1.3. 
Following administration of gene replacement therapy, patients should remain in the dosing suite 
or be moved to an appropriate designated setting to ensure close monitoring of vital signs and 
AEs for a minimum of 24 hours after the start of gene replacement therapy. 
10.7. 
Dose Adjustment Criteria 
The study investigates a one-time IV infusion of AVXS-101; no dose adjustments are possible. 
10.8. 
Study 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 return of the used vessel to AveXis or destruction as per the Pharmacy Manual or the site’s 
local standard operating procedure. 
10.9. 
Study Product Handling and Disposal 
All materials used for injection, including sterile drapes, needles, and syringes in contact with the 
vector must be sealed in leak-proof containers.  All waste must be sealed in bags bearing the 
biohazard symbol and disposed of in a biohazard waste container. 
All transfers must be done in spill-proof containers.  Individuals manipulating the vector will be 
required to wear personal protective equipment, such as gloves. 
Any quality issue noticed with the receipt or use of AVXS-101 (e.g., deficiency in condition, 
appearance, pertaining to documentation, labeling, expiration date, etc.) should be promptly 
reported to the Sponsor in accord 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 study protocol, or dispose of 
AVXS-101 in any other manner. 
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11. 
ASSESSMENT OF EFFICACY 
The primary efficacy endpoint will be achievement of the key developmental milestone of 
functional independent sitting for at least 30 seconds at any visit up to the 18 months of age 
study visit for patients with bi-allelic deletions of SMN1 and 2 copies of SMN2.  The secondary 
endpoint of survival, the proportion of patients that have survived and have not required 
permanent ventilation in the absence of acute illness or perioperatively, will be assessed at 
14 months of age.  The secondary endpoint of ability to thrive (proportion of patients that have 
achieved the ability to maintain weight at or above the third percentile without need for 
non-oral/mechanical feeding support) will be assessed at any visit up to the 18 months of age for 
these patients.  Additional developmental milestones will be assessed using the WHO-MGRS 
and BSIDv03. 
The primary efficacy endpoint will be achievement of key developmental milestone of standing 
without support for at least 3 seconds at any visit up to the 24 months of age study visit for 
patients with bi-allelic deletions of SMN1 and 3 copies of SMN2.  The secondary efficacy 
endpoint of achievement of the ability to walk alone defined as 
 
will be assessed at any visit up to 
the 24 months of age for these patients.  Additional developmental milestones will be assessed 
using the WHO-MGRS and BSIDv03. 
As the two SMN2 copy number cohorts (2 and 3 copy) described in this protocol have different 
natural histories and different disease severities, and, appropriate to their differing severities and 
natural histories will have different primary endpoints and different follow-up time periods in 
this protocol, each copy number cohort is in essence a separate clinical study.  The 
two studies/cohorts have been combined under a single protocol for administrative efficiency.  
As such, efficacy will be assessed in each cohort independently of the other. 
Efficacy assessments will be performed at the times specified in the Table of Assessments 
(Appendix 1) and should be the first assessments performed at any scheduled visit.   
In the event of unforeseen catastrophe or other, serious situation (such as the COVID-19 
pandemic) that occurs during the study, which limits or prevents on-site study visits, alternative 
methods of data collection pertaining to efficacy assessments may be considered.  Critical data 
that pertain to the primary and secondary endpoints should be collected according to the overall 
study schedule and within the protocol-defined visit window.  The maintenance of the overall 
visit schedule and visit windows is especially important for the final scheduled study visit, as this 
may impact the overall interpretation of the evaluation of efficacy.  As described in Section 7.1, 
allowances are made for the collection of data remotely, when necessary.  
Video recordings demonstrating the attainment of any new developmental milestones should be 
obtained within the protocol-defined visit window, including those that are required to be 
assessed as part of the final study visit or are related to primary or secondary endpoints 
(e.g, sitting without support).  This may include submission of recordings made by the family or 
others as described in Section 11.3.   
Alternative methods of data collection for efficacy assessments depending on local regulations, 
institutional polices, and capabilities may include:  
− developmental/motor efficacy assessments by a qualified clinical evaluator during 
a visit to the participant´s home 
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− 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 using relevant definitions obtained from the 
BSIDv03 and WHO-MGRS (Appendix 5) (35), and will be analyzed to assess efficacy 
(Appendix 3 and Appendix 4).  Achievement of each developmental milestone will be 
determined by 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 as shown in the SoA. 
The developmental milestone of sitting independently (BSIDv03 item #26:  sits without support 
for at least 30 seconds) should be assessed until attainment of milestone, regardless of starting 
point on the scale.  This milestone must be assessed, documented, and video recorded at the 
18 months of age visit for patients with 2 copies of SMN2, regardless of previous 
attainment.  End of study maintenance of this developmental milestone will be submitted 
for review by an independent central reviewer. 
The developmental milestones of standing without support for at least 3 seconds and walking 
alone (BSIDv03 items #40 and #43, respectively) should be assessed until attainment of 
milestone, regardless of starting point on the scale.  These developmental milestones must also 
be assessed, documented, and video recorded at the 24 months of age visit for patients with 
3 copies of SMN2, regardless of previous attainment.  End of study maintenance of this 
developmental milestone will be submitted for review by an independent central reviewer. 
As the Bayley Scales do not necessarily require the child to repeat previously attained 
developmental milestones, it is essential that each attained milestone be captured on video. 
A developmental milestone will be considered achieved when demonstrated by a patient and 
observed with video capture confirmation during a physical assessment or observed with video 
as provided by the patient’s family and confirmed by a central reviewer.  Developmental 
milestones can be achieved at any point during the study.  However, cohort-dependent primary 
and secondary endpoints should be reconfirmed at the patient’s EOS visit at 18 or 24 months of 
age. 
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11.2. 
Motor Function Tests 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental Milestones and 
World Health Organization Multicentre Growth Reference 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 the BSIDv03 Gross 
Motor Subtest defined as developmental milestones for this protocol are specified in Appendix 4. 
During the Screening visit, the clinical evaluator will complete an assessment of baseline 
milestone achievement in accordance with Appendix 3; this assessment must address all 
milestones/items noted in Appendix 3, Gross Motor Subtest that are at or below the child’s 
baseline function, and be recorded on video.  The findings must be documented in the source.  
Items that are below the baseline level of assessment that are not successfully achieved during 
the baseline evaluation should be repeated at subsequent visits until successfully performed. 
The milestones of sitting independently (item #26) should be assessed, documented and recorded 
at every subsequent visit, until attainment of milestone, regardless of starting point on the scale.   
As the Bayley Scales do not necessarily require the child to repeat previously attained 
milestones, it is essential that each attained milestone be captured on video. 
The gross and fine motor subtests of the motor domain will be administered according to the 
SoA (Appendix 1).   
Each Bayley Scales/WHO MGRS developmental milestone assessment will be video recorded in 
accordance with the AVXS-101-CL-304 Physical Assessments Manual and will be submitted for 
review by an independent central reviewer (Section 11.3). 
The following developmental milestones will be 
 (Appendix 4 and Appendix 5): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11.2.2. 
CHOP INTEND 
The CHOP INTEND (Appendix 6) is a motor function scale developed and validated for use 
specifically to monitor motor function status and decline amongst children with SMA Type 1, 
and will be administered by a qualified clinical evaluator (42, 43).  The CHOP INTEND scale 
examines several aspects of motor function, including head control, righting reactions, and trunk 
movements in supported sitting, supine, and prone positions (Appendix 6).  Anti-gravity 
movements in assisted rolling, ventral suspension, and supported standing will also be measured.  
Additional information on contractures will also be collected as described in the Physical 
Assessments Manual. 
The CHOP INTEND will be performed according to the SoA for patients with 2 copies of SMN2 
(Appendix 1). For purposes of efficacy assessments, the CHOP INTEND assessment performed 
at Day -1 will be treated as baseline. 
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-304 
Physical Assessments Manual and may be submitted for review by an independent central 
reviewer (Section 11.3). 
11.3. 
Video Evidence 
Clinic assessments (WHO Motor Developmental Milestones, Bayley Scales, CHOP INTEND, 
developmental milestone assessments) will be video recorded in an effort to produce compelling, 
demonstrable, documented evidence of efficacy, as determined by changes in functional abilities.  
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 study 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 study. 
Videos demonstrating Developmental Milestones which meet WHO and BSIDv03 criteria will 
be submitted to an independent, central reviewer for unbiased assessment of developmental 
milestone achievement.  The independent central reviewer will document whether the video 
displays evidence of having achieved each developmental milestone.  The date of developmental 
milestone achievement will be computed as the earliest date on which video evidence 
demonstrates the achievement of the specified developmental milestone. 
Additionally, the Parent(s)/legal guardian(s) may submit additional videos demonstrating 
achievement of developmental milestones at any time during the study.  These videos will be 
handled in the same manner in which the study-derived videos are handled. 
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11.4. 
Compound Motor Action Potential 
Peroneal nerve CMAP amplitude will be measured by a qualified electrophysiologist using the 
procedures as described in the CMAP Manual.  CMAP will be measured at screening, every 
6 months starting at 6 months of age, and EOS when the patient reaches 18 or 24 months of age 
(or early termination) (Appendix 1), depending on respective cohort. 
The CMAP data will be collected for centralized review and interpretation. 
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12. 
ASSESSMENT OF SAFETY 
In the event of unforeseen catastrophe or other, serious situation (such as the COVID-19 
pandemic) that occurs during the study, which limits or prevents on-site study visits, regular 
phone or virtual video calls may occur (as per the Schedule of Assessments) for safety 
monitoring and discussion of the participant´s health status.  Visits by site staff/home nursing 
service to the participant´s home, or visits by the participant to a local hospital, laboratory, or 
imaging center, for performing certain safety assessments, depending on local regulations and 
capabilities, can replace on-site study visits, if necessary.  Analysis of laboratory samples 
(e.g., chemistry, hematology, urinalysis) may be performed at a local laboratory, if it is not 
possible to follow the central laboratory process.  Other safety assessments that cannot be 
conducted by telephone (such as vital signs, weight, length, cardiac testing etc.) may similarly be 
collected by the methods described above. 
12.1. 
Safety Parameters 
Safety parameters include physical examinations, pulmonary examinations, vital signs, weight 
and length measurements, 12-lead ECGs, 24-hour Holter monitoring, echocardiograms, 
swallowing tests, laboratory assessments, AE monitoring, and photographs of the infusion site.  
In general, safety assessments will be performed at the times specified in the SoA (Appendix 1).  
Visits prior to and including the Day 72 visit are timed based on the Day of AVXS-101 dose 
(Day 1).  Visits following Day 72 are based on 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/weight/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 
Patients are encouraged to follow all routinely scheduled immunizations, as recommended by 
local health authorities, throughout the study.  Vaccinations that include palivizumab prophylaxis 
(also known as Synagis) to prevent RSV infections are also recommended in accordance with the 
guidance of local health authorities. 
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12.1.2. 
Physical Examinations 
Physical examinations will be conducted by the Investigator or designee as specified in the SoA 
(Appendix 1).  The Day 1 physical examination will be performed prior to the start of gene 
replacement therapy infusion.  Physical examinations include a review of the following systems: 
head, eyes, ears, nose and throat (HEENT), lungs/thorax, cardiovascular, abdomen, 
musculoskeletal, neurologic, dermatologic, lymphatic, 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 AE.  Further clinical evaluation should be considered 
as per judgment of the investigator. 
The head circumference shall be measured with each physical examination.  To measure head 
circumference, the examiner should securely wrap a flexible measuring tape around the 
circumference of the head, above the eyebrows over the broadest part of the forehead, above the 
ears, and over the most prominent part of the occiput.  The measurement should be taken 3 times, 
and the largest measurement should be recorded to an accuracy of 0.1 centimeters. 
12.1.3. 
Vital Signs/Weight and Length 
Vital sign parameters include blood pressure, respiratory rate, pulse, temperature, and pulse 
oximetry.  Vital signs will be obtained as specified in the SoA (Appendix 1).  On Day 1, vital 
signs with the exception of blood pressure will be recorded pre-dose and then continuously 
monitored as specified in the SoA (Appendix 1).  Temperature will be recorded pre- and 
post-infusion. 
Weight and length will be measured at each study visit (as specified in Appendix 1).  Screening 
weight shall be obtained 14 days prior to Day 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 (or early termination) (Appendix 1).  
Additional ECG 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 (or early 
termination) (Appendix 1).  
The echocardiogram will be interpreted locally by a cardiologist (or designee) for immediate 
safety evaluation.  The echocardiograms will also be collected for centralized review and 
interpretation by a cardiologist. 
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12.1.6. 
Twenty-Four Hour Holter Monitoring 
Twenty-four-hour Holter monitoring will be performed as specified in the SoA (Appendix 1).  
Holter monitors will be provided to study sites along with a dedicated laptop for uploading the 
data from the memory cards for centralized review and analysis by a cardiologist or designee 
within 72 hours of data upload.  AveXis will be notified of any safety concerns from the 
centralized review. 
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 study entry, a 
pulmonologist or appropriate individual as per standard institutional practice will review and 
document lack of requirement for ventilator usage in the 2 Weeks prior to screening. 
Patients may be fitted with non-invasive ventilatory support at the discretion of the 
pulmonologist (or appropriate individual as per standard institutional practice and/or 
Investigator).  Non-invasive ventilatory support equipment will be provided by AveXis, Inc. 
through a third-party vendor if not covered by the patient’s insurance.  Should the patient require 
non-invasive ventilatory support at any time during the study, the usage should be recorded in 
eCRF.  Patients requiring non-invasive ventilatory support will be asked to bring their 
machine(s) to each study 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 
for consistencies tested during the assessment.  The swallowing test at Screening can be 
performed at the investigator site.  If the test is positive for aspiration, there may be a 
recommendation for the patient to use an alternate method to oral feeding for the duration of the 
study 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.  Day 1 infusion site photograph will be performed after 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 study 
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 study. 
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12.1.10. 
Laboratory Assessments 
Blood samples will be collected at each scheduled visit as specified in the SoA (Appendix 1) and 
in accordance with laboratory manuals provided for this study.  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-101infusion period will be 
collected and processed by the investigative site’s local laboratory to ensure receipt of results 
prior to discharge.  Local laboratory tests should assess the same analytes listed in the protocol 
and include normal ranges appropriate for the age of the patient. 
Table 3 - Total Blood Volume: Patient 
Visit 
Tests 
Total Volume (mL) 
Screeningc 
Hematology, chemistry, CK-MB or troponin Ib,d,f, genetic re-confirmation testing 
5.6g 
Day 2 
Hematology, chemistry 
2.3 
Day 7 
Hematology, chemistry, CK-MB or troponin I 
3.6 
Day 14 
Chemistry 
1.3e 
Day 21 
Hematology, chemistry 
2.3 
Day 30 
Chemistry, CK-MB or troponin I 
2.6 
Day 44 
Chemistry 
1.3e 
Day 60 
Hematology, chemistry 
2.3 
Day 72 
Chemistry 
1.3e 
Month 3 
Hematology, chemistry 
2.3 
Quarterly 
Hematology, chemistry, CK-MB or troponin I 
3.6 
End of Study/ET 
Hematology, chemistry, CK-MB or troponin I 
3.6 
Maximum Total Volume for Studya: patients with 2 copies of SMN2 
42.9 
Maximum Total Volume for Studya: patients with 3 copies of SMN2 
50.1 
CK-MB = Creatine kinase isoenzyme; EOS = End of Study; ET = early termination 
a. Patients will have different numbers of monthly visits, depending on the number of copies of SMN2.  Maximum total volume 
based on a completion of all blood draws with maximum volume at each visit, provided mother virus and anti-AAV9 serology 
is not positive at screening requiring additional testing 
b. Patients will also have a 1 mL sample collected for baseline anti-AAV9 antibody titer if the biological mother’s result is 
>1:50 or if biological mother is not available for testing 
c. Screening labs must be completed within 14 days before AVXS-101 dosing 
d. An additional 1 mL of blood would be required at screening for patients enrolled in regions where newborn screening results 
do not include SMN2 copy number 
e. All sites to collect chemistry at Days 14, 44, and 72. 
f. CK-MB or troponin-I will be collected at Screening, at the Day 7 and Day 30 visit, and every three months starting at the 
6 months of age visit through and including the EOS visit.  Patients screened and dosed before IRB/EC approval of Protocol 
version 2.0 incorporating Amendment 1 will be tested for CK-MB throughout the study. Patients screened before IRB/EC 
approval of Protocol version 2.0 incorporating Amendment 1 but dosed afterwards, will be tested for CK-MB at screening but 
for Troponin I at baseline and all subsequent visits.  Patients screened after IRB/EC approval of Protocol version 2.0 
incorporating Amendment 1 will be tested for Troponin I from screening onwards. The pre-and post-dose cardiac laboratory 
analytes must match. 
g. Troponin I requires 0.3 mL less blood than CK-MB, thus total blood volumes will be less for participants receiving troponin I 
testing. 
 
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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 → CK-MB (or troponin I) 
2. Serum antibody to AAV9, if required 
3. Genetic re-confirmation testing 
Table 4 - Total Blood Volume: Biological Mother 
Visit 
Tests 
Total Volume (mL) 
Screening 
Viral testing, immunology sample (AAV9 Ab only) 
9.8 
Maximum Total Volume for Study 
9.8 
 
12.1.10.1. Hematology 
Hematology analysis will include a complete blood count with differential and platelet count.  
Samples will be collected and shipped in accordance with the laboratory manual provided by the 
central laboratory.  Blood samples for hematology analysis will be collected as specified in SoA 
(Appendix 1). 
Immediate/same-Day hematology analyses required during in-patient dosing, as determined by 
the Investigator, and on Day 2 prior to discharge, will be performed as per investigational site 
standard procedures at the local laboratory.  Investigators will receive hematology results from 
all other study visits from the central laboratory. 
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 at scheduled visits in 
accord with (Appendix 1). 
Immediate/same-Day chemistry analyses required during in-patient dosing, as determined by the 
Investigator, and on Day 2 prior to discharge, will be performed as per investigational site 
standard procedures at the local laboratory. 
Chemistry analysis will include the following at all study visits: 
• Serum GGT 
• AST/ALT 
• Serum total bilirubin 
• Direct bilirubin 
• Albumin 
• Glucose 
• Total CK 
• Creatinine 
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• BUN 
• Electrolytes (potassium, chloride, CO2, calcium, inorganic phosphorus, sodium) 
• Alkaline phosphatase 
Creatine kinase isoenzyme (CK-MB), or troponin I, will be collected as specified in SoA 
(Appendix 1). 
• Patients screened and dosed before IRB/EC approval of Protocol version 2.0 
incorporating Amendment 1 will be tested for CK-MB throughout the study.   
• Patients screened before IRB/EC approval of Protocol version 2.0 incorporating 
Amendment 1 but dosed afterwards, will be tested for CK-MB at screening but for 
Troponin I at baseline and all subsequent visits.   
• Patients screened after IRB/EC approval of Protocol version 2.0 incorporating 
Amendment 1 will be tested for Troponin I from screening onwards.  The pre- and 
post-dose cardiac laboratory analytes must match. 
12.1.10.3. Urinalysis 
Urine samples will be collected in accordance with the laboratory manual provided by the central 
laboratory at study visits in accord with (Appendix 1).  Immediate/same-Day urinalysis required 
during in-patient dosing, as determined by the Investigator, and on Day 2 prior to discharge, will 
be performed as per investigational site standard procedures at the local laboratory. 
Urinalysis will include the following parameters: 
• Color 
• Clarity/turbidity 
• pH 
• Specific gravity 
• Glucose 
• Ketones 
• Nitrites 
• Leukocyte esterase 
• Bilirubin 
• Blood 
• Protein 
• Red Blood Cell 
• White Blood Cell 
• Squamous epithelial cells 
• Casts 
• Crystals 
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• Bacteria 
• Yeast 
12.1.10.4. Biological Mother Infectious Disease Testing 
The administration of an AAV vector has the risk of causing immune-mediated hepatitis.  For 
patients with HIV, hepatitis B or C, or Zika virus, administration of AAV vector may represent 
an unreasonable risk; therefore, negative results for the biological mother must be confirmed at 
screening, prior to treatment.  If biological mother is not reasonably available, blood samples 
must be collected from the patient.  These samples will be collected at screening (Appendix 1) 
and shipped in accordance with the laboratory manual provided by the central laboratory. 
Zika testing will only be required for biological mothers with clinical suspicion of Zika virus that 
meet CDC Zika virus epidemiological criteria including history of residence in or travel to a 
geographic region with active Zika transmission at the time of travel. 
12.1.10.5. Blood for Diagnostic Re-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 of exon 7 gene modifier mutation (c.859G>C).  Only genetic 
results from the central laboratory will be used to determine patients’ inclusion in the 
ITT population; this will ensure consistency in diagnostic testing practices. 
Results of the diagnostic re-confirmation testing are not required prior to enrollment/dosing; 
however, this must be completed during screening with results received prior to 
enrollment/dosing for patients in regions where newborn screening results do not include 
SMN2 copy number. 
12.1.10.6. AAV9 Antibody Screen in Biological Mother 
There is potential that the biological mother of the enrolled patient may have pre-existing 
antibodies to AAV9 that may be transferred to the patient via placental transfer in utero or 
theoretically through breastmilk.  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 and shipped to the central laboratory for screening of anti-AAV9 antibodies.  If 
AAV9 antibodies are identified, the investigator should discuss with the mother whether to 
continue or to stop breastfeeding.  Patients consuming banked breast milk from donor sources 
that cannot be tested for anti-AAV9 antibodies must be transitioned to formula prior to 
participation.  Patients whose biological mothers test positive for antibodies to AAV9 will have 
blood drawn for screening of anti-AAV9 antibodies.  Patients who do not have a biological mother 
available to screen for antibodies to AAV9 will have blood drawn for screening of anti-AAV9 
antibodies. 
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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 study treatment has been administered. 
All AEs (related or unrelated) that occur after signing of the informed consent through the last 
study 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 5. 
Table 5 - 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) (44). 
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 
An SAE is an AE occurring during any study phase (e.g., baseline, treatment, washout, or 
follow-up), and at any dose of the investigational product, or comparator that fulfils one or more 
of the following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• 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. 
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All SAEs (related and unrelated) that occur after signing of the informed consent through 30 days 
after the last study visit must be collected and recorded on forms provided by the Contract 
Research Organization within 24 hours of the site becoming aware. 
13.1.3. 
Adverse Events of Special Interest 
The following are considered AEs of special interest (AESIs): 
• Hepatotoxicity 
• Thrombocypenia 
• Cardiac AEs 
• Sensory abnormalities suggestive of ganglionopathy 
All AESIs (related or unrelated) 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 the Contract Research Organization within 24 hours of the site becoming aware.  
13.2. 
Relationship to Study Product 
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 study personnel or revealed by observation will be recorded during the study at the 
investigational site.  Information about AEs (related and unrelated) 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 during Visit 2]), resolution 
(date [and time if start date during Visit 2]), intensity, causality, action taken, serious outcome 
(if applicable), and whether or not it caused the patient to discontinue the study. 
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. 
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13.4. 
Reporting Serious Adverse Events 
All SAEs (related and unrelated) will be recorded after signing of the informed consent through 
30 days after the last study visit.  Any SAEs considered possibly, probably, or definitely related to 
the investigational product and discovered by the Investigator at any time after the study 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 study file. 
AveXis is responsible for notifying the relevant regulatory authorities of certain events.  It is the 
Principal Investigator’s responsibility to notify the IRB or IEC of all SAEs that occur at his or 
her site.  Investigators will also be notified of all unexpected, serious, product-related events 
(7/15 Day Safety Reports) that occur during the clinical study.  Each site is responsible for 
notifying its IRB or IEC of these additional SAEs. 
13.4.1. 
Reporting to Regulatory Authorities 
All SUSARs will be reported to regulatory authorities within the 15-day expedited timeline. 
Fatal/life-threatening suspected events will be reported according to the 7-day timeline. 
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14.
STATISTICS
This section summarizes key aspects of the analysis plan including definitions of primary, 
secondary, and exploratory efficacy endpoints and safety endpoints, 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. 
This is a Phase 3 study assessing the efficacy and safety of AVXS-101.  The primary efficacy 
analysis for each SMN2 copy number cohort will be completed separately at such time that 
enrollment in the respective cohort is complete and the last patient has completed the EOS visit 
at the respective age (SMN2 = 2, EOS = 18 months of age; SMN2 = 3, EOS = 24 months of age). 
Details of all analyses will be contained within the SAP. 
The primary and secondary efficacy analyses will be performed on the populations of patients 
with bi-allelic SMN1 deletions and 2 or 3 copies of SMN2 without the SMN2 gene modifier 
mutation (c.859G>C).  The above will comprise the population for evaluation of the primary and 
secondary endpoints and will be referred to as the ITT populations hereafter.  Study power is 
based upon efficacy analysis of these subpopulations.  Patients with SMN1 point mutations or the 
SMN2 gene modifier mutation (c.859G>C) will be evaluated separately as part of additional 
subgroup analyses. 
14.1. 
Study Endpoints and Populations 
14.1.1. 
Study Endpoints 
14.1.1.1. Primary Efficacy Endpoint 
Primary Efficacy Endpoint for patients with bi-allelic SMN1 deletions and 2 copies of 
SMN2: 
•
Primary Efficacy Endpoint for patients with bi-allelic SMN1 deletions and 3 copies of 
SMN2: 
•
Proportion of patients achieving the ability to stand without support for at least
3 seconds at any visit up to 24 months of age
14.1.1.2. Secondary Efficacy Endpoint 
Secondary Efficacy Endpoints for patients with bi-allelic SMN1 deletions and 2 copies of 
SMN2: 
•
Proportion of patients that have survived and have not required permanent ventilation
in the absence of acute illness and perioperatively, assessed at 14 months of age
•
Proportion of patients that have achieved the ability to maintain weight at or above
the 3rd percentile without need for non-oral/mechanical feeding support at any visit up
to 18 months of age
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Secondary Efficacy Endpoints for patients with bi-allelic SMN1 deletions and 3 copies of 
SMN2: 
• Proportion of patients demonstrating the ability to walk alone defined as 
 
at any visit up 
to 24 months of age 
14.1.1.3. Exploratory Endpoints 
Exploratory Efficacy Endpoints for patients with bi-allelic SMN1 deletions and 2 copies of 
SMN2: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Exploratory Efficacy Endpoints for patients with bi-allelic SMN1 deletions and 3 copies of 
SMN2: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14.1.1.4. Safety Endpoints 
Assessment of the safety and tolerability of AVXS-101 treatment includes evaluation of AEs, 
laboratory data, vital signs, and concomitant medications. 
14.1.2. 
Statistical Analysis Populations 
14.1.2.1. Intent-to-Treat Population (ITT) 
The ITT population will consist of all enrolled patients with bi-allelic SMN1 deletions and 2 or 
3 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) who receive 
AVXS-101.  Patients will be analyzed according to the assigned SMN2 copy number cohort.  All 
efficacy analyses will be conducted using the ITT population as the primary population, unless 
specified otherwise. 
While the study may enroll a small number of patients with SMN1 point mutations or patients 
who are positive for the SMN2 gene modifier mutation (c.859G>C), the population described as 
the ITT Population above will comprise the population for evaluation of the primary and 
secondary endpoints. 
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14.1.2.2. Efficacy Completers Population 
The efficacy completers analysis population is a subset of the ITT population and will consist of 
all patients who are given an AVXS-101 injection and who complete an EOS visit relevant for 
their assigned cohort (based upon copy number) following the AVXS-101 dose procedure.  
Patients who terminate early due to other reasons will not be included in the efficacy completers 
population. 
14.1.2.3. All Enrolled Population 
The all enrolled population will consist of all patients enrolled (i.e., completed the informed 
consent process) who receive AVXS-101.  Unless specified otherwise, this set will be used for 
patient listings and for summaries of patient disposition. 
14.1.2.4. Safety Population 
The safety analysis population will consist of all patients who are given an AVXS-101 injection.  
The safety population will be used for all analyses of safety endpoints and for the presentation of 
patients in all patient listings. 
14.2. 
Sample Size Calculation 
At least fourteen (14) patients with bi-allelic SMN1 deletions and 2 copies of SMN2 and at least 
12 patients with bi-allelic SMN1 deletions and 3 copies of SMN2 will be enrolled.   
One natural history study population is available for comparison with the study population.  
Distinct control populations drawn from the PNCR study will be used as a comparison for the 
secondary endpoint of survival for the cohort of patients with bi-allelic SMN1 deletions and 
2 copies of SMN2, and for the primary and secondary endpoints for the cohort of patients with 
bi-allelic SMN1 deletions and 3 copies of SMN2.  Exploratory endpoints will utilize PNCR (2 or 
3 copies of SMN2) cohorts as appropriate. 
The PNCR Natural History dataset (22) is drawn from a large natural history study performed on 
a large cohort of 337 patients with any form of SMA followed at 3 large, internationally 
recognized tertiary medical centers with significant expertise in the management of SMA 
 
  Previously identified patients followed in 
PNCR site clinics and newly diagnosed patients were enrolled.  All eligible patients were offered 
participation in the PNCR study.  Study visits were scheduled at baseline and at 2, 4, 6, 9, and 
12 months and every 6 months thereafter.  The SMA standard of care guidelines published in 
2007 were used as a basis for providing uniform care among the study sites. 
14.2.1. 
Patients with bi-allelic SMN1 deletions and 2 copies of SMN2 
The primary efficacy endpoint for patients with bi-allelic SMN1 deletions and 2 copies of SMN2 
will be the proportion of patients who achieve the ability to sit without support for at least 
30 seconds at any visit up to the 18 months of age study visit.  Based upon two widely cited 
natural history studies of the disease (NeuroNext (45), PNCR (22)), it is expected that no patient 
meeting the study entrance criteria (SMN2 copy number of 2 without the SMN2 gene modifier 
mutation (c.859G>C)) would be expected to attain the ability to sit without support. 
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The primary efficacy endpoint hypothesis for patients with bi-allelic SMN1 deletions and 
2 copies of SMN2: 
𝐇𝟎: 𝑝𝐴𝑉𝑋𝑆−101 ≤0.1%  
𝑣𝑒𝑟𝑠𝑢𝑠 𝑡ℎ𝑒 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒  
𝐇𝐚: 𝑝𝐴𝑉𝑋𝑆−101 > 0.1%, 
where 𝑝 is the proportion of functional independent sitting for at least 30 seconds at any visit up 
to the 18 month study visit. 
Based upon data from the completed AVXS-101-CL-101 study, we expect at least 60% of 
treated patients with 2 copies of SMN2 to achieve the ability to sit without support for at least 
30 seconds.  With this efficacy, a sample size of 14 patients would provide power of >90% to 
detect a significant difference compared with a rate of 0.1% (in lieu of zero) with α = 0.025 using 
a 1-sided exact test for a binomial proportion. 
14.2.2. 
Patients with bi-allelic SMN1 deletions and 3 copies of SMN2 
The primary efficacy endpoint for patients with 3 copies of SMN2 will be the proportion of 
patients who achieve the ability to stand without support for at least 3 seconds at any visit up to 
the 24 months of age study visit. 
The natural history comparison dataset drawn from the PNCR will include all patients with SMA 
of any type who provided sufficient records for evaluation and met the basic entry criteria for 
this cohort of the AVXS-101-CL-304 study (3 copies of SMN2) and had at least one study visit.  
The SMN2 modifier mutation (c.859G>C) described by Prior and colleagues (16) was not 
assessed in the PNCR study cohort. 
Based upon this approach, patient-level data from a cohort of 81 patients drawn from the PNCR 
Network natural history study of SMA will serve as a “population-matched” control cohort.  This 
comparison cohort encompasses all 81 patients enrolled in the PNCR study who met the criteria 
of having 3 copies of SMN2.  Of this cohort, 19/81 (23.5%) of the natural history cohort attained 
the ability to stand alone (defined as achieving a score of 2 on item #19 of the Hammersmith 
Functional Motor Scale – Expanded); 17/81 (21%) attained the ability to walk alone (defined as 
achieving a score of 2 on item #20 of the Hammersmith Functional Motor Scale – Expanded). 
The primary efficacy endpoint hypothesis for patients with bi-allelic SMN1 deletions and 
3 copies of SMN2: 
𝐇𝟎: 𝑝𝐴𝑉𝑋𝑆−101 = 𝑝𝐻𝐼𝑆𝑇𝑂𝑅𝐼𝐶𝐴𝐿−𝑃𝑁𝐶𝑅  
𝑣𝑒𝑟𝑠𝑢𝑠 𝑡ℎ𝑒 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒  
𝐇𝐚: 𝑝𝐴𝑉𝑋𝑆−101 ≠𝑝𝐻𝐼𝑆𝑇𝑂𝑅𝐼𝐶𝐴𝐿−𝑃𝑁𝐶𝑅, 
where 𝑝 is the proportion of patients who achieve the ability to stand without support for at least 
3 seconds at any visit up to the 24 months of age study visit. 
Based upon the patient-level data available from the PNCR dataset, 23.5% of patients with 
SMN2=3 who meet the study criteria achieved the ability to stand without support.  Extrapolating 
from the experience from the AVXS-101 Phase 1 study in infants with SMA Type 1, we expect 
85% of treated patients with bi-allelic SMN1 deletions and 3 copies of SMN2 to achieve the 
ability to stand without support.  With this efficacy, a sample size of 12 patients would provide 
power of >90% to detect a significant difference compared with the matched control cohort with 
α = 0.05 using a two sample 2-sided Fisher exact test. 
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14.3. 
Efficacy Analysis 
14.3.1. 
General Considerations 
Primary and secondary efficacy analyses will be based on those patients with bi-allelic deletion 
mutations of SMN1; study cohorts will be based upon SMN2 copy number, with children with 
2 and 3 copies of SMN2 subject to separate analysis.  These analyses are to test the superiority of 
AVXS-101 to the results from the natural observation study (PNCR) as described above. 
Two cohorts of patients (i.e., 2-copies, 3-copies) are evaluated separately in this protocol.  
Hence, family-wise type I error is controlled within each population cohort, as each cohort is 
considered its own experiment. 
14.3.2. 
Primary and Secondary Efficacy Analysis for patients with bi-allelic SMN1 
deletions and 2 copies of SMN2 
14.3.2.1. Primary Efficacy Endpoint for patients with bi-allelic SMN1 deletions and 
2 copies of SMN2 
The primary efficacy endpoint hypothesis for patients with bi-allelic SMN1 deletions and 
2 copies of SMN2: 
𝐇𝟎: 𝑝𝐴𝑉𝑋𝑆−101 ≤0.1%  
𝑣𝑒𝑟𝑠𝑢𝑠 𝑡ℎ𝑒 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒  
𝐇𝐚: 𝑝𝐴𝑉𝑋𝑆−101 > 0.1%, 
where 𝑝 is the proportion of 
 at any visit up 
to the 18 month study visit. 
Testing for functional independent sitting on the cohort of patients with 2 copies of SMN2 will 
first be performed using 1-sided exact binomial test with α = 0.025.  Only if the null hypothesis 
of equality in proportion of functional independent sitting is rejected at p<0.025, will the result 
be considered statistically significant. 
14.3.2.2. Secondary Efficacy Endpoints for patients with bi-allelic SMN1 deletions and 
2 copies of SMN2 
The first secondary efficacy hypothesis for patients with bi-allelic SMN1 deletions and 2 copies 
of SMN2 to be tested is: 
𝐇𝟎: 𝑝𝐴𝑉𝑋𝑆−101 = 𝑝𝐻𝐼𝑆𝑇𝑂𝑅𝐼𝐶𝐴𝐿−𝑃𝑁𝐶𝑅    
𝑣𝑒𝑟𝑠𝑢𝑠 𝑡ℎ𝑒 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒  
𝐇𝐚: 𝑝𝐴𝑉𝑋𝑆−101 ≠𝑝𝐻𝐼𝑆𝑇𝑂𝑅𝐼𝐶𝐴𝐿−𝑃𝑁𝐶𝑅 , 
where 𝑝 is the proportion surviving and not requiring ventilation at 14 months of age. 
Testing for the proportion of patients that have survived and not required permanent ventilation 
will only be conducted if the result for the functional independent sitting endpoint is statistically 
significant.  Survival will be compared with the control cohort with α = 0.05 using a two sample 
2-sided Fisher exact test, comparing to patients from natural observational study (PNCR), and 
the result will be considered statistically significant if p<0.05. 
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The second secondary efficacy endpoint hypothesis for patients with bi-allelic SMN1 deletions 
and 2 copies of SMN2: 
𝐇𝟎: 𝑝𝐴𝑉𝑋𝑆−101 ≤0.1%  
𝑣𝑒𝑟𝑠𝑢𝑠 𝑡ℎ𝑒 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒  
𝐇𝐚: 𝑝𝐴𝑉𝑋𝑆−101 > 0.1%, 
where 𝑝 is the proportion of patients who have achieved the ability to maintain weight at or 
above the third percentile without need for non-oral/mechanical feeding support at any visit up to 
18 months of age (ability to thrive).  Only if the primary endpoint and the first secondary 
endpoint (survival) for patients with 2 copies of SMN2 as described above meet statistical 
significance will this second secondary endpoint of ability to thrive be deemed potentially 
statistically significant.  Testing for ability to thrive for the cohort of patients with 2 copies of 
SMN2 will be performed using 1-sided exact binomial test with α = 0.025.  Only if the null 
hypothesis of equality in proportion of survival is rejected at p<0.05, will the result be 
considered statistically significant.  This hierarchy approach strongly protects against Type I 
error within the 2 copy cohort. 
14.3.3. 
Primary and Secondary Efficacy Analysis for patients with bi-allelic SMN1 
deletions and 3 copies of SMN2 
14.3.3.1. Primary Efficacy Endpoint for patients with bi-allelic SMN1 deletions and 
3 copies of SMN2 
The primary efficacy endpoint hypothesis for patients with bi-allelic SMN1 deletions and 
3 copies of SMN2: 
𝐇𝟎: 𝑝𝐴𝑉𝑋𝑆−101 = 𝑝𝐻𝐼𝑆𝑇𝑂𝑅𝐼𝐶𝐴𝐿−𝑃𝑁𝐶𝑅  
𝑣𝑒𝑟𝑠𝑢𝑠 𝑡ℎ𝑒 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒  
𝐇𝐚: 𝑝𝐴𝑉𝑋𝑆−101 ≠𝑝𝐻𝐼𝑆𝑇𝑂𝑅𝐼𝐶𝐴𝐿−𝑃𝑁𝐶𝑅, 
where 𝑝 is the proportion of patients who achieve the ability to stand without support for at least 
3 seconds at any visit up to the 24 months of age study visit. 
The proportion of patients that stand without support for at least 3 seconds endpoint for the 
cohort with 3 copies of SMN2 will be compared with the control cohort with α = 0.05 using a 
2-sided two sample Fisher exact test.  The result will be considered statistically significant if 
p<0.05. 
14.3.3.2. Secondary Efficacy Endpoint for patients with bi-allelic SMN1 deletions and 
3 copies of SMN2 
The secondary efficacy endpoint hypothesis for patients with bi-allelic SMN1 deletions and 
3 copies of SMN2: 
𝐇𝟎: 𝑝𝐴𝑉𝑋𝑆−101 = 𝑝𝐻𝐼𝑆𝑇𝑂𝑅𝐼𝐶𝐴𝐿−𝑃𝑁𝐶𝑅  
𝑣𝑒𝑟𝑠𝑢𝑠 𝑡ℎ𝑒 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒  
𝐇𝐚: 𝑝𝐴𝑉𝑋𝑆−101 ≠𝑝𝐻𝐼𝑆𝑇𝑂𝑅𝐼𝐶𝐴𝐿−𝑃𝑁𝐶𝑅, 
where 𝑝 is the proportion of patients who achieve the ability to walk alone at any visit up to the 
24 months of age study visit. 
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The secondary efficacy endpoint for the cohort with 3 copies of SMN2 will be compared with the 
control cohort with α = 0.05 using a two sample 2-sided Fisher exact test.  Only if the primary 
endpoint for patients with 3 copies of SMN2 (standing without support) is statistically significant 
will the secondary endpoint for patients with 3 copies of SMN2 (walk alone) be assessed as 
potentially significant.  This hierarchy approach strongly protects against Type I error within the 
3-copy cohort. 
14.4. 
Safety Analysis 
Safety will be assessed through the incidence and toxicity grade of AEs, vital sign assessments, 
cardiac assessments, laboratory evaluations (chemistry, hematology, urinalysis, immunology), 
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 and summarized by cohort and overall. 
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 
three components:   
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control 
drug or placebo; 
2. Among trial patients showing such aminotransferase (AT) elevations, often with ATs 
much greater than 3×ULN, one or more patients also shows elevation of serum total 
bilirubin (TBL) to ≥2×ULN, without initial findings of cholestasis (elevated serum ALP);  
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C, pre-existing or acute liver disease, or another drug capable of 
causing the observed injury (46). 
 
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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 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 study and will act in an advisory capacity to AveXis.  A detailed description of the 
DSMB/DMC, its role in this study, 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 study.  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 study, 
a modification to the study, 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. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of AveXis will 
visit the investigational study 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 Study Agreement between AveXis and the 
Investigator. 
During the study, 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 study.  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 patients. 
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16.2. 
Audits and Inspections 
Authorized representatives of AveXis, a regulatory authority, an IEC or an IRB 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 study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP) 
guidelines of the International Council for Harmonisation (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/Genetically Modified Organisms 
(GMO) Committee/Competent Authority for Biosafety 
As this study involves gene therapy, the Principal Investigator must obtain approval/favorable 
opinion for the investigation from a designated institutional, local, or independent biosafety 
committee/GMO Committee/Competent Authority for Biosafety in accordance with institutional, 
local, regional, and or national requirements and/or guidelines. 
16.4. 
Institutional Review Board/Institutional Ethics Committee 
The Principal Investigator must obtain IRB/IEC approval for the investigation (Section 18.1).  
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study 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. 
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18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC, as appropriate.  The 
Investigator must submit written approval to AveXis before he or she can enroll any patient into 
the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study 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 study 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 Study 
The study 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 study.  The parent(s)/legal guardian(s) must also be notified that they are free to 
discontinue the patient from the study 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 study 
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 and virus/serology screening informed 
consent form 
• Post-mortem tissue/organ sample collection informed consent form (Appendix 1); if 
the parent(s)/legal guardian(s) decline an autopsy, it will not prevent the patient from 
participating in the study) 
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In the event of unforeseen catastrophe or other, serious situation (such as the COVID-19 
pandemic) that occurs during the study, the ability to obtain a standard written informed consent 
may be challenged due to limits that prevent an on-site visit.  In this situation, the Investigator 
may conduct the informed consent discussion remotely (e.g., telephone, videoconference).  
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g., the presence of an impartial witness, sign/dating separate 
informed consent forms (ICFs) by trial participant and person obtaining informed consent; a 
video or other recording of the consent process and affirmation of consent may be considered to 
supplement the documentation of obtaining consent, if allowable by local regulations etc.). 
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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Electronic Case Report Forms 
Adequate and accurate case records will be maintained, and all relevant observations and data 
related to the study will be recorded.  This will include medical history/ physical examination, 
hematology, clinical chemistry and virus/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. 
Full date of birth will be recorded to determine satisfaction of inclusion criterion 
(age ≤6 Weeks (≤42 days) at time of dose). 
Electronic CRFs will be used in this study.  The eCRF will be electronically signed and dated by 
the Principal Investigator or designee after his/her review.  After the completion of the study, 
completed eCRFs will be retained in the archives. 
Completed eCRFs will be reviewed by the study 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 study.  The Investigator agrees to allow the monitor to 
inspect the product storage area, study product stocks, product accountability records, patient 
charts and study source documents, and other records relative to study conduct. 
19.3. 
Retention of Records 
All primary data that are a result of the original observations and activities of the study and that 
are necessary for the reconstruction and evaluation of any study report will be retained in a 
secure archive at the study site for a period not less than 2 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have lapsed since the formal 
discontinuation of the clinical development of the investigational product.  All country/region 
specific requirements that may be more stringent than the 2 years included in ICH shall be 
followed. 
The site will maintain all 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 study.  During the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation.  Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (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 Study Site Agreement.  In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
If the study is being conducted as part of a multicenter clinical study, data from all sites 
participating in the study will be pooled and analyzed by the Sponsor or the Sponsor’s designee.  
The first publication of the study results shall be made in conjunction with the results from other 
study sites as a multicenter publication.  If a multicenter publication is not forthcoming within 
24 months of completion of the study 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, Akmaev VR, Zhou Z, Rohlfs EM, 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, McNaught TP, Wride MC, Reyna SP, et al. Natural 
history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann 
Neurol. 2005;57(5):704-12. 
3. Le TT, McGovern VL, Alwine IE, Wang X, Massoni-Laporte A, Rich MM, et al. 
Temporal requirement for high SMN expression in SMA mice. Hum Mol Genet. 
2011;20(18):3578-91. 
4. Farrar MA, Vucic S, Johnston HM, Kiernan MC. Corticomotoneuronal integrity and 
adaptation in spinal muscular atrophy. Arch Neurol. 2012;69(4):467-73. 
5. Riessland M, Ackermann B, Forster A, Jakubik M, Hauke J, Garbes L, et al. SAHA 
ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy. Hum 
Mol Genet. 2010;19(8):1492-506. 
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-
4. 
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. Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 
2011;68(8):979-84. 
10. 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. 
1995;80(1):155-65. 
11. 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 U S 
A. 1999;96(11):6307-11. 
12. 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):1177-83. 
13. Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, et al. Correlation 
between severity and SMN protein level in spinal muscular atrophy. Nature genetics. 
1997;16(3):265. 
14. Park GH, Kariya S, Monani UR. Spinal muscular atrophy: new and emerging insights 
from model mice. Curr Neurol Neurosci Rep. 2010;10(2):108-17. 
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15. 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):358-68. 
16. Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, et al. A positive 
modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 
2009;85(3):408-13. 
17. Farrar MA, Vucic S, Johnston HM, du Sart D, Kiernan MC. Pathophysiological insights 
derived by natural history and motor function of spinal muscular atrophy. J Pediatr. 
2013;162(1):155-9. 
18. Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, et al. Rescue of the 
spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. 
Nat Biotechnol. 2010;28(3):271-4. 
19. Butchbach ME, Edwards JD, Burghes AH. Abnormal motor phenotype in the 
SMNDelta7 mouse model of spinal muscular atrophy. Neurobiol Dis. 2007;27(2):207-19. 
20. Hinderer C, Katz N, Buza EL, Dyer C, Goode T, Bell P, 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;29(3):285-98. 
21. Hordeaux J, Hinderer C, Goode T, Katz N, Buza EL, Bell P, 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;10:79-88. 
22. Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, et al. 
Observational study of spinal muscular atrophy type I and implications for clinical trials. 
Neurology. 2014;83(9):810-7. 
23. AVXS-101. Investigators Brochure Version 6.0. 17 September 2019. 
24. Narver HL, Kong L, Burnett BG, Choe DW, Bosch-Marce M, Taye AA, et al. Sustained 
improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition. 
Ann Neurol. 2008;64(4):465-70. 
25. Paes BA, Mitchell I, Banerji A, Lanctôt KL, Langley JM. A decade of respiratory 
syncytial virus epidemiology and prophylaxis: translating evidence into everyday clinical 
practice. Can Respir J. 2011;18(2):e10-9. 
26. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, 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(9725):1545-55. 
27. Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med. 
2001;344(25):1917-28. 
28. Palivizumab SmPC. wwwemaeuopaeu/en/documents/product-information/synagis-epar-
product-information_enpdfApril 6, 2019. 
29. Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, et al. 
Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute 
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care; medications, supplements and immunizations; other organ systems; and ethics. 
Neuromuscul Disord. 2018;28(3):197-207. 
30. McCarty DM, Young SM, Jr., Samulski RJ. Integration of adeno-associated virus (AAV) 
and recombinant AAV vectors. Annu Rev Genet. 2004;38:819-45. 
31. Kotin RM, Siniscalco M, Samulski RJ, Zhu XD, Hunter L, Laughlin CA, et al. Site-
specific integration by adeno-associated virus. Proc Natl Acad Sci U S A. 
1990;87(6):2211-5. 
32. Surosky RT, Urabe M, Godwin SG, McQuiston SA, Kurtzman GJ, Ozawa K, et al. 
Adeno-associated virus Rep proteins target DNA sequences to a unique locus in the 
human genome. J Virol. 1997;71(10):7951-9. 
33. Srivastava A, Carter BJ. AAV Infection: Protection from Cancer. Hum Gene Ther. 
2017;28(4):323-7. 
34. Favre D, Provost N, Blouin V, Blancho G, Cherel Y, Salvetti A, et al. Immediate and 
long-term safety of recombinant adeno-associated virus injection into the nonhuman 
primate muscle. Mol Ther. 2001;4(6):559-66. 
35. Wijnhoven TM, de Onis M, Onyango AW, Wang T, Bjoerneboe GE, Bhandari N, et al. 
Assessment of gross motor development in the WHO Multicentre Growth Reference 
Study. Food Nutr Bull. 2004;25(1 Suppl):S37-45. 
36. Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, et al. Consensus 
statement for standard of care in spinal muscular atrophy. J Child Neurol. 
2007;22(8):1027-49. 
37. WHO Multicentre Growth Reference Study Group, de Onis M. WHO Child Growth 
Standards based on length/height, weight and age. Acta paediatrica. 2006;95:76-85. 
38. Zoorob RJ, Cender D. A different look at corticosteroids. Am Fam Physician. 
1998;58(2):443-50. 
39. Kroger A, Duchin J, Vazquez M. General Best Practice Guidelines for Immunization In: 
(ACIP) CoIP, [www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-
recs.pdf], editors. 2017. 
40. Palivizumab Summary of Product Characteristics.  
[https://www.ema.europa.eu/en/documents/product-information/synagis-epar-product-
information_en.pdf] 2018 
41. American Academy of Pediatrics: Policy statements--Modified recommendations for use 
of palivizumab for prevention of respiratory syncytial virus infections. Committee on 
Infectious Diseases. Pediatrics. 2009 Dec;124(6):1694-701 
42. Glanzman AM, McDermott MP, Montes J, Martens WB, Flickinger J, Riley S, et al. 
Validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders (CHOP INTEND). Pediatr Phys Ther. 2011;23(4):322-6. 
43. Glanzman AM, Mazzone E, Main M, Pelliccioni M, Wood J, Swoboda KJ, et al. The 
Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP 
INTEND): test development and reliability. Neuromuscul Disord. 2010;20(3):155-61. 
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44. US Department of Health and Human Services. Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03. June 14, 2010. 2014. 
45. Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, et al. Natural 
history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017;82(6):883-91. 
46. 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 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Study Period 
Screening 
Gene 
Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
–30 
to  
–2 
–14 
to  
–2 
-1 
1 
2 
7 
14 
21 
30 
44 
60 
72 
 
 
End of 
Study 
Day 1 assessments will be performed prior to the 
start of gene replacement therapy infusion.  Day 7, 
14, 21, 30, 44, 60, and 72 visits are timed based on 
the Day of AVXS-101 dose (Day 1). Visits on 
Study Days 44 and 72 are for blood chemistry only. 
Months of Age 
 
 
 
 
 
 
3a 
6, 9, 12, 
15, 21 
18, 24, 
(or ET) 
Please see footnote “a” at the bottom of the 
Appendix 1 table for guidance on scheduling visits 
for Study Days 44, 60, 72, and 3 Months of Age. 
Window 
 
 
 
 
± 2 days 
± 7 days 
± 14 days  
0–14 
days 
The End of Study visit must occur within 0 to 
14 days after the date on which the patient reaches 
18 or 24 months of age (or ET), depending on the 
respective cohort.  Visits prior to and including the 
Day 72 visit are timed based on the Day of 
AVXS-101 dose.  Visits following Day 72 are 
based on the patient’s date of birth. 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 18.3. 
Prophylactic 
Prednisolone 
 
 
X 
X 
X 
X 
X 
X 
X 
(X) 
(X) 
 
 
 
 
See Section 9.2.1.  Prednisolone to be given 
24 hours prior to scheduled AVXS-101 dosing and 
continued as per protocol. 
(X):  Taper prednisolone per protocol between 30 
and 60 days after AVXS-101 treatment.   
AVXS-101 
Infusion 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
See Section 10.6. 
Bayley Scales 
(Fine and Gross 
Motor 
Assessment with 
video) 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
The Bayley Gross and Fine Motor Subtests are 
performed at Screening, Day 30 post-dose, Day 60 
post-dose, and then every 3 months from 3 months 
of age visit. See Sections 11.1, 11.2.1, and 11.3. 
BSIDv03/WHO 
Developmental 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Developmental milestones will be assessed as 
defined by BSIDv03 and WHO Multicentre Growth 
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Study Period 
Screening 
Gene 
Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
–30 
to  
–2 
–14 
to  
–2 
-1 
1 
2 
7 
14 
21 
30 
44 
60 
72 
 
 
End of 
Study 
Day 1 assessments will be performed prior to the 
start of gene replacement therapy infusion.  Day 7, 
14, 21, 30, 44, 60, and 72 visits are timed based on 
the Day of AVXS-101 dose (Day 1). Visits on 
Study Days 44 and 72 are for blood chemistry only. 
Months of Age 
 
 
 
 
 
 
3a 
6, 9, 12, 
15, 21 
18, 24, 
(or ET) 
Please see footnote “a” at the bottom of the 
Appendix 1 table for guidance on scheduling visits 
for Study Days 44, 60, 72, and 3 Months of Age. 
Window 
 
 
 
 
± 2 days 
± 7 days 
± 14 days  
0–14 
days 
The End of Study visit must occur within 0 to 
14 days after the date on which the patient reaches 
18 or 24 months of age (or ET), depending on the 
respective cohort.  Visits prior to and including the 
Day 72 visit are timed based on the Day of 
AVXS-101 dose.  Visits following Day 72 are 
based on the patient’s date of birth. 
Milestones (with 
video) 
Reference Study.  Videos may be submitted for 
review by an independent central reviewer. See 
Sections 11.1, 11.2.1, and 11.3. 
CHOP INTEND 
(with video) 
X 
 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
CHOP INTEND will be performed only for patients 
with 2 copies of SMN2.  Patients who achieve 
3 consecutive CHOP INTEND scores ≥58 will not 
continue CHOP INTEND assessments. See 
Sections 11.2.2 and 11.3. 
CMAP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
To be completed every 6 months, starting at 
6 months of age through and including the EOS. . 
Demographic/ 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 12.1.1. 
Physical Exam 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
See Section 12.1.2. 
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Study Period 
Screening 
Gene 
Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
–30 
to  
–2 
–14 
to  
–2 
-1 
1 
2 
7 
14 
21 
30 
44 
60 
72 
 
 
End of 
Study 
Day 1 assessments will be performed prior to the 
start of gene replacement therapy infusion.  Day 7, 
14, 21, 30, 44, 60, and 72 visits are timed based on 
the Day of AVXS-101 dose (Day 1). Visits on 
Study Days 44 and 72 are for blood chemistry only. 
Months of Age 
 
 
 
 
 
 
3a 
6, 9, 12, 
15, 21 
18, 24, 
(or ET) 
Please see footnote “a” at the bottom of the 
Appendix 1 table for guidance on scheduling visits 
for Study Days 44, 60, 72, and 3 Months of Age. 
Window 
 
 
 
 
± 2 days 
± 7 days 
± 14 days  
0–14 
days 
The End of Study visit must occur within 0 to 
14 days after the date on which the patient reaches 
18 or 24 months of age (or ET), depending on the 
respective cohort.  Visits prior to and including the 
Day 72 visit are timed based on the Day of 
AVXS-101 dose.  Visits following Day 72 are 
based on the patient’s date of birth. 
Vital Signs/ 
Weight & Length 
(X) 
 
X 
(X)* 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
See Section 12.1.3. Vital signs include blood 
pressure, respiratory rate, pulse, temperature, and 
pulse oximetry.  
(X)*:  On Day 1, vital signs, with the exception of 
blood pressure will be recorded pre-dose and then 
continuously monitored throughout the gene 
replacement therapy infusion as follows:  Every 15 
(± 5) minutes from the start of the infusion for the 
first 1 hour; Every 30 minutes (± 10 minutes) until 
2 hours; Every 2 hours (+ 15 minutes) until 6 hours; 
Every 4 hours (+ 30 minutes) until 24 hours.   
Blood pressure will be recorded pre-dose and every 
8 hours through 24 hours.  Additional monitoring of 
vital signs will be at the discretion of the 
Investigator. 
Temperature will be recorded pre- and post 
infusion.    
(X): Screening weight shall be obtained 14 days 
prior to Day 1.   
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Study Period 
Screening 
Gene 
Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
–30 
to  
–2 
–14 
to  
–2 
-1 
1 
2 
7 
14 
21 
30 
44 
60 
72 
 
 
End of 
Study 
Day 1 assessments will be performed prior to the 
start of gene replacement therapy infusion.  Day 7, 
14, 21, 30, 44, 60, and 72 visits are timed based on 
the Day of AVXS-101 dose (Day 1). Visits on 
Study Days 44 and 72 are for blood chemistry only. 
Months of Age 
 
 
 
 
 
 
3a 
6, 9, 12, 
15, 21 
18, 24, 
(or ET) 
Please see footnote “a” at the bottom of the 
Appendix 1 table for guidance on scheduling visits 
for Study Days 44, 60, 72, and 3 Months of Age. 
Window 
 
 
 
 
± 2 days 
± 7 days 
± 14 days  
0–14 
days 
The End of Study visit must occur within 0 to 
14 days after the date on which the patient reaches 
18 or 24 months of age (or ET), depending on the 
respective cohort.  Visits prior to and including the 
Day 72 visit are timed based on the Day of 
AVXS-101 dose.  Visits following Day 72 are 
based on the patient’s date of birth. 
12-Lead ECG 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
A 12-lead ECG, echocardiogram, and 24-hour 
Holter Monitor are to be completed at Screening, at 
3, 6, 9, and 12 months of age, and every 6 months 
after 12 months of age. For patients not already 
undergoing 12-lead ECG/24-Hour Holter 
monitoring/ECHO from 3 months of age, these tests 
will be performed when patients are initially 
consented for them (ICF corresponding to protocol 
version 3.0 or later), and then according to the 
Schedule of Assessments. Note that 12-lead ECG 
and 24-hour Holter monitor are also performed 
during Days -1, 1, and 2.  See Section 12.1.4, 
12.1.5, and 12.1.6 for more details. 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
24-Hour Holter 
Monitor 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
Pulmonary 
Examination 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
See Section 12.1.7. 
Swallowing Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Completed every 6 months, starting at 6 months of 
age through and including the EOS vist.  Each test 
should include consistency tested.  
See Section 12.1.8. 
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Study Period 
Screening 
Gene 
Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
–30 
to  
–2 
–14 
to  
–2 
-1 
1 
2 
7 
14 
21 
30 
44 
60 
72 
 
 
End of 
Study 
Day 1 assessments will be performed prior to the 
start of gene replacement therapy infusion.  Day 7, 
14, 21, 30, 44, 60, and 72 visits are timed based on 
the Day of AVXS-101 dose (Day 1). Visits on 
Study Days 44 and 72 are for blood chemistry only. 
Months of Age 
 
 
 
 
 
 
3a 
6, 9, 12, 
15, 21 
18, 24, 
(or ET) 
Please see footnote “a” at the bottom of the 
Appendix 1 table for guidance on scheduling visits 
for Study Days 44, 60, 72, and 3 Months of Age. 
Window 
 
 
 
 
± 2 days 
± 7 days 
± 14 days  
0–14 
days 
The End of Study visit must occur within 0 to 
14 days after the date on which the patient reaches 
18 or 24 months of age (or ET), depending on the 
respective cohort.  Visits prior to and including the 
Day 72 visit are timed based on the Day of 
AVXS-101 dose.  Visits following Day 72 are 
based on the patient’s date of birth. 
Photographs of 
Infusion Site 
 
 
 
(X) 
X 
X 
X 
X 
X 
 
 
 
 
 
 
(X):  Day 1 photograph of infusion site should be 
performed after infusion.  See Section 12.1.9. 
Hematology/ 
Chemistry/ 
Urinalysis 
 
X 
 
 
(X) 
X 
(X)# 
X 
(X)* 
(X)# 
X 
(X)# 
X 
X 
X 
(X): Laboratory samples collected on Day 2 to be 
processed locally. 
(X)*: Chemisry and urinalysis only.  No 
hematology 
(X)#: Chemistry only. 
See Sections 0, 12.1.10.2, and 12.1.10.3. 
CK-MB or  
Troponin I 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
CK-MB or troponin-I will be collected at 
Screening, at the Day 7 and Day 30 visits, and 
every three months starting at the 6 months of age 
visit through and including the EOS visit. Patients 
screened and dosed before IRB/EC approval of 
Protocol version 2.0 incorporating Amendment 1 
will be tested for CK-MB throughout the study. 
Patients screened before IRB/EC approval of 
Protocol version 2.0 incorporating Amendment 1 
but dosed afterwards, will be tested for CK-MB at 
screening but for Troponin I at baseline and all 
subsequent visits. Patients screened after IRB/EC 
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Study Period 
Screening 
Gene 
Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
–30 
to  
–2 
–14 
to  
–2 
-1 
1 
2 
7 
14 
21 
30 
44 
60 
72 
 
 
End of 
Study 
Day 1 assessments will be performed prior to the 
start of gene replacement therapy infusion.  Day 7, 
14, 21, 30, 44, 60, and 72 visits are timed based on 
the Day of AVXS-101 dose (Day 1). Visits on 
Study Days 44 and 72 are for blood chemistry only. 
Months of Age 
 
 
 
 
 
 
3a 
6, 9, 12, 
15, 21 
18, 24, 
(or ET) 
Please see footnote “a” at the bottom of the 
Appendix 1 table for guidance on scheduling visits 
for Study Days 44, 60, 72, and 3 Months of Age. 
Window 
 
 
 
 
± 2 days 
± 7 days 
± 14 days  
0–14 
days 
The End of Study visit must occur within 0 to 
14 days after the date on which the patient reaches 
18 or 24 months of age (or ET), depending on the 
respective cohort.  Visits prior to and including the 
Day 72 visit are timed based on the Day of 
AVXS-101 dose.  Visits following Day 72 are 
based on the patient’s date of birth. 
approval of Protocol version 2.0 incorporating 
Amendment 1 will be tested for Troponin 1 from 
screening onwards. The pre-and post-dose cardiac 
laboratory analytes must match.   
See Secton 12.1.10.2. 
Biological 
Mother 
Virus/Serology 
Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Secton 12.1.10.4. 
Anti-AAV9 Ab 
Screen in 
Biological 
Mother 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient samples for anti-AAV9 screening must be 
collected if biological mother’s titer result is >1:50. 
See Secton 12.1.10.6. 
Genetic Re-
confirmation 
Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Secton 12.1.10.5. 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 13 
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Study Period 
Screening 
Gene 
Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
–30 
to  
–2 
–14 
to  
–2 
-1 
1 
2 
7 
14 
21 
30 
44 
60 
72 
 
 
End of 
Study 
Day 1 assessments will be performed prior to the 
start of gene replacement therapy infusion.  Day 7, 
14, 21, 30, 44, 60, and 72 visits are timed based on 
the Day of AVXS-101 dose (Day 1). Visits on 
Study Days 44 and 72 are for blood chemistry only. 
Months of Age 
 
 
 
 
 
 
3a 
6, 9, 12, 
15, 21 
18, 24, 
(or ET) 
Please see footnote “a” at the bottom of the 
Appendix 1 table for guidance on scheduling visits 
for Study Days 44, 60, 72, and 3 Months of Age. 
Window 
 
 
 
 
± 2 days 
± 7 days 
± 14 days  
0–14 
days 
The End of Study visit must occur within 0 to 
14 days after the date on which the patient reaches 
18 or 24 months of age (or ET), depending on the 
respective cohort.  Visits prior to and including the 
Day 72 visit are timed based on the Day of 
AVXS-101 dose.  Visits following Day 72 are 
based on the patient’s date of birth. 
Prior and 
Concomitant 
Medications 
Collected from 2 Weeks before gene replacement therapy until End of Study visit 
See Secion 9.2.2. 
Note: Missed visits should be rescheduled as soon as possible, but within 7 days. 
Ab = antibody; BSIDv03 = Bayley Scales of Infant and Toddler Development, version 3; CHOP INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders; CMAP = compound motor action potential; ECG = electrocardiogram; EOS = End of Study; ET = early termination; ICF = informed consent form; SAE = serious 
adverse event; WHO = World Health Organization 
a. The 3 months of age visit (also known as the Day 90 visit) is based on age (90 days=3 months of age) and all assessments at this visit may coincide with Day 44, Day 60 or Day 
72. If visit windows for these visits overlap, study sites should schedule the visits as far apart as possible within the respective visit windows (i.e. schedule the earlier visit in the 
earlier part of its’ window and schedule the later visit in the latter part of the window). In instances where this is not possible, it is acceptable for an overlapping visit to occur as long 
as all assessments between visits are performed. In such instances, the lab requisition form should be marked for all visits that apply and 
 must be notified. At combined 
visits, one of each assessment scheduled to occur in both visits must be completed.  If the visit is a combination of Day 44 or Day 72 and Day 90, then the visit will be conducted as 
Day 90.  If the visit is a combination of Day 44 or Day 72 and Day 60, then the visit will be conducted as Day 60.  If the visit combines Day 60 and Day 90, with or without Days 44 
and/or 72, then the visit will be conducted as Day 60.  Sites are advised to collect chemistry samples at each visit during the prednisolone administration period and any visits 
up to two weeks after last dose of prednisolone.  If visits are combined as described above, then the site investigator should make every effort to monitor chemistry at the 
appropriate time points using unscheduled visits if necessary. 
 
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APPENDIX 2. POST-MORTEM PLAN 
Post-mortem tissue/organ collection and autopsy, where possible, will be requested for any 
patient who receives treatment with AVXS-101 and subsequently expires, at any timepoint.  The 
tissue and organ collection will be performed by a contracted vendor or hospital pathologist who 
will deploy a pathologist and pathology assistant, as necessary, to the funeral home of the 
deceased or other appropriate location to perform the autopsy and tissue collection. 
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 6.  Tissue samples will be frozen or fixed (e.g., 2% paraformaldehyde) for 
appropriate analysis. 
Families will be asked to consent to authorization for tissue and organ collection and prior to any 
sign of moribund or death by the clinical team conducting the study.  Declining the post-mortem 
tissue/organ collection will not prevent patients from participating in the study. 
Table 6 - Tissue Sample for Analysis 
Brain 
Spinal Cord 
Muscles 
Organs 
Motor cortex 
Cervical spinal cord 
Diaphragm 
Spleen 
Layer 5 motor cortex 
Thoracic spinal cord 
#6/#7 Rib with intercostal muscle and 
nerve 
Kidney 
Brain stem 
Lumbar spinal cord 
Psoas muscle 
Small intestine 
Sacral spinal cord 
Large intestine 
Dorsal root 
Pancreas 
Cervical level 
Stomach 
Ventral root 
Lung 
Cervical level 
Heart 
DRG root 
Liver 
Cervical level 
Inguinal lymph node 
Cerebrospinal fluid 
Gonads 
 
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APPENDIX 3. BAYLEY SCALES OF INFANT AND TODDLER 
DEVELOPMENT (VERSION 3) 
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APPENDIX 4. PERFORMANCE CRITERIA FOR BAYLEY SCALES OF 
INFANT AND TODDLER DEVELOPMENT (VERSION 3) 
DEVELOPMENTAL MILESTONES 
Developmental Milestone 
Performance Criteria 
Head Control – Gross Motor Subtest Item #4  
Rolls from Back to Sides – Gross Motor Subtest 
Item #20 
Sits Without Support – Gross Motor Subtest Item #26 
Stands With Assistance - Gross Motor Subtest Item #33 
Crawls – Gross Motor Subtest Item #34 
Pulls to Stand – Gross Motor Subtest Item #35 
Walks With Assistance – Gross Motor Subtest Item #37 
Stands Alone – Gross Motor Subtest Item #40 
Walks Alone – Gross Motor Subtest Item #43 
 
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APPENDIX 5. PERFORMANCE CRITERIA FOR WORLD HEALTH 
ORGANIZATION (WHO) DEVELOPMENT 
MILESTONES 
Gross Motor Milestone 
Performance Criteria 
Sitting without support 
Hands-and-knees 
crawling 
Standing with assistance 
Walking with assistance 
Standing alone 
Walking alone 
WHO = World Health Organization 
Source: World Health Organization Multicentre Growth Reference Trial Group [22] 
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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 
1. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when providing medical care.” 
2. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research.  The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
3. Medical progress is based on research that ultimately must include studies involving Human 
subjects. 
4. The primary purpose of medical research involving Human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments).  Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
5. Medical research is subject to ethical standards that promote and ensure respect for all Human 
subjects and protect their health and rights. 
6. While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research patients. 
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7. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information 
of research patients.  The responsibility for the protection of research patients must always rest 
with the physician or other health care professionals and never with the research patients, even 
though they have given consent. 
8. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving Human subjects in their own countries as well as applicable international norms and 
standards.  No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research patients set forth in this Declaration. 
9. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
10. Medical research involving Human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications.  Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. 
11. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
12. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the research 
study will not adversely affect the health of the patients who serve as research patients. 
13. Appropriate compensation and treatment for patients who are harmed as a result of participating 
in research must be ensured. 
Risks, Burdens and Benefits 
1. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving Human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research patients. 
2. All medical research involving Human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by the 
condition under investigation. 
Measures to minimize the risks must be implemented.  The risks must be continuously monitored, 
assessed and documented by the researcher. 
3. Physicians may not be involved in a research study 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 
study. 
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Vulnerable Groups and Individuals 
1. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
2. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable 
group.  In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research. 
Scientific Requirements and Research Protocols 
1. Medical research involving Human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation.  The welfare of 
animals used for research must be respected. 
2. The design and performance of each research study 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 study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
1. The research protocol must be submitted for consideration, comment, guidance and approval to 
the concerned research ethics committee before the study 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 study, the researchers must submit a final report to the committee 
containing a summary of the study’s findings and conclusions. 
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Privacy and Confidentiality 
1. Every precaution must be taken to protect the privacy of research patients and the confidentiality 
of their personal information. 
Informed Consent 
1. Participation by individuals capable of giving informed consent as patients in medical research 
must be voluntary.  Although it may be appropriate to consult family members or community 
leaders, no individual capable of giving informed consent may be enrolled in a research study 
unless he or she freely agrees. 
2. In medical research involving Human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible 
conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study.  The potential subject must be informed of the right to refuse to 
participate in the study 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. 
All medical research patients should be given the option of being informed about the general 
outcome and results of the study. 
3. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress.  In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
4. For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorized representative.  These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the group represented by the potential subject, the research cannot instead 
be performed with persons capable of providing informed consent, and the research entails only 
minimal risk and minimal burden. 
5. When a potential research subject who is deemed incapable of giving informed consent is able to 
give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorized representative.  The potential subject’s dissent 
should be respected. 
6. Research involving patients who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group.  In such 
circumstances the physician must seek informed consent from the legally authorized 
representative.  If no such representative is available and if the research cannot be delayed, the 
study 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 
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the research protocol and the study has been approved by a research ethics committee.  Consent 
to remain in the research must be obtained as soon as possible from the subject or a legally 
authorized representative. 
7. The physician must fully inform the patient which aspects of their care are related to the research.  
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the 
study must never adversely affect the patient-physician relationship. 
8. For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse.  There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research.  In such situations the research may be 
done only after consideration and approval of a research ethics committee. 
Use of Placebo 
1. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those 
of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention and the patients who receive any intervention 
less effective than the best proven one, placebo, or no intervention will not be subject to 
additional risks of serious or irreversible harm as a result of not receiving the best proven 
intervention.  Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
1. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all patients who still need an intervention identified as 
beneficial in the trial.  This information must also be disclosed to patients during the informed 
consent process. 
Research Registration and Publication and Dissemination of Results 
1. Every research study involving Human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
2. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research.  Researchers have a duty to make 
publicly available the results of their research on Human subjects and are accountable for the 
completeness and accuracy of their reports.  All parties should adhere to accepted guidelines for 
ethical reporting.  Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available.  Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication.  Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
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Unproven Interventions in Clinical Practice 
1. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorized representative, may use an unproven intervention 
if in the physician's judgement it offers hope of saving life, re-establishing health or alleviating 
suffering.  This intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy.  In all cases, new information must be recorded and, where 
appropriate, made publicly available. 
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APPENDIX 8. SUMMARY OF CHANGES 
See next page.  
 
 
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AVXS-101 
AVXS-101-CL-304 
Protocol Title: 
A Global Study of a Single, One-Time Dose of AVXS-101 
Delivered to Infants with Genetically Diagnosed and 
Pre-symptomatic Spinal Muscular Atrophy with Multiple Copies 
of SMN2 
Summary of Changes: 
Protocol Version 6.0, Amendment 5, 28 July 2020 
 
SUMMARY AND JUSTIFICATION OF CHANGES 
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 
− update the schedule of assessments to align protocol changes for consistency 
− address specific requests from Competent Authorities regarding Safety Reporting 
timelines and Hy’s Law Criteria 
− remove text that is not applicable for sample size calculation 
− make administrative changes 
− make minor changes and edits for error correction, clarification, and overall 
consistency. 
The following changes were made to the Protocol from Version 5.0 Amendment 4 dated 
26 Nov 2019 to Version 6.0 Amendment 5 dated 28 Jul 2020. 
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SUMMARY OF CHANGES: 
The section below describes the changes incorporated into this version of the protocol.   
Protocol Version 6.0 Incorporating Amendment 5 includes the following changes 
Description of Change 
Location(s) 
Rationale for Change 
Replaced 
 
 
 
Signature page 
To update per company administrative 
changes 
Updated the list of abbreviations by adding 
ADL, AT, BSIDv03, and TBL 
Section 4: List of 
Abbreviations and 
Definitions of Terms 
To align changes in the protocol 
Text added to allow changes in study conduct 
during the COVID-19 pandemic (or other similar 
catastrophic event): 
- 
change to the conduct of study visits  
- 
when a patient may be considered 
withdrawn due these factors, versus 
withdrawn consent 
- 
change to the manner in which efficacy and 
safety assessments are performed  
- 
change to the manner in which monitoring 
visits are performed 
- 
the process of obtaining remote informed 
consent  
Section 7.1: Overall Trial 
Design 
Section 8.3: Patient 
Withdrawal Criteria 
Section 11: Assessment 
of Efficacy 
Section 12: Assessment 
of Safety 
Section 16.1: Study 
Monitoring 
Section 18.3: Written 
Informed Consent 
To address the impact of the COVID-19 
pandemic (or other similar catastrophic 
event) on: 
- 
a site’s ability to conduct on-site study 
visits and efficacy and safety 
assessments per protocol 
- 
a subject’s willingness or ability to 
continue participating in the study 
- 
a monitor’s ability to perform on-site 
monitoring visits 
- 
a site’s ability to follow the usual 
process of obtaining written informed 
consent 
References to developmental milestones were 
added to further define the primary/secondary 
objectives 
Synopsis: Objectives 
Sections 6.2: Efficacy 
Objectives   
For clarification 
Text for exploratory objectives/endpoints was 
revised 
 
 
Synopsis: Exploratory 
Objectives 
Sections 6.2.1.3 and 
6.2.2.3: Exploratory 
Objectives 
Section 14.1.1.3: 
Exploratory Endpoints 
To algin with Appendix 4 
Updated text to include that safety monitoring 
will continue 30 days after the EOS visit and all 
visits will be scheduled based on 30-day month 
calender 
Synopsis: Methodology, 
Statistical Methods 
Section 7.1: Overall 
Study Design 
Figure 4 footnotes 
To align with Section 13.3 for consistency 
and for clarification  
Text was added to state that all developmental 
milestones should be assessed, documented and 
video recorded regardless of previous attainment 
Section 11.1: 
Developmental 
Milestones 
For clarification 
Text added to state that additional information 
on contractures will also be collected, as 
described in the Physical Assessments Manual 
Section 11.2.2: CHOP 
INTEND 
Collection of contractures data was included 
in the scoring sheet provided in Appendix 6 
of previous protocol versions, but is not 
included in the new scoring sheet provided 
by CHOP. The Physical Assessment Manual 
contains a supplemental CHOP-INTEND 
contractures data collection sheet for use by 
investigator sites, to ensure consistency in 
the data collected throughout the study 
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Description of Change 
Location(s) 
Rationale for Change 
Text added to clarify that videos domonstrating 
Developmental Milestones which meet WHO 
and BSIDv03 criteria will be submitted to an 
independent, central reviewer for unbiased 
assessment of developmental milestone 
achievement   
Section 11.3: Video 
Evidence 
For clarification 
Text added to include that local laboratory tests 
should include normal ranges appropriate for the 
age of the patient 
Section 12.1.10: 
Laboratory Assessments 
For clarification 
Table 3 was updated to add blood sampling for 
CK-MB or troponin I at the EOS visit and to 
remove text to reduce redundancy 
Table 3: Total Blood 
Volume: Patient 
To align protocol changes and for 
clarification 
Deleted text that is no longer applicabe within 
the protocol 
Section 14.2: Sample Sie 
Calculation 
For clarification 
Section 14.4.1 Hy’s Law Criteria and definition 
inserted, with a link in Section 5.5 
Section 14.4: Safety 
Analysis 
At the request of the Belgium FAMPH 
Video Manual changed to Physical Assessments 
Manual 
Throughout 
The Physical Assessments Manual is the new 
reference document for Clinical Evaluators 
Schedule of Assessments was updated with 
minor editting and to specify the schedule of 
BSIDv03 Gross and Fine Motor Subtests (with 
video), to include the cross-link sections, and to 
add CK-MB or Troponin test to the EOS visit 
Appendix 1: Schedule of 
Assessments 
To align with protocol changes and for 
clarification 
Addition of copyright information at the bottom 
of each page of the Bayley record 
Appendix 3: Bayley 
Scales of Infant and 
Toddler Development 
(Version 3) 
Per copyright requirements 
Scoring sheet has been replaced with an updated 
version 
Appendix 6: CHOP 
INTEND 
A new scoring sheet was provided by CHOP  
 
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