Phase I Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 Delivering AVXS-101
Phase: PHASE1
Conditions: Spinal Muscular Atrophy 1
Sponsor: Novartis Gene Therapies

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Protocol Number: 
AVXS-101-CL-101 (formerly AVXS-101) 
IND Number: 
15699 
Protocol Title: 
Phase I Gene Transfer Clinical Trial for Spinal 
Muscular Atrophy Type 1 Delivering AVXS-101 
Indication Studied: 
Spinal muscular atrophy Type 1 
Sponsor Address: 
2275 Half Day Road, Suite 160 
Bannockburn, IL  60015 
Protocol Version/Date: 
Version 14.0 / 21 April 2016 
 
 
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 trial 
subjects are protected, consistent with the principles that have their origin in the Declaration of 
Helsinki. 
 
 
 
Confidentiality Statement 
The information in this document contains trade and commercial information that is privileged or 
confidential and may not be disclosed unless such disclosure is required by federal or state law or 
regulations.  In any event, persons to whom the information is disclosed must be informed that 
the information is privileged or confidential and may not be further disclosed by them.  These 
restrictions on disclosure will apply equally to all future information supplied to you which is 
indicated as privileged or confidential.

AveXis, Inc. 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
Protocol Version 14.0 / 21 Apr 2016 
 
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1 ADMINISTRATIVE INFORMATION 
1.1 
Summary of Changes 
This version of the protocol reflects the change in sponsorship of the study from Sophia’s Cure and NCH 
to AveXis, Inc.  This protocol was prepared utilizing the AveXis, Inc. clinical study protocol template, 
and combines the latest version of the protocol, version 13.0 dated 10 June 2015 and the Protocol 
Addendum #2 version 1.0 dated 24 June 2015. 
The following table outlines the transfer of protocol sections from the previous NCH version(s) of the 
protocol template to the current AveXis, Inc. protocol template. 
Table 1 
Summary of Protocol Section Changes and Additions 
NCH 
AveXis 
Section # 
Section Title 
Section # 
Section Title 
Sections Existing in previous versions of protocol(s) 
1.0 
Synopsis 
2.0 
Synopsis 
2.0 
Abstract 
5 
Introduction 
3.0 
Clinical Trial and Principal Investigator 
N/A 
N/A 
3.2 
Rationale for Gene Transfer to SMA Type
1 Patients 
5.2 
Rationale for Gene Transfer to SMA 
Type 1 Patients 
3.3 
Background and Preliminary Data 
5.1 
Background and Preliminary Data 
4.0 
Preliminary Data 
5.3 
Non-clinical Studies 
5.0  
Research 
6 
Trial Objectives and Purpose 
5.2 
Pre-Treatment Assessment 
8 
Selection and Withdrawal of Subjects 
5.3 
Dosing Plan 
9, 10.5, 10.6 
Treatment of Subjects, Administration, 
Dose Escalation 
5.4 
Clinical Trial Monitoring Plan 
11 
Assessments 
5.5 
Outcome Measures 
6 (6.1–6.3) 
Trial Objectives and Purpose 
5.6 
Statistical Analysis 
13 
Statistics 
5.7 
Timeline of Assessments 
Table 6 
Schedule of Assessments 
6.0 
Dose Limiting Toxicity 
11.1.1 
Dose Limiting Toxicity 
6.1 
The classification for adverse events 
11.1.1 
Dose Limiting Toxicity 
6.3 
Stopping/Discontinuation Rules 
8.3 
Subject Withdrawal Criteria 
6.4 
Dose Escalation 
10.6 
Dose Escalation 
7.0 
Adverse Event Monitoring and Reporting 12 
Adverse and Serious Adverse Events, 
Relationship to Study Drug, Recording 
Adverse Events, Reporting Adverse 
Events 
8.0 
Study Reports 
N/A 
N/A 
Study reports are a sponsor 
responsibility, outlined in sponsor SOPs 
8.3 
Data Safety Monitoring Plan 
13 
Data Safety Monitoring Board 
8.4 
Clinical Monitoring of the Study 
15.1 
Study Monitoring 
9.0 
References 
19 
References 

AveXis, Inc. 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
Protocol Version 14.0 / 21 Apr 2016 
 
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NCH 
AveXis 
Section # 
Section Title 
Section # 
Section Title 
Addendum 1 
Autopsy Plan 
Appendix 2 
Autopsy Plan 
New Sections that were not present in previous version(s) of protocol(s) 
N/A 
N/A 
15.2 
Audits and Inspections 
N/A 
N/A 
16 
Ethics 
N/A 
N/A 
17 
Data Handling and Recordkeeping 
N/A 
N/A 
18 
Publication Policy 
  
N/A 
Appendix 1 
Declaration of Helsinki 
 
N/A 
Appendix 3 
CHOP-INTEND 
 
N/A 
Appendix 4 
Bayley Scale of Infant Development, 
version 3 
 
N/A 
Appendix 5 
Gross Motor Skills Checklist 
The following sections were overhauled to reflect transition in sponsorship of study, 
supporting AveXis, Inc., as managing sponsor 
N/A 
N/A 
12 
Adverse and Serious Adverse Events 
N/A 
N/A 
13 
Data Safety Monitoring Board 
The section below highlights content changes represented in this version of the protocol.  
Language deleted from the previous version of the protocol appears in italics.  Language added 
to the previous version of the protocol appears in bold. 
Section 6.2: 
Secondary Objectives 
A secondary outcome will include time from birth to either (a) requirement of ≥16-hour 
respiratory assistance per day (includes BiPAP) continuously for >2 weeks in the absence of an 
acute reversible illness or (b) death. 
Secondary outcomes will also include the change in CHOP-INTEND from baseline score 
and demonstration of improvement of motor function and muscle strength as determined 
by achievement of significant development milestones including but not limited to the 
ability to sit alone and roll over unassisted.  Additionally, AveXis, Inc. may opt to provide 
videos of the physical exams, CHOP-INTEND assessments, and/or Bayley Scale 
assessments to an independent, blinded reviewer for confirmation of the development 
milestones. 
Rationale for Change 
Achievement of motor milestones will serve as a more clinically meaningfully efficacy endpoint. 
 
Section 6.3: 
Exploratory Objectives 
Exploratory outcome measures will be tested during the study as part of the program and product 
development plan; however if exploratory measurement results show efficacy and primary 
outcomes do not reach statistical significance, the only interpretation is that the results show a 
trend toward benefit but can never supersede primary measures.  These exploratory outcome 
measures will include: 

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• 
ACTIVE-mini (Ability Captured Through Interactive Video Evaluation-mini) evaluation of 
infant movement ability. 
• 
Patient functional measures using the Children’s Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders (CHOP-INTEND).  This test has been studied and validated in 
infants with spinal muscular atrophy and was found to be reliable in this population.19 
• 
Bayley Scales of Infant Development version 3 is a standardized, norm-referenced infant 
assessment.  The gross and fine motor portions of this test will administered if the child 
reaches or exceeds a score of 60 out of 64 on the CHOP-INTEND. 
• 
Motor neuron function will be assessed via evoked compound motor action potentials 
(CMAP) and motor unit number estimation (MUNE). 
• 
Pathological status of muscles will be quantified by Electrical Impedance Myography (EIM). 
• 
The age at which significant motor milestones are achieved will be assessed using a standard 
Motor Milestone Development Survey shown in Table 10 in Section 11.1.10. 
• 
Compelling, demonstrable, documented evidence of efficacy as determined by changes 
in functional abilities as captured during videotaping sessions during site visits and/or 
captured by subject/parent/legal guardian at home. 
Rationale for Change 
Determination that “compelling evidence” of efficacy may be documented via video-taped 
physical therapy sessions, showing motor milestone achievement. 
 
Section 7.1: 
Overall Study Design 
The proposed clinical trial is an open-label, single injection ascending dose study of self-
complementary AAV9 carrying the SMN gene under the control of a hybrid CMV 
enhancer/chicken AVXS-101 delivered one-time through a venous catheter inserted into a 
peripheral vein (arm, leg, or scalp) of Type 1 spinal muscular atrophy subjects. 
The primary analysis for efficacy will be assessed when all patients reach 13.6 months of 
age (a database lock will be performed at the time point at which all patients reach 13.6 
months of age).  A follow-up safety analysis will be completed at the time point at which the 
last patient reaches 24 months post-dose. 
Rationale for Change 
In a natural history study of SMA Type 1 survival,20 the distribution of the age at reaching the 
combined endpoint of death or respiratory failure differed by SMN2 copy number.  The median 
age at the combined endpoint for subjects with two (2) SMN2 copies was 10.5 (IQR 8.1-13.6).  
Therefore, 13.6 months is the expected age at which 75% of SMA Type 1 patients with two (2) 
SMN2 copies will have met the endpoint of death and/or respiratory failure. 
 
The following are procedures that are being conducted for study purposes, but were not 
described/outlined as appropriate in previous versions of the protocol(s): 
Section 8.1 
Inclusion Criteria 

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Subjects must meet all of the following Inclusion Criteria: 
1. Six months of age and younger1 at day of vector infusion with Type 1 SMA as defined by 
the following features: 
a. Bi-allelic SMN1 gene mutations (deletion or point mutation) with two copies of 
SMN2 (no more and no fewer). 
b. Patients 6 months and younger with a disease onset up to 6 months of age 
c. Hypotonia by clinical evaluation with delay in motor skills, poor head control, round 
shoulder posture and hypermobility of joints. 
1 
First nine subjects enrolled under previous version(s) of the protocol could be nine months of age or 
younger.  Inclusion revised to reflect six months of age or younger in 24 Jun 2015 Protocol Addendum #2. 
Initial genetic testing and diagnosis completed at an institution/laboratory other than 
Nationwide Children’s Hospital/Ohio State University is acceptable if proper 
documentation is received at Nationwide Children’s Hospital, verified by the PI, and filed 
in the patient’s medical record. 
AveXis, Inc. may opt to confirm all genetic diagnoses through a contracted third-party 
laboratory utilizing an additional blood sample collected during a post-dose visit. 
Rationale for Change 
For clarification purposes, added notation that baseline diagnostic genetic testing was not 
completed at Nationwide Children’s Hospital in all cases.  As noted, AveXis, Inc. may opt to 
have baseline blood samples for all subjects re-tested at a commercial laboratory to ensure 
consistent results for all subjects in the trial.  As these samples would be run after 
enrollment/dosing was complete, results would not impact subject eligibility. 
Section 11.8.1 
CHOP-INTEND 
CHOP-INTEND including head control, righting reactions, and trunk movements in supported 
sitting, supine, and prone positions.  Anti-gravity movements in assisted rolling, ventral 
suspension, and supported standing are also measured.  See Appendix 3. 
At such time that a subject achieves two consecutive CHOP-INTEND scores of ≥62, a 
teleconference will be conducted between PI, physical therapist, and AveXis, Inc. to review 
the subject status and determine whether or not continued CHOP-INTEND assessments 
are necessary.  A decision will be reached and confirmed in writing following the 
teleconference.  If decided that no further assessments are necessary, the physical therapist 
will cease completion of the CHOP-INTEND assessment at subsequent visits; otherwise 
CHOP-INTEND assessments will continue monthly. 
CHOP-INTEND examinations will be videotaped in accord with the Videotaping Manual. 
Rationale for Change: 
As patients on a normal development course age, CHOP-INTEND scores decrease over time as 
there are portions of the assessment that are specific to infant development.  As patients develop 
out of infancy, they no longer exhibit some motor functions in an appropriate way for some of 
the assessment sections to be scored.  As study subjects achieve a score of 64, more in line with a 

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normal development course, it would be inappropriate to continue with the CHOP-INTEND for 
the same reason. 
 
Section 11.8.2 
Bayley Scale of Infant Development version 3 
Bayley Scales of Infant Development version 3 is a standardized, norm-referenced infant 
assessment.  The gross and fine motor portions and cognition portions of this test will 
administered if the child reaches or exceeds a score of 60 out of 64 on the CHOP-INTEND.  
The gross and fine motor portion will be completed monthly during the first year and the 
cognition portion will be completed every three months.  During the second year all 
required portions of the Bayley Scale will be conducted every three months, except for 
subjects still being seen monthly for CHOP-INTEND assessments.  For those subjects the 
gross and fine motor and cognition portions will be administered as in Year 1.  See 
Appendix 4. 
Bayley scales examinations will be videotaped in accord with the Videotaping Manual. 
 
Section 11.9 
Development Milestones Checklist 
The age at which significant motor milestones are achieved will be assessed using a standard 
Motor Milestone Development Survey shown in Table 10 and a Gross Motor Skills Checklist 
shown in Appendix 5.  The Gross Motor Skills Checklist was designed by physical therapists 
at Nationwide Children’s Hospital specifically to assess SMA Type 1 subjects in this trial; it 
is source from a collection of existing motor assessments.  See Appendix 5. 
Additionally, CHOP-INTEND and Bayley physical therapy assessment videos may be 
transferred to a centralized reviewer for independent determination of milestones achieved. 
Rationale for Change 
The Gross Motor Skills Checklist was developed as an assessment and added to the protocol as a 
method by which to evaluate subjects achieving a maximum CHOP-INTEND score of 64. 
 
Section 11.10 
Video Evidence 
Physical therapy assessments and physician physical examinations required at each study visit 
will be videotaped in an effort to produce compelling, demonstrable, documented evidence of 
efficacy as determined by changes in functional abilities.  Parent(s)/legal guardian(s) may also 
share home videos demonstrating achievement of functional abilities.  AveXis, Inc. will provide 
a secure and confidential upload process for transfer and storage of the videos from NCH to a 
contracted third-party vendor that will compile and arrange videos as per AveXis, Inc. 
submission requirements.  Any/all videos received at AveXis, Inc. or the contracted vendor will 
be treated as confidential study data and will be the sole property of AveXis, Inc.  AveXis, Inc. 
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 and/or the medical community. 

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Investigational Product: AVXS-101 
Protocol Version 14.0 / 21 Apr 2016 
 
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Videos will be provided in a blinded fashion to an independent, centralized reviewer for 
unbiased assessment of milestone achievement. 
 
Section 11.18 
Photographs of Infusion Site 
Photographs will be taken of the infusion site at the time points specified in Table 6.  
AveXis, Inc. will provide a secure and confidential upload process for transfer and storage 
of the photographs from NCH to a contracted third-party vendor that will compile and 
arrange photographs as per AveXis, Inc. submission requirements.  Any/all photographs 
received at AveXis, Inc. or the contracted vendor will be treated as confidential study data 
and will be the sole property of AveXis, Inc.  AveXis, Inc. 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 and/or the medical community. 
 
Section 11.19.11 
Saliva, Urine, Stool Collection 
Saliva, urine, and stool samples will be collected for viral shedding studies.  Saliva will be 
collected from the patient’s mouth with a pipette and oral swab.  200−500 µL of urine will 
be collected from patients’ soiled diapers by soaking a cotton ball.  Pea-sized fecal samples 
will be collected from patients’ soiled diapers.  Each of these samples will be placed in a 
DNAse/RNAse-free Eppendorf tube with locking top.  The tubes will be stored in a -80°C 
freezer. 
Rationale for Change 
Saliva, urine, and stool samples will be collected to study viral shedding. 
1.2 
Contact Information 
Table 2 
Important Study Contact Information 
Role in Study 
Name 
Address and Telephone number 
Clinical Study Leader 
Courtney Wells, AveXis Director, 
Clinical Trials Management - 
Clinical Operations 
2275 Half Day Road, Suite 160 
Bannockburn, IL  60015 
Office:  (847) 572-8405 
Mobile:  (773) 818-2111 
cwells@avexis.com 
Responsible Physician 
Doug Sproule, MD, AveXis Vice 
President, Clinical Development 
2275 Half Day Road, Suite 160 
Bannockburn, IL 60015 
Office:  (847) 572-8406 
Mobile:  (978) 505-2524 
dsproule@avexis.com 

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Role in Study 
Name 
Address and Telephone number 
Drug Safety Physician 
NCH Safety Monitor  
Gloria Galloway, MD 
OSU Safety Monitor 
Ohio State University 
395 W 12th Avenue 
Columbus, OH  43210 
Office:  (614) 293-4969 
Mobile:  (614) 937-2417 
Galloway.58@osu.edu 
24-Hour Emergency Contact 
Jerry Mendell, MD 
Samiah Al-Zaidy, MD 
NCH 
700 Children’s Drive- WA 3011 
Columbus, OH  43205 
Mendell: (614) 355-5247 
Al-Zaidy: (614) 355-3682 
SAE Reporting 
AveXis 
safetyreporting@avexis.com 
FAX:  (847) 510-0775 
CRO Project Manager 
Toni Miller, Sr. Project Manager, 
Novella Clinical 
1700 Perimeter Park Drive 
Morrisville, NC 27560, United States 
Office: 919-972-7391    
Mobile: 765-481-6257 
tmiller@novellaclinical.com 
 
Table 3: 
Study Vendor Listing 
Role in Study 
Name 
Address 
Clinical Research Organization 
Novella 
1700 Perimeter Park Drive 
Morrisville, NC  27560 
Video 
Video 1 Productions 
1820 W. Webster Ave., Ste. 201 
Chicago, IL  60614 
Central Laboratory- confirmatory 
genetic testing 
Q2 Solutions 
200 Forest Street, Suite 200 
Marlborough, MA 01752 USA 
Autopsy 
Regional Pathology and Autopsy 
Services, Inc. 
Oakland, CA 
877-330-7727 
 

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Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
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2 SYNOPSIS 
Name of Sponsor/Company:  AveXis, Inc. 
Name of Investigational Product:  AVXS-101 
Name of Active Ingredient:  Survival Motor Neuron Gene by Self‐Complementary AAV9 
Title of Study:  Phase I Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 Delivering 
AVXS-101 
Study center(s):  Nationwide Children’s Hospital 
Principal Investigator:  Jerry Mendell, MD 
Studied period (years): 
Estimated date first patient enrolled: May 2014 
Estimated date last patient completed: Jan 2017 
Phase of development:  1 
Objectives: 
Primary: 
• 
Determination of safety based on the development of unacceptable toxicity: defined as the 
occurrence of any one Grade III or higher, unanticipated, treatment-related toxicity. 
Secondary: 
• 
The time from birth until death or until patient requires at least 16-hour per day of ventilation support 
for breathing for ≥14 consecutive days in the absence of an acute reversible illness, excluding 
perioperative use. 
Methodology: 
Open-label, dose-escalation clinical trial of AVXS-101 injected intravenously through a peripheral limb 
vein.  Short-term safety will be evaluated over a two year period.  Patients will be tested at baseline and 
return for follow up visits on days 7, 14, 21, 30, followed by once every month through 12 months post 
dose, and then every three months through two (2) years post infusion.  Unscheduled visits may occur if 
the PI determines that they are necessary. 
 
The primary analysis for efficacy will be assessed when all patients reach 13.6 months of age (a 
database lock will be performed at the time point at which all patients reach 13.6 months of 
age).  A follow-up safety analysis will be completed at the time point at which the last patient 
reaches 24 months post-dose. 
 
Upon completion of the 2-year study period, patients will be monitored annually as per standard of care 
for up to 15 years. 
Number of patients (planned):  15 
Diagnosis and main criteria for inclusion: 
Inclusion Criteria 
• 
Six months of age and younger at day of vector infusion with Type 1 SMA as defined by the 
following features: 

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• 
Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or 
point mutations) and 2 copies of SMN2. 
• 
Onset of disease at birth: up to 6 months of age. 
• 
Hypotonia by clinical evaluation with delay in motor skills, poor head control, round shoulder 
posture and hypermobility of joints 
Exclusion Criteria 
• 
Active viral infection (includes HIV or serology positive for hepatitis B or C) 
• 
Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry <95% 
saturation at the screening visit. 
o Patients may be managed using non-invasive ventilator support (BiPAP) for less than 16 
hours per day at the discretion of their physician or study staff. 
• 
Concomitant illness that in the opinion of the PI creates unnecessary risks for gene transfer 
• 
Concomitant use of any of the following drugs: drugs for treatment of myopathy or neuropathy, 
agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy or 
immunosuppressive therapy within 3 months of starting the trial (eg, corticosteroids, 
cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, 
rituximab) 
• 
Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding immunoassay. 
• 
Abnormal laboratory values considered to be clinically significant (GGT >3 X ULN, Bilirubin 
≥3.0 mg/dL , Creatinine ≥1.8 mg/dL, Hgb <8 or >18 g/Dl; WBC >20,000 per cmm) 
• 
Participation in recent SMA treatment clinical trial that in the opinion of the PI creates 
unnecessary risks for gene transfer. 
• 
Family does not want to disclose patient's study participation with primary care physician and 
other medical providers. 
• 
Patient with signs of aspiration based on a swallowing test and unwilling to use an alternative 
method to oral feeding. 
• 
Patients with a single base substitution in SMN2 (c.859G>C in exon 7) will be excluded based 
on predicted mild phenotype. 
Investigational product, dosage and mode of administration: 
Cohort 1 will consist of three (3) SMA patients followed by Cohort 2A with a minimum of three (3) and 
no more than six (6) SMA patients to receive a single infusion at escalating doses. 
• 
Cohort 1 (Low Dose): 6.7 X 1013 vg/kg (n=3) 
• 
Cohort 2A (Intermediate Dose): 2.0 X 1014 vg/kg (n≥3 and n≤6) 
Cohort 2B and Cohort 3 will each consist of three (3) SMA patients to receive a single infusion at 
escalating doses. 
• 
Cohort 2B: 2.0 X 1014 vg/kg (n=3) 
• 
Cohort 3 (High Dose): 3.3 X 1014 vg/kg (n=3) 
Cohort 2B will be done first and if efficacy is favorable but does not fully improve subjects to normal, 
Cohort 3 at high dose will be implemented. 
Treatment of Cohort 3 is permitted based on safety assessment presented in the IND.  A score of 8 or 
higher on the Bayley Scales of Infant Development will be considered the low end of normal. 
Duration of treatment:  The vector will be delivered approximately in 10−20 mL/kg of normal saline 
infused approximately for 60 minutes. 

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Reference therapy, dosage and mode of administration:  N/A 
Criteria for evaluation: 
Safety: 
• 
Incidence of Grade III or higher, unanticipated, treatment-related toxicity. 
Efficacy: 
• 
Time to death or until patient requires at least 16-hour per day of ventilation support for breathing for 
≥14 consecutive days in the absence of an acute reversible illness, excluding perioperative use 
• 
A successful measure for efficacy for this study will be 50% of SMA Type 1 subjects living 
independently of 16 or more hours of ventilator support at 2 years. 
• 
Change in CHOP-INTEND from baseline measure score of age. 
• 
To determine efficacy by demonstrating improvement of motor function and muscle strength as 
determined by achievement of significant development milestones including but not limited to the 
ability to sit alone and roll over unassisted.  Additionally, AveXis, Inc. may opt to provide videos of 
the physical exams, CHOP-INTEND assessments, and/or Bayley Scale assessments to an 
independent, blinded reviewer 
Statistical methods:  This is a Phase I trial, with safety as the primary measure.  Sample size was not 
determined through statistical justification. 
 

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3 TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 
TABLE OF CONTENTS 
1 
ADMINISTRATIVE INFORMATION ..................................................................2 
1.1 
Summary of Changes .........................................................................................2 
1.2 
Contact Information ...........................................................................................7 
2 
SYNOPSIS ...............................................................................................................9 
3 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ..........12 
TABLE OF CONTENTS ...................................................................................................12 
LIST OF TABLES .............................................................................................................15 
LIST OF FIGURES ...........................................................................................................15 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................16 
5 
INTRODUCTION .................................................................................................18 
5.1 
Background and Preliminary Data ...................................................................18 
5.2 
Rationale for Gene Transfer to SMA Type 1 Patients .....................................18 
5.3 
Non-Clinical Studies ........................................................................................21 
6 
TRIAL OBJECTIVES AND PURPOSE ...............................................................24 
6.1 
Primary Objective ............................................................................................24 
6.2 
Secondary Objectives.......................................................................................24 
6.3 
Exploratory Objectives ....................................................................................24 
7 
INVESTIGATIONAL PLAN ................................................................................25 
7.1 
Overall Study Design .......................................................................................25 
7.2 
Number of Subjects..........................................................................................25 
7.3 
Treatment Assignment .....................................................................................26 
7.4 
Criteria for Study Termination.........................................................................26 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS .........................................30 
8.1 
Subject Inclusion Criteria ................................................................................30 
8.2 
Subject Exclusion Criteria ...............................................................................30 
8.3 
Subject Withdrawal Criteria ............................................................................31 
9 
TREATMENT OF SUBJECTS .............................................................................31 
9.1 
Description of Study Drug ...............................................................................31 
9.2 
Concomitant Medications ................................................................................32 
9.2.1 
Prophylactic Administration of Prednisolone ......................................32 
9.2.2 
Prohibited Medications ........................................................................33 
10 
STUDY DRUG MATERIALS AND MANAGEMENT ......................................33 
10.1 
Study Drug .......................................................................................................33 
10.2 
Study Drug Packaging and Labeling ...............................................................33 
10.3 
Study Drug Storage ..........................................................................................33 
10.4 
Study Drug Preparation....................................................................................33 

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10.5 
Administration .................................................................................................35 
10.6 
Dose Escalation ................................................................................................35 
10.7 
Study Drug Accountability ..............................................................................36 
10.8 
Study Drug Handling and Disposal .................................................................36 
11 
ASSESSMENTS ....................................................................................................36 
11.1 
Safety Parameters.............................................................................................36 
11.1.1 
Dose Limiting Toxicity ........................................................................36 
11.1.2 
Discontinuation Rules ..........................................................................37 
11.2 
Demographic/Medical History.........................................................................37 
11.3 
Vital Signs ........................................................................................................37 
11.4 
Pulse Oximetry.................................................................................................37 
11.5 
Weight and Height ...........................................................................................37 
11.6 
Physical Examination.......................................................................................37 
11.7 
Vaccination Recommendations .......................................................................38 
11.8 
Physical Therapy Assessments ........................................................................38 
11.8.1 
CHOP-INTEND ...................................................................................38 
11.8.2 
Bayley Scale of Infant Development version 3 ...................................38 
11.9 
Development Milestones Checklists ................................................................38 
11.10 
Video Evidence ................................................................................................39 
11.11 
ACTIVE-mini ..................................................................................................39 
11.12 
Electrophysiology Assessments .......................................................................39 
11.12.1 
EIM ......................................................................................................39 
11.12.2 
CMAP ..................................................................................................40 
11.12.3 
MUNE ..................................................................................................40 
11.13 
Chest X-ray ......................................................................................................40 
11.14 
Swallowing Test...............................................................................................40 
11.15 
Echocardiography ............................................................................................40 
11.16 
Electrocardiogram (ECG) ................................................................................40 
11.17 
Pulmonary Assessment ....................................................................................40 
11.18 
Photographs of Infusion Site ............................................................................40 
11.19 
Laboratory Assessments ..................................................................................41 
11.19.1 
Hematology ..........................................................................................42 
11.19.2 
Blood Chemistry ..................................................................................42 
11.19.3 
Urinalysis .............................................................................................42 
11.19.4 
Coagulation Studies .............................................................................43 
11.19.5 
Capillary Blood Gas .............................................................................43 
11.19.6 
Virus Serology .....................................................................................43 
11.19.7 
Research Immunology Blood ..............................................................43 

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11.19.8 
Baseline Screening of Mother ..............................................................43 
11.19.9 
IFN-γ ELISpots ....................................................................................43  
11.19.10 
Research Blood Sample .......................................................................43 
11.19.11 
Saliva, Urine, and Stool Collection......................................................43 
12 
ADVERSE AND SERIOUS ADVERSE EVENTS ..............................................44 
12.1 
Definition of Adverse Events...........................................................................44 
12.1.1 
Adverse Event (AE) .............................................................................44 
12.1.2 
Serious Adverse Event (SAE) ..............................................................44 
12.1.3 
Other Adverse Event (OAE) ................................................................44 
12.2 
Relationship to Study Drug ..............................................................................44 
12.3 
Recording Adverse Events ...............................................................................45 
12.4 
Reporting Adverse Events ...............................................................................45 
13 
DATA SAFETY MONITORING BOARD...........................................................46 
13.1 
DSMB Reporting and Meetings.......................................................................46 
13.2 
DSMB Membership .........................................................................................47 
14 
STATISTICS .........................................................................................................47 
15 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................48 
15.1 
Study Monitoring .............................................................................................48 
15.2 
Audits and Inspections .....................................................................................48 
15.3 
Institutional Review Board (IRB) ....................................................................48 
15.4 
Quality Control and Quality Assurance ...........................................................48 
16 
ETHICS..................................................................................................................49 
16.1 
Ethics Review ..................................................................................................49 
16.2 
Ethical Conduct of the Study ...........................................................................49 
16.3 
Written Informed Consent ...............................................................................49 
17 
DATA HANDLING AND RECORDKEEPING ..................................................49 
17.1 
Electronic Case Report Forms .........................................................................49 
17.2 
Inspection of Records ......................................................................................50 
17.3 
Retention of Records........................................................................................50 
17.4 
Retention of Samples .......................................................................................50 
18 
PUBLICATION POLICY .....................................................................................50 
19 
LIST OF REFERENCES .......................................................................................52 
20 
APPENDICES .......................................................................................................54 
Appendix 1 
Declaration of Helsinki: Ethical Principles for Medical Research 
Involving Human Subjects ...............................................................................54 
Appendix 2 
Autopsy Plan ........................................................................................60 
Appendix 3 
Chop-intend..........................................................................................61 
Appendix 4 
Bayley Scale of Infant Development version 3: Gross and Fine Motor 
Skills Subparts and Speech and cognition subparts .........................................65 

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Appendix 5 
Gross Motor Skills Checklist ...............................................................81 
LIST OF TABLES 
Table 1 
Summary of Protocol Section Changes and Additions ................................2 
Table 2 
Important Study Contact Information ..........................................................7 
Table 3: 
Study Vendor Listing ...................................................................................8 
Table 4 
Abbreviations and Specialist Terms ..........................................................16 
Table 5 
Spinal Muscular Atrophy Classification ....................................................19 
Table 6 
Schedule of Assessments ...........................................................................28 
Table 7 
Investigational Product ..............................................................................32 
Table 8 
Total Dose ..................................................................................................34 
Table 9 
Adverse Event Classification .....................................................................37 
Table 10 
Motor Milestone Development Survey ......................................................38 
Table 11 
Total Blood Volume ..................................................................................41 
Table 12 
Tissue Samples for Analysis ......................................................................60 
Figure 1 
LIST OF FIGURES 
Kaplan-Meier survival curves and survival probabilities for SMA Type 1, 
2, and 3 .......................................................................................................20 
Figure 2 
Study results, including staining of transduced spinal motor neurons, SMN 
expression levels, righting ability, and weight and survival curves ..........22 
Figure 3 
Body mass of treated and control mice showed no difference ..................23 
Figure 4 
Study Design ..............................................................................................27 

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4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term Definition 
ACTIVE 
Ability Captured Through Interactive Video Evaluation 
AE 
Adverse event 
Alk Phos 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BiPAP 
Non-invasive Positive Pressure Ventilator 
BUN 
Blood urea nitrogen 
CBER 
Center for Biologics Evaluation and Research 
CHOP-INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders 
CK 
Creatine kinase 
CMAP 
Compound Muscle Action Potentials 
cmm 
Cubic millimeter 
DLT 
Dose Limiting Toxicity 
DRP 
DNAse-Resistant Particle.  Titer is based off the original certificate of 
analysis 
DSMB 
Data Safety Monitoring Board 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
EIM 
Electrical Impedance Myography 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICJME 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
mo 
months 

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Abbreviation or Specialist Term Definition 
MUNE 
Motor Unit Number Estimation 
NHP 
Non-human primate 
OAE 
Other significant adverse event 
PI 
Principal Investigator.  The investigator who leads the study conduct at an 
individual study center.  Every study center has a principal investigator. 
SAE 
Serious adverse event 
scAAV 
Self-complimentary adeno-associated virus 
SMA 
Spinal muscular atrophy 
SMN 
Survival motor neuron 
WT 
Wild type.  Wild type mice are those not affected with SMA. 
yo 
Years old 
 

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5 INTRODUCTION 
This is the first clinical gene therapy trial for spinal muscular atrophy (SMA).  The 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 SMN-Δ7 mouse model for SMA from a median of 15.5 days to over 1 year, following 
intravenous delivery to the facial vein.  This clinical trial is an open-label, single injection 
ascending dose study in which AVXS-101 will be delivered one-time through a venous catheter 
inserted into a peripheral vein (arm, leg, or scalp) in SMA Type 1 subjects with 2 copies of 
SMN2. 
5.1 
Background and Preliminary Data 
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.  SMA is an autosomal recessive, early childhood 
disease with an incidence of 1:11,000 live births.14  SMA is the leading cause of infant mortality 
due to genetic diseases.  Disease severity and clinical prognosis depends on the number of copies 
of SMN2.  In its most common and severe form (Type 1), hypotonia and progressive weakness 
are recognized in the first few months of life, leading to diagnosis by 6 months of age and then 
death due to respiratory failure by age two.  SMA Type 1 is the leading genetic cause of infant 
death.  Motor neuron loss in SMA Type 1 is profound in the early postnatal period (or may even 
start in the pre-natal period), whereas motor neurons in Type 2 and 3 SMA patients adapt and 
compensate during development and persist into adult life.  The findings from various 
neurophysiological and animal studies have shown an early loss of motor neurons in the 
embryonic and early postnatal periods.10,11,12  From a clinical perspective, these findings 
emphasize the importance of targeting the SMA Type 1 group for gene transfer of SMN2 in 
hopes of rescuing neurons at this critical stage.  Our goal is to modify the SMA Type 1 
phenotype, which will hopefully lead to a milder disease course and prolonged survival as seen 
in SMA Type 2 and 3 patients. 
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.15-16  However, clinical trials 
employing several of these agents, most notably phenylbutyrate, valporic acid, and hydroxyurea, 
have not resulted in clinical benefit (www.ClinicalTrials.gov, and Darbar, et al17).  A dose 
escalation trial of scAAV9.CB.SMN will provide information for the potential gene transfer has 
in treating Type 1 SMA patients and will hopefully show promise for success in modifying the 
disease prognosis.  This will be a dose escalation study that includes 15 Type 1 patients with 2 
copies of SMN2. 
5.2 
Rationale for Gene Transfer to SMA Type 1 Patients 
We have chosen Spinal Muscular Atrophy (SMA) Type 1 as the target for this gene therapy 
study.  We believe there is a strong rationale for this based on studies of the natural history of 
this disease.  The classification of SMA is shown below (Table 5); Type 0 to Type 4 SMA is 
described.  SMA is conventionally classified into four phenotypes on the basis of age of onset 

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and highest motor function achieved, with an additional phenotype (type 0) to describe the 
severe forms of antenatal-onset spinal muscular atrophy.1,2 
Table 5 
Spinal Muscular Atrophy Classification 
 
 
SMA Type 1 patients by definition never attain independent sitting and have hypotonia within 
the first 6 months of life.  SMA Type 1 is the leading genetic cause of infant death.  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.  SMA Type 3 patients attain the 
ability to walk unaided [Type 3a have onset <3yo; Type 3b have onset >3 yo].  SMA 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 mutations of the survival motor neuron 1 (SMN1) gene.  Humans also carry a second nearly 
identical copy of the SMN1 gene called SMN2.3  Both the SMN1 and SMN2 genes express 
SMN protein, however, the amount of functional full-length protein produced by SMN2 is much 
less (by 10-15%) than that produced by SMN1.3-5  Although SMN2 cannot completely 
compensate for the loss of the SMN1 gene, patients with milder forms of SMA generally have 
higher SMN2 copy numbers.6-7  Quantitative analysis of SMN2 copies in 375 patients with Type 
1, Type 2, or Type 3 SMA showed a significant correlation between SMN2 copy number and 
SMA type, as well as, duration of survival.  80% of patients with Type 1 SMA carry one or two 
SMN2 copies, 82% of patients with Type 2 SMA carry three SMN2 copies, and 96% of patients 
with Type 3 SMA carry three or four SMN2 copies.8  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 33–66 months.  Even more refined data, describing this 
relationship, has been generated and has also influenced our choice of the study target group.  
The median survival for patients with SMA Type 1 is 7.4 months with the age of onset being the 
most predictive factor in survival.9 
The severity of SMA type 1 is unequivocally demonstrated by prognosis as illustrated in Kaplan-
Meier survival curves shown in Figure 1. 

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Figure 1 
Kaplan-Meier survival curves and survival probabilities for SMA Type 1, 
2, and 3 
 
 
In Figure 1, the relative stability of the clinical course of SMA Types 2 and 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 postnatal period (or may even start in the pre-natal period, 
especially for SMA Type 1 patients presenting in first three months of life).  The findings in 
Figure 1 confirm other pieces of evidence from neurophysiological studies and animal studies 
that also show early loss of motor neurons in the embryonic and early postnatal periods.10,11,12  
From a clinical trials perspective these findings emphasize the importance of targeting SMA 
Type 1 for gene transfer of SMN2 in hopes of rescuing neurons at this critical stage.  Ultimately, 
the goal is to modify the SMA Type 1 phenotype leading to a milder course and prolonged 
survival, as we see in SMA Type 2 or 3 patients. 
These findings more clearly provide the rationale for a clinical gene transfer trial in the younger 
patients making it more difficult to justify even Phase I safety trials in older (SMA Type 2 or 3) 
subjects.  Based upon what we know about the natural history of SMA, gene transfer in the older, 
less severe SMA types (2, 3, and 4), is less likely to have a significant, clinical effect than it 
would in the younger Type 1 patients.  Since the motor neuron pool is stable in older patients due 
to higher copy number of SMN2, asking Type 2, 3, or 4 patients to undergo safety trials with 
possibly only minimal benefit is highly unreasonable.  It is much more appropriate and safe to 
prove tolerability in the younger SMA Type 1 group, in which death is the unequivocal outcome.  
Also, the poor prognosis of the SMA Type 1 patients, who only have 2 copies of SMN2, 
warrants the rescue of their lives as our top priority at this time. 
Factors other than risk-benefit discourage Phase I trials in older SMA patients.  The gene transfer 
viral dose for older patients, which is based on body weight, is much greater than what would be 
needed for an infant.  Not only does this add significantly to the cost of the clinical trial, in some 

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cases, it could exceed the capacity of the vector manufacturing facility.  These added costs, in 
addition to an increased risk prior to an established proof of principle provide a clear rationale 
for treating the younger Type 1 patients who have only 2 copies of SMN2.  Also present is the 
issue of a greater chance of encountering pre-existing immunity to AAV in these older, Type 2 
and 3 patients. 
We also have good reason to believe that there are very few safety issues to be concerned about 
when targeting the SMA Type 1 group for this clinical gene therapy trial.  Overexpression of 
SMN has been shown to be well tolerated in both mice and non-human primates, and in humans 
high copy number of SMN2 poses no risk (as seen in Type 2, 3, and 4 patients who have high 
SMN2 copy number).  This allows us to utilize robust, ubiquitous expression systems (like the 
CB-promoter) to ensure sustained, high-level SMN expression.  Additionally, it is important to 
point out that recombinant scAAV can be employed for this trial because of the small size of the 
SMN gene.  This enables efficient packaging and allows for efficient gene transfer with lower 
viral titers (a safety consideration), compared with prototypical single-stranded AAV vectors. 
Our recent studies using scAAV9.CB.SMN show a robust postnatal rescue of SMA mice with 
correction of motor function, neuromuscular electrophysiology and survival after a onetime 
delivery of vector.13  Intravenous scAAV9 is able to transduce neurons, muscle and vascular 
endothelium, all of which have been proposed as target cells for SMA treatment. 
Taken altogether, our preclinical efficacy and toxicology studies in mice and non-human 
primates have increased our confidence that our Phase Ib trial will be safe and will have a high 
potential for success in treating this devastating disease. 
5.3 
Non-Clinical Studies 
A mouse model was developed by the Arthur Burghes Laboratory after a generation of multiple 
variants.  It was found that the double transgenic, referred to as the SMN-Δ7 mouse, provided the 
most suitable model to study gene transfer.18  Studies performed in the Kaspar laboratory have 
shown that injecting 5 X 1011 viral genomes of scAAV9.CB.SMN into the facial vein on day 1 
old mice rescues the SMN-Δ7 mouse model.13  Figure 2 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.SMN treated mice.  SMN levels were increased as well, in brain, 
spinal cord, and muscle of scAAV9.CB.SMN-treated animals, compared to untreated SMA mice 
(although lower than WT controls).  SMA animals treated with either scAAV9.CB.SMN or 
scAAV9.CB.GFP on P1 were assessed for their righting ability and were compared to WT 
control mice and untreated mice.  WT 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 SMA animals compared with GFP-treated SMA 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 17g 

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(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. 
Figure 2 
Study results, including staining of transduced spinal motor neurons, 
SMN expression levels, righting ability, and weight and survival curves 
 
 
Toxicology biodistribution studies were generated by the Kaspar laboratory.  In the non-GLP 
studies, 24 mice and 4 non-human primates (NHPs) were injected, by way of vascular delivery, 
with scAAV9.CB.SMN.  To assess toxicity and safety scAAV9.CB.SMN was injected into P1 
wild type FVB mice with either vehicle (PBS) (3 males/6 females) or 3.3 x 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 Δ7 mouse model of SMA16.  P1 mice were used in 
anticipation of simulating potential clinical studies in infants, which is the planned population for 
the first-in-human clinical trial.  All mice survived the injection procedure and the initial 24-hour 
observation period without any signs of distress or weight loss.  Body mass was measured and 
hands-on observations were performed weekly for the remainder of the study; neither revealed 
any difference between control and treated cohorts (Figure 3). 
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 

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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 
and clinical chemistries assessment (ALT, AST, ALK Phos, creatinine, BUN, electrolytes, and 
CK).  All were normal except for one variant at the 90 day time point.  This difference appeared 
to be due to a technical problem relating to the site of blood draw, which differed from that of all 
other mice.  For histopathology, 13 mice were necropsied at 120 days post-injection and 8 mice 
at 180 days.  All organs were normal; in particular there was no inflammation seen in any section 
from any organ (heart, liver, kidney, muscle, gonads, brain, lung, lymph nodes, and intestines). 
In the safety study for the four male Cynomolgus Macaques, subjects were injected at 90 days of 
age to closely mimic the likely age of administration of treatment in SMA Type 1 infants.  The 
scAAV9.CB.SMN vector was administered one time by catheterization of the saphenous vein 
with a dose of 6.7 x 1013/kg, which corresponds to the lowest dose tested for which SMN-Δ7 
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 ELISpot in peripheral blood 
mononuclear cells (PBMCs), and all were negative at 6 months post injection. 
These mouse and monkey studies can be summarized as follows.  The serum chemistry and 
hematology studies were unremarkable as was the histopathology assessment.  The NHP subjects 
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.13 
Formal IND-enabling GLP pharmacology, toxicology, and biodistribution studies were discussed 
with the FDA at the Pre-IND meeting held January 2012.  The toxicology plan discussed with 
CBER was found to be acceptable for the initiation of this Phase I trial. 

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6 TRIAL OBJECTIVES AND PURPOSE 
6.1 
Primary Objective 
The primary outcome for this clinical trial is safety.  Discontinuation criteria are based on the 
development of unacceptable toxicity, defined as the occurrence of any one Grade III or higher, 
unanticipated, treatment-related toxicity that presents with clinical symptoms and requires 
medical treatment. 
6.2 
Secondary Objectives 
A secondary outcome will include time from birth to either (a) requirement of ≥16-hour 
respiratory assistance per day (includes BiPAP) continuously for ≥2 weeks in the absence of an 
acute reversible illness, excluding perioperative ventilation or (b) death. 
Secondary outcomes will also include the change in CHOP-INTEND from baseline score and 
demonstration of improvement of motor function and muscle strength as determined by 
achievement of significant development milestones including but not limited to the ability to sit 
alone and roll over unassisted.  Additionally, sponsor may choose to provide videos of the 
physical exams, CHOP-INTEND assessments, and/or Bayley Scale assessments to an 
independent, blinded reviewer for confirmation of the development milestones. 
6.3 
Exploratory Objectives 
Exploratory outcome measures will be tested during the study as part of the program and product 
development plan; however if exploratory measurement results show efficacy and primary 
outcomes do not reach statistical significance, the only interpretation is that the results show a 
trend toward benefit but can never supersede primary measures.  These exploratory outcome 
measures will include: 
• 
ACTIVE-mini (Ability Captured Through Interactive Video Evaluation-mini) evaluation of 
infant movement ability. 
• 
Patient functional measures using the Children’s Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders (CHOP-INTEND).  This test has been studied and validated in 
infants with spinal muscular atrophy and was found to be reliable in this population.19 
• 
Bayley Scale of Infant Development version 3 is a standardized, norm-referenced infant 
assessment.  The gross and fine motor portions as well as speech and cognition portions of 
this test will administered if the child reaches or exceeds a score of 60 out of 64 on the 
CHOP-INTEND. 
• 
Motor neuron function will be assessed via evoked compound motor action potentials 
(CMAP) and motor unit number estimation (MUNE). 
• 
Pathological status of muscles will be quantified by Electrical Impedance Myography (EIM). 
• 
The age at which significant motor milestones are achieved will be assessed using a standard 
Motor Milestone Development Survey shown in Table 10 in Section 11.1.10. 
• 
Compelling, demonstrable, documented evidence of efficacy as determined by changes in 
functional abilities as captured during videotaping sessions during site visits and/or captured 
by subject/parent/legal guardian at home. 

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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design 
The proposed clinical trial is an open-label, single injection ascending dose study of self-
complementary AAV9 carrying the SMN gene under the control of a hybrid CMV 
enhancer/chicken AVXS-101 delivered one-time through a venous catheter inserted into a 
peripheral vein (arm, leg, or scalp) of Type 1 spinal muscular atrophy subjects. 
The primary analysis for efficacy will be assessed when all patients reach 13.6 months of age (a 
database lock will be performed at the time point at which all patients reach 13.6 months of 
age).  A follow-up safety analysis will be completed at the time point at which the last patient 
reaches 24 months post-dose. 
This dose escalation study involves four cohorts.  There will be at least a 3 week intra-cohort 
dosing interval between dosing of patients within a cohort to allow review of the safety analysis 
from five time points (days 1, 2, 7, 14, and 21) prior to dosing of the next patient.  There will be 
at least a 4-week inter-cohort dosing interval between dosing of patients between cohorts to 
allow time for review of the safety analysis of at least six time points (days 1, 2, 7, 14, 21, and 
30) from all the patients within a cohort.  Safety analysis will be done by the investigators and 
the DSMB, as well as, time for decisions to be made about whether to implement a higher dose 
group.  Dose escalation will be based on dose-limiting toxicity (DLT). 
Cohort 1 will consist of three (3) SMA patients followed by Cohort 2A with a minimum of three 
(3) and no more than six (6) SMA patients to receive a single infusion at escalating doses. 
• 
Cohort 1 (Low Dose): 6.7 X 1013 vg/kg (n=3) 
• 
Cohort 2A (Intermediate Dose): 2.0 X 1014 vg/kg (n≥3 and n≤6) 
Cohort 2B and Cohort 3 will each consist of three (3) SMA patients to receive a single infusion 
at escalating doses. 
• 
Cohort 2B: 2.0 X 1014 vg/kg (n=3) 
• 
Cohort 3 (High Dose): 3.3 X 1014 vg/kg (n=3) 
Cohort 2B will be done first and if efficacy is favorable but does not fully improve subjects to 
normal, Cohort 3 at high dose will be implemented. 
Treatment of Cohort 3 is permitted based on safety assessment presented in the IND.  A score of 
8 or higher on the Bayley Scales of Infant Development will be considered the low end of 
normal.  If efficacy (defined as any clinical improvement from baseline of either primary or 
exploratory outcome measures) is observed at the intermediate dose (2.0 X 1014 vg/kg), the 
Principal Investigator may continue to enroll at the intermediate dose up to a maximum of 9 
patients. 
If no clinically significant improvement without toxicity is observed, the possibility of adding an 
additional escalation cohort at a higher dose will be discussed with the FDA, DSMB and relevant 
oversight regulatory agencies. 
7.2 
Number of Subjects 
A total of 15 subjects may be enrolled. 

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7.3 
Treatment Assignment 
This is an open-label study.  Treatment will be assigned in accord with the dose escalation 
schedule specified in Section 10.6. 
7.4 
Criteria for Study Termination 
An independent Data Safety Monitoring Board (DSMB) and safety monitor will monitor safety 
data on a continual basis throughout the trial.  The DSMB can recommend early termination of 
the trial for reasons of safety.  Study enrollment will be halted by the investigators when any 
subject experiences a Grade III, or higher adverse event toxicity that is unanticipated and 
possibly, probably, or definitely related to the study drug that presents with clinical symptoms 
and requires medical treatment.  This will include any patient death, important clinical laboratory 
finding, or any severe local complication in the injected area related to administration of the 
study agent.  If after review by the DSMB, IRB, IBCSC, NIH-OBA and FDA, the decision is 
made to continue, the study will proceed according to the dose escalation schedule. 
Subjects may be discontinued from further study participation or the trial may be terminated for 
the following reasons: 
• 
Development of unacceptable toxicity, defined as the occurrence of any one Grade III or 
higher, unanticipated, treatment-related toxicity that presents with clinical symptoms and 
requires medical treatment. 
• 
Patient requires at least 16-hour per day of ventilation support for breathing, including 
BiPAP use, for ≥14 consecutive days in the absence of an acute reversible illness, excluding 
perioperative use 
• 
Death 
• 
Failure to comply with protocol-required visits or procedures 
• 
Study is terminated by sponsor 
• 
Subject withdrawal of consent to participate further 
 

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6.7 X 1013 vg/kg 
 
2.0 X 1014 vg/kg 
 
2.0 X 1014 vg/kg 
 
3.3 X 1014 vg/kg 
 
 
30 DAYS 
DAY -1 to 2 
2 YEARS 
15 YEARS 
Figure 4 
Study Design 
SCREENING 
IN-PATIENT DOSE 
SAFETY FOLLOW-UP 
LONG-TERM FOLLOW-UP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 6 
Schedule of Assessments 
 
Study Interval 
Baseline 
Vector Infusion 
Follow Up Year 1 
Follow Up Year 2 
Long Term 
Monitor 
Screening 
(Inpatient) 
(Outpatient) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Monthly Every 3 
Months 
Every 6 
Months 
Every  
Monthg 
Q3 
Months 
Q6 
Months 
Annually 
Days in Studya 
-30 (± 7) 
-1 
0 
1 
2 
7 
14 
21 
30 
60 
90 
Up to 12 Months 
13-24 Months 
Through 
15 years 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-Ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam + 
Vitals 
X 
Xc 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
X 
X 
Pulmonary 
Assessment 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
X 
X 
Photograph 
Injection site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
X 
 
Swallowing Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Pulse Oximetryd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
X 
 
Capillary Blood Gas 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Labs (Blood) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Xg 
X 
X 
 
Coagulation Studies 
(PT/INR/PTT) 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
Safety Labs 
(Urinalysis) 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Xg 
X 
X 
 
Immunology 
(AntiAAV9/SMN Ab 
& T-Cells) 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Research Bloode 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
CHOP-INTENDf 
(with video) 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Xg 
X 
X 
 

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Study Interval 
Baseline 
Vector Infusion 
Follow Up Year 1 
Follow Up Year 2 
Long Term 
Monitor 
Screening 
(Inpatient) 
(Outpatient) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Monthly Every 3 
Months 
Every 6 
Months 
Every  
Monthg 
Q3 
Months 
Q6 
Months 
Annually 
Days in Studya 
-30 (± 7) 
-1 
0 
1 
2 
7 
14 
21 
30 
60 
90 
Up to 12 Months 
13-24 Months 
Through 
15 years 
Bayleyb 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Xb 
Xb 
Xb 
Xg 
X 
X 
 
ACTIVE-mini 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
CMAP/MUNE/EIM 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
Research Urine 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Research Saliva & 
Stool 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Development 
Milestones/Gross 
Motor Skills 
Checklist (with 
video) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Xg 
X 
 
X 
ECHO/ECG 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Prednisolone 
Dosing 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Gene Transfer 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
X 
X 
Concomitant 
Medications 
To be collected from 2 weeks before study dose until final study visit, recorded on separate CRF 
X 
a Visits on Days 7, 14 and 21 allow a window of ±2 days; all monthly visits following (Visit 6 to 29) allow a window of ±7 days. 
b The gross and fine motor portions of this test will be administered monthly through 14 months post-dose if a patient reaches or exceeds a score of 60 out of 64 on the CHOP-
INTEND.  The cognition portion of this test will be administered every three months if a patient reaches or exceeds a score of 60 out of 64 on the CHOP-INTEND.  CHOP-INTEND 
assessment will be discontinued and only the Bayley will be administered for subjects that achieve two consecutive scores of 64. 
c Vital signs recorded every four (4) hours during inpatient hospitalization. 
d Continuous monitoring during gene transfer procedure.  Axillary temperature to be captured pre- and post- infusion. 
e Research blood sample will be used to perform baseline exon 7 modification testing and could also be used to re-confirm SMA Type 1 diagnosis, SMN2 copy number, and exon-7 
modification testing through a third-party laboratory. 
f Subjects that achieve two consecutive scores of ≥62 may cease further CHOP-INTEND assessments, as per PI, physical therapist, and sponsor decision. 
g Subjects for whom the decision is made to continue CHOP-INTEND assessments, or who don’t reach score ≥62, will continue to complete monthly visits during Year 2. 

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8 SELECTION AND WITHDRAWAL OF SUBJECTS 
SMA Type 1 subjects, six months and younger with proven mutations of the SMN1 gene will be 
enrolled in this clinical trial.  Patients will be of any racial, ethnic, or gender background.  
Enrollment will be staggered with at least 4 weeks between patient infusions.  The assessment 
and full treatment plan will be used for all subjects in Cohort 2B (n=3) and potentially for 
subjects in Cohort 3 (n=6) to be included if subjects in Cohort 2B do not achieve a status of 
normal: a score of 8 or higher on the Bayley Scales of Infant Development will be considered the 
low end of normal. 
8.1 
Subject Inclusion Criteria 
Subjects must meet all of the following Inclusion Criteria: 
1. Six months of age and younger1 at day of vector infusion with Type 1 SMA as defined by 
the following features: 
a. Bi-allelic SMN1 gene mutations (deletion or point mutation) with two copies of 
SMN2 (no more and no fewer). 
b. Patients 6 months and younger with a disease onset up to 6 months of age. 
c. Hypotonia by clinical evaluation with delay in motor skills, poor head control, round 
shoulder posture and hypermobility of joints. 
1 
First nine subjects enrolled under previous version(s) of the protocol could be nine months of age or 
younger.  Inclusion revised to reflect six months of age or younger in 24 Jun 2015 Protocol Addendum #2. 
Initial genetic testing and diagnosis completed at an institution/laboratory other than Nationwide 
Children’s Hospital/Ohio State University is acceptable if proper documentation is received at 
Nationwide Children’s Hospital, verified by the PI, and filed in the patient’s medical record. 
AveXis, Inc. may opt to confirm all genetic diagnoses through a contracted third-party laboratory 
utilizing an additional blood sample collected during a post-dose visit. 
8.2 
Subject Exclusion Criteria 
Subjects must not meet any of the following Exclusion Criteria: 
1. Active viral infection (includes HIV or serology positive for hepatitis B or C). 
2. Use of invasive ventilatory support (tracheotomy with positive pressure)* or pulse 
oximetry <95% saturation at the screening visit. 
a. Patients may be managed using non-invasive ventilator support (BiPAP) for less than 
16 hours a day at the discretion of their physician or research staff. 
3. Concomitant illness that in the opinion of the PI creates unnecessary risks for gene 
transfer. 
4. Concomitant use of any of the following drugs: drugs for treatment of myopathy or 
neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive 
therapy or immunosuppressive therapy within 3 months of starting the trial (eg, 
corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous 
immunoglobulin, rituximab). 

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5. Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding 
immunoassay. 
6. Abnormal laboratory values considered clinically significant (GGT >3XULN, bilirubin 
≥3.0 mg/dL, creatinine ≥1.8 mg/dL, Hgb <8 or >18 g/Dl; WBC >20,000 per cmm). 
7. Participation in a recent SMA treatment clinical trial that in the opinion of the PI creates 
unnecessary risks for gene transfer. 
8. Family does not want to disclose patient's study participation with primary care physician 
and other medical providers. 
9. Patient with signs of aspiration based on a swallowing test and unwilling to use an 
alternative method to oral feeding. 
10. Patients with c.859G>c modification in exon 7, based on predicted mild phenotype. 
8.3 
Subject Withdrawal Criteria 
Subjects meeting the following criteria will be withdrawn: 
- 
Development of unacceptable toxicity, defined as the occurrence of any one Grade III or 
higher, unanticipated, treatment-related toxicity that presents with clinical symptoms and 
requires medical treatment during the 2-year post-dose period 
- 
Patient requires at least 16-hour per day of ventilation support for breathing, including 
BiPAP use, for 14 consecutive days in the absence of an acute reversible illness 
excluding perioperative use 
- 
Death 
◦ 
Autopsies will be requested of any subjects that expire following participation in a 
gene transfer study as per the National Institutes of Health’s Guidelines for Research 
Involving Recombinant or Synthetic Nucleic Acid Molecules; see Autopsy Plan in 
Appendix 2. 
- 
Withdrawal of consent from further participation 
Further guidance regarding determination of withdrawal criteria is outlined in Section 11.1. 
9 TREATMENT OF SUBJECTS 
Subjects will receive the gene transfer intravenous infusion under sterile conditions in a PICU 
patient room.  The vector is formulated in the Nationwide Children’s Investigational Pharmacy 
in approximately 10−20 mL/kg of normal saline and delivered to the PICU patient room in pre-
labeled syringes sealed in double leak-proof bags, carried in a designated lockable cooler. 
The final formulated vector will be administered approximately at 10−20 mL/kg and slowly 
infused for approximately 60 minutes.  The vector will be administered to the patient within 8 
hours of preparation. 
9.1 
Description of Study Drug 
The biological product is a non-replicating recombinant self-complementary adeno-associated 
virus serotype 9 (AAV9) containing the cDNA of the human SMN gene under the control of the 
cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB).  The AAV inverted 

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terminal repeat (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 
scAAV9.CB.hSMN, expresses the human SMN protein. 
Table 7 
Investigational Product 
 
Investigational Product 
Product Name: 
AVXS-101 
Dosage Form: 
1.96 X 1013 DRP/mL (based off supercoiled qPCR) in either a 2 mL vial (with 1 mL 
fill) or 5 mL vial (with 5 mL fill) 
All vials are screwcap polypropylene vials 
Unit Dose 
10−20 mL/kg, in accord with dose escalation schedule 
Route of Administration 
Peripheral vein intravenous infusion 
Physical Description 
AVXS-101 is provided in frozen 1 mL and 5 mL vials.  Once thawed AVXS-101 is a 
clear liquid. 
Manufacturer 
Nationwide Children’s Hospital 
Clinical Manufacturing Facility 
Center for Gene Therapy 
700 Children’s Drive 
Columbus, OH 43205 
 
9.2 
Concomitant Medications 
Prior and concomitant medications will be captured in the eCRF from two weeks prior to study 
dosing through the last study visit. 
9.2.1 
Prophylactic Administration of Prednisolone 
In every gene therapy study NCH has completed, including the first SMA patient, an antigen 
specific T-cell response to the AAV vector has been observed.  This is an expected response 
between 2−4 weeks following gene transfer.  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, patients will be started 
on prophylactic prednisolone (glucocorticoid) (approximately 1 mg/kg/day) 24 hours prior to the 
gene transfer as agreed upon with FDA in the revised protocol submitted an IND update Serial 
No. 004, 31 Oct 2014.  Treatment will continue for approximately 30 days with the following 
guidelines for tapering:  When AST and ALT exceed 120 IU/L prednisolone will be maintained 
until enzymes fall below this level while at the same time monitoring T-cell response for 
decreases below 100 SFC per 106 PBMCs.  Discrepancies from these precise recommendations 
will be at the discretion of the investigator based on potential safety issues for participating 
patients. 
 

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9.2.2 
Prohibited Medications 
Concomitant use of any of the use of any of the following medications is prohibited: 
- 
Drugs for treatment of myopathy or neuropathy 
- 
Agents used to treat diabetes mellitus 
- 
Ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of 
starting the trial (e.g, corticosteroids, cyclosporine, tacrolimus, methotrexate, 
cyclophosphamide, intravenous immunoglobulin, rituximab). 
10 STUDY DRUG MATERIALS AND MANAGEMENT 
AVXS-101 is manufactured in the cGMP facility of the Center for Gene Therapy at the Research 
Institute at Nationwide Children’s Hospital.  Only the number of vials required for stability 
testing and clinical retains will be stored at the cGMP facility. 
10.1 Study Drug 
AVXS-101 
10.2 Study Drug Packaging and Labeling 
Each vial is labeled with a specific log number and reagent code. 
10.3 Study Drug Storage 
AVXS-101 will be maintained at the Investigational Drug Service Pharmacy in the Hazardous 
Ultralow -80°C freezer located in room D01616 at NCH for the duration of the study. 
10.4 Study Drug Preparation 
Preparation of the gene vector will be done by the NCH research pharmacist according to the 
Manual of Operation Procedures.  Immediately prior to transportation to the clinical setting, 
appropriate dilutions of the test article will be completed by the pharmacy.  Documentation of 
the dilution will be completed by the pharmacy following standard pharmacy protocol.  The 
vector will be diluted and manipulated in polypropylene syringes. 
The vector is to be filled by the cGMP staff in screw cap vials at volumes of 5.0 mL (5 mL 
cryovial size) and 1.0 mL (2 mL cryovial size).  The appropriate number of vials and volume of 
each will be determined for each patient based on body weight and specified dose cohort as 
illustrated in Table 8.  The total vector genome dose will be calculated based on patient’s body 
weight and rounded down to the closest 1 kg. 
 
 

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Table 8 
Total Dose 
Low Dose (6.7e13) vg/kg 
Total Dose 
(vg) 
Vector Volume 
(mL) 
Total Volume 
(mL) 
Syringe # 
Syringe 
Volume (mL) 
Vector 
Volume (mL) 
Saline 
Volume (mL) 
2.68E+14 
13.7 
67.3 
1 
33.7 
6.8 
26.8 
2 
33.7 
6.8 
26.8 
3.35E+14 
17.1 
84.2 
1 
42.1 
8.5 
33.5 
2 
42.1 
8.5 
33.5 
4.02E+14 
20.5 
101.0 
1 
50.5 
10.3 
40.3 
2 
50.5 
10.3 
40.3 
4.69E+14 
23.9 
117.9 
1 
58.9 
12.0 
47.0 
2 
58.9 
12.0 
47.0 
5.36E+14 
27.3 
134.7 
1 
44.9 
9.1 
35.8 
2 
44.9 
9.1 
35.8 
3 
44.9 
9.1 
35.8 
6.03E+14 
30.8 
151.5 
1 
50.5 
10.3 
40.3 
2 
50.5 
10.3 
40.3 
3 
50.5 
10.3 
40.3 
6.7E+14 
34.2 
168.4 
1 
56.1 
11.4 
44.7 
2 
56.1 
11.4 
44.7 
3 
56.1 
11.4 
44.7 
 
Intermediate Dose (2.0e14 vg/kg) 
Weight 
(kg) 
Total Dose 
(vg) 
Vector Volume 
(mL) 
Total Volume 
(mL) 
Syringe # Syringe Volume 
(mL) 
Vector Volume 
(mL) 
Saline Volume 
(mL) 
4 
8.00E+14 
40.8 
67.3 
1 
33.7 
20.4 
13.3 
2 
33.6 
20.4 
13.2 
5 
1.00E+15 
51.0 
84.2 
1 
42.1 
25.5 
16.6 
2 
42.1 
25.5 
16.6 
6 
1.20E+15 
61.2 
101.0 
1 
50.5 
30.6 
19.9 
2 
50.5 
30.6 
19.9 
7 
1.40E+15 
71.4 
117.9 
1 
59.0 
35.7 
23.3 
2 
58.9 
35.7 
23.2 
8 
1.60E+15 
81.6 
134.7 
1 
44.9 
27.2 
17.7 
2 
44.9 
27.2 
17.7 
3 
44.9 
27.2 
17.7 
9 
1.80E+15 
91.8 
151.5 
1 
50.5 
30.6 
19.9 
2 
50.5 
30.6 
19.9 
3 
50.5 
30.6 
19.9 
10 
2.00E+15 
102.0 
168.4 
1 
56.2 
34.0 
22.2 
2 
56.1 
34.0 
22.1 
3 
56.1 
34.0 
22.1 
 

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High Dose (3.3e14 vg/kg) 
Weight 
(kg) 
Total Dose 
(vg) 
Vector Volume 
(mL) 
Total Volume 
(mL) 
Syringe # 
Syringe Volume 
(mL) 
Vector Volume 
(mL) 
Saline Volume 
(mL) 
4 
1.32E+15 
67.3 
67.3 
1 
33.7 
33.7 
0 
2 
33.7 
33.7 
0 
5 
1.65E+15 
84.2 
84.2 
1 
42.1 
42.1 
0 
2 
42.1 
42.1 
0 
6 
1.98E+15 
101.0 
101.0 
1 
50.5 
50.5 
0 
2 
50.5 
50.5 
0 
7 
2.31E+15 
117.9 
117.9 
1 
58.9 
58.9 
0 
2 
58.9 
58.9 
0 
8 
2.64E+15 
134.7 
134.7 
1 
44.9 
44.9 
0 
2 
44.9 
44.9 
0 
3 
44.9 
44.9 
0 
9 
2.97E+15 
151.5 
151.5 
1 
50.5 
50.5 
0 
2 
50.5 
50.5 
0 
3 
50.5 
50.5 
0 
10 
3.3E+15 
168.4 
168.4 
1 
56.1 
56.1 
0 
2 
56.1 
56.1 
0 
3 
56.1 
56.1 
0 
 
In general, the high dose will not be diluted for a total dose of 3.3 X 1014 vg/kg.  The low doses 
will be diluted to the same volume as the high dose and split equally.  Thus, the vector will be 
withdrawn from each vial for the low doses, pooled together, and diluted in an amount of 
normosol-R to equal the total volume used in the high dose cohort in a given weight range for a 
total dose of 6.7 X 1013 vg/kg. 
Preparation of the vector will be done aseptically in a class II BSC by the research staff 
according to the Manual of Operating Procedures.  The vector will be allowed to warm to room 
temperature prior to infusion to avoid the possibility of particle aggregation following product 
thaw.  The vector-containing syringes will be delivered to the designated PICU suite at NCH.  It 
will be delivered inside a sealed leak-proof bag, carried in a designated container at room 
temperature and administered to the subject within 8 hours from removal from the -80°C freezer. 
10.5 Administration 
The gene transfer infusion procedure will be performed under sterile conditions in a PICU 
patient room.  The final formulated vector will be administered at 10−20 mL/kg and slowly 
infused for approximately 60 minutes.  Patient-specific dosage based on patient weight recorded 
during hospital admission on Day -1 will be provided by the pharmacy on procedure date. 
10.6 Dose Escalation 
There will be at least a 3 week intra-cohort dosing interval between dosing of subjects within a 
cohort to allow review of the safety analysis from five time points (days 1, 2, 7, 14, and 21) prior 
to dosing of the next subject.  There will be at least a 4 week inter-cohort dosing interval 

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between dosing of subjects in each cohort to allow time for review of the safety analysis of at 
least six time points (days 1, 2, 7, 14, 21, and 30) from all the subjects within a cohort.  Safety 
analysis will be done by the investigators and the DSMB, as well as, time for decisions to be 
made about whether to implement a higher dose group.  Dose escalation will be based on dose-
limiting toxicity (DLT) as described in Section 11.1.1. 
The investigators will confer with the IRB and DSMB on all Grade III or higher adverse events 
with 48 hours that are unanticipated and possibly, probably, or definitely related to the study 
agent before continuing enrollment.  Based on the outcome of the safety and efficacy analysis at 
the end of each cohort decisions will be made to proceed with dose escalation for the following 
cohort. 
10.7 Study Drug Accountability 
Upon withdrawal of a vial, the Investigational Product Accountability Log will be recorded with 
the specific lot number and code of the reagent. 
10.8 Study Drug Handling and Disposal 
Handling of scAAV9.CB.SMN gene will follow compliance standards for Biosafety level 1 
vectors following the NIH guidelines.  Individuals manipulating the vector will be required to 
wear adequate personal protective equipment. 
All materials used for injection, including sterile drapes, needles, and syringes in contact with the 
vector will be sealed in leak-proof primary and secondary containers.  All waste will be double 
bagged in autoclave bags bearing the biohazard symbol and sealed with autoclave tape.  The bag 
will then be autoclaved and disposed of in a biohazard waste container. 
The empty syringes used for delivery of the vector will be resealed in the procedure room and 
placed into a small labeled box.  The empty vials used to prepare the syringes will also be 
maintained in the pharmacy.  Both will be returned to a secure -80°C freezer archival storage 
separate from the unused vector storage. 
11 ASSESSMENTS 
11.1 Safety Parameters 
The primary outcome for this clinical trial is safety.  Withdrawal criteria are based on the 
development of unacceptable toxicity, defined as the occurrence of any one Grade III or higher 
treatment-related toxicity. 
11.1.1 
Dose Limiting Toxicity 
Dose limiting toxicity is defined as any adverse event that is possibly, probably, or definitely 
related to the study agent.  This would include any grade III event, according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03; these classifications are 
outlined in Table 9. 
 
 

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Table 9 
Adverse Event Classification 
1 
Mild adverse event; did not require treatment 
2 
Moderate adverse event; resolved with treatment 
3 
Severe adverse event; inability to carry on normal activities; required professional 
medical attention 
4 
Life-threatening or permanently disabling adverse event 
5 
Fatal adverse event 
 
Study enrollment will be halted by the investigators when any subject experiences a Grade III, 
or higher adverse event toxicity that is unanticipated and possibly, probably, or definitely 
related to the study drug.  The event will then be reviewed by the Data Safety Monitoring Board 
(DSMB) and an evaluation will be made as to whether the trial should be terminated early 
following the Discontinuation Rules. 
11.1.2 
Discontinuation Rules 
An independent Data Safety Monitoring Board (DSMB) and safety monitor will monitor safety 
data on a continual basis throughout the trial.  The DSMB can recommend early termination of 
the trial for reasons of safety.  Study enrollment will be halted by the investigators when any 
subject experiences a Grade III, or higher adverse event toxicity that is unanticipated and 
possibly, probably, or definitely related to the study drug that presents with clinical symptoms 
and requires medical treatment.  This will include any patient death, important clinical laboratory 
finding, or any severe local complication in the injected area related to administration of the 
study agent.  If after review by the DSMB, IRB, IBCSC, NIH-OBA and FDA, the decision is 
made to continue, the study will proceed according to Section 10.6 of this protocol. 
11.2 Demographic/Medical History 
Patient demographics and medical history information will be collected at baseline and captured 
in the CRF. 
11.3 Vital Signs 
Vital signs will include blood pressure, respiratory rate, pulse, and axillary temperature at the 
time points specified in Table 6. 
11.4 Pulse Oximetry 
Pulse oximetry will be measured through a small infrared light attached to the end of the 
patient’s finger. 
11.5 Weight and Height 
Weight and height will be measured as per the time points specified in Table 6. 
11.6 Physical Examination 
Physical examination will include review of the following systems: HEENT, lungs/thorax, 
cardiovascular, abdomen, musculoskeletal, neurologic, and genitourinary. 

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11.7 Vaccination Recommendations 
Patients are encouraged to follow all routinely scheduled immunizations as recommended by the 
Center for Disease Control (CDC).  We also recommend seasonal vaccinations that include 
palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) 
infections. 
11.8 Physical Therapy Assessments 
11.8.1 
CHOP-INTEND 
CHOP-INTEND including head control, righting reactions, and trunk movements in supported 
sitting, supine, and prone positions.  Anti-gravity movements in assisted rolling, ventral 
suspension, and supported standing are also measured.  See Appendix 3. 
At such time that a subject achieves two consecutive CHOP-INTEND scores of ≥62, a 
teleconference will be conducted between PI, physical therapist, and AveXis, Inc. to review the 
subject status and determine whether or not continued CHOP-INTEND assessments are 
necessary.  A decision will be reached and confirmed in writing following the teleconference.  If 
decided that no further assessments are necessary, the physical therapist will cease completion of 
the CHOP-INTEND assessment at subsequent visits; otherwise CHOP-INTEND assessments 
will continue monthly. 
CHOP-INTEND examinations will be videotaped in accord with the Videotaping Manual. 
11.8.2 
Bayley Scale of Infant Development version 3 
Bayley Scales of Infant Development version 3 is a standardized, norm-referenced infant 
assessment.  The gross and fine motor portions as well as the cognition portion of this test will be 
administered if the child reaches or exceeds a score of 60 out of 64 on the CHOP-INTEND.  The 
gross and fine motor portion will be completed monthly during the first year and the cognition 
portion will be completed every three months.  During the second year all required portions of the 
Bayley Scale will be conducted every three months, except for subjects still being seen monthly for 
CHOP-INTEND assessments.  For those subjects the gross and fine motor and cognition portions 
will be administered as in Year 1.  See Appendix 4. 
Bayley scales examinations will be videotaped in accord with the Videotaping Manual. 
11.9 Development Milestones Checklists 
The age at which significant motor milestones are achieved will be assessed using a standard 
Motor Milestone Development Survey shown in Table 10 and a Gross Motor Skills Checklist 
show in Appendix 5.  The Gross Motor Skills Checklist was designed by physical therapists at 
Nationwide Children’s Hospital specifically to assess SMA Type 1 subjects in this trial; it is source 
from a collection of existing motor assessments. 
Additionally, CHOP-INTEND and Bayley physical therapy assessment videos may be transferred 
to a centralized reviewer for independent determination of milestones achieved. 
Table 10 
Motor Milestone Development Survey 
4 months 
Prone: Holds head up to vertical axis and legs extended 
6 months 
Supine: Rolls over back to front 
9 months 
Sits alone, with back straight 

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12 months 
Cruises, holding on and may stand without help 
15 months 
Walks independently 
18 months 
Runs, walks down stairs one hand held 
24 months 
Up and down stairs, one step at a time; jumps both feet off floor 
30 months 
Reciprocal stair climbing; stands on one foot 
36 months 
Reciprocal stairs going down; rides tricycle 
48 months 
Hops on one foot; throws ball overhand 
60 months 
Able to skip 
11.10 Video Evidence 
Physical therapy assessments and physician physical examinations required at each study visit 
will be videotaped in an effort to produce compelling, demonstrable, documented evidence of 
efficacy, as determined by changes in functional abilities.  Parent(s)/legal guardian(s) may also 
share home videos demonstrating achievement of functional abilities.  AveXis, Inc. will provide 
a secure and confidential upload process for transfer and storage of the videos from NCH to a 
contracted third-party vendor that will compile and arrange videos as per AveXis, Inc. 
submission requirements.  Any/all videos received at AveXis, Inc. or the contracted vendor will 
be treated as confidential study data and will be the sole property of AveXis, Inc.  AveXis, Inc. 
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 and/or the medical community. 
Videos will be provided in a blinded fashion to an independent, centralized reviewer for 
unbiased assessment of milestone achievement. 
11.11 ACTIVE-mini 
ACTIVE-mini will be conducted to evaluate infant movement ability.  This assessment utilizes 
the Microsoft Kinect camera interface to capture infant movement with an inexpensive, 
commercially available camera system with real-time quantitative data output provided.  Using 
the 3 cameras built into the Kinect video, depth and color data of an infant’s movement is 
recorded and analyzed.  The Kinect's ability to capture images and simultaneously the distance to 
every point in each image, provides significantly more information for an assessment of infants, 
than are captured by current post-processed video-based computer vision systems. 
11.12 Electrophysiology Assessments 
11.12.1 
EIM 
Pathological status of muscles will be quantified by EIM.  Skulpt, Inc., has developed a handheld 
device specifically for performing EIM measurements in infants.  This device will be used to 
measure EIM in this study.  The device is not yet approved by FDA, but has been tested in over 
30 other individuals with no adverse events (AEs) (serious or otherwise) reported to date and 
currently being tested in SMA infants as part of the Network for Excellence in Neuroscience 
Clinical Trials (NeuroNEXT) trials.  The device has undergone independent electrical safety 
testing by Intertek (www.intertek.com) to the requirements contained in the following standards: 

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• 
IEC 60601-1 Issue 1998/12/01 Ed: 2 Medical Electrical Equipment Part 1: General 
Requirements and Safety; [Amd. 1-1991(CENELEC EN 60601-1: 1990) (Amd. 2- 1995) 
(Corrigendum-1995)] 
11.12.2 
CMAP 
The compound muscle action potential (CMAP) size is found using supramaximal stimulation of 
the motor nerve to the muscle or muscle group (similar to a nerve conduction study).  It is 
recorded using surface electrodes.  This is representative of the sum of the surface detected 
motor unit action potentials from muscles innervated by that nerve. 
11.12.3 
MUNE 
Motor Unit Number Estimation (MUNE) is a technique that uses electromyography to estimate the 
number of motor units in a muscle.  MUNE uses a general formula of: 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢=
𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠−𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 
11.13 Chest X-ray 
A chest x-ray will be performed at screening/baseline. 
11.14 Swallowing Test 
A swallowing test will be performed to determine if the patient has signs of aspiration.  If the test 
is positive for aspiration the patient may be instructed to use an alternative method to oral 
feeding for the duration of the trial. 
11.15 Echocardiography 
An ECHO will be performed at screening/baseline and other time points as specified in Table 6. 
11.16 Electrocardiogram (ECG) 
An ECG will be performed at screening/baseline and other time points as specified in Table 6. 
11.17 Pulmonary Assessment 
Patients will be assessed by a pulmonologist and may be fitted with a non-invasive positive 
pressure ventilator (BiPAP) at the discretion of the investigator or study staff. 
As part of the pulmonary assessment the parent(s)/legal guardian(s) will be asked by the 
pulmonologist to recall and report the number of hours per day the subject required ventilation 
support (including BiPAP) over the two weeks prior to the visit.  The response will be recorded 
in the source documentation. 
11.18 Photographs of Infusion Site 
Photographs will be taken of the infusion site at the time points specified in Table 6.  AveXis, 
Inc. will provide a secure and confidential upload process for transfer and storage of the 
photographs from NCH to a contracted third-party vendor that will compile and arrange 
photographs as per AveXis, Inc. submission requirements.  Any/all photographs received at 
AveXis, Inc. or the contracted vendor will be treated as confidential study data and will be the 
sole property of AveXis, Inc.  AveXis, Inc. and the contracted vendor will provide this secure, 

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encrypted transfer and storage solution to properly protect the identities of patients/families in 
the photographs, which may be shared with regulatory agencies and/or the medical community. 
11.19 Laboratory Assessments 
Biological samples will be collected throughout the trial at the time points specified in Table 6. 
Laboratory tests with values within the clinically significant range will be repeated during the 
same visit whenever possible.  If the test result returns after the subject leaves the clinic, they 
will be immediately contacted.  Local residents may be asked to return to the outpatient clinic for 
a repeat test.  For non-local residents, arrangements will be made to have the blood test redrawn 
in a laboratory close to home or by their primary care physician. 
Table 11 
Total Blood Volume 
Visit 
Tests 
Total Volume 
Screening 
Safety, immunology, research 
20 mL 
Day 0 
Safety, immunology 
15 mL 
Day 7 
Safety, immunology 
15 mL 
Day 14 
Safety, immunology 
15 mL 
Day 21 
Safety, immunology, research 
20 mL 
Day 30 
Safety, immunology, research 
20 mL 
Day 60 
Safety, immunology, research 
20 mL 
Day 90 
Safety, immunology, research 
20 mL 
Day 180 
Safety, immunology, research 
20 mL 
Day 270 
Safety, immunology, research 
20 mL 
Day 360 
Safety, immunology, research 
20 mL 
Day 450 
Safety, immunology, research 
20 mL 
Day 540 
Safety, immunology, research 
20 mL 
Day 630 
Safety, immunology, research 
20 mL 
Last Study Visit 
Safety, immunology, research 
20 mL 
Total Volume for Study 2-Year Duration 
285 mL 
 
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 blood labs 
2. Serum antibody to AAV9 
3. IFN-γ ELISpots to detect T-cell responses 
4. Research Blood sample stored for future purposes 

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11.19.1 
Hematology 
Hematology analysis will include a CBC with differential and platelet with smear. 
11.19.2 
Blood Chemistry 
Chemistry analysis will include the following at all study visits: 
• 
serum GGT 
• 
AST/ALT 
• 
serum total bilirubin 
• 
direct bilirubin 
• 
albumin 
• 
glucose 
• 
total creatine kinase and iso-enzyme (CK-MB) 
• 
troponin 
• 
creatinine/BUN 
• 
electrolytes 
• 
alkaline phosphatase 
• 
amylase 
Study Visit 2 will also include: 
• 
serum protein electrophoresis (SPEP) 
11.19.3 
Urinalysis 
Urine samples will be collected via cotton swabs.  Urinalysis will include the following 
parameters: 
• 
Color 
• 
Clarity/turbidity 
• 
pH 
• 
Specific gravity 
• 
Glucose 
• 
Ketones 
• 
Nitrites 
• 
Leukocyte esterase 
• 
Bilirubin 
• 
Urobilirubin 
• 
Blood 
• 
Protein 
• 
RBCs 
• 
WBCs 
• 
Squamous epithelial cells 
• 
Casts 

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• 
Crystals 
• 
Bacteria 
• 
Yeast 
11.19.4 
Coagulation Studies 
Coagulation studies including prothrombin time (PT), PTT, and INR will be performed at the 
time points specified in Table 6. 
11.19.5 
Capillary Blood Gas 
A puncture or small incision will be made with a lancet or similar device into the cutaneous layer 
of the patient’s skin at a highly vascularized area (heel, finger, toe).  To accelerate blood flow 
and reduce the difference between the arterial and venous gas pressures, the area will be warmed 
prior to the puncture.  As the blood flows freely from the puncture site, the sample will be 
collected in a heparinized glass capillary tube. 
11.19.6 
Virus Serology 
Patients will be tested for HIV and have a serology test for hepatitis B and C. 
11.19.7 
Research Immunology Blood 
Blood samples will be collected to test for serum antibodies to AAV9 and SMN. 
11.19.8 
Baseline Screening of Mother 
There is a potential that the mother of the enrolled infant may have pre-existing antibodies to 
AAV9 that may be transferred to the patient through breast milk or theoretically via placental 
transfer in utero.  Informed consent will be requested from the mother of the infant to screen the 
mother for circulating antibodies to AAV9.  Once informed consent has been obtained, the 
mother will have her blood drawn from a peripheral vein for screening of anti-AAV9 antibodies. 
11.19.9 
IFN-γ ELISpots 
Blood will be collected to perform IFN-γ ELISpots to detect T-cell responses to AAV9 and 
SMN. 
11.19.10 Research Blood Sample 
Blood samples will be collected for future research purposes, to examine/research potential 
disease modifiers and/or biomarkers.  Research blood will also be used for exon 7 modifier 
testing at screening.  Additionally, blood samples collected for research may be transferred to an 
independent third-party laboratory contracted by AveXis, Inc. such that genetic testing 
confirming SMA Type 1 diagnosis can be re-confirmed for each subject. 
An additional blood sample may be collected and provided to an independent laboratory for re-
confirmatory genetic testing. 
11.19.11 Saliva, Urine, and Stool Collection 
Saliva, urine, and stool samples will be collected for viral shedding studies.  Saliva will be 
collected from the patient’s mouth with a pipette and oral swab.  200-500 µL of urine will be 
collected from patients’ soiled diapers by soaking a cotton ball.  Pea-sized fecal samples will be 
collected from patients’ soiled diapers.  Each of these samples will be placed in a 

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DNAse/RNAse-free Eppendorf tube with locking top.  The tubes will be stored in a -80°C 
freezer. 
12 ADVERSE AND SERIOUS ADVERSE EVENTS 
12.1 Definition of Adverse Events 
12.1.1 
Adverse Event (AE) 
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 that occur after any patient has been enrolled, before treatment, during treatment, or 
within 30 days of the last study visit, whether or not they are related to the study, must be 
recorded in the eCRF. 
12.1.2 
Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any study phase (i.e., baseline, treatment, 
washout, or follow-up), and at any dose of the investigational product, comparator or placebo, 
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 
• 
It 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. 
All SAEs that occur after any patient has signed informed consent, before treatment, during 
treatment, or within 30 days following the last study visit, whether or not they are related to the 
study, must be recorded on forms provided by AveXis, Inc. 
12.1.3 
Other Adverse Event (OAE) 
OAEs may be identified by the Drug Safety Physician and, if applicable, also by the Clinical 
Study Team Physician during the evaluation of safety data for the Clinical Study Report.  
Significant adverse events of particular clinical importance, other than SAEs and those AEs 
leading to discontinuation of the patient/subject from the study, will be classified as OAEs.  For 
each OAE, a narrative may be written and included in the Clinical Study Report. 
12.2 Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related or Probably 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 

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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” the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 
12.3 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.  Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as AEs.  However, abnormal values that constitute an SAE or lead to 
discontinuation of administration of study drug must be reported and recorded as an AE.  
Information about AEs will be collected from Day -1 until the end of the study.  Serious Adverse 
Event information will be collected from signing of the consent form until 30 days following 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), resolution (date 
and time), intensity, causality, action taken, serious outcome (if applicable), and whether or not it 
caused the patient to discontinue the study. 
Events will be graded in accord with Table 9. 
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 12.1.2.  An AE of severe intensity 
may not be considered serious. 
12.4 Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from the signing of consent form until 30 days 
following the last study visit.  Any SAEs considered possibly or probably 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, Inc. 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 
notification to AveXis, Inc., as per the Safety Management Plan. 
Additional follow-up information, if required or available, should all be provided to AveXis, Inc. 
within 5 calendar days of receipt for events that are unexpected and/or 
possibly/probably/definitely related to the investigational product.  This information should be 
provided 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.  Follow-up information for events that are 
not unexpected and are not related to the investigational product should be provided to AveXis, 
Inc. within 7 calendar days of receipt. 
AveXis, Inc. is responsible for notifying the relevant regulatory authorities of certain events.  It 
is the Principal Investigator’s responsibility to notify the IRB of all SAEs that occur at his or her 
site, as per the IRB’s reporting guidelines. 

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AveXis, Inc. will review the safety database at least quarterly; this data will also be provided to 
the DSMB for quarterly review.  If AveXis or the DSMB determines there are any emerging safety 
signals and/or trends that may warrant reporting to appropriate regulatory authorities, AveXis will 
report these events in aggregate. 
13 DATA SAFETY MONITORING BOARD 
The Data and Safety Monitoring Board (DSMB) will act in an advisory capacity to review 
participant safety and study progress for the clinical trial.  Responsibilities of the DSMB are to: 
• 
review the research protocol, informed consent documents and plans for data and safety 
monitoring; 
• 
evaluate the progress of the trial, including periodic assessments of data quality and 
timeliness, participant recruitment, accrual and retention, participant risk versus benefit, trial 
site performance, and other factors that can affect study outcome; 
• 
consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on participant safety or the 
ethics of the trial; 
• 
review study performance, make recommendations and assist in the resolution of problems 
reported by the Principal Investigator; 
• 
protect the safety of the study participants; 
• 
review safety data to determine whether to recommend dose escalation; 
• 
review quarterly safety data to determine safety signals or trends; 
• 
ensure the confidentiality of the trial data and the results of monitoring; and, 
• 
assist by commenting on any problems with study conduct, enrollment, and sample size 
and/or data collection. 
13.1 DSMB Reporting and Meetings 
Reports describing the status of the study will be prepared by AveXis, Inc. and/or the Principal 
Investigator’s staff and sent to the DSMB at least quarterly, or at the DSMB’s request.  A 
meeting (either by teleconference or webcast) with the DSMB will be scheduled after Day 30 
visit of the last patient in each cohort, or at the DSMB’s request.  Reports will be submitted prior 
to a scheduled meeting for review by the DSMB. 
Reports will include the following: 
• 
A brief narrative of the study status, including the target enrollment, current and projected 
time to completing enrollment.  Any significant events and/or difficulties should be briefly 
described in this narrative; 
• 
A brief narrative for each participant describing gender, age, race and ethnicity and other 
relevant demographic characteristics.  The narrative for each participant should briefly 
describe his/her study status (i.e., dose level, visit number, adverse event information); 

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• 
A timeline outlining the study progress relative to visit number for each participant, as well 
as time points for each SAE/Dose Limiting Toxicity.  A total for Adverse Events (AEs) for 
each participant should be included; 
• 
A summary of AEs by classification; 
• 
A listing of AE details grouped by participant; 
• 
A listing of SAE details grouped by participant; 
• 
A listing of deaths; 
• 
A summary of clinically significant laboratory test results; 
• 
A listing of protocol deviations. 
13.2 DSMB Membership 
The DSMB membership will consist of persons completely independent of the investigator and 
sponsor who have no financial, scientific, or other conflicts of interest with the trial.  Current or 
past collaborators or associates of Dr. Mendell or AveXis, Inc. must note any conflict of interest 
before their eligibility to serve on the DSMB is approved.  The DSMB will include experts in or 
representatives of the fields of: 
• 
Neurology and Neuromuscular Diseases 
• 
Immunology 
• 
Gene Therapy 
• 
Spinal Muscular Atrophy Clinical Care 
• 
Clinical Research and Clinical Trials 
• 
Statistics (non-voting member) 
Individuals invited to serve on the DSMB as either voting or non-voting members must disclose 
any potential conflicts of interest, whether real or perceived.  Conflicts of interest can include 
professional, proprietary, and miscellaneous interests as described in 45 CFR Part 94.  Potential 
conflicts that develop during a member’s tenure on a DSMB must also be disclosed.  Written 
documentation attesting to an absence of conflict of interest is required annually. 
AveXis, Inc. will employ a third party to provide planning, organization, preparation, and 
oversight services for the DSMB meetings. 
14 STATISTICS 
This is a Phase I trial, with safety as the primary measure.  A secondary outcome includes the 
time to death or ≥16-hour respiratory assistance per day continuously for ≥2 weeks in the 
absence of an acute reversible illness.  Only patients with 2 copies of SMN2 will be enrolled.  
92% of SMA Type 1 patients with two copies of SMN2 live <21 months.  For this study the 
primary end point for efficacy will be death or ≥16 hour respiratory assistance per day (includes 
BiPAP).  A successful measure for efficacy for this study will be 50% of SMA Type 1 subjects 
living with less than 16 hour respiratory assistance at 2 years of age. 

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15 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1 Study Monitoring 
During the study, a monitor from AveXis, Inc. or representative will have regular contact 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 and ICH/GCP 
guidelines, 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) including access to the site’s Electronic Medical Record 
(EMR) and the videos captured during specified visit assessments. 
- 
Record and report any protocol deviations not previously sent to AveXis, Inc. 
- 
Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to AveXis, Inc. and those SAEs that met criteria for reporting 
have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
15.2 Audits and Inspections 
Authorized representatives of AveXis, Inc., a regulatory authority, or an Institutional Review 
Board may visit the site to perform audits or inspections, including source data verification.  The 
purpose of an AveXis, Inc. 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 guidelines of the International Conference on Harmonization, and any applicable 
regulatory requirements.  The investigator should contact AveXis, Inc. immediately if contacted 
by a regulatory agency about an inspection. 
15.3 Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
15.4 Quality Control and Quality Assurance 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
AveXis, Inc. may conduct a quality assurance audit.  Please see Section 15.2 for more details 
regarding the audit process. 

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16 ETHICS 
16.1 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 Principal Investigator is responsible for informing the IRB of any amendment to the protocol 
in accordance with local requirements.  The protocol must be re-approved by the IRB upon 
receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  AveXis, Inc. will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
according to local regulations and guidelines. 
16.2 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 1) and are consistent with ICH/Good Clinical Practice, 
applicable regulatory requirements and AveXis, Inc.’s policy on Bioethics. 
16.3 Written Informed Consent 
The Principal Investigator(s) will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Patients 
must also be notified that they are free to discontinue from the study at any time.  The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The patient’s 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 patient. 
Per the National Institutes of Health’s Guidelines for Research Involving Recombinant or 
Synthetic Nucleic Acid Molecules (http://oba.od.nih.gov), an autopsy must be requested should a 
study participant die following participation in a gene transfer trial, no matter what the cause of 
death.  An autopsy is requested to obtain vital information about the safety and efficacy of gene 
transfer.  Patients’ parent(s)/legal guardians will be asked to provide consent for an autopsy in 
advance of any death.  Consent is requested at the beginning of the study to relieve the burden of 
making such a decision at the time of death should such a terrible and unfortunate event occur. 
17 DATA HANDLING AND RECORDKEEPING 
17.1 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 serology results, a check list of inclusion and exclusion 

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criteria, urinary screening, drug administration, and a record of sample collection, hemodynamic 
measurements, clinical assessments, AEs, and final evaluation. 
Electronic CRFs will be used in this study.  The eCRF will be electronically signed and dated by 
the Principal Investigator or his 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. 
17.2 Inspection of Records 
AveXis, Inc. 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 
drug storage area, study drug stocks, drug accountability records, subject charts, study source 
documents, and other records relative to study conduct. 
17.3 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. 
The site will maintain a Clinical Study Document Binder, which will be maintained at the study 
site.  In this binder, there will be tabbed sections for study documents including the following: 
study personnel identification and signature list, subject screening records, subject roster (names 
omitted), protocol and amendments or administrative changes, FDA Form 1572 (if required), 
study staff Curricula Vitae, IRB documentation, an approved sample ICF, drug accountability 
records, correspondence, site monitoring reports, blank Data Documentation form, and lab 
accreditations and normal values.  The site must keep this binder current and available for review 
by the Sponsor, IRB, and/or FDA. 
17.4 Retention of Samples 
The identified storage laboratory will be responsible for arranging storage of any remaining or 
unused biological samples as well as properly documenting the storage procedures, once all 
study-required analyses are complete, as per sample processing requirements until such time that 
AveXis, Inc. provides external storage vendor transfer or destruction instructions. 
18 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 or as otherwise agreed upon in writing by Sponsor and investigator.  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. 

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Manuscript authorship for any peer-reviewed publication will appropriately reflect contributions 
to the production and review of the document (in accordance with ICJME).  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. 
The investigator will provide the Sponsor with a copy of any proposed publication or 
presentation for review and comment at least 30 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 30-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 60 days to permit the Sponsor to take necessary actions to protect its intellectual 
property interests.  In the event of any discrepancy between the protocol and the Clinical Study 
Site Agreement, the Clinical Study Site Agreement will prevail. 

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19 LIST OF REFERENCES 
1. Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies  and 
challenges. Lancet neurology 2012; 11(5): 443-52. 
2. Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Archives of neurology 2011; 
68(8): 979-84. 
3. 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): 155-64. 
4. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene 
regulates splicing and is responsible for spinal muscular atrophy. Proceedings of the National 
Academy of Sciences of the United States of America 1999; 96(11): 6307-11 
5. 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. Human molecular genetics 1999; 8(7): 1177-83. 
6. 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): 
264-9. 
7. Park GH, Kariya S, Monani UR. Spinal muscular atrophy: new and emerging insights from 
model mice. Current neurology and neuroscience reports 2010; 10(2): 108-17. 
8. 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. American journal of human genetics 2002; 
70(2): 358-68. 
9. Farrar MA, Vucic S, Johnston HM, du Sart D, Kiernan MC. Pathophysiological Insights 
Derived by Natural History and Motor Function of Spinal Muscular Atrophy. The Journal of 
pediatrics 2012. 
10. 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. Annals of 
neurology 2005; 57(5): 704-12. 
11. Le TT, McGovern VL, Alwine IE, Wang X, Massoni-Laporte A, Rich MM et al. Temporal 
requirement for high SMN expression in SMA mice. Human molecular genetics 2011; 
20(18): 3578-91. 
12. Farrar MA, Vucic S, Johnston HM, Kiernan MC. Corticomotoneuronal integrity and 
adaptation in spinal muscular atrophy. Archives of neurology 2012; 69(4): 467-73. 
13. 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. 
Nature biotechnology 2010; 28(3): 271-4. 
14. 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. European journal of human genetics : EJHG 2012; 20(1): 27-32. 

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15. 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. Human 
molecular genetics 2010; 19(8): 1492-506. 
16. 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. 
17. 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. 
18. Butchbach ME, Edwards JD, Burghes AH. Abnormal motor phenotype in the SMNDelta7 
mouse model of spinal muscular atrophy. Neurobiology of disease 2007; 27(2): 207-19. 
19. Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, Kota J, Coley BD, Galloway G et al. 
Limb-girdle muscular dystrophy type 2D gene therapy restores alphasarcoglycan and 
associated proteins. Annals of neurology 2009; 66(3): 290-7. 
20. Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, Kang PB, 
Foley AR, Yang ML, Martens WB, Oskoui M, Glanzman AM, Flickinger J, Montes J 
Dunaway S, O'Hagen J, Quigley J, Riley S, Benton M, Ryan PA, Montgomery M, Marra J, 
Gooch C, De Vivo DC. Finkel et al 2014: Observational study of spinal muscular atrophy 
type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-7. 

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20 APPENDICES 
APPENDIX 1 
DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians.  The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research.  The physician's knowledge 
and conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments).  Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 

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8. While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects.  The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms 
and standards.  No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications.  Research on patients 
or healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by 
the condition under investigation. 
Measures to minimize the risks must be implemented.  The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 

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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. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group.  In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal experimentation.  
The welfare of animals used for research must be respected. 
22. The design and performance of each research 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 subjects and information regarding provisions for treating and/or 
compensating subjects 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 
23. 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 subjects 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 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects 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. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the 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 subjects 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 subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. 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. 
28. For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorized representative.  These individuals 
must not be included in a research 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. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorized representative.  The potential 
subject’s dissent should be respected. 
30. Research involving subjects 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, 

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the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in 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. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research.  The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent 
for its collection, storage and/or reuse.  There may be exceptional situations where consent 
would be impossible or impracticable to obtain for such research.  In such situations the 
research may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
any intervention less effective than the best proven one, placebo, or no intervention will not 
be subject to additional risks of serious or irreversible harm as a result of not receiving the 
best proven intervention.  Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial.  This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research.  Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable 
for the completeness and accuracy of their reports.  All parties should adhere to accepted 
guidelines for ethical reporting.  Negative and inconclusive as well as positive results must 
be published or otherwise made publicly available.  Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication.  Reports of research 
not in accordance with the principles of this Declaration should not be accepted for 
publication. 

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Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering.  This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy.  In all cases, new 
information must be recorded and, where appropriate, made publicly available. 

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APPENDIX 2 
AUTOPSY PLAN 
Regional Pathology and Autopsy Services, Inc., a nationwide company that provides autopsy and 
tissue collection services, will perform autopsy and tissue collection for the patients in the 
clinical trial.  This company will deploy a pathology assistant to the funeral home of the 
deceased to perform the autopsy and tissue collection.  Standard autopsy incisions are used to 
perform the autopsy and pathology necessary to determine the cause of death, which will be 
completed by Regional Pathology and Autopsy Services. 
During the procedure, multiple tissues along with the entire spinal cord will be collected for 
research purposes.  Up to 7 sections or pieces from each organ and each region of the spinal cord 
will be collected and returned to the principal investigator of the trial at Nationwide Children’s 
Hospital.  Analysis of the tissue will be done to determine whether the vector transduced the 
expected motor neurons and if the SMN gene was expressed.  These results 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 following organs and regions of the spinal cord and brain 
will be collected (see Table 12 below).  Tissue sample will be frozen or fixed (eg. 2% 
paraformaldehyde) for appropriate analysis. 
Families will be asked to consent to the autopsy and tissue collection prior to any sign of 
moribund or death by the clinical team conducting the trial.  There are distinct consent forms for 
the formal autopsy and for the research tissue collection.  This allows the families the flexibility 
to participate in one or both of the research activities. 
 
Table 12 
Tissue Samples for Analysis 
 

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APPENDIX 3 
CHOP-INTEND 
CHILDREN’S HOSPITAL of PHILADELPHIA INFANT TEST OF NEUROMUSCULAR DISORDERS 
Time of evaluation: ___________________________________ (AM/PM) 
Hours off BiPAP at testing:  ________________________(h) 
Item 
Position 
Test Procedure 
Graded Response 
Score 
1 
Spontaneous 
movement 
(Upper 
extremity) 
Supine 
Observe throughout 
testing 
May unweight limb or stimulate infant 
to facilitate response 
Antigravity shoulder movement (achieves elbow off surface) 
4 
L 
R 
Best side: 
State: 
Antigravity elbow movement (achieves hand and forearm off surface) 
3 
Wrist movement 
2 
Finger movement 
1 
No movement of limbs 
0 
2 
Spontaneous 
movement 
(Lower 
extremity) 
Supine 
Observe throughout 
testing 
May unweight limb or stimulate infant 
to facilitate response 
Antigravity hip movement (achieves feet and knees off surface) 
4 
L 
R 
Best side: 
State: 
Antigravity hip adduction/internal rotation (knees off surface) 
3 
Active gravity eliminated knee movement 
2 
Ankle movement 
1 
No movement of limbs 
0 
3 
Hand grip 
Supine 
Grip strength: place finger in palm and 
lift until shoulder comes off surface 
observe when infant loses grasp 
May use toy of similar diameter for 
older children 
Maintains hand grip with shoulder off bed 
4 
L 
R 
Best side: 
State: 
Maintains grip with elbow off surface 
(shoulders on surface) 
3 
Maintains grip with forearm off surface 
(elbow supported on surface) 
2 
Maintains grip only with no traction 
1 
No attempt to maintain grasp 
0 
4 
Head in midline 
with visual 
stimulation* 
Supine head midline 
Visual stimulation is given with toy. 
If head is maintained in midline for 5 
seconds: Place head in maximum 
available rotation and provide visual 
stimulation to encourage midline 
Rotates from maximum rotation to midline 
4 
L>R
R>L
Best side: 
State: 
Turns head part way back to midline 
3 
Maintains midline for 5 or more seconds 
2 
Maintains midline, less than 5 seconds 
1 
Head falls to side, no attempts to regain midline 
0 

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Investigational Product: AVXS-101 
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Time of evaluation: ___________________________________ (AM/PM) 
Hours off BiPAP at testing:  ________________________(h) 
Item 
Position 
Test Procedure 
Graded Response 
 
Score 
 
5 
Hip adductors 
Supine, no diaper 
Hips flexed and adducted Feet hip width 
apart and thighs parallel, knees slightly 
apart 
Keeps knee off surface of bed >5 sec or lifts foot off surface 
4 
L 
 
R 
Best side: 
 
State: 
Keeps knees off surface of bed 1-5 sec 
2 
No attempt to maintain knees off surface 
0 
6 
Rolling: elicited 
from legs* 
Supine 
(arms at side) Keep side tested 
up roll away from the Side 
tested 
1. Holding infant’s lower thigh, flex hip 
and knee and adduct across midline 
bringing pelvis vertical maintain 
traction and pause in this position. 
2. If infant rolls to side apply traction at 
a 45º diagonal to body and pause to 
allow infant to attempt to de-rotate body 
When traction is applied at the end of the maneuver, rolls to prone with 
lateral head righting 
4 
To R 
 
 
 
To L 
Best side: 
 
 
 
State: 
Rolls through side lying into prone without lateral head righting, clears 
weight-bearing arm to complete roll 
3 
Pelvis, trunk and arm lift from support surface, head turns and rolls onto 
side, arm comes thru to front of body 
2 
Pelvis and trunk lift from support surface and head turns to side.  Arm 
remains behind trunk 
1 
Pelvis lifted passively off support surface. 
0 
7 
Rolling: 
elicited from 
arms* 
Supine (arms at side) Keep 
side tested up roll away from 
the Side tested 
1. Hold infant at the elbow move toward 
opposite shoulder maintain traction on 
limb and pause with the shoulders 
vertical allow infant to de-rotate 
 
2. if the pelvis achieves vertical 
continue to provide traction 
Rolls to prone with lateral head righting 
4 
To R 
 
 
To L 
Best side: 
 
 
 
State: 
Rolls into prone without lateral head righting; must clear weight-bearing 
arm completely to finish roll 
3 
Rolls onto side, leg comes thru and adducts, bringing the pelvis vertical 
2 
Head turns to side and shoulder and trunk lift from surface 
1 
Head turns to side; body remains limp or shoulder lifts passively 
0 
8 
Shoulder and 
elbow flexion 
And horizontal 
abduction 
Side-lying with upper arm 
at 30º of shoulder extension 
and elbow flexion and 
supported on body  
(restrain lower arm if 
needed) 
Prompt reach for a toy presented at 
arm’s length at shoulder level (may 
provide stimulation and observe 
spontaneous movement) 
Clears hand from surface with antigravity arm movement 
4 
L 
 
 
 
R 
Best side: 
 
 
 
State: 
Able to flex shoulder to 45 degrees, without antigravity arm 
movement 
3 
Flexes elbow after arm comes off body 
2 
Able to get arm off body 
1 
No attempt 
0 
9 
Shoulder flexion 
& Elbow flexion 
Sitting in lap or on mat with 
head and trunk support (20º 
recline) 
Present stimulus at midline and at 
shoulder level at arm’s length (may 
provide stimulation and observe 
spontaneous movement) 
Abducts or flexes shoulder to 60 degrees 
4 
L 
 
 
R 
Best side: 
 
 
 
State: 
Abducts or flexes shoulder to 30 degrees 
3 
Any shoulder flexion or abduction 
2 
Flexes elbow only 
1 
No attempt to lift arm 
0 

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Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
Version 14.0 / 21 Apr 2016 
 
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Time of evaluation: ___________________________________ (AM/PM) 
Hours off BiPAP at testing:  ________________________(h) 
Item 
Position 
Test Procedure 
Graded Response 
 
Score 
 
10 
Knee extension 
Sitting in lap or over edge of 
mat with head and trunk 
support (20º recline) thigh 
horizontal to ground 
Tickle plantar surface of foot or 
gently pinch toe 
Extends knee to >45 degrees 
4 
L 
 
 
R 
Best side: 
 
 
State: 
Extends knee 15 to 45 degrees 
2 
Any visible knee extension 
1 
No visible knee extension 
0 
11 
Hip flexion and 
foot dorsiflexion 
Hold infant against your body 
with legs free, facing outward.  
Support at the abdomen with 
the child’s head resting 
between your arm and thorax 
Stroke the foot or pinch the toe 
Hip flexion or knee flexion >30º 
4 
L 
 
 
R 
Best side: 
 
 
State: 
Any hip flexion or knee flexion 
3 
Ankle dorsiflexion only 
2 
No active hip, knee or ankle motion 
1 
Hip flexion or knee flexion >30º 
0 
12 
Head control* 
Sitting with support at the 
shoulders and trunk erect 
Place the infant in ring sit with head 
erect and assistance given at the 
shoulders (front and back) (may delay 
scoring a grade of 1 and 4 until end of 
test). 
Attains head upright from flexion and turns head side to side 
4 
L 
 
 
R 
Best side: 
 
 
State: 
Maintains head upright for >15 sec (for bobbing head control score a 2) 
3 
Maintains head in midline for >5 sec. with the head tipped in up to 30º 
of forward flexion or extension 
2 
Actively lifts or rotates head twice from flexion within 15 seconds (do 
not credit if movement is in time with breathing) 
1 
No response, head hangs 
0 
13 
Elbow flexion 
Score with item 
14 
Supine 
Traction response: pull to sit extend 
arms at 45 degree angle, to point of 
nearly lifting head off surface 
Flexes elbow 
4 
L 
 
R 
Best side: 
 
State: 
 
Visible biceps contraction without elbow flexion 
2 
No visible contraction 
0 
14 
Neck Flexion 
Score with item 
13 
Supine 
Traction response: hold in neutral proximal 
to wrist and shoulder at 45º, to point of 
nearly lifting head off surface 
Lifts head off bed 
4 
 
Score: 
 
State: 
 
Visible muscle contraction of SCM 
2 
No muscle contraction 
0 
15 
Head/Neck 
Extension 
(Landau) 
Ventral suspension: Prone, 
held in one hand upper 
abdomen 
Stoke along spine from neck to sacrum.  The 
coronal axis of the head when parallel to the 
bed surface = 0 degrees (horizontal) 
Extends head to horizontal plane or above 
4 
 
Score: 
 
State: 
 
Extends head partially, but not to horizontal 
2 
No head extension 
0 
 
 
 
 
 
 
 

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Investigational Product: AVXS-101 
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Time of evaluation: ___________________________________ (AM/PM) 
Hours off BiPAP at testing:  ________________________(h) 
Item 
Position 
Test Procedure 
Graded Response 
 
Score 
 
16 
Spinal 
Incurvation 
(Galant) 
Ventral suspension: Prone, 
held in one hand upper 
abdomen 
Stroke Right then Left throacolumbar 
paraspinals or tickle abdomen or foot or tilt in 
infants with For infant over 10 kg knees and 
head may touch 
Twists pelvis towards stimulus off axis 
4 
L 
 
R 
Best side: 
 
State: 
 
Visible paraspinal muscle contraction 
2 
No response 
0 
Total score, best score on each side for e ach item (maximum 64 points): 
Comments: 
 
* Adapted from the Test of Infant Motor Performance, Campbell, SK; et al. 2001. 
 
Contractures : 
 
 
Behavioral State : (Brazelton, TB.Neonatal Behavioral Assessment Scale, 2nd ed.,1984) 
□ None 
 
 
State 1 
Deep sleep 
State 2 
Light sleep 
L □  R □   Knee flexion 
 
State 3 
Drowsy or semi-dozing 
State 4 
Alert, with bright look 
L □  R □   Ankle plantar flexion 
(Present <20 degrees knee extended) 
State 5 
Eyes open, considerable activity 
State 6 
Crying 
L □  R □   Hip adductor 
L □  R □     ITB contracture 
 
 
 
(Note if leg cannot abduct and ext. rot. to contact surface in supine) 
Testing environment: 
L □  R □   Shoulder protraction 
 
Ideally test first thing in the AM or same time of day about 1 hour after feeding 
L □  R □   Elbow flexion 
 
Test on a firm padded mat 
L □  R □   Neck rotation 
 
Diaper /onesie only unless the infant is cold 
L □  R □   Neck lateral flexion 
 
 
Test with toys 
□ Plagiocephaly 
 
May use pacifier only if needed to maintain state 4 or 5 (see definition). 
□ Fixed spinal curve 
 
Mark as CNT (could not test) if patient could not be tested DO NOT MARK 0 
 
 _______________________________________________________________________________________________________ 
 _____________________________________________________________________  
SIGNATURE 
 
DATE 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
65 
APPENDIX 4 
BAYLEY SCALE OF INFANT DEVELOPMENT VERSION 3: 
GROSS AND FINE MOTOR SKILLS SUBPARTS AND SPEECH 
AND COGNITION SUBPARTS 
 

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Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
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AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
67 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
68 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
69 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
70 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
71 
 
 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
72 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
73 
 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
74 
 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
75 
 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
76 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
77 
 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
78 
 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
79 
 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
80 
 

AveXis, Inc. 
 
Protocol Number: AVXS-101-CL-101 
Investigational Product: AVXS-101 
 
Version 14.0 / 21 Apr 2016 
 
Confidential 
81 
APPENDIX 5 
GROSS MOTOR SKILLS CHECKLIST 
 
 
 

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Investigational Product: AVXS-101 
 
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