Clinical trial NCT02462759
Conditions: Spinal Muscular Atrophy
Keywords: EMBRACE SMA
Sponsor: Biogen
Start date: 2015-08-19; Completion date: 2018-09-24
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of Part 1 of this study is to assess the safety and tolerability of Nusinersen in participants with SMA who are not eligible to participate in the clinical studies ISIS 396443-CS3B (NCT02193074) or ISIS 396443-CS4 (NCT02292537). The secondary objective of Part 1 of this study is to examine the pharmacokinetics (PK) of Nusinersen in participants with SMA. The primary objective of Part 2 of this study is to assess the long-term safety and tolerability of Nusinersen in participants with SMA who participated in Part 1 and completed their End of Part 1 Evaluation assessments. The secondary objective of Part 2 of this study is to examine the PK of Nusinersen in participants with SMA who participated in Part 1 and completed their End of Part 1 Evaluation assessments.

Detailed description:
Part 2 is an Open Label extension phase.

Arms: arm 1: Administered by intrathecal injection. arm 2: Small needle prick on the lower back at the location where the IT injection is normally made.
Interventions: intervention 1: Nusinersen intervention 2: Sham Procedure
Intervention descriptions: intervention 1: Administered by intrathecal injection. intervention 2: Small needle prick on the lower back at the location where the IT injection is normally made.

Protocol documents:
Prot_001.pdf: 




TABLE OF CONTENTS
1.
SPONSOR INFORMATION .......................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................10
3.
SYNOPSIS .................................................................................................................11
4.
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR 
STUDY 232SM202 ....................................................................................................22
4.1.
Study Schematic .........................................................................................................22
4.2.
Schedule of Events .....................................................................................................23
4.2.1.
Schedule of Events:  Part 1.........................................................................................23
4.2.2.
Schedule of Events:  Part 2.........................................................................................26
5.
INTRODUCTION......................................................................................................34
5.1.
Overview of Spinal Muscular Atrophy.......................................................................35
5.2.
Current Therapies for Spinal Muscular Atrophy........................................................35
5.3.
Profile of Previous Experience With Nusinersen .......................................................35
5.3.1.
Nonclinical Experience...............................................................................................35
5.3.2.
Clinical Experience.....................................................................................................37
5.4.
Study Rationale...........................................................................................................39
5.4.1.
Rationale for Part 1.....................................................................................................39
5.4.2.
Rationale for Part 2:  Open-Label Extension Phase ...................................................39
5.5.
Rationale for Dose and Schedule Selection................................................................39
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................40
6.1.
Primary Objectives and Endpoints .............................................................................40
6.2.
Secondary Objectives and Endpoints .........................................................................41
6.3.
Exploratory Objectives and Endpoints.......................................................................42
7.
STUDY DESIGN .......................................................................................................43
7.1.
Study Overview ..........................................................................................................43
7.2.
Overall Study Duration and Follow-Up .....................................................................43
7.2.1.
Screening ....................................................................................................................44
7.2.2.
Treatment....................................................................................................................44
7.2.3.
Follow-Up...................................................................................................................46
7.3.
Study Stopping Rules .................................................................................................46
7.4.
End of Study ...............................................................................................................46
7.5.
Safety Monitoring and Data and Safety Monitoring Board........................................46


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8.
SELECTION OF SUBJECTS ....................................................................................47
8.1.
Inclusion Criteria ........................................................................................................47
8.2.
Exclusion Criteria.......................................................................................................48
9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................49
9.1.
Screening and Enrollment...........................................................................................49
9.2.
Registration and Randomization of Subjects..............................................................49
9.3.
Blinding Procedures....................................................................................................50
9.3.1.
Emergency Unblinding of Treatment Assignment.....................................................50
10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY...........................................51
10.1.
Discontinuation of Study Treatment...........................................................................51
10.2.
Withdrawal of Subjects From Study...........................................................................51
11.
STUDY TREATMENT USE .....................................................................................52
11.1.
Regimen......................................................................................................................52
11.1.1.
Study Treatment..........................................................................................................52
11.1.2.
Sham Procedure..........................................................................................................53
11.2.
Modification of Dose and/or Treatment Schedule......................................................53
11.3.
Precautions..................................................................................................................53
11.4.
Compliance.................................................................................................................53
11.5.
Concomitant Therapy and Procedures........................................................................53
11.5.1.
Concomitant Therapy .................................................................................................53
11.5.2.
Concomitant Procedures.............................................................................................54
12.
STUDY TREATMENT MANAGEMENT................................................................54
12.1.
Study Treatment..........................................................................................................54
12.1.1.
Study Treatment Preparation......................................................................................55
12.1.2.
Study Treatment Storage ............................................................................................55
12.1.3.
Study Treatment Handling and Disposal....................................................................55
12.1.4.
Study Treatment Accountability.................................................................................55
13.
EFFICACY, PHARMACOKINETIC, AND IMMUNOGENICITY 
ASSESSMENTS.........................................................................................................56
13.1.
Clinical Efficacy Assessments....................................................................................56
13.2.
Pharmacokinetic (Nusinersen Concentration) Assessments.......................................56
13.3.
Immunogenicity Assessments ....................................................................................56


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14.
SAFETY ASSESSMENTS ........................................................................................57
14.1.
Clinical Safety Assessments.......................................................................................57
14.2.
Laboratory Safety Assessments..................................................................................57
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................58
15.1.
Definitions ..................................................................................................................58
15.1.1.
Adverse Event.............................................................................................................58
15.1.2.
Serious Adverse Event................................................................................................58
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................59
15.2.
Safety Classifications..................................................................................................59
15.2.1.
Investigator Assessment of Events.............................................................................59
15.2.2.
Relationship of Events to Study Treatment................................................................59
15.2.3.
Severity of Events.......................................................................................................60
15.2.4.
Expectedness of Events ..............................................................................................60
15.3.
Monitoring and Recording Events..............................................................................60
15.3.1.
Adverse Events ...........................................................................................................60
15.3.2.
Serious Adverse Events..............................................................................................60
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................61
15.3.3.1.
Deaths .........................................................................................................................62
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................62
15.4.
Procedures for Handling Special Situations ...............................................................62
15.4.1.
Dosing Errors..............................................................................................................62
15.4.2.
Medical Emergency....................................................................................................62
15.4.2.1.
Unblinding for Medical Emergency...........................................................................63
15.5.
Safety Responsibilities................................................................................................63
15.5.1.
The Investigator..........................................................................................................63
15.5.2.
The Sponsor................................................................................................................63
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........64
16.1.
Demographic and Baseline Characteristics ................................................................64
16.2.
Safety and Tolerability ...............................................................................................64
16.2.1.
Analysis Population....................................................................................................64
16.2.2.
Methods of Analysis...................................................................................................64


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16.2.2.1.
Neurological Examinations ........................................................................................64
16.2.2.2.
Adverse Events ...........................................................................................................65
16.2.2.3.
Vital Signs ..................................................................................................................65
16.2.2.4.
ECGs...........................................................................................................................65
16.2.2.5.
Clinical Laboratory Results........................................................................................65
16.2.2.6.
Coagulation Parameters..............................................................................................65
16.3.
Efficacy.......................................................................................................................66
16.3.1.
Analysis Population....................................................................................................66
16.3.2.
Methods of Analysis...................................................................................................66
16.3.2.1.
Sibling SMA Data Collection.....................................................................................66
16.4.
Pharmacokinetics........................................................................................................66
16.4.1.
Analysis Population....................................................................................................66
16.4.2.
Methods of Analysis...................................................................................................66
16.5.
Immunogenicity..........................................................................................................66
16.5.1.
Analysis Population....................................................................................................66
16.5.2.
Methods of Analysis...................................................................................................66
16.6.
Interim Analyses.........................................................................................................66
16.7.
Sample Size Considerations .......................................................................................67
17.
ETHICAL REQUIREMENTS ...................................................................................68
17.1.
Declaration of Helsinki...............................................................................................68
17.2.
Ethics Committee........................................................................................................68
17.3.
Subject Information and Consent ...............................................................................68
17.4.
Subject Data Protection ..............................................................................................69
17.5.
Compensation for Injury.............................................................................................69
17.6.
Conflict of Interest......................................................................................................69
17.7.
Registration of Study and Disclosure of Study Results..............................................69
18.
ADMINISTRATIVE PROCEDURES.......................................................................70
18.1.
Study Site Initiation....................................................................................................70
18.2.
Quality Assurance.......................................................................................................70
18.3.
Monitoring of the Study..............................................................................................70
18.4.
Study Funding.............................................................................................................70
18.5.
Publications.................................................................................................................70


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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................71
19.1.
External Contract Organizations.................................................................................71
19.1.1.
Contract Research Organization.................................................................................71
19.1.2.
Interactive Response Technology...............................................................................71
19.1.3.
Electronic Data Capture..............................................................................................71
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................71
19.2.
Study Committees.......................................................................................................71
19.3.
Changes to Final Study Protocol ................................................................................71
19.4.
Ethics Committee Notification of Study Completion or Termination........................72
19.5.
Retention of Study Data..............................................................................................72
19.6.
Study Report Signatory...............................................................................................72
20.
REFERENCES ...........................................................................................................73
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................75


LIST OF TABLES
Table 1
Nusinersen Dose Volume To Be Injected ..................................................................17
Table 2:
Part 1 Schedule of Activities ......................................................................................23
Table 3:
Part 2 Schedule of Activities for Subjects Randomized to Receive 
Nusinersen in Part 1....................................................................................................26
Table 4:
Part 2 Schedule of Activities for Subjects Randomized to Receive Sham 
Procedure in Part 1......................................................................................................29
Table 5
Part 1 Pharmacokinetic Sampling Schedule1..............................................................32
Table 6
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive Nusinersen in Part 11.....................................................................................32
Table 7
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive Sham Procedure in Part 11 ............................................................................33
LIST OF FIGURES
Figure 1:
Study Schematic .........................................................................................................22
Figure 2:
Antisense Oligonucleotide Therapeutic Approach for Treatment of Spinal 
Muscular Atrophy.......................................................................................................34




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2.
LIST OF ABBREVIATIONS
2′ MOE
2′ O (2 methoxyethyl)
ACEND
Assessment of Caregiver Experience with Neuromuscular Disease
AE
adverse event
aPTT
activated partial thromboplastin time
ASO
antisense oligonucleotide
Bi-PAP
bi-level positive airway pressure 
CNS
central nervous system
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
DHA
Directions for Handling and Administration
DSMB
Data and Safety Monitoring Board
ECG
electrocardiogram
GCP
Good Clinical Practice
HINE
Hammersmith Infant Neurological Examination
ICF
informed consent form
ICH
International Council for Harmonisation
INR
international normalized ratio
IRT
interactive response technology
LP
lumbar puncture
mRNA
messenger ribonucleic acid
OLE
open-label extension
PK
pharmacokinetic(s)
PTT
partial thromboplastin time
RNA
ribonucleic acid
SAE
serious adverse event
SMA
spinal muscular atrophy
SMN
survival motor neuron
SMN1
survival motor neuron 1
SMN2
survival motor neuron 2
SUSAR
suspected unexpected serious adverse reaction
Tmax
time to reach maximum observed concentration
US
United States
WHO
World Health Organization


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3.
SYNOPSIS
This is a brief summary.  For details, refer to the body of the protocol.
Protocol Number:
232SM202
Protocol Title:
A Phase 2, randomized, double-blind, sham-procedure controlled study 
to assess the safety and tolerability and explore the efficacy of 
ISIS 396443 (BIIB058) administered intrathecally in subjects with spinal 
muscular atrophy who are not eligible to participate in the clinical 
studies ISIS 396443-CS3B or ISIS 396443-CS4 
Version Number:
4 
Name of Study 
Treatment:
Nusinersen (also known as BIIB058 and ISIS 396443)
Note:  For the purposes of this protocol, when referring to “study drug,” 
Nusinersen will be used in place of ISIS 396443.  When referring to the 
protocol title or previous (“index”) studies, ISIS 396443 will be used.  
The term “study treatment” refers to administration of Nusinersen or the 
sham procedure during the blinded portion of the study.
Study Indication:
Spinal muscular atrophy (SMA)
Phase of 
Development:
2
Study Rationale:
The rationale of Part 1 of the study is to assess the safety and tolerability 
and evaluate the utility of selected exploratory efficacy endpoints in 
subjects with SMA treated intrathecally with Nusinersen who are not 
eligible for the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4.
Based on emergent data from the Nusinersen clinical development 
program, the Sponsor may decide to terminate Part 1 early, and all 
subjects may be offered the opportunity to transition to Part 2 (the open-
label extension phase) prior to completion of all Part 1 evaluations.  The 
rationale of Part 2 of the study is to assess the long-term safety and 
tolerability of Nusinersen in subjects with SMA who participated in 
Part 1 and completed their End of Part 1 Evaluation assessments.
Study Objectives and 
Endpoints:
Part 1
Primary objective:
The primary objective of Part 1 of this study is: 

To assess the safety and tolerability of Nusinersen in subjects 


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with SMA who are not eligible to participate in the clinical 
studies ISIS 396443-CS3B or ISIS 396443-CS4.
The primary endpoints that relate to this objective are:

Incidence of adverse events (AEs) and serious AEs (SAEs)

Change from baseline in clinical laboratory parameters, 
electrocardiograms (ECGs), and vital signs

Change from baseline in neurological examination outcomes
Secondary objective:
The secondary objective and endpoint of Part 1 of this study are as 
follows:

To examine the pharmacokinetics (PK) of Nusinersen in 
subjects with SMA who are not eligible to participate in the 
clinical studies ISIS 396443-CS3B or ISIS 396443-CS4

Nusinersen concentrations in plasma and cerebrospinal fluid 
(CSF)
Part 2
Primary objective:
The primary objective of Part 2 of this study is:

To assess the long-term safety and tolerability of Nusinersen 
in subjects with SMA who participated in Part 1 and 
completed their End of Part 1 Evaluation assessments.
The primary endpoints that relate to this objective are:

Incidence of AEs and SAEs

Change from baseline in clinical laboratory parameters, 
ECGs, vital signs, and growth parameters

Change from baseline in neurological examination outcomes

Coagulation parameters (activated partial thromboplastin 
time, partial thromboplastin time, and international 
normalized ratio) and urine total protein
Secondary objective:
The secondary objective and endpoint of Part 2 of this study are as 
follows:

To examine the PK of Nusinersen in subjects with SMA who 
participated in Part 1 and completed their End of Part 1 
Evaluation assessments


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
Nusinersen concentrations in plasma and CSF
Exploratory objectives and endpoints are listed in Section 6.3.
Study Design:
This is a Phase 2 multicenter study conducted in 2 parts:
Part 1 was originally designed as a randomized, double-blind, 
sham-procedure controlled study to assess the safety and tolerability and 
explore the efficacy of intrathecally administered Nusinersen over a 
period of approximately 14 months (from the first dose until the End of 
Part 1 Evaluation).  Up to 21 subjects will be randomized in a ratio of 
2:1 to receive Nusinersen by intrathecal lumbar puncture (LP) injection 
or a sham-procedure control.  Randomization will be stratified based on 
age at onset of clinical signs and symptoms consistent with SMA:  
>6 months versus <6 months.
After informed consent is obtained, subjects will undergo a screening 
evaluation no greater than 28 days prior to administration of the first 
dose of study treatment.  Subjects who meet the eligibility criteria will be 
randomized to receive Nusinersen or sham procedure.  Subjects will be 
admitted to the study site on Part 1 Day 1, undergo predose evaluations, 
and then receive an LP injection of study treatment or sham procedure.  
Subjects will return to the study site on Days 15, 29, 64, 183, and 302 for 
follow-up evaluations and subsequent injections or sham procedures.  
For subjects receiving Nusinersen or sham procedure, a CSF sample will
be taken predose on each injection day in a manner that maintains the 
blind.
After the study treatment dosing or sham procedure on Day 1, subjects 
will remain at the study site for at least 24 hours for safety monitoring.  
Following all subsequent injections, all subjects will remain at the study 
site for at least 6 hours postdose for safety monitoring. 
Safety monitoring will occur on the day following each injection of 
study treatment or sham procedure.  Subjects receiving the dosing or 
sham procedure on Days 15, 29, 64, 183, and 302 will be monitored by 
telephone contact on Days 16, 30, 65, 184, and 303.
In addition, subjects will also be monitored through telephone contact 
throughout the duration of the study.
An End of Part 1 Evaluation will occur up to 4 months after the last dose 
of Nusinersen or sham procedure, or sooner (if the Sponsor decides to 
terminate Part 1 early based on emergent data from the Nusinersen 
clinical development program, as described below).  Subjects who 
terminate early from Part 1 of the study will be encouraged to complete 
the End of Part 1 Evaluation assessments at the time of withdrawal.
After completing End of Part 1 Evaluation assessments according to the 
study schedule or sooner, if emergent data from the Nusinersen clinical 


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development program necessitate the early termination of Part 1 by the 
Sponsor, all eligible subjects may elect to enroll in Part 2.  All subjects 
enrolled in the study at the time that the Sponsor terminates Part 1 will 
be considered Part 1 completers.  The next study evaluation for those 
subjects will serve as an End of Part 1 Evaluation, which may occur at 
any time prior to the next scheduled Part 1 study evaluation. 
Based on emergent data from the Nusinersen clinical development 
program, the Sponsor may decide to terminate Part 1 early, and all 
subjects may then be offered the opportunity to be unblinded and 
transition to Part 2 prior to completion of all Part 1 evaluations.  Part 2 is 
an open-label extension (OLE) phase that will assess long-term safety 
and tolerability and explore the efficacy of intrathecally administered 
Nusinersen for approximately 24 additional months.
Part 2 study procedures will be determined based on the treatment 
assignment in Part 1.
Subjects who were randomized to receive Nusinersen in Part 1
End of Part 1 Evaluation assessments will be used to determine subject 
eligibility for Part 2 of the study.  For subjects who were receiving 
Nusinersen in Part 1, Part 2 Day 1 will occur following the End of Part 1 
Evaluation or approximately 4 months following the last injection of 
Nusinersen in Part 1.  On Part 2 Day 1, subjects will undergo predose 
evaluations according to the schedule of events and then receive their 
first dose of Nusinersen for Part 2 (next maintenance dose).  Subjects 
will return to the study site on Days 120, 239, 358, 477, 596, and 715 for 
follow-up evaluations and subsequent maintenance dose injections.  All 
subjects will remain at the study site for at least 1 hour postdose for 
safety monitoring and can be discharged at the discretion of the site 
Investigator and in compliance with the institutional requirements once 
the subjects have adequately recovered from the dosing procedure. 
Safety monitoring by telephone contact will occur on the day after 
injection of study treatment.  Subjects will be monitored by telephone 
contact on Days 2, 121, 240, 359, 478, 597, and 716.
In addition, subjects will be monitored through telephone contact 
throughout the duration of the study.
A Part 2 Final Follow-up Evaluation will occur approximately 4 months 
after the last dose in Part 2.  Subjects who terminate early from Part 2 of 
the study will be encouraged to complete the Part 2 Early Termination 
Evaluation assessments at the time of withdrawal. 
Subjects who were randomized to receive sham procedure in Part 1
End of Part 1 Evaluation assessments will be used to determine 
eligibility for Part 2 of the study.  For subjects who were receiving sham 


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procedure in Part 1, Part 2 Day 1 will occur following the End of Part 1 
Evaluation or as soon as possible following the End of Part 1 Evaluation, 
in the event of early termination due to emergent data from the 
Nusinersen clinical development program.  On Part 2 Day 1, subjects 
will undergo predose evaluations according to the schedule of events and 
then receive their first dose of Nusinersen (first loading dose).  Subjects 
will return to the study site on Days 15, 29, 64, 183, 302, 421, 540, 659, 
and 778 for follow-up evaluations and subsequent injections.  Subjects 
will remain at the study site for at least 24 hours on Day 1.  Following all 
subsequent injections, all subjects will remain at the study site for at least 
1 hour postdose for safety monitoring and can be discharged at the 
discretion of the site Investigator and in compliance with the institutional 
requirements once the subjects have adequately recovered from the 
dosing procedure. 
Safety monitoring by telephone contact will occur on the day after 
injection of study treatment after Day 1.  Subjects will be monitored by 
telephone contact on Days 16, 30, 65, 184, 303, 422, 541, 660, and 779.
In addition, subjects will be monitored through telephone contact 
throughout the duration of the study.
A Part 2 Final Follow-up Evaluation will occur approximately 4 months 
after the last dose in Part 2.  Subjects who terminate early from Part 2 
will be encouraged to complete the Part 2 Early Termination Evaluation 
assessments at the time of withdrawal.


Rationale for Dose 
and Schedule 
Selection:
In Part 1, a scaled equivalent dose of 12 mg Nusinersen will be 
administered at each of the 6 doses (i.e., on Study Days 1, 15, 29, 64, 
183, and 302) over a dosing period of approximately 10 months to 
subjects randomized to receive active treatment.
In Part 2, a scaled equivalent dose of 12 mg Nusinersen will be 
administered at each dose over a dosing period of approximately 
24 months.
The volume of the injection will be adjusted based on the subject’s age 
on the day of dosing as shown in Table 1, such that each subject will 
receive a 12-mg scaled equivalent dose based on CSF volume scaling.  
Thus, younger subjects will be given a lower absolute mg dose of study 
treatment, achieved by injecting a smaller volume that is proportional to 
estimated CSF volume for age, such that dose volume will be equivalent 
to 5 mL for 2 years of age to adult.
The dose regimen and the dose interval for this study were selected 
based on nonclinical toxicology and PK observations from monkey 
studies using single-dose and repeat-dose intrathecal administration, 
consideration of the target tissue concentration anticipated for drug 
pharmacology, and safety data in the completed and ongoing clinical 
studies of Nusinersen to date.  Based on pharmacology and PK results in 
SMA transgenic mice, it is estimated that a target spinal cord tissue 
concentration between 1 and 10 μg/g will produce 50% to 90% SMN2 
exon 7 inclusion.  Nonclinical studies in juvenile monkeys receiving 
intrathecal doses of Nusinersen showed a resulting gradient of 
distribution of Nusinersen along the spinal cord, with mean lumbar 
spinal cord concentrations ranging from 1.6- to 2.3-fold and 2.0- to 
3.5-fold higher than thoracic and cervical spinal cord levels, 
respectively.  The dose selected for this multiple-dose clinical study 
(equivalent to 12 mg of Nusinersen) is predicted to achieve levels at the 
high end of this range (approximately 10 μg/g lumbar and 3 μg/g 
cervical spinal cord tissue concentrations) after the first dose.  The 
loading dose interval (i.e., doses on Days 1, 15, 29, and 64) was selected 
based on the nonclinical PK and pharmacology data in order to achieve 
and maintain Nusinersen spinal cord tissue levels that are predicted to be 
above or within the upper end of the pharmacologically active range by 
Day 64 (approximately 30 μg/g lumbar and 10 μg/g cervical tissue 
concentration), while at the same time considering subject safety and 
convenience for repeated intrathecal injections by LP.  The higher 
number of loading doses would allow for the evaluation of safety and 
tolerability and preliminary exploratory efficacy endpoints in a broader 
population of subjects with SMA, including those who have onset of 
clinical signs and symptoms at >6 months of age but who were not 


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eligible for Study ISIS 396443-CS4.  The maintenance dose interval 
(once every 4 months) was selected based on the estimated spinal tissue 
and CSF drug half-life (4 to 6 months) and was selected to maintain 
spinal cord tissue levels of Nusinersen at a steady-state level within the 
estimated pharmacologically active range.  In Part 1, maintenance doses 
will be given on Day 183 and Day 302, for a total of 6 doses over 
approximately 10 months.  Subjects who were receiving Nusinersen in 
Part 1 will continue receiving maintenance doses in Part 2 every 4 
months.  Subjects who were receiving sham in Part 1 will receive 
maintenance doses starting on Day 183 of Part 2.
Table 1
Nusinersen Dose Volume To Be Injected
Age
Estimated 
CSF Volume 
(mL)
Injection 
Volume (mL)
Dose (mg)
0-3 months 
(0-90 days)
120
4
9.6
3-6 months 
(91-182 days)
130
4.3
10.3
6-12 months 
(183-365 days)
135
4.5
10.8
12-24 months 
(366-730 days)
140
4.7
11.3
>24 months
(>730 days)
150
5.0
12.0
Source:  [Matsuzawa 2001]
CSF = cerebrospinal fluid.
Study Location:
Global, multicenter
Number of Planned 
Subjects:
In Part 1, up to 21 subjects are planned (14 Nusinersen; 7 sham 
procedure).
In Part 2, up to 21 subjects are planned (21 Nusinersen).
Study Population:
Part 1 of this study will be conducted in subjects who have clinical signs 
and symptoms of SMA at ≤6 months of age or at >6 months of age and 
who are not eligible for the clinical studies ISIS 396443-CS3B or 
ISIS 396443-CS4. 
Part 2 will include only subjects who participated in Part 1 and 
completed their End of Part 1 Evaluation assessments.  Subjects 
enrolling in Part 2 must meet the Part 2-specific criteria.
Detailed eligibility criteria are described in Section 8.


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Treatment Groups:
In Part 1, subjects will receive either Nusinersen intrathecally or 
sham-procedure control in a 2:1 ratio.  Randomization will be balanced 
for the stratification factor (age of symptom onset >6 months versus 
<6 months).  A single dose level of 12 mg Nusinersen will be scaled by 
age at the time of dosing for each subject.
In Part 2, all subjects will receive open-label Nusinersen.  A single dose 
level of 12 mg Nusinersen will be scaled by age at the time of dosing for 
each subject.
Duration of 
Treatment and 
Follow-up:
For subjects who meet the eligibility criteria and enroll in Part 1 of the 
study, the duration of Part 1 will be approximately 15 months (450 days) 
and will include a Screening Period of no greater than 28 days, a 
302-day Treatment Period, and an End of Part 1 Evaluation 
approximately 4 months after the last dose.  Based on emergent data 
from the Nusinersen clinical development program, the Sponsor may 
decide to terminate Part 1 early, and all subjects may be offered the 
opportunity to transition to Part 2 prior to completion of all Part 1 
evaluations.
For subjects who meet the eligibility criteria and enroll in Part 2 of the 
study, the duration of Part 2 will be approximately 28 months and will 
include an open-label Treatment Period of approximately 24 months and 
a Part 2 Final Follow-up Evaluation approximately 4 months after the 
last dose of study treatment.
Total study duration for subjects who participate in both Part 1 and 
Part 2 will be approximately 43 months.
Criteria for 
Evaluation:
The criteria for evaluation for Part 1 and Part 2 include:
Safety:

Neurological examinations (assessment of mental status, level of 
consciousness, sensory motor function, cranial nerve function, 
and reflexes) 

AEs, including SAEs

Vital signs (resting systolic and diastolic blood pressure, pulse 
rate, respiratory rate, temperature, pulse oximetry, and 
transcutaneous carbon dioxide)

Growth parameters

Physical examinations

Medical history

12-Lead ECGs


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
Use of concomitant medications

Clinical laboratory tests (blood chemistry, hematology, 
urinalysis, urine total protein, and coagulation parameters)
Pharmacokinetics:

Plasma Nusinersen concentrations

CSF Nusinersen concentrations
Efficacy:

Ventilator use 

World Health Organization motor milestones and Hammersmith 
Infant Neurological Examination (HINE, Section 2)

Growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for 
length, and head to chest circumference ratio)

Clinical Global Impression of Change (physician and caregiver 
assessment) and Assessment of Caregiver Experience With 
Neuromuscular Disease
Immunogenicity:

Anti-Nusinersen plasma antibody concentrations


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Statistical Methods:
Analysis Population
The intent-to-treat population is defined as all subjects who are 
randomized and receive at least 1 dose of study treatment or sham 
procedure in Part 1.
The safety population will include all subjects who are randomized and 
receive at least 1 dose of study treatment or sham procedure in Part 1. 
The PK population will include all subjects who are randomized and 
have at least 1 evaluable postdose or postsham-procedure PK sample. 
Part 1
Safety Analysis
The analysis of safety will be performed on the safety population.  The 
incidence of treatment-emergent AEs and SAEs will be tabulated.  
Changes from baseline in clinical laboratory parameters, vital signs, and 
ECG parameters will be summarized.  Incidence of clinically relevant 
changes from baseline in vital signs and ECGs will be summarized.  
Laboratory parameters will also be summarized using shift tables, as 
appropriate.
PK Analysis
Summary statistics for plasma and CSF concentrations of Nusinersen 
will be provided.  
Exploratory Analysis
For continuous endpoints, the mean change from baseline will be 
estimated with 95% confidence limits.  For categorical outcomes, the 
proportion of subjects attaining a specified category will be estimated.  
Selected endpoints may be pooled across subsets as appropriate. 
Part 2
No formal statistical analyses will be performed.  Descriptive statistics 
will be presented for safety and efficacy data collected.
Interim Analysis: 
No formal interim analyses are planned.  However, if the Sponsor 
decides to terminate Part 1 early, data prior to the unblinding of the first 
subject in Part 1 may be archived; no analyses are planned to be
conducted based on the archived data.  Full analysis of Part 1 data will 
be done following database lock at the end of Part 1. 
Sample Size 
Determination:
Since this study is exploratory, sample size determination will not be 
based on power consideration.  The sample size considered for this study 
will allow exploration of safety, tolerability, and selected efficacy 
endpoints in the selected study population.


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Study Stopping 
Rules:
The Sponsor may terminate this study at any time, after informing 
Investigators.  Investigators will be notified by the Sponsor if the study is 
placed on hold, completed, or closed.




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4.2.
Schedule of Events
4.2.1.
Schedule of Events:  Part 1
Table 2:
Part 1 Schedule of Activities 
Study Period
Screen1
Part 1 Treatment/Follow-Up
Study Day
Days -28
to -1
Day 1
Day 22
Day 15 (±1 day)
Day 
162
Day 29 (±1 day)
Day 
302
Days 64, 183, 302 
(±7 days)
Days 
65, 
184, 
3032
End of 
Part 13,4,5
Predose LP Postdose
Predose LP Postdose
Predose LP Postdose
Predose LP Postdose
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
X
Medical History
X
Vital Signs6
X
X
4X7
X8
X
X
X
4X7
X
4X7
X
Weight
X
X
X
X
X
X
X
Growth Parameters9
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
Ventilator Use
X
X
X
X
X
X
X
X
X
X
Neurological 
Examination10
X
X
X11
X
X
X11
X
X11
X
X11
X
ECG 
X
X
X
X
Safety Laboratory 
Tests12
X
X13
X14
Coagulation 
Laboratory Tests
X
Immunogenicity 
Sample
X
X
X
CSF PK15
X
X
X
X
Plasma PK
X16
X17
X
Study Treatment 
Injection or Sham 
X
X
X
X


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Study Period
Screen1
Part 1 Treatment/Follow-Up
Study Day
Days -28
to -1
Day 1
Day 22
Day 15 (±1 day)
Day 
162
Day 29 (±1 day)
Day 
302
Days 64, 183, 302 
(±7 days)
Days 
65, 
184, 
3032
End of 
Part 13,4,5
Predose LP Postdose
Predose LP Postdose
Predose LP Postdose
Predose LP Postdose
Procedure
Inpatient Stay18
X
Telephone Contact for 
Safety Monitoring2
X
X
X
HINE Motor 
Milestone
X
X
X
Clinical Global 
Impression of Change
X
X
Con Med Recording19
X ----------------------------------------------------------------------------------------------------------------------- X
Adverse Event 
Collection20
X ----------------------------------------------------------------------------------------------------------------------- X
AE = adverse event; Bi-PAP = bilevel positive airway pressure; Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; 
HINE = Hammersmith Infant Neurological Examination; LP = lumbar puncture; PK = pharmacokinetic(s); SAE = serious adverse event; SMA = spinal 
muscular atrophy; SMN2 = survival motor neuron 2
1 A blood sample will be collected at Screening for SMN2 copy number only from those subjects without genetic documentation of SMN2 copy number.  For all 
other subjects, a blood sample will be collected at any time during the study for analysis of SMN2 copy number by the central laboratory.
2 After the injection of study treatment or sham procedure on Day 1, subjects will remain at the study site for at least 24 hours (Day 2) for safety monitoring.  On 
the day following the injection of study treatment or sham procedure on Days 15, 29, 64, 183, and 302, there will be safety monitoring through telephone 
contact.  During that telephone contact (i.e., Days 16, 30, 65, 184 and 303), changes in concomitant medications and AEs, information on the subject’s daily 
ventilator/Bi-PAP use, and health status will be recorded.  
3 End of Part 1 is one of the following:  Part 1 Final Follow-up Evaluation (Day 422 [±7 days]) according to the study schedule, early Part 1 Final Follow-up 
Evaluation to allow for rollover into Part 2, or Early Termination Evaluation for subjects who withdraw from the study during Part 1.
4 For subjects not transitioning into Part 2, the date of the End of Part 1 Evaluation assessments will be the end of study.  For subjects who transition to Part 2, 
the date of the End of Part 1 will be the date of first dose in Part 2.
5 At the End of Part 1 evaluation, in order to allow transition to Part 2, subjects will be unblinded. 
6 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each evaluation.  For subjects who are not receiving noninvasive ventilation, 
pulse oximetry will be measured overnight once a week at home.  
7 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected at 4 timepoints:  1, 2, 4, 
and 6 hours (all ±15 minutes) after the injection of study treatment.
8 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected within 20 to 24 hours 
after the injection of study treatment or sham procedure.


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9 At the evaluations scheduled for injection of study treatment or sham procedure, subjects will be assessed for the following growth parameters:  body length, 
head circumference, chest circumference, and arm circumference.  
10Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes.
11Neurological examinations will occur between 4 to 6 hours after the injection of study treatment or sham procedure.
12Blood chemistry, hematology, and urinalysis panels. 
13Samples for safety laboratory tests will be collected before the injection of study treatment or sham procedure on Days 64 and 183 only. 
14End of Part 1 safety laboratory tests may be performed locally in addition to centrally to accommodate the Part 2 Day 1 dosing.
15Refer to Table 5 for CSF PK sample schedule.  The CSF samples will be analyzed for Nusinersen concentrations.  The remaining CSF sample will be stored for 
optional future biomarker analyses.  
16Blood samples for PK assessment will be collected 4 hours (±1 hour) after the injection of study treatment or sham procedure only on Day 1.  Refer to Table 5
for the plasma PK sample schedule.
17Blood samples for PK assessment will be collected before the injection of study treatment or sham procedure on Days 64 and 183 only.  Refer to Table 5 for the 
plasma PK sample schedule.
18Overnight stay (at least 24 hours) is required after the first injection of study treatment or sham procedure.  Following all subsequent injections or sham 
procedures, a stay of at least 6 hours at the study site is required; overnight stays are optional on these days.
19In addition to concomitant medications, ancillary procedures will be recorded.
20AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2.


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4.2.2.
Schedule of Events:  Part 2
Table 3:
Part 2 Schedule of Activities for Subjects Randomized to Receive Nusinersen in Part 1 
Study Period
Part 2 Treatment/Follow-Up
Study Day
Day 1
Day 21
Days 120, 239, 358, 477, 596, 715 (±7 days)2
Days 121, 240, 
359, 478, 597, 
7161
Part 2 Final Follow-Up
(Day 835 [±7 days])3or Part 2 
Early Termination4
Predose5
LP
Postdose
Predose
LP
Postdose
Informed Consent
X5
Inclusion/ Exclusion 
Criteria
X5
Vital Signs6
X7
X8
X
X8
X
Weight
X7
X
X
Growth Parameters9
X7
X
X
Physical Examination
X7
X
X
Ventilator Use
X7
X
X
X
X
Neurological 
Examination10
X7,11
X11
X11
X11
X
ECG
X7
X12
X12
Safety Laboratory 
Tests13
X7
X14
X
Immunogenicity 
Sample 
X7
X15
X
CSF PK16
X5, 7
X
Plasma PK17
X17
X17
X
Study Treatment 
Injection 
X
X
Telephone Contact for 
Safety Monitoring 
(+3 Days)
X
X
HINE and WHO 
Motor Milestone
X
X
Clinical Global 
Impression of Change 
X
X


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Study Period
Part 2 Treatment/Follow-Up
Study Day
Day 1
Day 21
Days 120, 239, 358, 477, 596, 715 (±7 days)2
Days 121, 240, 
359, 478, 597, 
7161
Part 2 Final Follow-Up
(Day 835 [±7 days])3or Part 2 
Early Termination4
Predose5
LP
Postdose
Predose
LP
Postdose
and ACEND
Optional Sibling 
SMA Data 
Collection18
X
X
Con Med Recording19
X---------------------------------------------------------------------------------------------------------------------------------X
Adverse Event 
Collection20
X---------------------------------------------------------------------------------------------------------------------------------X
ACEND = Assessment of Caregiver Experience with Neuromuscular Disease; AE = adverse event; Bi-PAP = bilevel positive airway pressure; 
Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; HINE = Hammersmith Infant Neurological Examination; 
LP = lumbar puncture; PK = pharmacokinetic(s); SAE = serious adverse event; WHO = World Health Organization.
1 There will be safety monitoring through telephone contact on the day following the injection of study treatment (i.e., Days 2, 121, 240, 359, 478, 597, and 716).  
During that telephone contact, changes in concomitant medications and AEs, information on the subject’s daily ventilator/Bi-PAP use, and health status will be 
recorded.
2 If the study continues beyond Year 2 (i.e., beyond Day 715), then from Day 835 onwards, subjects will maintain evaluations for study treatment injection every 
4 months with the assessments for those additional timepoints to alternate between the assessments done on Day 120 and those done on Day 239.  Day 120 
assessments would be performed at Day 835 and Day 239 assessments would be performed at Day 954.  The alternating pattern would continue until the end of 
the study.  Part 2 Final Follow-up Evaluation would then occur approximately 4 months after the last injection of study treatment.
3 The Part 2 Final Follow-up Evaluation will occur 4 months after the last injection of study treatment, which will either be on Day 716 or later, if Part 2 of the 
study continues beyond Year 2. 
4 Subjects who terminate early will be encouraged to complete the safety evaluations scheduled for the Part 2 Early Termination Evaluation.
5 Inclusion/Exclusion Criteria, Informed Consent, and CSF PK must be performed on Part 2 Day 1.
6 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each evaluation.
7 If Part 2 Day 1 study treatment injection is delayed more than 24 hours after the End of Part 1 visit, the following procedures must be done on Part 2 Day 1 
predose:  vital signs, weight, growth parameters, physical examination, ventilator use, neurological examination, and CSF PK.  If Part 2 Day 1 study treatment 
injection is delayed more than 24 hours after End of Part 1 due to an AE, SAE, or other safety concern, or if Part 2 Day 1 study treatment injection is delayed 
more than 30 days after End of Part 1 for any reason, the following procedures must be done on Part 2 Day 1 predose:  vital signs, weight, growth parameters, 
physical examination, ventilator use, neurological examination, ECG, CSF PK, and safety laboratory tests.  Immunogenicity testing must also be repeated 
predose if Part 2 Day 1 study treatment injection is delayed more than 30 days after End of Part 1 for any reason. 
8 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected 1 hour (±15 minutes) 
after the injection of study treatment.  
9 At the evaluations scheduled for injection of study treatment, subjects will be assessed for the following growth parameters:  body length, head circumference, 
chest circumference, and arm circumference.  Growth parameters and weight are to be collected at the same time.
10Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes.  
If sedation was used, please allow sufficient recovery time for the subject to be fully engaged in the examination because it is important that the data collected 
truly reflect the subject’s neurological performance.


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11Predose and postdose.
12ECG will be performed on Days 239, 477, and 715, and at the Part 2 Final Follow-up Evaluation.  ECG must be performed before obtaining blood samples for 
safety laboratory tests.
13Blood chemistry, hematology, urinalysis, urine total protein panels, and coagulation parameters.  Urine total protein and coagulation parameters will be 
assessed by local laboratories.
14Samples for safety laboratory tests will be collected before the injection of study treatment at each dosing visit. 
15Blood samples for immunogenicity testing will be collected before the injection of study treatment on Days 239, 477, and 715.
16Refer to Table 6 for CSF PK sample schedule.  The CSF samples will be analyzed for Nusinersen concentrations.  The remaining CSF sample will be stored for 
optional future biomarker analyses.
17Blood samples for PK assessment will be collected 4 hours (±1 hour) after the injection of study treatment only on Day 1.  Refer to Table 6 for the plasma PK 
sample schedule.  Plasma PK samples will be collected predose on Days 239, 477, and 715.
18The optional assessment of sibling SMA data collection will be performed only after obtaining consent.
19In addition to concomitant medications, ancillary procedures will be recorded.
20AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2.


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Table 4:
Part 2 Schedule of Activities for Subjects Randomized to Receive Sham Procedure in Part 1
Study Period
Part 2 Treatment/Follow-Up
Study Day
Day 1
Day 
21
Day 15 (±1 day)
Day 
161
Day 29 (±1 day)
Day 
301
Days 64, 183, 302, 
421, 540, 659, 778 
(±7 days)2
Days 
65, 184, 
303, 
422, 
541, 
660, 
7791
Part 2 Final 
Follow-Up
(Day 897 
[±7 days])3 or
Part 2 Early 
Termination4
Predos
e5
LP Postdose
Predose
LP
Postdose
Predose LP Postdose
Predose LP Postdose
Informed Consent
X5
Inclusion/Exclusion 
Criteria
X5
Vital Signs6
X7
X8
X9
X
X8
X
X8
X
X8
X
Weight
X7
X
X
X
X
X
Growth 
Parameters10
X7
X
X
X
X
Physical 
Examination
X7
X
X
X
X
Ventilator Use
X7
X
X
X
X
X
X
X
X
Neurological 
Examination11
X7
X12
X
X
X12
X
X12
X
X12
X
ECG
X7
X
X
X13
X13
Safety Laboratory 
Tests14
X7
X
X
X15
X
Immunogenicity 
Sample
X7
X16
X
CSF PK17
X5, 7
X
X
X
Plasma PK18
X18
X18
X
Study Treatment 
Injection 
X
X
X
X
Inpatient Stay19
X
Telephone Contact 
for Safety 
Monitoring 
X
X
X


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Study Period
Part 2 Treatment/Follow-Up
Study Day
Day 1
Day 
21
Day 15 (±1 day)
Day 
161
Day 29 (±1 day)
Day 
301
Days 64, 183, 302, 
421, 540, 659, 778 
(±7 days)2
Days 
65, 184, 
303, 
422, 
541, 
660, 
7791
Part 2 Final 
Follow-Up
(Day 897 
[±7 days])3 or
Part 2 Early 
Termination4
Predos
e5
LP Postdose
Predose
LP
Postdose
Predose LP Postdose
Predose LP Postdose
(+3 Days)
HINE and WHO 
Motor Milestone
X
X
Clinical Global 
Impression of 
Change and 
ACEND
X
X
Optional Sibling 
SMA Data 
Collection20
X
X
Con Med 
Recording21
X-------------------------------------------------------------------------------------------------------------------X
Adverse Event 
Collection22
X-------------------------------------------------------------------------------------------------------------------X
ACEND = Assessment of Caregiver Experience with Neuromuscular Disease; AE = adverse event; Bi-PAP = bilevel positive airway pressure; 
Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; HINE = Hammersmith Infant Neurological Examination; 
LP = lumbar puncture; PK = pharmacokinetic(s); SAE = serious adverse event; WHO = World Health Organization.
1 After the injection of study treatment on Day 1, subjects will remain at the study site for at least 24 hours (Day 2) for safety monitoring.  There will be safety 
monitoring through telephone contact on the day following the injection of study treatment (i.e., Days 16, 30, 65, 184, 303, 422, 541, 660, and 779).  During 
that telephone contact, changes in concomitant medications and AEs, information on the subject’s daily ventilator/Bi-PAP use, and health status will be 
recorded.
2 If the study continues beyond Year 2 (i.e., beyond Day 778), then from Day 897 onwards, subjects will maintain evaluations for study treatment injection every 
4 months with the schedule of events for those additional timepoints to alternate between the assessments done on Day 183 and those done on Day 302.  Day 
302 assessments would be performed at Day 897 and Day 183 assessments would be performed at Day 1016.  That pattern would continue until the end of the 
study.  Part 2 Final Follow-up Evaluation would then occur approximately 4 months after the last injection of study treatment.
3 The Part 2 Final Follow-up Evaluation will occur 4 months after the last injection of study treatment, which will either be on Day 778 or later, if Part 2 of the 
study continues beyond Year 2.
4 Subjects who terminate early will be encouraged to complete the safety evaluations scheduled for the Part 2 Early Termination Evaluation.
5 Inclusion/Exclusion Criteria, Informed Consent, and CSF PK must be performed on Part 2 Day 1 predose.
6 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each evaluation.


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7 If Part 2 Day 1 study treatment injection is delayed more than 24 hours after the End of Part 1 visit, the following procedures must be done on Part 2 Day 1 
predose:  vital signs, weight, growth parameters, physical examination, ventilator use, neurological examination, and CSF PK.  If Part 2 Day 1 study treatment 
injection is delayed more than 24 hours after End of Part 1 due to an AE, SAE, or other safety concern, or if Part 2 Day 1 study treatment injection is delayed 
more than 30 days after End of Part 1 for any reason, the following procedures must be done on Part 2 Day 1 predose:  vital signs, weight, growth parameters, 
physical examination, ventilator use, neurological examination, ECG, CSF PK, and safety laboratory tests.  Immunogenicity testing must also be repeated if 
Part 2 Day 1 study treatment injection is delayed more than 30 days after End of Part 1 for any reason.
8 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected at 4 timepoints:  1, 2, 4, 
and 6 hours (all ±15 minutes) after the injection of study treatment only on Part 2 Day 1.  On subsequent study days, vital signs will be collected 1 hour after 
the injection of study treatment.
9 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected on Day 2 within 20 to 
24 hours after the injection of study treatment only.
10At the evaluations scheduled for injection of study treatment, subjects will be assessed for the following growth parameters:  body length, head circumference, 
chest circumference, and arm circumference.  Growth parameters and weight are to be collected at the same time.
11Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes.  
If sedation was used, please allow sufficient recovery time for the subject to be fully engaged in the examination because it is important that the data collected 
truly reflect the subject’s neurological performance.
12Predose and postdose.
13ECG will be performed at Days 64, 183, 540, and 778, and at the Part 2 Final Follow-up Evaluation.  ECG must be performed before obtaining blood samples 
for safety laboratory tests.
14Blood chemistry, hematology, urinalysis, urine total protein panels, and coagulation parameters.  Urine total protein and coagulation parameters will be 
assessed by local laboratories.
15Samples for safety laboratory tests will be collected before the injection of study treatment at each dosing visit.
16Blood samples for immunogenicity testing will be collected before the injection of study treatment on Days 64, 183, 302, 421, 540, 659, and 778.
17Refer to Table 7 for CSF PK sample schedule.  The CSF samples will be analyzed for Nusinersen concentrations.  The remaining CSF sample will be stored for 
optional future biomarker analyses.
18Blood samples for PK assessment will be collected 4 hours (±1 hour) after the injection of study treatment only on Day 1.  Refer to Table 7 for the plasma PK 
sample schedule.  Plasma PK samples will be collected predose on Days 64, 183, 540, and 778.
19Overnight stay (at least 24 hours) is required after the first injection of study treatment.  Following all subsequent injections, a stay of at least 1 hour at the study 
site is required; overnight stays are optional on these days.
20The optional assessment of sibling SMA data collection will be performed only after obtaining consent.
21In addition to concomitant medications, ancillary procedures will be recorded.
22AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2.


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Table 5
Part 1 Pharmacokinetic Sampling Schedule1
Treatment Period
Part 1 Study Day
Timepoints
Blood
Collection
(mL)
CSF Collection
(mL)2
Multiple Dose:
LP Injection 
Day 1
Predose
NA
0.5
4 h (±1 h) postdose 
0.5
NA
Day 15
Predose
NA
0.5
Day 29
Predose
NA
0.5
Day 64
Predose
0.5
0.5
Day 183
Predose
0.5
0.5
Day 302
Predose
NA
0.5
End of Part 1
NA
0.5
NA
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy.
1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual.
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of Nusinersen with plasma and CSF constituents.
Table 6
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive Nusinersen in Part 11
Treatment Period
Part 2 Study Day
Timepoints
Blood
Collection
(mL)
CSF Collection
(mL)2
Multiple Dose:
LP Injection 
Day 1
Predose
NA
0.5
4 h (±1 h) postdose 
0.5
NA
Day 120
Predose
NA
0.5
Day 239
Predose
0.5
0.5
Day 358
Predose
NA
0.5
Day 477
Predose
0.5
0.5
Day 596
Predose
NA
0.5
Day 715
Predose
0.5
0.5
Part 2 Final 
Follow-Up
NA
0.5
NA
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy.


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1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual.
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of Nusinersen with plasma and CSF constituents.
Table 7
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive Sham Procedure in Part 11
Treatment Period
Part 2 Study Day
Timepoints
Blood
Collection
(mL)
CSF Collection
(mL)2
Multiple Dose:
LP Injection 
Day 1
Predose
NA
0.5
4 h (±1 h) postdose 
0.5
NA
Day 15
Predose
NA
0.5
Day 29
Predose
NA
0.5
Day 64
Predose
0.5
0.5
Day 183
Predose
0.5
0.5
Day 302
Predose
NA
0.5
Day 421
Predose
NA
0.5
Day 540
Predose
0.5
0.5
Day 659
Predose
NA
0.5
Day 778
Predose
0.5
0.5
Part 2 Final 
Follow-Up
NA
0.5
NA
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy.
1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual.
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of Nusinersen with plasma and CSF constituents.


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5.
INTRODUCTION 
Nusinersen (also known as ISIS 396443 or BIIB058) is a uniformly modified second generation, 
2′-O-(2-methoxyethyl) (2′-MOE), antisense oligonucleotide (ASO) drug in development for the 
treatment of spinal muscular atrophy (SMA) due to genetic defects in the survival motor 
neuron 1 (SMN1) gene.
Note:  For the purposes of this protocol, when referring to “study drug,” Nusinersen will be used 
in place of ISIS 396443.  When referring to the protocol title or previous (“index”) studies, 
ISIS 396443 will be used.  The term “study treatment” refers to administration of Nusinersen or 
the sham procedure during the blinded portion of the study.
ASOs are short synthetic strings of nucleotides designed to alter the expression of a targeted 
protein by selectively binding to the ribonucleic acid (RNA) that encodes the targeted protein.  In 
patients with SMA, the number of survival motor neuron 2 (SMN2) gene copies and the resulting 
amount of survival motor neuron (SMN) protein are correlated with disease onset and severity.  
A therapeutic approach predicted to benefit patients with SMA is to increase the levels of 
full-length SMN2 pre-messenger ribonucleic acid (mRNA) by restoring the splicing pattern that 
gives rise to full-length SMN2 mRNA, thus increasing full-length SMN protein levels and SMN 
protein activity.  Nusinersen is designed to bind to intron 7 of the SMN2 pre-mRNA, restoring 
the splicing pattern that gives rise to full-length SMN2 mRNA and thus increases full-length 
SMN protein levels (Figure 2).
Figure 2:
Antisense Oligonucleotide Therapeutic Approach for Treatment of Spinal 
Muscular Atrophy
ASO = antisense oligonucleotide; FL = full-length; mRNA = messenger ribonucleic acid; SMA = spinal muscular 
atrophy; SMN = survival motor neuron; SMN1 = survival motor neuron 1; SMN2 = survival motor neuron 2.


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5.1.
Overview of Spinal Muscular Atrophy
SMA is an autosomal recessive neuromuscular disease characterized by degeneration of the 
motor neurons in the anterior horn of the spinal cord, resulting in atrophy of the voluntary 
muscles of the limbs and trunk.  With an incidence of 1:6000 to 1:10,000 live births, SMA is the 
most common genetic cause of infant mortality, and a major cause of childhood morbidity due to 
weakness, in developed countries.  The natural history of SMA includes 4 major recognized 
phenotypes that are dependent on age of onset and achieved motor abilities.  The most severe 
form, Type I SMA, has a disease onset within the first few months of life; these children are 
never able to sit or walk and usually die from respiratory failure by the age of 2 years.  Patients 
with Type II SMA are able to sit but never walk unaided, with symptoms typically presenting 
between 6 and 18 months of age.  Patients with Type III SMA are able to sit and walk but may 
become severely and increasingly disabled.  Patients with Type IV or adult-onset SMA have an 
age of onset over 18 years and have normal life expectancies.
SMA is caused by loss of SMN protein due to a homozygous deletion or mutation or compound 
heterozygous mutation in the SMN1 gene on chromosome 5q11-q13. Humans have a duplication 
of the chromosome region where SMN1 is found, resulting in a second copy of the gene, SMN2.  
In SMN2, a C to T nucleotide substitution in exon 7 results in an alternative splicing event such 
that the majority of transcripts produced (~90%) lack exon 7, and a defective truncated protein is 
produced.  The remainder, SMN2 transcripts containing exon 7, produces a full-length protein 
product identical to the SMN1 protein, since the C to T substitution is silent.  Humans have a 
variable copy number of the SMN2 gene (0 to 8 copies) [Wirth 2006].  The number of SMN2
copies and the resulting amount of full-length SMN protein expressed in patients with SMA 
(10% to 40% of normal SMN protein levels) correlate with SMA disease severity; thus, SMN2 is 
a key modifier of disease phenotype [Coovert 1997; Feldkötter 2002; Lefebvre 1997; Prior 
2004].
5.2.
Current Therapies for Spinal Muscular Atrophy
The first approval of Nusinersen for commercial use occurred in the United States (US) in 
December 2016 for the treatment of SMA in pediatric and adult patients.  Nusinersen has since 
been approved in Europe.  Current medical care is supportive and focused on respiratory support, 
nutritional support, and management of resulting musculotendinous contractures and 
neuromuscular scoliosis through bracing, physical therapy, and surgery [Wang 2007].
5.3.
Profile of Previous Experience With Nusinersen
5.3.1.
Nonclinical Experience
Nusinersen was identified after an extensive screen of greater than 500 2′-MOE oligonucleotides 
in reporter gene assays, in vitro splicing assays, and SMA patient fibroblasts [Hua 2007; Hua 
2008].  Data have shown that Nusinersen promotes a concentration-dependent increase in 
full-length transcripts (including exon 7) in patient fibroblast cells, achieving >90% full-length 
SMN2 transcripts, and forms nuclear structures called gems, known to contain SMN protein [Liu 
and Dreyfuss 1996].  In a mild mouse model of SMA, Nusinersen promoted inclusion of exon 7 
in the SMN2 transgene in a variety of peripheral tissues when dosed systemically [Hua 2008]


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and in central nervous system (CNS) tissue, including the spinal cord, when injected into the 
lateral ventricle [Hua 2010].  Nusinersen produced >90% exon 7 inclusion in the transgenic mice 
and increased SMN protein production in motor neurons, resulting in the appearance of gems in 
motor neurons.  These studies were extended to a more severe mouse model of SMA (SMA Δ7) 
[Le 2005], where the CNS delivery of drug produced a dose-dependent effect on SMN2 exon 7 
inclusion, SMN protein production, and survival.  These mice treated with Nusinersen 
demonstrated improved weight gain; improvements in muscle morphology, muscle strength, and 
motor coordination; and improved morphology of the motor neuron junctions [Passini 2011].  
Furthermore, Nusinersen was shown to distribute widely in the CNS after intrathecal 
administration in monkeys [Passini 2011]. 
The pharmacokinetics (PK) and toxicity of Nusinersen were assessed in adult monkeys (single 
intrathecal lumbar bolus injections of 1 to 7 mg) and in juvenile monkeys (repeated intrathecal 
lumbar bolus injections of 0.3 to 3 mg/dose [4/14-week study] or 0.3 to 4 mg/dose [53-week 
study]).  In addition, a dedicated multiple-dose PK study in adult monkeys (3-week dosing 
period) was performed to assess the half-life of Nusinersen in cerebrospinal fluid (CSF), tissues, 
and plasma. 
In the single-dose study, following intrathecal dose administration, Nusinersen distributed from 
the CSF into the spinal cord, brain, and systemic circulation via CSF turnover.  Plasma 
concentrations of Nusinersen were relatively low compared to CSF concentrations.
In the multiple-dose PK study, concentrations of Nusinersen in both CSF and plasma exhibited 
multiphasic disposition following intrathecal administration.  The terminal elimination half-life 
of Nusinersen in CSF was 102 days.  CSF concentrations peaked 1 hour after intrathecal 
injection, while plasma concentrations peaked 4 hours after the intrathecal injection.  Animals 
were sacrificed at multiple times after intrathecal administration, and analysis demonstrated that 
Nusinersen was slowly cleared from CNS tissues with terminal elimination half-lives between 
various brain and spinal cord regions ranging from 74 to 275 days (median:  116 days). 
In the 14-week and 53-week repeat-dose studies, concentrations of Nusinersen in CSF, plasma, 
and tissue were consistent with the pattern established in the 4-week multiple dose PK study.  
CSF and plasma concentrations increased in a dose-dependent manner in both studies.  
Consistent with previous studies, the time to reach maximum observed concentration (Tmax) in 
the plasma occurred approximately 2 to 5 hours after intrathecal bolus administration.  Tissue 
concentrations were measured for CNS tissues, and consistent values were obtained between the 
14- and 53-week studies of intrathecally administered Nusinersen after adjusting for the 
difference in dosing regimens.
In both repeat-dose toxicology studies, dose-dependent increases in tissue concentrations of 
Nusinersen were seen in the brain, spinal cord, and liver.  In the 53-week study, during which 
Nusinersen was administered every 6 weeks, tissue concentrations were lower compared to the 
14-week study, as expected.  CNS tissues had half-lives of 117 to 195 days (median:  174 days), 
which is consistent with the range of elimination half-lives determined from the multiple-dose 
PK study.  To provide additional safety data based on systemic exposure margins for use of 
Nusinersen in pediatric patients, a 13-week toxicity study using subcutaneous dose 
administration was conducted in juvenile mice.
See the Investigator’s Brochure for detailed information on nonclinical studies.


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5.3.2.
Clinical Experience
Completed studies in subjects with SMA
Nusinersen has been evaluated in 4 completed open-label studies in subjects with SMA 
diagnosed during childhood:  ISIS 396443-CS1, ISIS 396443-CS2, ISIS 396443-CS10, and 
ISIS 396443-CS12.  Nusinersen has also been evaluated in 2 controlled studies in subjects with 
SMA diagnosed during infancy and childhood:  ISIS 396443-CS3B and ISIS 396443-CS4.
Study ISIS 396443-CS1 was a single-ascending dose Phase 1 study designed to assess the safety, 
tolerability, and PK of Nusinersen in subjects with later-onset SMA.  A single dose of 
Nusinersen was administered by intrathecal injection to subjects with SMA who were 2 to 
14 years of age.  Four doses (1, 3, 6, and 9 mg) were evaluated sequentially.  Each dose was 
studied in a cohort of 6 or 10 subjects.  All subjects received study treatment.  Twenty-eight 
subjects were dosed in the clinical trial, and all subjects completed dosing and follow-up visits 
per protocol.  Nusinersen was well tolerated, and no safety concerns were reported when 
administered as a single dose up to 9 mg.  Mild adverse events (AEs) of headache were the most 
commonly reported events.  The 2 events related to Nusinersen (palpitations and paresthesia) 
were mild in severity, were not dose related, and had resolved.  No serious AEs (SAEs) and no 
discontinuations due to AEs were reported.  There were no clinically significant changes in vital 
signs or safety laboratory parameters related to Nusinersen.  CSF and plasma drug concentrations 
of Nusinersen were dose dependent and consistent with the nonclinical data.
Study ISIS 396443-CS2 was an open-label, multiple-ascending dose, Phase 1/2a study designed 
to assess the safety, tolerability, and PK of Nusinersen in subjects with later-onset SMA.  
Multiple doses of Nusinersen were administered by intrathecal injection to subjects with SMA 
who were 2 to 15 years of age.  Four dose levels (3, 6, 9, and 12 mg) were evaluated 
sequentially.  Each dose level was studied in a cohort of 8 or 9 subjects, where all subjects 
received study treatment.  The 6 subjects who participated in Cohort 1 of ISIS 396443-CS1 were 
eligible to enroll in ISIS 396443-CS2; 3 of these subjects enrolled in ISIS 396443-CS2 Cohort 1 
and the other 3 enrolled in ISIS 396443-CS2 Cohort 2.  Thirty-four subjects were enrolled, and 
all but 1 subject completed the study.  One subject in the 12-mg Nusinersen dose cohort 
discontinued treatment early because of the Investigator’s decision.  The Investigator concluded 
that the subject and the parents could not tolerate the study procedures associated with dosing 
and PK draws, and thus, the subject was withdrawn.  Nusinersen was well tolerated, and no 
safety concerns were reported when Nusinersen was administered as multiple doses up to 12 mg.  
Post lumbar puncture (LP) syndrome was the most commonly reported AE.  None of the AEs 
reported during the study were considered related to Nusinersen or resulted in discontinuation 
from the study or of the study treatment.  Three SAEs were reported during the study; all were 
assessed as unrelated to Nusinersen.  There were no clinically significant changes in vital signs, 
neurological or physical examination findings, or safety laboratory parameters related to 
Nusinersen.  There were no dose-related safety concerns.
Study ISIS 396443-CS10 was a single-dose open-label study to assess the safety and tolerability 
of a single intrathecal dose in subjects with later-onset SMA who participated in 
ISIS 396443-CS1 Cohorts 2, 3, and 4 (3, 6, or 9 mg).  Eighteen subjects (4 subjects at 6-mg dose 
and 14 subjects at 9-mg dose) were enrolled and received study treatment.  All 18 subjects 
completed the study. 


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Study in subjects with infantile-onset SMA
Study ISIS 396443-CS3B was a pivotal, randomized, double-blind, sham procedure-controlled, 
Phase 3, multicenter study to assess the clinical efficacy and safety of Nusinersen in infants with 
SMA (onset of clinical signs and symptoms consistent with SMA at ≤6 months of age) who have 
2 SMN2 copies.  Subjects were randomized in a 2:1 ratio to receive either a scaled equivalent 
12-mg dose of Nusinersen or a sham procedure control, respectively.  There were 121 subjects 
enrolled in this study, and 37 subjects completed the follow-up visit as of the end of study.
Studies in subjects with later-onset SMA
Study ISIS 396443-CS4 was a pivotal, randomized, multicenter, double-blind, sham 
procedure-controlled, Phase 3 study in subjects with later-onset SMA (onset of clinical signs and 
symptoms consistent with SMA at >6 months of age) conducted to assess the clinical efficacy 
and safety of Nusinersen.  Subjects were randomized in a 2:1 ratio to receive either a scaled 
equivalent 12 mg dose of Nusinersen or a sham procedure control, respectively.  There were 
126 subjects who completed the study.
Study ISIS 396443-CS12 was an open-label study to assess the safety, tolerability, and PK of 
Nusinersen (12 mg) administered intrathecally to subjects with later-onset SMA who previously 
participated in either ISIS 396443-CS2 or ISIS 396443-CS10.  There were 45 subjects who 
completed the study.
Ongoing studies in subjects with SMA
Nusinersen is also being evaluated in 4 ongoing studies:  ISIS 396443-CS3A, 232SM201, 
ISIS 396443-CS11, and 232SM202 (the present study).
Studies in subjects with SMA diagnosed during infancy
Study ISIS 396443-CS3A is an ongoing, open-label, Phase 2 study to assess the efficacy, safety, 
tolerability, and PK of multiple doses of Nusinersen.  Enrollment has been completed with 
21 subjects enrolled.  Two loading dose levels (scaled by infant age to be equivalent to either 
6- or 12-mg dose for children >2 years of age based on CSF volume) were evaluated sequentially 
in symptomatic infants with SMA who were between ≥21 and ≤7 months of age at screening.  
Loading doses were administered on Days 1, 15, and 85.  Maintenance dosing commenced 
24 weeks following Day 85 and at 18-week intervals thereafter.
Study 232SM201 is an open-label, multicenter, global, single-arm study to assess the efficacy, 
safety, tolerability, and PK of multiple doses of Nusinersen in presymptomatic subjects with 
genetically diagnosed SMA.  The study is being conducted in subjects ≤6 weeks of age with 
genetic documentation of 5q SMA homozygous gene deletion or mutation or compound 
heterozygous mutation, genetic documentation of 2 or 3 copies of the SMN2 gene, 
CMAP ≥1 mV, and the absence of signs or symptoms of SMA.  Up to 25 subjects are planned to 
be treated in the study.  All subjects will receive a scaled equivalent 12-mg dose of Nusinersen.  
Study in subjects with infantile-onset or later-onset SMA
Study ISIS 396443-CS11 is an ongoing OLE study being conducted to evaluate the long-term 
safety, tolerability, and efficacy of Nusinersen administered intrathecally to subjects with SMA 


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who previously participated in investigational studies of Nusinersen.  Up to 274 subjects are 
planned to be treated in the study. 
5.4.
Study Rationale
There is reasonably high genotype-phenotype correlation such that the SMN2 copy number can 
be used to predict the severity of disease (moderate or severe) with approximately 80% to 
85% accuracy [Burghes and Beattie 2009; Prior 2010; Swoboda 2005].  Evaluation of 
relationship between categories of functional status and number of SMN2 copies have indicated 
that as SMN2 copy number increases so does functional status [Feldkötter 2002; Swoboda 2005].  
However, assessment of various outcome measures over time have indicated that there is overlap 
among SMA types, and values vary widely with age and gross motor functional status with an 
overall age dependent decline [Swoboda 2005]. 
5.4.1.
Rationale for Part 1
The intent of Part 1 of this study is to assess safety, tolerability, and explore the utility of selected 
efficacy endpoints in subjects who have onset of clinical signs and symptoms that are consistent 
with SMA at age ≤6 months or >6 months.  These subjects have either 2 or 3 SMN2 copies and 
were not eligible to participate in the 2 pivotal clinical studies, ISIS 396443-CS3B and 
ISIS 396443-CS4.  ISIS 396443-CS3B was a randomized, double-blind, sham 
procedure-controlled study investigating the therapeutic benefit of Nusinersen in subjects with 
2 SMN2 copies who have onset of clinical signs and symptoms of SMA at ≤6 months of age.  
ISIS 396443-CS4 was a randomized, double-blind, sham procedure-controlled study 
investigating the therapeutic benefit of Nusinersen in subjects who have onset of clinical signs 
and symptoms of SMA at >6 months of age.  To be consistent with the study design of the 
2 pivotal clinical studies and to understand the safety and tolerability of Nusinersen compared 
with natural history, the present study is designed to include sham procedure control in Part 1 for 
an unbiased assessment of safety, tolerability, and selected efficacy endpoints in the study 
population that was not eligible to participate in Studies ISIS 396443-CS3B or ISIS 396443-CS4.  
The design of the present study will also allow exploration of the safety and tolerability of a 
higher dose regimen in subjects who have onset of clinical signs and symptoms at >6 months of 
age, but who were not eligible for Study ISIS 396443-CS4.
5.4.2.
Rationale for Part 2:  Open-Label Extension Phase
The rationale for Part 2 of this study is to assess the long-term safety and tolerability of 
Nusinersen in subjects with SMA who participated in Part 1 and completed their End of Part 1 
Evaluation assessments.
5.5.
Rationale for Dose and Schedule Selection
The Nusinersen dose and dose interval for this study were selected based on nonclinical 
toxicology and PK observations from monkey studies using single-dose and repeat-dosing 
intrathecal administration, consideration of the target tissue concentration anticipated for drug 
pharmacology, and safety data in the completed and ongoing clinical studies of Nusinersen.  
Based on pharmacology and PK results in SMA transgenic mice, it is estimated that a target 
spinal cord tissue concentration between 1 and 10 μg/g will produce 50% to 90% 


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SMN2 exon 7 inclusion.  Nonclinical studies in juvenile monkeys receiving intrathecal doses of 
Nusinersen showed a resulting gradient of distribution of Nusinersen along the spinal cord, with 
mean lumbar spinal cord concentrations ranging from 1.6- to 2.3-fold and 2.0- to 3.5-fold higher 
than thoracic and cervical spinal cord levels, respectively.  The dose selected for this 
multiple-dose clinical study (equivalent to 12 mg of Nusinersen) is predicted to achieve levels at 
the high end of this range (approximately 10 μg/g lumbar and 3 μg/g cervical spinal cord tissue 
concentrations) after the first dose.  The loading dose interval (i.e., doses on Days 1, 15, 29, and 
64) was selected based on the nonclinical PK and pharmacology data in order to achieve and 
maintain Nusinersen spinal cord tissue levels that are predicted to be above or within the upper 
end of the pharmacologically active range by Day 64 (approximately 30 μg/g lumbar and 10 μg/g 
cervical tissue concentration), while at the same time considering subject safety and convenience 
for repeated intrathecal injections by LP.  The higher number of loading doses would allow for 
the evaluation of safety and tolerability and preliminary exploratory efficacy endpoints in a 
broader population of subjects with SMA, including those who have onset of clinical signs and 
symptoms at >6 months of age but who were not eligible for Study ISIS 396443-CS4.  The 
maintenance dose interval (once every 4 months ) was selected based on the estimated spinal 
tissue and CSF drug half-life (4 to 6 months) and was selected to maintain spinal cord tissue 
levels of Nusinersen at a steady-state level within the estimated pharmacologically active range. 
In Part 1, maintenance doses will be given on Day 183 and Day 302, for a total of 6 doses over 
approximately 10 months.  Subjects who were receiving Nusinersen in Part 1 will continue 
receiving maintenance doses in Part 2 every 4 months.  Subjects who were receiving sham in 
Part 1, will receive maintenance doses starting on Day 183 of Part 2.
Nusinersen will be administered as an intrathecal injection.  The volume of the injection, and 
thus the dose, will be adjusted based on the subject’s age on the day of dosing as shown in 
Table 1, such that each subject will receive a 12-mg scaled equivalent dose based on CSF 
volume scaling.  Thus, younger subjects will be given a lower dose of drug, achieved by 
injecting a smaller volume that is proportional to the estimated CSF volume for age, such that the 
dose volume will be equivalent to 5 mL for a 2-year-old child to adult.  Dosing instructions and 
details regarding administration will be provided in the Directions for Handling and 
Administration (DHA).
6.
STUDY OBJECTIVES AND ENDPOINTS
6.1.
Primary Objectives and Endpoints
Part 1
The primary objective of Part 1 of this study is:

To assess the safety and tolerability of Nusinersen in subjects with SMA who are not 
eligible to participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4.


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The endpoints that relate to this objective are:

Incidence of AEs and SAEs

Change from baseline (see Section 16.1) in clinical laboratory parameters, 
electrocardiograms (ECGs), and vital signs

Change from baseline (see Section 16.1) in neurological examination outcomes
Part 2
The primary objective of Part 2 of this study is:

To assess the long-term safety and tolerability of Nusinersen in subjects with SMA 
who participated in Part 1 and completed their End of Part 1 Evaluation assessments.
The endpoints that relate to this objective are:

Incidence of AEs and SAEs

Change from baseline (see Section 16.1) in clinical laboratory parameters, ECGs, 
vital signs, and growth parameters 

Change from baseline (see Section 16.1) in neurological examination outcomes

Coagulation parameters (activated partial thromboplastin time [aPTT], partial 
thromboplastin time [PTT], and international normalized ratio [INR]) and urine total 
protein
6.2.
Secondary Objectives and Endpoints
Part 1
The secondary objective of Part 1 of this study is:

To examine the PK of Nusinersen in subjects with SMA who are not eligible to 
participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4
The endpoint that relates to this objective is: 

Nusinersen concentrations in plasma and CSF
Part 2
The secondary objective of Part 2 of this study is:

To examine the PK of Nusinersen in subjects with SMA who participated in Part 1 
and completed their End of Part 1 Evaluation assessments
The endpoint that relates to this objective is: 

Nusinersen concentrations in plasma and CSF
The secondary immunogenicity endpoint is as follows:

Plasma antibodies to Nusinersen


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6.3.
Exploratory Objectives and Endpoints
Part 1
The exploratory objective of Part 1 of this study is:

To explore the efficacy of Nusinersen in subjects with SMA who are not eligible to 
participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4.
The endpoints that relate to this objective are:

Change from baseline in ventilator use 

Attainment of motor milestones assessed by Section 2 of the Hammersmith Infant 
Neurological Examination (HINE) 

Change from baseline in growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for length, and head to 
chest circumference ratio) through final safety follow-up evaluation

Clinical Global Impression of Change (physician and caregiver assessment) through 
final safety follow-up evaluation 
The exploratory immunogenicity endpoint is as follows:

Plasma antibodies to Nusinersen
Part 2
The exploratory objective of Part 2 of this study is:

To explore the efficacy of Nusinersen in subjects with SMA who participated in 
Part 1 and completed their End of Part 1 Evaluation assessments.
The endpoints that relate to this objective are:

Change from baseline in ventilator use 

Attainment of motor milestones assessed by World Health Organization (WHO) 
motor milestones and Section 2 of the HINE 

Change from baseline in growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for length, and head to 
chest circumference ratio) through Part 2 Final Follow-up Evaluation

Clinical Global Impression of Change (physician and caregiver assessment) through 
Part 2 Final Follow-up Evaluation and Assessment of Caregiver Experience with 
Neuromuscular Disease (ACEND)


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7.
STUDY DESIGN
7.1.
Study Overview
This is a Phase 2 multicenter study conducted in 2 parts.  The study was originally designed as a 
randomized, double-blind, sham-procedure controlled study to assess the safety and tolerability 
and explore the efficacy of intrathecally administered Nusinersen up to approximately 14 months 
(from the first dose until End of Part 1 Evaluation).  Based on emergent data from the Nusinersen 
clinical development program, the Sponsor may decide to terminate Part 1 early, and all subjects 
may then be offered the opportunity to be unblinded and transition to Part 2 prior to completion 
of all Part 1 evaluations.  Part 2 is an OLE phase that will assess long-term safety and tolerability 
and explore the efficacy of intrathecally administered Nusinersen for approximately 
24 additional months.  In Part 1 of the study, up to 21 subjects will be randomized in a ratio of 
2:1 to receive Nusinersen by intrathecal LP injection (n = 14) or to a sham procedure-control 
(n = 7).  Randomization will be stratified based on age at onset of clinical signs and symptoms 
consistent with SMA:  >6 months versus ≤6 months.  In Part 2 of the study, all subjects who 
participated in Part 1, who completed their End of Part 1 Evaluation assessments, and who 
elected to enroll in Part 2 will receive Nusinersen by intrathecal injection.
Subjects who withdraw early from Part 1 will be encouraged to complete the End of Part 1 
Evaluation assessments at the time of withdrawal.  Subjects who withdraw early from Part 2 will 
be encouraged to complete the Part 2 Early Termination Evaluation assessments at the time of 
withdrawal. 
See Section 4.1 for a schematic of the study design.
7.2.
Overall Study Duration and Follow-Up
Part 1 of the study will consist of a Screening Period, Treatment Period, and post-treatment End 
of Part 1 Evaluation.  For subjects who meet eligibility criteria and enroll in Part 1, the duration 
of Part 1 will be approximately 15 months (450 days) and will include a Screening Period of no 
greater than 28 days, a 302-day Treatment Period, and an End of Part 1 Evaluation 
approximately 4 months after the last dose.  Based on emergent data from the Nusinersen clinical 
development program, the Sponsor may decide to terminate Part 1 early, and all subjects may be 
offered the opportunity to transition to Part 2 prior to completion of all Part 1 evaluations.
Part 2 will consist of a Treatment Period and a post-treatment Final Follow-up Evaluation.  For 
subjects who meet eligibility criteria and enroll in Part 2, the duration of Part 2 will be 
approximately 28 months and will include an open-label Treatment Period of approximately 
24 months and a Part 2 Final Follow-up Evaluation approximately 4 months after the last dose of 
study treatment in Part 2.
Total study duration for subjects who participate in both Part 1 and Part 2 will be approximately 
43 months.


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7.2.1.
Screening
Subject eligibility for Part 1 of the study will be determined within 4 weeks (Day -28 to Day -1) 
prior to the first injection of Nusinersen or administration of sham procedure and will be 
confirmed before randomization.  If a subject initially fails any of the screening criteria, they will 
be allowed to be rescreened 1 time during the Screening Period at the discretion of the 
Investigator.  End of Part 1 Evaluation assessments will be used to confirm subjects’ eligibility 
for Part 2.
7.2.2.
Treatment
Part 1
Eligible subjects will be admitted to the study site on Part 1 Day 1, undergo predose evaluations, 
and then receive an LP injection of Nusinersen or a sham procedure.  After the injection on 
Day 1, subjects will remain at the study site for at least 24 hours after the procedure for safety 
monitoring.
Subjects will return to the study site on Days 15, 29, 64, 183, and 302 (±1 day for Days 15 and 
29 and ±7 days for all other days) for follow-up evaluations and subsequent injections of study 
treatment or sham procedure, for a total of 6 injections or sham procedures over a dosing period 
of 10 months.  During these 5 evaluations, all subjects will remain at the study site for at least 
6 hours postdose for safety monitoring.  An overnight stay is optional, at the discretion of the 
Investigator.  Safety monitoring by telephone contact will occur on the day after injection of 
study treatment or sham procedure.  In addition, the study site will monitor the subject’s 
condition through telephone contact every other week (excluding weeks with study visit) 
throughout the study period.
After completing the End of Part 1 Evaluation assessments, all eligible subjects may elect to 
enroll in Part 2.
Based on emergent data from the Nusinersen clinical development program, the Sponsor may 
decide to terminate Part 1 early, and all subjects may be offered the opportunity to transition to 
Part 2 prior to completion of all Part 1 Evaluation assessments.  All subjects enrolled in the study 
at the time of Sponsor termination will be considered Part 1 completers.  The next study 
evaluation for those subjects will serve as an End of Part 1 Evaluation, which may occur at any 
time prior to the next scheduled Part 1 study evaluation. 
Unblinding will occur in order for the subjects to transition from Part 1 to Part 2.
End of Part 1 Evaluation assessments are required to be done prior to the transition to Part 2.  
After performing the End of Part 1 Evaluation assessments, the subject may immediately 
transition to Part 2.
Part 2
Part 2 study procedures and schedules will be determined based on the subject’s treatment 
assignment in Part 1.


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Subjects who were randomized to receive Nusinersen in Part 1
End of Part 1 Evaluation assessments will be used to determine subject eligibility for Part 2 of 
the study.  For subjects who were receiving Nusinersen in Part 1, Part 2 Day 1 will occur 
following the End of Part 1 Evaluation or approximately 4 months following the last injection of 
Nusinersen in Part 1.  On Part 2 Day 1, these subjects will undergo predose evaluations 
according to the schedule of events (Table 3) and then receive their first dose of Nusinersen for 
Part 2 (next maintenance dose).
Subjects will return to the study site on Days 120, 239, 358, 477, 596, and 715 (±7 days for all 
days) for follow-up evaluations and subsequent injections of Nusinersen over a dosing period of 
approximately 24 months.  Subjects will remain at the study site for at least 1 hour postdose for 
safety monitoring and can be discharged at the discretion of the site Investigator and in 
compliance with the institutional requirements once the subjects have adequately recovered from 
the dosing procedure.  An overnight stay is optional, at the discretion of the Investigator.  Safety 
monitoring by telephone contact will occur on the day after injection of study treatment.  In 
addition, the study site will monitor the subject’s condition through telephone contact every other 
week (excluding weeks with study visit) throughout the study period.
Subjects who were randomized to receive sham procedure in Part 1
End of Part 1 Evaluation assessments will be used to determine subject eligibility for Part 2 of 
the study.  For subjects who were receiving sham procedure in Part 1, Part 2 Day 1 will occur 
following the End of Part 1 Evaluation or as soon as possible following their End of Part 1 
Evaluation, in the event of early termination by the Sponsor due to emergent data from the 
Nusinersen clinical development program.  On Part 2 Day 1, these subjects will undergo predose 
evaluations according to the schedule of events (Table 4) and then receive their first injection of 
Nusinersen (first loading dose).  Subjects will remain at the study site for at least 24 hours after 
the procedure for safety monitoring.
Subjects will return to the study site on Days 15, 29, 64, 183, 302, 421, 540, 659, and 778 
(±1 day for Days 15 and 29 and ±7 days for all other days) for follow-up evaluations and 
subsequent injections of Nusinersen over a dosing period of approximately 24 months.  Subjects 
will remain at the study site for at least 1 hour postdose for safety monitoring and can be 
discharged at the discretion of the site Investigator and in compliance with the institutional 
requirements once the subjects have adequately recovered from the dosing procedure.  An 
overnight stay is optional, at the discretion of the Investigator.  Safety monitoring by telephone 
contact will occur on the day after injection of study treatment.  In addition, the study site will 
monitor the subject’s condition through telephone contact every other week (excluding weeks 
with study visit) throughout the study period. 
For both groups of subjects, Part 2 of the study will continue for approximately 24 months and in 
accordance with applicable laws and regulations.  From Year 2 onwards, subjects will maintain 
evaluations for injection of study treatment every 4 months as indicated in Table 3 and Table 4.


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7.2.3.
Follow-Up
Subjects who enroll in Part 1 but not Part 2 will return to the study site for an End of Part 1 
Evaluation approximately 4 months after the last dose of study treatment (End of Part 1 on 
Day 422 [±7 days]).
In the event of a decision by the Sponsor to terminate the study earlier than the end of Part 1 
based on emergent data from the Nusinersen clinical development program, subjects who do not 
elect to participate in Part 2 will complete their next evaluation after Part 1 is terminated and that 
visit will be the End of Part 1 Evaluation.
Subjects who enroll in Part 2 will have a Part 2 Final Follow-up Evaluation approximately 
4 months after the last open-label dose of Nusinersen.
Subjects who withdraw early from Part 1 will be encouraged to complete the End of Part 1 
Evaluation assessments at the time of withdrawal.  Subjects who withdraw early from Part 2 will 
be encouraged to complete the Part 2 Early Termination Evaluation assessments at the time of 
withdrawal.
7.3.
Study Stopping Rules
For Part 1 and Part 2 of the study, the Sponsor may terminate the study at any time by informing 
Investigators (who will subsequently inform the corresponding ethics committees) and any other 
applicable regulatory agencies.  Investigators will be notified by the Sponsor if the study is 
placed on hold, completed, or closed.  
Conditions that may warrant termination of the study include, but are not limited to, the 
following:

The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study.

A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product.  
7.4.
End of Study
The end of the study is the last subject’s completion of the last evaluation for Part 2.
7.5.
Safety Monitoring and Data and Safety Monitoring Board
Safety data will be reviewed on an ongoing basis by the Sponsor and the Medical Monitor.  
Safety data will also be reviewed on a quarterly basis, throughout Part 1 of the study, by an 
independent Data and Safety Monitoring Board (DSMB; see Section 19.2). 


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening or at the time point specified in the individual eligibility criterion listed:
1. Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study 
and provide signed and dated informed consent and authorization to use confidential 
health information in accordance with national and local subject privacy regulations.  
2. Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound 
heterozygote.
3. Onset of clinical signs and symptoms consistent with SMA at <6 months of age and have 
documentation of 3 SMN2 copies.
OR
Onset of clinical signs and symptoms consistent with SMA at <6 months of age, 
>7 months of age (211 days) at screening, and have documentation of 2 SMN2 copies.
OR
Onset of clinical signs and symptoms consistent with SMA at >6 months of age, are 
≤18 months of age at screening, and have documentation of 2 or 3 SMN2 copies.
4. Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is 
planned for study procedures (as assessed by the Investigator and either the 
anesthesiologist or pulmonologist).
5. Medical care, such as routine immunizations (including influenza vaccine, pneumococcus 
vaccine, and respiratory syncytial virus prophylaxis [palivizumab] if available), meets 
and is expected to continue to meet guidelines set out in the Consensus Statement for 
Standard of Care in SMA, in the opinion of the Investigator.
6. Subjects with 2 SMN2 copies must reside within approximately 9 hours’ ground-travel 
distance from a participating study site for the duration of the study.  Residents who are 
>2 hours’ ground-travel distance from a study site must obtain clearance from the 
Investigator and the study Medical Monitor. 
7. Able to complete all study procedures, measurements, and visits, and parent or legal 
guardian/subject has adequately supportive psychosocial circumstances, in the opinion of 
the Investigator.
For Part 2 only:
To be eligible to participate in Part 2 of this study, candidates must meet the following eligibility 
criteria at the time of consent to participate in Part 2:
1. Participation in Part 1 and completion of the End of Part 1 Evaluation assessments.
2. Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study 
and to provide signed and dated informed consent on the Part 2 informed consent form 


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(ICF) and authorization to use confidential health information in accordance with 
national and local subject privacy regulations.
3. Able to complete all study procedures, measurements, and visits, and parent or legal 
guardian/subject has adequately supportive psychosocial circumstances, in the opinion of 
the Investigator.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening or at the time point specified in the individual criterion listed:
1. Any previous exposure to Nusinersen; previous dosing in this study or previous studies 
with Nusinersen.
2. Signs or symptoms of SMA present at birth or within the first week after birth.
3. Ventilation for ≥16 hours per day continuously for >21 days at screening.
4. Permanent tracheostomy, implanted shunt for CSF drainage, or implanted CNS catheter 
at screening. 
5. History of brain or spinal cord disease that would interfere with the LP procedure, CSF 
circulation, or safety assessments.
6. Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional 
support within 2 months prior to screening, or hospitalization for surgery planned during 
the study.
7. Clinically significant abnormalities in hematology or clinical chemistry parameters or 
ECG, as assessed by the Investigator, at the Screening Visit that would render the subject 
unsuitable for inclusion.
8. Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole, 
carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device 
within 30 days prior to screening.  Any history of gene therapy, prior ASO treatment, or 
cell transplantation.
9. Ongoing medical condition that according to the Investigator would interfere with the 
conduct and assessments of the study.  Examples are medical disability (e.g., wasting or 
cachexia, severe anemia) that would interfere with the assessment of safety or would 
compromise the ability of the subject to undergo study procedures.
10. The subject’s parent or legal guardian is unable to understand the nature, scope, and 
possible consequences of the study, or does not agree to comply with the protocol’s 
schedule of assessments.
11. Subject’s parent or legal guardian is not willing to continue to meet standard of care 
guidelines for care (including vaccinations and respiratory syncytial virus prophylaxis if 
available), nor provide nutritional and respiratory support throughout the study.
12. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the 
subject unsuitable for enrollment.


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For Part 2 only:
Candidates will be excluded from the Part 2 if they meet the following exclusion criterion at the 
time of consent into Part 2 of the study:
1. Any significant change in clinical status, including laboratory tests that, in the opinion of 
the Investigator, would make them unsuitable to participate in Part 2.  The Investigator 
must reassess the subject’s medical fitness for participation and consider any diseases that 
would preclude treatment.
Note that subjects who have been previously exposed to Nusinersen in Part 1 of the study 
(Exclusion criterion 1 for Part 1) may participate in Part 2.
9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION 
9.1.
Screening and Enrollment
The subject’s legally authorized representative (e.g., parent or legal guardian) must provide 
informed consent for Part 1 before study-specific screening tests are performed and for Part 2 
before study-specific procedures are performed (see Section 17.3).  When a subject’s 
parent/guardian signs the ICF, that subject is assigned a unique subject identification number 
through the interactive response technology (IRT) system and is considered to be enrolled in the 
study.  Participating study sites are required to document all screened candidates initially 
considered for inclusion in this study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents, within the IRT system, and on 
the screening log.  If a subject initially fails any of the screening criteria, they will be allowed to 
be rescreened 1 time during the Screening Period, at the discretion of the Investigator. 
9.2.
Registration and Randomization of Subjects
In Part 1 of the study, subjects will be registered and randomized after all screening assessments 
have been completed and after the Investigator has verified that the subjects are eligible per 
criteria in Section 8.1 and Section 8.2.  No subject may begin treatment until the subject is 
documented as registered (assigned a unique identification number) and is randomized for the 
study in the IRT system.  Any subject identification numbers that are assigned will not be reused 
even if the subject does not receive treatment.  
In Part 1 of the study, using an IRT system, eligible subjects will be randomized to receive 
Nusinersen:sham procedure in a 2:1 ratio.  Randomization will be stratified based on age at onset 
of clinical signs and symptoms consistent with SMA:  >6 months versus <6 months.  Subjects 
who withdraw from the study may be replaced.
At the beginning of Part 2 of the study, the subject's treatment assignment will be unblinded via 
the IRT system.  Part 2 is the OLE phase of the study in which all subjects receive Nusinersen.
Refer to the Study Reference Guide for details on registration and randomization. 


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9.3.
Blinding Procedures
Part 1 of the study is a randomized, double-blind, sham-procedure controlled study.  The 
Sponsor, parents and/or legal guardians, and key study site personnel will be blinded throughout 
Part 1 of the study.  To maintain the study blind, it is imperative that subject treatment 
assignments are not shared with the subjects, their families, or any member of the study team, 
either at the study site or that of the Sponsor, except the unblinded site study staff (dedicated 
team) and the unblinded medical monitor or clinical research associate.  The DSMB may be 
unblinded as described in the DSMB charter. 
Before Part 2 Day 1, parents and/or legal guardians, key study site personnel, and the Sponsor 
will be unblinded to the treatment group to which the subjects were randomized in Part 1.  This 
will be performed according to the unblinding plan, which will be finalized prior to unblinding.  
Of note, in the event that the Sponsor decides to rollover subjects to Part 2 early, unblinding for 
key study site personnel will occur prior to the End of Part 1 Evaluation in order to facilitate 
bringing subjects who were randomized to receive sham in Part 1 as soon as possible and to 
maintain the 4-month dosing interval for subjects who were randomized to receive Nusinersen in 
Part 2.  Treatment in Part 2 will be open-label, and all study subjects will receive Nusinersen.
9.3.1.
Emergency Unblinding of Treatment Assignment 
In Part 1 of the study, if a subject has experienced an SAE (as defined in Section 15.1.2), and/or 
when knowledge of the treatment assignment will impact the clinical management of the subject, 
the Investigator will have the ability to unblind the treatment assignment for that subject using 
the IRT.  However, prior to unblinding, the Investigator should attempt to contact the blinded 
Medical Monitor to discuss the emergency.  The Sponsor or designee will be informed of the 
unblinding of a subject within 24 hours.  Every reasonable attempt should be made to complete 
the End of Part 1 Evaluation assessments prior to unblinding, as knowledge of the treatment arm 
could influence subject assessment.  The Investigator must document the reasons for unblinding 
in the subject’s source documents.  The Investigator is strongly advised not to divulge the 
subject’s treatment assignment to any individual not directly involved in managing the medical 
emergency, nor to personnel involved with the analysis and conduct of the study.  In cases where 
there are ethical reasons to have a subject whose treatment assignment was unblinded for safety 
reasons remain in the study, the Investigator must obtain specific approval from the Sponsor and 
the Medical Monitor for the subject to continue in the study. 
In addition, all suspected unexpected serious adverse reactions (SUSARs) will be unblinded by 
the Sponsor’s (or designee) Drug Safety and Quality Assurance personnel for the purpose of 
regulatory reporting (Section 15.3.4).


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10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
A subject must permanently discontinue study treatment for any of the following reasons:

The subject’s parent or legal guardian withdraws consent.  

The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment.

At the discretion of the Investigator for medical reasons.

At the discretion of the Investigator or the Sponsor for noncompliance.
The reason for discontinuation of study treatment must be recorded in the subject’s case report 
form (CRF).
In Part 1 of the study, subjects who discontinue treatment will continue follow-up evaluations 
(i.e., predose evaluations at regular study evaluations) but with no postdose safety monitoring 
telephone contacts (Section 4.2, Table 2) unless either consent is withdrawn (Section 10.2) or the 
Sponsor terminates Part 1 early, in the case of emergent data from the Nusinersen clinical 
development program.  If a subject is unable to come for study evaluations, the minimum 
requirement for follow up will be telephone calls on a monthly basis.  At these evaluations or 
telephone contact, changes in concomitant medications and AEs, information on the subject’s 
daily ventilator use/bi-level positive airway pressure (Bi-PAP), and health status will be 
recorded.  The methods used to continue follow up (i.e., site evaluations or telephone calls to the 
subject’s parent, guardian, or caregiver) should be documented in the source document.
In Part 2 of the study, subjects who discontinue treatment will continue follow-up evaluations 
unless consent is withdrawn (Section 10.2).  If a subject is unable to come for study evaluations, 
the minimum requirement for follow up will be telephone calls on a monthly basis.  The methods 
used to continue follow up (i.e., site evaluations or telephone calls to the subject’s parent, 
guardian, or caregiver) should be documented in the source document.  Follow-up evaluations 
for any subjects who discontinue treatment in Part 2 will continue through the end of Part 2.
10.2.
Withdrawal of Subjects From Study
Subjects must be withdrawn from the study for any one of the following reasons:

The subject’s parent or legal guardian withdraws consent.  

The subject’s parent or legal guardian is unwilling or unable to comply with the 
protocol.

The Sponsor terminates Part 1 early because of emergent data from the Nusinersen 
clinical development program, and the subject elects not to enroll in Part 2.

The Investigator or Sponsor decides to withdraw the subject for administrative 
reasons.


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Subjects who withdraw early from Part 1 will be encouraged to complete the End of Part 1 
Evaluation assessments (see Section 4.2 [Table 2]) at the time of withdrawal.  Subjects who 
withdraw early from Part 2 will be encouraged to complete the Part 2 Early Termination 
Evaluation assessments at the time of withdrawal (see Section 4.2 [Table 3 and Table 4]).  The 
reason for the subject’s withdrawal from the study must be recorded in the subject’s CRF.
11.
STUDY TREATMENT USE
11.1.
Regimen
Refer to and follow the DHA for complete details.
11.1.1.
Study Treatment
In Part 1 of the study, each subject will receive a single intrathecal bolus (1 to 3 minutes) LP 
injection of Nusinersen or sham procedure on Days 1, 15, 29, 64, 183, and 302 by dedicated 
study personnel who are unblinded to treatment group; this cannot be any of the key study site 
personnel (i.e., the Investigator, the study coordinator, or outcome assessors).  The study 
treatment administration will be performed in a dedicated room, and key study personnel and the 
parents will not be present during the procedure to ensure blinding.  
In Part 2 of the study, each subject will receive a single intrathecal bolus (1 to 3 minutes) LP 
injection of Nusinersen at the days determined by their Part 1 treatment assignment as specified 
in Table 3 and Table 4.  Treatment administration will not be blinded.
Nusinersen will be administered using a “spinal anesthesia” needle and a 5-mL syringe.  A 22G 
to 25G spinal anesthesia needle is recommended based on subject size or clinical condition.  The 
target site for needle insertion is the L3/L4 space but may be 1 segment above or 1 to 2 segments 
below this level, if needed.  Depending on institutional guidelines, anesthesia may be used for 
the LP procedure or for the sham procedure in Part 1, following institutional procedures.  Spinal 
ultrasound or other imaging techniques may be used to guide the intrathecal administration of 
Nusinersen if deemed necessary, but these are not required.  Subjects will be encouraged to lie 
down flat for 1 hour following injection of the study treatment, if possible.  Prior to each 
injection, 0.5 mL of CSF fluid will be collected for analyses.  CSF will be used for Nusinersen 
PK analyses.  Upon consent, extra CSF and blood samples will be stored for optional future 
investigation of possible biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF 
microRNA panel) or for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, immunogenicity assessments (including 
assay development and validation purposes), or other actions of Nusinersen with CSF 
constituents.  CSF analyses and data presentation will be conducted in a blinded manner in 
Part 1.  
The volume of the injection, and thus, the dose, will be adjusted for the subject’s age on the day 
of dosing, such that each subject will receive a 12-mg scaled equivalent dose based on CSF 
volume scaling (Table 1).  Thus, younger subjects will be given a lower dose of study treatment, 
achieved by injecting a smaller volume that is proportional to estimated CSF volume for age, 
such that dose volume will be equivalent to 5 mL for a 2-year-old child to adult.  


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11.1.2.
Sham Procedure
In Part 1 of the study, subjects randomized to the sham procedure control group will undergo a 
sham procedure, rather than study treatment administration, on Study Days 1, 15, 29, 64, 183, 
and 302.  Details regarding the sham procedure will be provided in the DHA.  The sham 
procedure will be administered by dedicated study personnel who are unblinded to treatment 
group; this cannot be any of the key study site personnel (i.e., the Investigator, study coordinator, 
or outcomes assessors).  The sham procedure in Part 1 will be performed in a dedicated room, 
and key study personnel and the parent or legal guardian will not be present during the procedure 
to ensure blinding. 
In general, the sham procedure in Part 1 will consist of a small needle prick on the lower back at 
the location where the LP injection is normally made.  The needle will break the skin, but no LP 
injection or needle insertion will occur.  The needle prick will be covered with the same bandage 
that is used to cover the LP injection normally, thus simulating the appearance of an LP 
injection.  If institutional guidelines require the use of anesthesia or sedation for an LP procedure 
in Nusinersen-treated subjects, then in order to maintain the blind, minimal sedation (i.e., a low 
dose of an anxiolytic) should be used for the sham procedure in Part 1, following institutional 
procedures.  The study subject will be kept in the procedure room for the same amount of time 
that subjects administered study treatment are kept, thus simulating the time period of the study 
treatment administration procedure.
Study treatment and sham kits will be packaged in a blinded fashion.  Blinded kits for the sham 
procedure in Part 1 contain artificial CSF (5.0 mL solution per 6 mL vial) that will not be 
injected but will be used to simulate CSF samples for that subject. 
11.2.
Modification of Dose and/or Treatment Schedule
No adjustment of dose is permitted.  In the event of a concurrent illness that would prevent the 
dosing procedure from being performed safely, an adjustment in the dose schedule may be 
permitted but must be approved by the Medical Monitor.  In this case, dosing will be resumed as 
soon as possible.
11.3.
Precautions
There are no protocol-required treatment precautions.
11.4.
Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff.
11.5.
Concomitant Therapy and Procedures
11.5.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between Screening and the Part 2 
Final Follow-up Evaluation/Telephone Call (or End of Part 1 Evaluation, if the subject does not 
enroll in Part 2).


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Allowed Concomitant Therapy
Throughout the study, Investigators or designated licensed physicians involved in the study may 
prescribe concomitant medications or treatments deemed necessary for AEs or to provide 
adequate supportive care.
Disallowed Concomitant Therapy
Subjects are prohibited from receiving other experimental agents, including gene therapy, during 
the study.  This includes marketed agents at experimental doses that are being tested for the 
treatment of SMA (e.g., albuterol/ salbutamol, riluzole, carnitine, sodium phenylbutyrate, 
valproate, hydroxyurea).
11.5.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and the Part 2 Final Follow-up Evaluation/Telephone 
Call (or End of Part 1 Evaluation, if the subject does not enroll in Part 2).
12.
STUDY TREATMENT MANAGEMENT
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol).
Study treatment must be dispensed only by a pharmacist or medically qualified staff.  Study 
treatment is to be dispensed only for subjects enrolled in this study.  Once study treatment is 
prepared for a subject, it can be administered only to that subject.  Study treatment vials are for 
one-time use only; any study treatment remaining in the vial should not be used for another 
subject.  
12.1.
Study Treatment
Nusinersen is formulated as an isotonic solution at 2.4 mg/mL and is provided as a 5.0-mL fill 
volume in a 6-mL clear glass vial. Nusinersen drug product contains the heptadecasodium salt of 
an 18-base residue phosphorothioate oligonucleotide.
The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements.  At a minimum, the label will include a study reference code, drug identifier, and 
quantity of dosage units, lot number, and other pertinent information in accordance with local 
laws.  The expiry or use-by date is stored in the IRT system, and printable assignment reports are 
available to site personnel.  Study treatment should not be used after the expiration date.  
For Part 1 of the study, the study drug (Nusinersen) and sham kits will be packaged in a blinded 
fashion.  Blinded kits for sham procedure contain artificial CSF provided as 5.0 mL solution per 
6 mL vial that will not be injected but will be used to simulate CSF samples for a subject.  
For Part 2 of the study, the study drug (Nusinersen) kits will be packaged in an open-label 
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12.1.1.
Study Treatment Preparation
The individual preparing Nusinersen or artificial CSF should carefully review the instructions 
provided in the DHA.  
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or drug, do not use it.  The vials in question should be saved at the study site and the 
problem immediately reported to the Sponsor (or designee).
12.1.2.
Study Treatment Storage
Study treatment must be stored in a secure location.
Nusinersen is to be protected from light and stored long term at 2°C to 8°C in a locked 
refrigerator with limited access. For additional information on storage requirements, follow the 
instructions provided in the DHA.
12.1.3.
Study Treatment Handling and Disposal
The Investigator must return all used and unused vials of Nusinersen and artificial CSF as 
instructed by the Sponsor (or designee).
If any used Nusinersen or artificial CSF supplies are to be destroyed at the study site, the 
institution or appropriate site personnel must obtain prior approval from the Sponsor (or 
designee), by providing, in writing, the destruction policy or details of the method of 
destruction. After such destruction, the Sponsor (or designee) must be notified, in writing, of the 
details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the date of 
destruction, and proof of destruction.
12.1.4.
Study Treatment Accountability
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), and accounts of any study treatment accidentally or 
deliberately destroyed.
Unless otherwise notified, all vials, both used and unused, must be saved for study treatment 
accountability. At the end of the study, reconciliation must be made between the amount of 
Nusinersen or artificial CSF supplied, dispensed, and subsequently destroyed or returned to the 
Sponsor (or designee).  A written explanation must be provided for any discrepancies.


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13.
EFFICACY, PHARMACOKINETIC, AND IMMUNOGENICITY 
ASSESSMENTS
See Section 4.2 (Table 2, Table 3, and Table 4) for the timing of all efficacy assessments.
13.1.
Clinical Efficacy Assessments
The following clinical assessments will be performed to evaluate the efficacy of Nusinersen:

Ventilator use 

WHO motor milestones and HINE (Section 2).  These assessments will be performed 
based on the subject’s abilities, as appropriate.

Growth parameters (body length, head circumference, chest circumference, arm 
circumference, weight for age, weight for length, and head to chest circumference 
ratio)

Clinical Global Impression of Change (physician and caregiver assessment) and 
ACEND
13.2.
Pharmacokinetic (Nusinersen Concentration) Assessments
The following tests will be performed to assess the PK of Nusinersen:

Plasma Nusinersen concentrations

CSF Nusinersen concentrations
13.3.
Immunogenicity Assessments
The following test will be performed to assess the immunogenicity of Nusinersen:

Anti-Nusinersen plasma antibody concentrations


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14.
SAFETY ASSESSMENTS
See Section 4.2 (Table 2, Table 3, and Table 4) for the timing of all safety assessments.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of 
Nusinersen:

Neurological examinations (assessment of mental status, level of consciousness, 
sensory motor function, cranial nerve function, and reflexes)

AEs, including SAEs

Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, 
temperature, pulse oximetry, and transcutaneous carbon dioxide)

Growth parameters

Physical examinations

Medical history

12-Lead ECGs

Use of concomitant medications
14.2.
Laboratory Safety Assessments
The following laboratory tests will be performed to evaluate the safety profile of Nusinersen:

Blood chemistry:  total protein, albumin, creatinine, cystatin C, creatine 
phosphokinase, blood urea nitrogen, total serum bilirubin (direct and indirect), 
alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, glucose, 
calcium, phosphorus, chloride, sodium, potassium, bicarbonate, creatine kinase (MB 
[isoenzyme expressed in the myocardium], BB [isoenzyme predominantly expressed 
in the brain], and MM [isoenzyme expressed in skeletal muscle]), gamma-glutamyl 
transferase

Hematology:  red blood cells, hemoglobin, hematocrit, platelets, white blood cells, 
white blood cell differential (% and absolute:  neutrophils, eosinophils, basophils, 
lymphoctyes, monocytes)

Urinalysis:  specific gravity, pH, protein, glucose, ketones, bilirubin, blood, red blood 
cells, white blood cells, epithelial cells, bacteria, casts, crystals

Urine total protein

Coagulation parameters:  aPTT, PTT, INR


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15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided.
At the signing of the ICF, each subject’s legally authorized representative and/or main 
caregiver(s) must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including a 
clinically significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator.  Abnormal laboratory findings that are considered by the Investigator 
as not clinically significant should not be reported as AEs.  Although abnormal laboratory values 
are typically not considered AEs, the following considerations may result in an abnormal 
laboratory value being considered an AE:

A laboratory test result that meets the criteria for an SAE

A laboratory test result that requires the subject to receive specific corrective therapy

A laboratory abnormality that the Investigator considers to be clinically significant
15.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization is defined as an admission of >24 hours to a medical facility and does 
not qualify as an AE  

Results in persistent or significant disability/incapacity

Results in a congenital anomaly/birth defect


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An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.)
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the study site must document all of the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining consent from 
the subject’s parent or legal guardian to participate in the study.

The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s parent‘s or legal guardian‘s consent to participate 
in the study and the time of the procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.
o
If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless 
one of the requirements in Section 15.1.2 is met.
15.2.
Safety Classifications
15.2.1.
Investigator Assessment of Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.2

The relationship of the event to study treatment as defined in Section 15.2.2

The severity of the event as defined in Section 15.2.3
15.2.2.
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment:








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15.4.2.1.
Unblinding for Medical Emergency
For Part 1 of this study, in a medical emergency when knowledge of the subject’s treatment 
assignment may influence the subject’s clinical care, the Investigator (or designee) should 
attempt to contact the blinded Biogen MA Inc. Medical Director or blinded 
Medical 
Monitor to discuss the emergency within 24 hours.  In these instances, the Investigator (or 
designee) may access the subject's treatment assignment by IRT.  
The Investigator must document the reasons for unblinding in the subject’s source documents.  
The Investigator is strongly advised not to divulge the subject’s treatment assignment to any 
individual not directly involved in managing the medical emergency or to personnel involved 
with the analysis and conduct of the study.  
15.5.
Safety Responsibilities
15.5.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, regardless of the severity or relationship
to study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

Complete an SAE form for each serious event and fax it as described in the Study 
Reference Guide within 24 hours of the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported as described in the Study Reference Guide within 24 hours of the 
study site staff becoming aware of new information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.

Report SAEs to local ethics committees, as required by local law.
15.5.2.
The Sponsor
The Sponsor’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor (or designee) 
is responsible for reviewing with study site staff the definitions of AE and SAE, as 
well as the instructions for monitoring, recording, and reporting AEs and SAEs.

The Sponsor (or designee) is to notify all appropriate regulatory authorities, central 
ethics committees, and Investigators of SAEs, as required by local law, within 
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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
Part 1 and Part 2 will be analyzed separately.  For Part 1, in general, continuous variables will be 
summarized by descriptive statistics, including number, mean, median, standard deviation, 
minimum, and maximum.  Categorical variables will be presented with the number and 
percentage in each category.  For Part 2, no formal statistical analyses will be performed.  
Descriptive statistics will be presented for safety and efficacy data collected.
For the Part 1 analysis, baseline is defined as the last nonmissing assessment prior to the first 
dose of study treatment in Part 1.  For the Part 2 analysis, baseline is defined as the last 
nonmissing assessment prior to the first dose of study treatment in Part 2.  In addition, a pooled 
analysis incorporating data from both Part 1 and Part 2 will be conducted to characterize the 
safety profile of Nusinersen.  For subjects on active treatment in Part 1, safety data from both 
Part 1 and Part 2 will be included in the pooled analysis and the Part 1 baseline will used for 
those subjects in the pooled analysis.  For subjects on sham procedure in Part 1, only safety data 
from Part 2 will be included in the pooled analysis and the Part 2 baseline will be used for those 
subjects in the pooled analysis.
Concomitant medication usage for each subject will be listed for review.
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
16.1.
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Subject disposition will be summarized by treatment group.  All subjects 
enrolled will be included in a summary of subject disposition. 
16.2.
Safety and Tolerability
Safety is the primary objective for the study.  All AEs, laboratory abnormalities, ECGs, and vital 
signs will be evaluated for safety.  
16.2.1.
Analysis Population
Safety analyses will be conducted in the safety population.  This safety set will include all 
subjects who are randomized and receive at least 1 dose of study treatment or sham procedure in 
Part 1.  Treatment duration and amount of study treatment received will be summarized by 
treatment group.  
16.2.2.
Methods of Analysis
16.2.2.1.
Neurological Examinations
Neurological examination findings will be listed for review, and as appropriate, results will be 
summarized descriptively for each treatment group.  The number and percentage of subjects with 
shifts from baseline normal to each of the categorical values denoting normal, abnormal, and 
abnormal (not AE) will be summarized.  


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Note:  If sedation was used, please allow sufficient recovery time for the subject to be fully 
engaged in the examination because change from baseline in neurological examinations outcome
is a primary study endpoint.  It is important that the data collected truly reflect the subject’s 
neurological performance.
16.2.2.2.
Adverse Events
All AEs will be analyzed based on the principle of treatment emergence.  An AE will be 
regarded as treatment emergent if it was present prior to the first dose of study treatment and 
subsequently worsened, or was not present prior to the first dose of study treatment but 
subsequently appeared.  The incidence of treatment-emergent AEs will be summarized overall, 
by severity, and by relationship to study treatment.  A subject having the same AE more than 
once will be counted only once in the incidence for that event.  The occurrence of the AE with 
the greatest severity will be used in the calculation of incidence by severity; the occurrence of the 
AE with the strongest relationship to study treatment will be used in the calculation of incidence 
by relationship to study treatment.
All treatment-emergent AEs and SAEs will be summarized for each treatment group using the 
Medical Dictionary for Regulatory Activities (MedDRA) coding system, by system organ class, 
preferred term, relationship to study treatment, and severity.  Narratives of deaths, SAEs, early 
withdrawals from study treatment and from study due to AEs will be provided. 
16.2.2.3.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities.  The number and 
percentage of subjects with clinically relevant postbaseline abnormalities will be presented.  
Summary statistics for actual values and change from Baseline will also be presented.
16.2.2.4.
ECGs
ECG results will be presented by subject, and as appropriate, results will be summarized 
descriptively for each treatment group.  The number and percentage of subjects with shifts from 
baseline normal to each of the categorical values denoting normal, abnormal clinically 
significant, and abnormal (not clinically significant) will be summarized.
16.2.2.5.
Clinical Laboratory Results
Clinical laboratory evaluations, including hematology, blood chemistry, urinalysis, and urine 
total protein, will be summarized using study visit for each treatment group.  These safety 
variables will also be presented over time after study treatment administration, as appropriate.  
Laboratory parameters will also be summarized using shift tables, as appropriate. 
For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation.
16.2.2.6.
Coagulation Parameters
Coagulation parameters (aPTT, PTT, and INR) will be collected.  The coagulation testing must 
be performed and reviewed prior to dosing.


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16.3.
Efficacy
16.3.1.
Analysis Population
The exploratory analysis of efficacy will be performed on the intent-to-treat population.  The 
intent-to-treat population is defined as all subjects who are randomized and receive at least 
1 dose of study treatment or sham procedure in Part 1. 
16.3.2.
Methods of Analysis
For continuous endpoints, the mean change from baseline will be estimated with 95% confidence 
limits.  For categorical outcomes, the proportion of subjects attaining a specified category will be 
estimated.  Selected endpoints may be pooled across subsets as appropriate.
16.3.2.1.
Sibling SMA Data Collection
If any subject has or had a sibling(s) with SMA and if consent is given, data for the sibling(s) 
will be collected at Day 1 and at the End of Study Evaluation/Early Termination Visit.  Data to 
be collected from siblings with SMA will be nonbiologic and noninvasive and will include 
historical data for SMN2 gene copy number and sibling treatment history.
16.4.
Pharmacokinetics
16.4.1.
Analysis Population
The PK population will include all subjects who are randomized and have at least 1 evaluable 
postdose or postsham-procedure PK sample.
16.4.2.
Methods of Analysis
Plasma PK parameters, as applicable, and Nusinersen concentrations in plasma and CSF for the 
PK population will be summarized using descriptive statistics and, where warranted, presented 
graphically.
16.5.
Immunogenicity
16.5.1.
Analysis Population 
The analysis population for immunogenicity will include all subjects with available 
immunogenicity data.
16.5.2.
Methods of Analysis
Results from the immunogenicity analyses for anti-Nusinersen plasma antibody status and titer 
will be summarized at the specified visits.  
16.6.
Interim Analyses
No formal interim analyses are planned.  However, if the Sponsor decides to terminate Part 1 
early, data prior to the unblinding of the first subject in Part 1 may be archived; no analyses are 


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planned to be conducted based on the archived data.  Full analysis of Part 1 data will be done 
following database lock at the end of Part 1. 
16.7.
Sample Size Considerations
Since this study is exploratory, sample size determination will not be based on power 
consideration.  The sample size considered for this study will allow exploration of safety, 
tolerability, and selected efficacy endpoints in the selected study population.  


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17.
ETHICAL REQUIREMENTS
The Sponsor, 
 (the contract research organization [CRO] for this study), and the 
Investigator must comply with all instructions, regulations, and agreements in this protocol and 
applicable International Council for Harmonisation (ICH) and Good Clinical Practice (GCP) 
guidelines and conduct the study according to local regulations.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  The Sponsor (or designee) will submit documents 
on behalf of the investigational sites in countries other than the US.  
If the Investigator makes any changes to the ICF, the Sponsor (or designee) must approve the 
changes before the ICF is submitted to the ethics committee.  A copy of the approved ICF must 
be provided to the Sponsor (or designee).  After approval, the ICF must not be altered without 
the agreement of the relevant ethics committee and the Sponsor (or designee).
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
The Sponsor (or designee) must receive a letter documenting ethics committee approval, which 
specifically identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  
Protocol amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and the Sponsor (or designee).
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations.  
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 


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subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study.
Subjects will be informed that their race and ethnicity will not be collected for the purposes of 
data analysis during the study. 
In addition, subjects who have the capacity should provide their assent to participate in the study.  
The level of information provided to subjects should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines.
A copy of the signed and dated ICF and assent, if applicable, must be given to the subject or the 
subject’s legally authorized representative.  The original signed and dated ICF will be retained 
with the study records.  Local regulations must be complied with in respect to the final 
disposition of the original (wet signature) and copies of the signed and dated ICFs.
Confirmation of informed consent and assent, if applicable, must also be documented in the 
subject’s medical record.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America).
During the study, subjects’ race and ethnicity will not be collected for the purposes of data 
analysis. 
Study reports will be used for research purposes only.  The subject will not be identified by name 
in CRFs, study-related forms, study reports, or any related publications.  Sponsor, its partners 
and designees, ethics committees, and various government health agencies may inspect the 
records of this study.  Every effort will be made to keep the subject’s personal medical data 
confidential.
17.5.
Compensation for Injury
The Sponsor (or designee) maintains appropriate insurance coverage for clinical studies and will 
follow applicable local compensation laws.
17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor with the subject before the subject makes a decision to participate in the study).
17.7.
Registration of Study and Disclosure of Study Results
The Sponsor (or designee) will register the study and post study results regardless of outcome on 
a publicly accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any subjects prior to completion of a study initiation visit 
conducted by the Sponsor (or designee).  This initiation visit will include a detailed review of the 
protocol and study procedures.
18.2.
Quality Assurance
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will 
be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories.
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate.
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved. 
CRFs will be not be used as source data.  Monitoring visits must be conducted according to the 
applicable ICH and GCP guidelines to ensure protocol adherence, quality of data, study 
treatment accountability, compliance with regulatory requirements, and continued adequacy of 
the investigational site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and the Sponsor.  Biogen will be 
responsible for managing the study globally.  All financial details are provided in the separate 
contract(s) between the institution, Investigator, and the Sponsor. 
18.5.
Publications
Details are included in the clinical trial agreement for this study.


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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
19.1.
External Contract Organizations
The Sponsor may transfer any or all of its study-related responsibilities to a CRO and other third 
parties; however, the Sponsor retains overall accountability for these activities.
19.1.1.
Contract Research Organization 
A CRO will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports and data management.  Before 
subjects are screened at each study site, the CRO will review study responsibilities with the 
Investigators and other study site staff, as appropriate.
19.1.2.
Interactive Response Technology
IRT will be used in this study.  Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system.
19.1.3.
Electronic Data Capture
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool that is developed and supported by an electronic data 
capture vendor and configured by Sponsor or CRO.
19.1.4.
Central Laboratories for Laboratory Assessments
A central laboratory will be selected by the Sponsor to analyze all hematology, blood chemistry, 
urine, and CSF samples collected at all study sites.  Local laboratories may be used to 
accommodate acute or urgent needs as discussed in in the Study Reference Guide.
During the Part 1 Screening Period, a blood sample will be collected for SMN2 copy number 
analysis by the central laboratory only from those subjects without genetic documentation of 
SMN2 copy number.  For all other subjects, a blood sample will be collected at any time during 
the study for analysis of SMN2 copy number by the central laboratory.
19.2.
Study Committees
Safety data will be reviewed on an ongoing quarterly basis throughout Part 1 of the study by an 
independent DSMB.  The DSMB will be assembled to review safety, tolerability, and efficacy 
(as needed) data collected on Nusinersen during the study.  Based on its ongoing assessment of 
the safety and tolerability of Nusinersen, the DSMB will provide recommendations to the 
Sponsor for modifying, stopping, or continuing the study as planned.
19.3.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 


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investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, the Sponsor (or designee) may, at any time, amend this protocol to eliminate an 
apparent immediate hazard to a subject.  In this case, the appropriate regulatory authorities will 
be notified subsequent to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 17.2 and Section 17.3).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify the Sponsor in writing and 
receive written authorization from the Sponsor to destroy study records.  In addition, the 
Investigator must notify the Sponsor of any changes in the archival arrangements including but 
not limited to archival at an offsite facility or transfer of ownership if the Investigator leaves the 
site.
19.6.
Study Report Signatory
The Sponsor will follow all applicable local regulations pertaining to study report signatories.


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20.
REFERENCES
Burghes AH, Beattie CE. Spinal muscular atrophy: why do low levels of survival motor neuron 
protein make motor neurons sick? Nature reviews. 2009;10(8):597-609.
Coovert DD, Le TT, McAndrew PE, et al. The survival motor neuron protein in spinal muscular 
atrophy. Hum Mol Genet. 1997;6(8):1205-14.
Feldkötter M, Schwarzer V, Wirth R, et al. Quantitative analyses of SMN1 and SMN2 based on 
real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of 
spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358-68.
Hua Y, Sahashi K, Hung G, et al. Antisense correction of SMN2 splicing in the CNS rescues 
necrosis in a type III SMA mouse model. Genes Dev. 2010;24(15):1634-44.
Hua Y, Vickers TA, Baker BF, et al. Enhancement of SMN2 exon 7 inclusion by antisense 
oligonucleotides targeting the exon. PLoS Biol. 2007;5(4):e73.
Hua Y, Vickers TA, Okunola HL, et al. Antisense masking of an hnRNP A1/A2 intronic splicing 
silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet. 2008;82(4):834-48.
Le TT, Pham LT, Butchbach ME, et al. SMNDelta7, the major product of the centromeric 
survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and 
associates with full-length SMN. Hum Mol Genet. 2005;14(6):845-57.
Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal 
muscular atrophy. Nat Genet. 1997;16(3):265-9.
Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. 
The EMBO journal. 1996;15(14):3555-65.
Matsuzawa J, Matsui M, Konishi T, et al. Age-related volumetric changes of brain gray and 
white matter in healthy infants and children. Cereb Cortex. 2001;11(4):335-42.
Passini MA, Bu J, Richards AM, et al. Antisense oligonucleotides delivered to the mouse CNS 
ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011;3(72):72ra18.
Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. 
2010;12(3):145-52.
Prior TW, Swoboda KJ, Scott HD, et al. Homozygous SMN1 deletions in unaffected family 
members and modification of the phenotype by SMN2. Am J Med Genet A. 2004;130A(3):307-
10.
Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to age, 
SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-12.


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Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal 
muscular atrophy. J Child Neurol. 2007;22(8):1027-49.
Wirth B, Brichta L, Schrank B, et al. Mildly affected patients with spinal muscular atrophy are 
partially protected by an increased SMN2 copy number. Hum Genet. 2006;119(4):422-8.


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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A phase 2, randomized, double-blind, sham-procedure 
controlled study to assess the safety and tolerability and explore the efficacy of ISIS 396443 
(BIIB058) administered intrathecally in subjects with spinal muscular atrophy who are not 
eligible to participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4” and agree 
to conduct the study according to the protocol and the applicable ICH guidelines and GCP 
regulations, and to inform all who assist me in the conduct of this study of their responsibilities 
and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)








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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .....................................................................................10 
2. 
LIST OF ABBREVIATIONS .....................................................................................11 
3. 
SYNOPSIS .................................................................................................................12 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR 
STUDY 232SM202 ....................................................................................................23 
4.1. 
Study Schematic .........................................................................................................23 
4.2. 
Schedule of Events .....................................................................................................24 
4.2.1. 
Schedule of Events:  Part 1 .........................................................................................24 
4.2.2. 
Schedule of Events:  Part 2 .........................................................................................27 
5. 
INTRODUCTION ......................................................................................................35 
5.1. 
Overview of Spinal Muscular Atrophy .......................................................................36 
5.2. 
Current Therapies for Spinal Muscular Atrophy ........................................................36 
5.3. 
Profile of Previous Experience With ISIS 396443 .....................................................36 
5.3.1. 
Nonclinical Experience ...............................................................................................36 
5.3.2. 
Clinical Experience .....................................................................................................38 
5.4. 
Study Rationale ...........................................................................................................40 
5.4.1. 
Rationale for Part 1 .....................................................................................................40 
5.4.2. 
Rationale for Part 2:  Open-Label Extension Phase ...................................................40 
5.5. 
Rationale for Dose and Schedule Selection ................................................................40 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................41 
6.1. 
Primary Objectives and Endpoints .............................................................................41 
6.2. 
Secondary Objectives and Endpoints .........................................................................42 
6.3. 
Exploratory Objectives and Endpoints .......................................................................42 
7. 
STUDY DESIGN .......................................................................................................44 
7.1. 
Study Overview ..........................................................................................................44 
7.2. 
Overall Study Duration and Follow-Up .....................................................................44 
7.2.1. 
Screening ....................................................................................................................45 
7.2.2. 
Treatment ....................................................................................................................45 
7.2.3. 
Follow-Up ...................................................................................................................47 
7.3. 
Study Stopping Rules .................................................................................................47 
7.4. 
End of Study ...............................................................................................................47 


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7.5. 
Safety Monitoring and Data and Safety Monitoring Board ........................................47 
8. 
SELECTION OF SUBJECTS ....................................................................................48 
8.1. 
Inclusion Criteria ........................................................................................................48 
8.2. 
Exclusion Criteria .......................................................................................................49 
9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................50 
9.1. 
Screening and Enrollment ...........................................................................................50 
9.2. 
Registration and Randomization of Subjects ..............................................................50 
9.3. 
Blinding Procedures ....................................................................................................51 
9.3.1. 
Emergency Unblinding of Treatment Assignment .....................................................51 
10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................52 
10.1. 
Discontinuation of Study Treatment ...........................................................................52 
10.2. 
Withdrawal of Subjects From Study ...........................................................................52 
11. 
STUDY TREATMENT USE .....................................................................................53 
11.1. 
Regimen ......................................................................................................................53 
11.1.1. 
Study Treatment ..........................................................................................................53 
11.1.2. 
Sham Procedure ..........................................................................................................53 
11.2. 
Modification of Dose and/or Treatment Schedule ......................................................54 
11.3. 
Precautions ..................................................................................................................54 
11.4. 
Compliance .................................................................................................................54 
11.5. 
Concomitant Therapy and Procedures ........................................................................54 
11.5.1. 
Concomitant Therapy .................................................................................................54 
11.5.2. 
Concomitant Procedures .............................................................................................55 
12. 
STUDY TREATMENT MANAGEMENT ................................................................55 
12.1. 
Study Treatment ..........................................................................................................55 
12.1.1. 
Study Treatment Preparation ......................................................................................56 
12.1.2. 
Study Treatment Storage ............................................................................................56 
12.1.3. 
Study Treatment Handling and Disposal ....................................................................56 
12.1.4. 
Study Treatment Accountability .................................................................................56 
13. 
EFFICACY, PHARMACOKINETIC, AND IMMUNOGENICITY 
ASSESSMENTS .........................................................................................................57 
13.1. 
Clinical Efficacy Assessments ....................................................................................57 
13.2. 
Pharmacokinetic (ISIS 396443 Concentration) Assessments .....................................57 


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13.3. 
Immunogenicity Assessments ....................................................................................57 
14. 
SAFETY ASSESSMENTS ........................................................................................58 
14.1. 
Clinical Safety Assessments .......................................................................................58 
14.2. 
Laboratory Safety Assessments ..................................................................................58 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................59 
15.1. 
Definitions ..................................................................................................................59 
15.1.1. 
Adverse Event .............................................................................................................59 
15.1.2. 
Serious Adverse Event ................................................................................................59 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................60 
15.2. 
Safety Classifications ..................................................................................................60 
15.2.1. 
Investigator Assessment of Events .............................................................................60 
15.2.2. 
Relationship of Events to Study Treatment ................................................................61 
15.2.3. 
Severity of Events .......................................................................................................61 
15.2.4. 
Expectedness of Events ..............................................................................................61 
15.3. 
Monitoring and Recording Events ..............................................................................61 
15.3.1. 
Adverse Events ...........................................................................................................61 
15.3.2. 
Serious Adverse Events ..............................................................................................62 
15.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................62 
15.3.3.1. 
Deaths .........................................................................................................................63 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................63 
15.4. 
Procedures for Handling Special Situations ...............................................................63 
15.4.1. 
Overdose .....................................................................................................................63 
15.4.2. 
Medical Emergency ....................................................................................................63 
15.4.2.1. 
Unblinding for Medical Emergency ...........................................................................63 
15.5. 
Safety Responsibilities ................................................................................................64 
15.5.1. 
The Investigator ..........................................................................................................64 
15.5.2. 
The Sponsor ................................................................................................................64 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........65 
16.1. 
Demographic and Baseline Characteristics ................................................................65 
16.2. 
Safety and Tolerability ...............................................................................................65 
16.2.1. 
Analysis Population ....................................................................................................65 


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16.2.2. 
Methods of Analysis ...................................................................................................65 
16.2.2.1. 
Neurological Examinations ........................................................................................65 
16.2.2.2. 
Adverse Events ...........................................................................................................66 
16.2.2.3. 
Vital Signs ..................................................................................................................66 
16.2.2.4. 
ECGs ...........................................................................................................................66 
16.2.2.5. 
Clinical Laboratory Results ........................................................................................66 
16.3. 
Efficacy .......................................................................................................................66 
16.3.1. 
Analysis Population ....................................................................................................66 
16.3.2. 
Methods of Analysis ...................................................................................................66 
16.4. 
Pharmacokinetics ........................................................................................................67 
16.4.1. 
Analysis Population ....................................................................................................67 
16.4.2. 
Methods of Analysis ...................................................................................................67 
16.5. 
Immunogenicity ..........................................................................................................67 
16.5.1. 
Analysis Population ....................................................................................................67 
16.5.2. 
Methods of Analysis ...................................................................................................67 
16.6. 
Interim Analyses .........................................................................................................67 
16.7. 
Sample Size Considerations .......................................................................................67 
17. 
ETHICAL REQUIREMENTS ...................................................................................68 
17.1. 
Declaration of Helsinki ...............................................................................................68 
17.2. 
Ethics Committee ........................................................................................................68 
17.3. 
Subject Information and Consent ...............................................................................68 
17.4. 
Subject Data Protection ..............................................................................................69 
17.5. 
Compensation for Injury .............................................................................................69 
17.6. 
Conflict of Interest ......................................................................................................69 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................69 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................70 
18.1. 
Study Site Initiation ....................................................................................................70 
18.2. 
Quality Assurance .......................................................................................................70 
18.3. 
Monitoring of the Study ..............................................................................................70 
18.4. 
Study Funding .............................................................................................................70 
18.5. 
Publications .................................................................................................................70 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................71 


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19.1. 
External Contract Organizations .................................................................................71 
19.1.1. 
Contract Research Organization .................................................................................71 
19.1.2. 
Interactive Response Technology ...............................................................................71 
19.1.3. 
Electronic Data Capture ..............................................................................................71 
19.1.4. 
Central Laboratories for Laboratory Assessments .....................................................71 
19.2. 
Study Committees .......................................................................................................71 
19.3. 
Changes to Final Study Protocol ................................................................................71 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................72 
19.5. 
Retention of Study Data ..............................................................................................72 
19.6. 
Study Report Signatory ...............................................................................................72 
20. 
REFERENCES ...........................................................................................................73 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................75 
 
 
 


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LIST OF TABLES 
Table 1 
ISIS 396443 Dose Volume To Be Injected ................................................................18 
Table 2: 
Part 1 Schedule of Activities ......................................................................................24 
Table 3: 
Part 2 Schedule of Activities for Subjects Randomized to Receive ISIS 
396443 in Part 1 ..........................................................................................................27 
Table 4: 
Part 2 Schedule of Activities for Subjects Randomized to Receive Sham 
Procedure in Part 1 ......................................................................................................30 
Table 5 
Part 1 Pharmacokinetic Sampling Schedule1 ..............................................................33 
Table 6 
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive ISIS 396443 in Part 11 ..................................................................................33 
Table 7 
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive Sham Procedure in Part 11 ............................................................................34 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................23 
Figure 2: 
Antisense Oligonucleotide Therapeutic Approach for Treatment of Spinal 
Muscular Atrophy .......................................................................................................35 
 




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2. 
LIST OF ABBREVIATIONS 
 
2′ MOE 
2′ O (2 methoxyethyl) 
AE 
adverse event 
ASO 
antisense oligonucleotide 
Bi-PAP 
bi-level positive airway pressure  
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
DHA 
Directions for Handling and Administration 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
GCP 
Good Clinical Practice 
HINE 
Hammersmith Infant Neurological Examination 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRT 
interactive response technology 
LP 
lumbar puncture 
mRNA 
messenger ribonucleic acid 
OLE 
open-label extension 
PK 
pharmacokinetic(s) 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SMA 
spinal muscular atrophy 
SMN 
survival motor neuron 
SMN1 
survival motor neuron 1 
SMN2 
survival motor neuron 2 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time to reach maximum observed concentration 


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3. 
SYNOPSIS 
This is a brief summary.  For details, refer to the body of the protocol. 
Protocol Number: 
232SM202 
Protocol Title: 
A Phase 2, randomized, double-blind, sham-procedure controlled study 
to assess the safety and tolerability and explore the efficacy of 
ISIS 396443 (BIIB058) administered intrathecally in subjects with spinal 
muscular atrophy who are not eligible to participate in the clinical 
studies ISIS 396443-CS3B or ISIS 396443-CS4  
Version Number: 
3  
Name of Study 
Treatment: 
ISIS 396443 (BIIB058) 
Study Indication: 
Spinal muscular atrophy (SMA) 
Phase of 
Development: 
2 
Study Rationale: 
The rationale of Part 1 of the study is to assess the safety and tolerability 
and evaluate the utility of selected exploratory efficacy endpoints in 
subjects with SMA treated intrathecally with ISIS 396443 who are not 
eligible for the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4. 
Based on emergent data from the ISIS 396443 clinical development 
program, the Sponsor may decide to terminate Part 1 early, and all 
subjects may be offered the opportunity to transition to Part 2 (the open-
label extension phase) prior to completion of all Part 1 evaluations.  The 
rationale of Part 2 of the study is to assess the long-term safety and 
tolerability of ISIS 396443 in subjects with SMA who participated in 
Part 1 and completed their End of Part 1 Evaluation assessments. 
Study Objectives and 
Endpoints: 
Part 1 
Primary objective: 
The primary objective of Part 1 of this study is:  
 To assess the safety and tolerability of ISIS 396443 in 
subjects with SMA who are not eligible to participate in the 
clinical studies ISIS 396443-CS3B or ISIS 396443-CS4. 
The primary endpoints that relate to this objective are: 
 Incidence of adverse events (AEs) and serious AEs (SAEs) 


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 Change from baseline in clinical laboratory parameters, 
electrocardiograms (ECGs), and vital signs 
 Change from baseline in neurological examination outcomes 
Secondary objective: 
The secondary objective and endpoint of Part 1 of this study are as 
follows: 
 To examine the pharmacokinetics (PK) of ISIS 396443 in 
subjects with SMA who are not eligible to participate in the 
clinical studies ISIS 396443-CS3B or ISIS 396443-CS4 
 ISIS 396443 concentrations in plasma and cerebrospinal fluid 
(CSF) 
Part 2 
Primary objective: 
The primary objective of Part 2 of this study is: 
 To assess the long-term safety and tolerability of ISIS 396443 
in subjects with SMA who participated in Part 1 and 
completed their End of Part 1 Evaluation assessments. 
The primary endpoints that relate to this objective are: 
 Incidence of AEs and SAEs 
 Change from baseline in clinical laboratory parameters, 
ECGs, and vital signs 
 Change from baseline in neurological examination outcomes 
Secondary objective: 
The secondary objective and endpoint of Part 2 of this study are as 
follows: 
 To examine the PK of ISIS 396443 in subjects with SMA 
who participated in Part 1 and completed their End of Part 1 
Evaluation assessments 
 ISIS 396443 concentrations in plasma and CSF 
Exploratory objectives and endpoints are listed in Section 6.3. 
Study Design: 
This is a Phase 2 multicenter study conducted in 2 parts: 
Part 1 was originally designed as a randomized, double-blind, 
sham-procedure controlled study to assess the safety and tolerability and 
explore the efficacy of intrathecally administered ISIS 396443 over a 
period of approximately 14 months (from the first dose until the End of 
Part 1 Evaluation).  Up to 21 subjects will be randomized in a ratio of 


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2:1 to receive ISIS 396443 by intrathecal lumbar puncture (LP) injection 
or a sham-procedure control.  Randomization will be stratified based on 
age at onset of clinical signs and symptoms consistent with SMA:  
>6 months versus <6 months. 
After informed consent is obtained, subjects will undergo a screening 
evaluation no greater than 28 days prior to administration of the first 
dose of study treatment.  Subjects who meet the eligibility criteria will be 
randomized to receive ISIS 396443 or sham procedure.  Subjects will be 
admitted to the study site on Part 1 Day 1, undergo predose evaluations, 
and then receive an LP injection of study treatment or sham procedure.  
Subjects will return to the study site on Days 15, 29, 64, 183, and 302 for 
follow-up evaluations and subsequent injections or sham procedures.  
For subjects receiving ISIS 396443 or sham procedure, a CSF sample 
will be taken predose on each injection day in a manner that maintains 
the blind. 
After the study treatment dosing or sham procedure on Day 1, subjects 
will remain at the study site for at least 24 hours for safety monitoring.  
Following all subsequent injections, all subjects will remain at the study 
site for at least 6 hours postdose for safety monitoring.  
Safety monitoring will occur on the day following each injection of 
study treatment or sham procedure.  Subjects receiving the dosing or 
sham procedure on Days 15, 29, 64, 183, and 302 will be monitored by 
telephone contact on Days 16, 30, 65, 184, and 303. 
In addition, subjects will also be monitored through telephone contact 
throughout the duration of the study. 
An End of Part 1 Evaluation will occur up to 4 months after the last dose 
of ISIS 396443 or sham procedure, or sooner (if the Sponsor decides to 
terminate Part 1 early based on emergent data from the ISIS 396443 
clinical development program, as described below).  Subjects who 
terminate early from Part 1 of the study will be encouraged to complete 
the End of Part 1 Evaluation assessments at the time of withdrawal. 
After completing End of Part 1 Evaluation assessments according to the 
study schedule or sooner, if emergent data from the ISIS 396443 clinical 
development program necessitate the early termination of Part 1 by the 
Sponsor, all eligible subjects may elect to enroll in Part 2.  All subjects 
enrolled in the study at the time that the Sponsor terminates Part 1 will 
be considered Part 1 completers.  The next study evaluation for those 
subjects will serve as an End of Part 1 Evaluation, which may occur at 
any time prior to the next scheduled Part 1 study evaluation.  
Based on emergent data from the ISIS 396443 clinical development 
program, the Sponsor may decide to terminate Part 1 early, and all 
subjects may then be offered the opportunity to be unblinded and 


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transition to Part 2 prior to completion of all Part 1 evaluations.  Part 2 is 
an open-label extension (OLE) phase that will assess long-term safety 
and tolerability and explore the efficacy of intrathecally administered 
ISIS 396443 for approximately 24 additional months (or until 
availability of commercial product). 
Part 2 study procedures will be determined based on the treatment 
assignment in Part 1. 
Subjects who were randomized to receive ISIS 396443 in Part 1 
End of Part 1 Evaluation assessments will be used to determine subject 
eligibility for Part 2 of the study.  For subjects who were receiving 
ISIS 396443 in Part 1, Part 2 Day 1 will occur following the End of 
Part 1 Evaluation or approximately 4 months following the last injection 
of ISIS 396443 in Part 1.  On Part 2 Day 1, subjects will undergo 
predose evaluations according to the schedule of events and then receive 
their first dose of ISIS 396443 for Part 2 (next maintenance dose).  
Subjects will return to the study site on Days 120, 239, 358, 477, 596, 
and 715 for follow-up evaluations and subsequent maintenance dose 
injections.  All subjects will remain at the study site for at least 1 hour 
postdose for safety monitoring and can be discharged at the discretion of 
the site Investigator and in compliance with the institutional 
requirements once the subjects have adequately recovered from the 
dosing procedure.  
Safety monitoring by telephone contact will occur on the day after 
injection of study treatment.  Subjects will be monitored by telephone 
contact on Days 2, 121, 240, 359, 478, 597, and 716. 
In addition, subjects will be monitored through telephone contact 
throughout the duration of the study. 
A Part 2 Final Follow-up Evaluation will occur approximately 4 months 
after the last dose in Part 2.  Subjects who terminate early from Part 2 of 
the study will be encouraged to complete the Part 2 Early Termination 
Evaluation assessments at the time of withdrawal.  
Subjects who were randomized to receive sham procedure in Part 1 
End of Part 1 Evaluation assessments will be used to determine 
eligibility for Part 2 of the study.  For subjects who were receiving sham 
procedure in Part 1, Part 2 Day 1 will occur following the End of Part 1 
Evaluation or as soon as possible following the End of Part 1 Evaluation, 
in the event of early termination due to emergent data from the 
ISIS 396443 clinical development program.  On Part 2 Day 1, subjects 
will undergo predose evaluations according to the schedule of events and 
then receive their first dose of ISIS 396443 (first loading dose).  Subjects 
will return to the study site on Days 15, 29, 64, 183, 302, 421, 540, 659, 
and 778 for follow-up evaluations and subsequent injections.  Subjects 


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will remain at the study site for at least 24 hours on Day 1.  Following all 
subsequent injections, all subjects will remain at the study site for at least 
1 hour postdose for safety monitoring and can be discharged at the 
discretion of the site Investigator and in compliance with the institutional 
requirements once the subjects have adequately recovered from the 
dosing procedure.  
Safety monitoring by telephone contact will occur on the day after 
injection of study treatment after Day 1.  Subjects will be monitored by 
telephone contact on Days 16, 30, 65, 184, 303, 422, 541, 660, and 779. 
In addition, subjects will be monitored through telephone contact 
throughout the duration of the study. 
A Part 2 Final Follow-up Evaluation will occur approximately 4 months 
after the last dose in Part 2.  Subjects who terminate early from Part 2 
will be encouraged to complete the Part 2 Early Termination Evaluation 
assessments at the time of withdrawal. 
 
 


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Rationale for Dose 
and Schedule 
Selection: 
 
In Part 1, a scaled equivalent dose of 12 mg ISIS 396443 will be 
administered at each of the 6 doses (i.e., on Study Days 1, 15, 29, 64, 
183, and 302) over a dosing period of approximately 10 months to 
subjects randomized to receive active treatment. 
In Part 2, a scaled equivalent dose of 12 mg ISIS 396443 will be 
administered at each dose over a dosing period of approximately 
24 months (or until availability of the commercial product). 
The volume of the injection will be adjusted based on the subject’s age 
on the day of dosing as shown in Table 1, such that each subject will 
receive a 12-mg scaled equivalent dose based on CSF volume scaling.  
Thus, younger subjects will be given a lower absolute mg dose of study 
treatment, achieved by injecting a smaller volume that is proportional to 
estimated CSF volume for age, such that dose volume will be equivalent 
to 5 mL for 2 years of age to adult. 
The dose regimen and the dose interval for this study were selected 
based on nonclinical toxicology and PK observations from monkey 
studies using single-dose and repeat-dose intrathecal administration, 
consideration of the target tissue concentration anticipated for drug 
pharmacology, and safety data in the completed and ongoing clinical 
studies of ISIS 396443 to date.  Based on pharmacology and PK results 
in SMA transgenic mice, it is estimated that a target spinal cord tissue 
concentration between 1 and 10 μg/g will produce 50% to 90% SMN2 
exon 7 inclusion.  Nonclinical studies in juvenile monkeys receiving 
intrathecal doses of ISIS 396443 showed a resulting gradient of 
distribution of ISIS 396443 along the spinal cord, with mean lumbar 
spinal cord concentrations ranging from 1.6- to 2.3-fold and 2.0- to 
3.5-fold higher than thoracic and cervical spinal cord levels, 
respectively.  The dose selected for this multiple-dose clinical study 
(equivalent to 12 mg of ISIS 396443) is predicted to achieve levels at the 
high end of this range (approximately 10 μg/g lumbar and 3 μg/g 
cervical spinal cord tissue concentrations) after the first dose.  The 
loading dose interval (i.e., doses on Days 1, 15, 29, and 64) was selected 
based on the nonclinical PK and pharmacology data in order to achieve 
and maintain ISIS 396443 spinal cord tissue levels that are predicted to 
be above or within the upper end of the pharmacologically active range 
by Day 64 (approximately 30 μg/g lumbar and 10 μg/g cervical tissue 
concentration), while at the same time considering subject safety and 
convenience for repeated intrathecal injections by LP.  The higher 
number of loading doses would allow for the evaluation of safety and 
tolerability and preliminary exploratory efficacy endpoints in a broader 
population of subjects with SMA, including those who have onset of 
clinical signs and symptoms at >6 months of age but who are not eligible 
for Study ISIS 396443-CS4.  The maintenance dose interval (once every 


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4 months) was selected based on the estimated spinal tissue and CSF 
drug half-life (4 to 6 months) and was selected to maintain spinal cord 
tissue levels of ISIS 396443 at a steady-state level within the estimated 
pharmacologically active range.  In Part 1, maintenance doses will be 
given on Day 183 and Day 302, for a total of 6 doses over approximately 
10 months.  Subjects who were receiving ISIS 396443 in Part 1 will 
continue receiving maintenance doses in Part 2 every 4 months.  
Subjects who were receiving sham in Part 1 will receive maintenance 
doses starting on Day 183 of Part 2. 
 
Table 1 
ISIS 396443 Dose Volume To Be Injected 
Age 
Estimated 
CSF Volume 
(mL) 
Injection 
Volume (mL) 
Dose (mg) 
0-3 months 
(0-90 days) 
120 
4 
9.6 
3-6 months 
(91-182 days) 
130 
4.3 
10.3 
6-12 months 
(183-365 days) 
135 
4.5 
10.8 
12-24 months 
(366-730 days) 
140 
4.7 
11.3 
>24 months 
(>730 days) 
150 
5.0 
12.0 
Source: [Matsuzawa 2001] 
CSF = cerebrospinal fluid. 
Study Location: 
Global, multicenter 
Number of Planned 
Subjects: 
In Part 1, up to 21 subjects are planned (14 ISIS 396443; 7 sham 
procedure). 
In Part 2, up to 21 subjects are planned (21 ISIS 396443). 
Study Population: 
Part 1 of this study will be conducted in subjects who have clinical signs 
and symptoms of SMA at ≤6 months of age or at >6 months of age and 
who are not eligible for the clinical studies ISIS 396443-CS3B or 
ISIS 396443-CS4.  
Part 2 will include only subjects who participated in Part 1 and 
completed their End of Part 1 Evaluation assessments.  Subjects 
enrolling in Part 2 must meet the Part 2-specific criteria. 
Detailed eligibility criteria are described in Section 8. 


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Treatment Groups: 
In Part 1, subjects will receive either ISIS 396443 intrathecally or 
sham-procedure control in a 2:1 ratio.  Randomization will be balanced 
for the stratification factor (age of symptom onset >6 months versus 
<6 months).  A single dose level of 12 mg ISIS 396443 will be scaled by 
age at the time of dosing for each subject. 
In Part 2, all subjects will receive open-label ISIS 396443.  A single dose 
level of 12 mg ISIS 396443 will be scaled by age at the time of dosing 
for each subject. 
Duration of 
Treatment and 
Follow-up: 
For subjects who meet the eligibility criteria and enroll in Part 1 of the 
study, the duration of Part 1 will be approximately 15 months (450 days) 
and will include a Screening Period of no greater than 28 days, a 
302-day Treatment Period, and an End of Part 1 Evaluation 
approximately 4 months after the last dose.  Based on emergent data 
from the ISIS 396443 clinical development program, the Sponsor may 
decide to terminate Part 1 early, and all subjects may be offered the 
opportunity to transition to Part 2 prior to completion of all Part 1 
evaluations. 
For subjects who meet the eligibility criteria and enroll in Part 2 of the 
study, the duration of Part 2 will be approximately 28 months and will 
include an open-label Treatment Period of approximately 24 months (or 
until availability of commercial product) and a Part 2 Final Follow-up 
Evaluation approximately 4 months after the last dose of study treatment. 
Total study duration for subjects who participate in both Part 1 and 
Part 2 will be approximately 43 months. 
Criteria for 
Evaluation: 
The criteria for evaluation for Part 1 and Part 2 are as follows: 
Safety: 
 Neurological examinations (assessment of mental status, level of 
consciousness, sensory motor function, cranial nerve function, 
and reflexes)  
 AEs, including SAEs 
 Vital signs (resting systolic and diastolic blood pressure, pulse 
rate, respiratory rate, temperature, pulse oximetry, and 
transcutaneous carbon dioxide) 
 Weight 
 Physical examinations 
 Medical history 
 12-Lead ECGs 


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 Use of concomitant medications 
 Clinical laboratory tests (blood chemistry, hematology, and 
urinalysis) 
Pharmacokinetics: 
 Plasma ISIS 396443 concentrations 
 CSF ISIS 396443 concentrations 
Efficacy: 
 Ventilator use  
 Hammersmith Infant Neurological Examination (HINE, 
Section 2) 
 Growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for 
length, and head to chest circumference ratio) 
 Clinical Global Impression of Change (physician and caregiver 
assessment) 
Immunogenicity: 
 Anti-ISIS 396443 plasma antibody concentrations 


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Statistical Methods: 
 
Analysis Population 
The intent-to-treat population is defined as all subjects who are 
randomized and receive at least 1 dose of study treatment or sham 
procedure. 
The safety population will include all subjects who are randomized and 
receive at least 1 dose of study treatment or sham procedure.  
The PK population will include all subjects who are randomized and 
have at least 1 evaluable postdose or postsham-procedure PK sample.  
Part 1 
Safety Analysis 
The analysis of safety will be performed on the safety population.  The 
incidence of treatment-emergent AEs and SAEs will be tabulated.  
Changes from baseline in clinical laboratory parameters, vital signs, and 
ECG parameters will be summarized.  Incidence of clinically relevant 
changes from baseline in vital signs and ECGs will be summarized.  
Laboratory parameters will also be summarized using shift tables, as 
appropriate. 
PK Analysis 
Summary statistics for plasma and CSF concentrations of ISIS 396443 
will be provided.   
Exploratory Analysis 
For continuous endpoints, the mean change from baseline will be 
estimated with 95% confidence limits.  For categorical outcomes, the 
proportion of subjects attaining a specified category will be estimated.  
Selected endpoints may be pooled across subsets as appropriate.  
Part 2 
No formal statistical analyses will be performed.  Descriptive statistics 
will be presented for safety and efficacy data collected. 
Interim Analysis:  
No formal interim analyses are planned.  However, if the Sponsor 
decides to terminate Part 1 early, data prior to the unblinding of the first 
subject in Part 1 may be archived; no analyses are planned to be 
conducted based on the archived data.  Full analysis of Part 1 data will 
be done following database lock at the end of Part 1.  
Sample Size 
Determination: 
 
Since this study is exploratory, sample size determination will not be 
based on power consideration.  The sample size considered for this study 
will allow exploration of safety, tolerability, and selected efficacy 
endpoints in the selected study population. 


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Study Stopping 
Rules: 
The Sponsor may terminate this study at any time, after informing 
Investigators.  Investigators will be notified by the Sponsor if the study is 
placed on hold, completed, or closed. 


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4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR STUDY 232SM202 
4.1. 
Study Schematic 
Figure 1: 
Study Schematic 
 
1Study visits may continue every 4 months beyond Year 2 if commercial product is not yet available. 


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4.2. 
Schedule of Events 
4.2.1. 
Schedule of Events:  Part 1 
Table 2: 
Part 1 Schedule of Activities  
Study Period 
Screen1 
Part 1 Treatment/Follow-Up 
Study Day 
Days -28 
to -1 
Day 1 
Day 22 
Day 15 (±1 day) 
Day 
162  
Day 29 (±1 day) 
Day 
302  
Days 64, 183, 302 
(±7 days) 
Days 
65, 
184, 
3032  
End of 
Part 13,4,5 
 
 
Predose LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs6 
X 
X 
 
4X7 
X8 
X 
 
X 
 
X 
 
4X7 
 
X 
 
4X7 
 
X 
Weight 
X 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Growth Parameters9 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Ventilator Use 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Neurological 
Examination10 
X 
X 
 
X11 
X 
X 
 
X11 
 
X 
 
X11 
 
X 
 
X11 
 
X 
ECG  
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Safety Laboratory 
Tests12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
 
 
 
X14 
Coagulation 
Laboratory Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
Sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
CSF PK15 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Plasma PK 
 
 
 
X16 
 
 
 
 
 
 
 
 
 
X17 
 
 
 
X 
Study Treatment 
Injection or Sham 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 


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Study Period 
Screen1 
Part 1 Treatment/Follow-Up 
Study Day 
Days -28 
to -1 
Day 1 
Day 22 
Day 15 (±1 day) 
Day 
162  
Day 29 (±1 day) 
Day 
302  
Days 64, 183, 302 
(±7 days) 
Days 
65, 
184, 
3032  
End of 
Part 13,4,5 
 
 
Predose LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
Procedure 
Inpatient Stay18  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone Contact for 
Safety Monitoring2 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
HINE Motor 
Milestone 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical Global 
Impression of Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Con Med Recording19 
X ----------------------------------------------------------------------------------------------------------------------- X 
Adverse Event 
Collection20 
X ----------------------------------------------------------------------------------------------------------------------- X 
AE = adverse event; Bi-PAP = bilevel positive airway pressure; Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; 
HINE = Hammersmith Infant Neurological Examination; LP = lumbar puncture; PK = pharmacokinetic(s); SAE = serious adverse event; SMA = spinal 
muscular atrophy; SMN2 = survival motor neuron 2 
1 A blood sample will be collected at Screening for SMN2 copy number only from those subjects without genetic documentation of SMN2 copy number.  For all 
other subjects, a blood sample will be collected at any time during the study for analysis of SMN2 copy number by the central laboratory. 
2 After the injection of study treatment or sham procedure on Day 1, subjects will remain at the study site for at least 24 hours (Day 2) for safety monitoring.  On 
the day following the injection of study treatment or sham procedure on Days 15, 29, 64, 183, and 302, there will be safety monitoring through telephone 
contact.  During that telephone contact (i.e., Days 16, 30, 65, 184 and 303), changes in concomitant medications and AEs, information on the subject’s daily 
ventilator/Bi-PAP use, and health status will be recorded.   
3 End of Part 1 is one of the following:  Part 1 Final Follow-up Evaluation (Day 422 [±7 days]) according to the study schedule, early Part 1 Final Follow-up 
Evaluation to allow for rollover into Part 2, or Early Termination Evaluation for subjects who withdraw from the study during Part 1. 
4 For subjects not transitioning into Part 2, the date of the End of Part 1 Evaluation assessments will be the End of study.  For subjects who transition to Part 2, 
the date of the End of Part 1 will be the date of first dose in Part 2. 
5 At the End of Part 1 evaluation, in order to allow transition to Part 2, subjects will be unblinded.  
6 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each evaluation.  For subjects who are not receiving noninvasive ventilation, 
pulse oximetry will be measured overnight once a week at home.   
7 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected at 4 timepoints:  1, 2, 4, 
and 6 hours (all ±15 minutes) after the injection of study treatment. 
8 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected within 20 to 24 hours 
after the injection of study treatment or sham procedure. 


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9 At the evaluations scheduled for injection of study treatment or sham procedure, subjects will be assessed for the following growth parameters:  body length, 
head circumference, chest circumference, and arm circumference.   
10 Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes. 
11Neurological examinations will occur between 4 to 6 hours after the injection of study treatment or sham procedure. 
12Blood chemistry, hematology, and urinalysis panels.  
13 Samples for safety laboratory tests will be collected before the injection of study treatment or sham procedure on Days 64 and 183 only.  
14End of Part 1 safety laboratory tests may be performed locally in addition to centrally to accommodate the Part 2 Day 1 dosing.  
15Refer to Table 5 for CSF PK sample schedule.  The CSF samples will be analyzed for ISIS 396443 concentrations.  The remaining CSF sample will be stored 
for optional future biomarker analyses.   
16Blood samples for PK assessment will be collected 4 hours (±1 hour) after the injection of study treatment or sham procedure only on Day 1.  Refer to Table 5 
for the plasma PK sample schedule. 
17Blood samples for PK assessment will be collected before the injection of study treatment or sham procedure on Days 64 and 183 only.  Refer to Table 5 for the 
plasma PK sample schedule. 
18Overnight stay (at least 24 hours) is required after the first injection of study treatment or sham procedure.  Following all subsequent injections or sham 
procedures, a stay of at least 6 hours at the study site is required; overnight stays are optional on these days. 
19In addition to concomitant medications, ancillary procedures will be recorded. 
20AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2. 
 


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4.2.2. 
Schedule of Events:  Part 2 
Table 3: 
Part 2 Schedule of Activities for Subjects Randomized to Receive ISIS 396443 in Part 1  
Study Period 
Part 2 Treatment/Follow-Up 
Study Day 
Day 1 
Day 21 
Days 120, 239, 358, 477, 596, 715 (±7 days)2 
Days 121, 240, 
359, 478, 597, 
7161 
Part 2 Final Follow-Up 
(Day 835 [±7 days])3or Part 2 
Early Termination4 
 
 
Predose5 
LP 
Postdose 
Predose 
LP 
 
Postdose 
Informed Consent 
X5 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
Criteria 
X5 
 
 
 
 
 
 
 
 
Vital Signs6 
X7 
 
X8 
 
X 
 
X8 
 
X 
Weight 
X7 
 
 
 
X 
 
 
 
X 
Growth Parameters9 
X7 
 
 
 
X 
 
 
 
X 
Physical Examination 
X7 
 
 
 
X 
 
 
 
X 
Ventilator Use 
X7 
 
 
X 
X 
 
 
X 
X 
Neurological 
Examination10 
X7 
 
X11 
 
X 
 
X11 
 
X 
ECG 
X7 
 
 
 
X12 
 
 
 
X12 
Safety Laboratory 
Tests13 
X7 
 
 
 
X14 
 
 
 
X 
Immunogenicity 
Sample  
X7 
 
 
 
X15 
 
 
 
X 
CSF PK16 
X5, 7 
 
 
 
X 
 
 
 
 
Plasma PK17 
 
 
X17 
 
X17 
 
 
 
X 
Study Treatment 
Injection  
 
X 
 
 
 
X 
 
 
 
Telephone Contact for 
Safety Monitoring 
 
 
 
X 
 
 
 
X 
 
HINE Motor 
Milestone 
 
 
 
 
X 
 
 
 
X 
Clinical Global 
Impression of Change 
 
 
 
 
X 
 
 
 
X 


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Study Period 
Part 2 Treatment/Follow-Up 
Study Day 
Day 1 
Day 21 
Days 120, 239, 358, 477, 596, 715 (±7 days)2 
Days 121, 240, 
359, 478, 597, 
7161 
Part 2 Final Follow-Up 
(Day 835 [±7 days])3or Part 2 
Early Termination4 
 
 
Predose5 
LP 
Postdose 
Predose 
LP 
 
Postdose 
Con Med Recording18 
X---------------------------------------------------------------------------------------------------------------------------------X 
Adverse Event 
Collection19 
X---------------------------------------------------------------------------------------------------------------------------------X 
AE = adverse event; Bi-PAP = bilevel positive airway pressure; Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; 
HINE = Hammersmith Infant Neurological Examination; LP = lumbar puncture; PK = pharmacokinetic(s); SAE = serious adverse event. 
1 There will be safety monitoring through telephone contact on the day following the injection of study treatment (i.e., Days 2, 121, 240, 359, 478, 597, and 716).  
During that telephone contact, changes in concomitant medications and AEs, information on the subject’s daily ventilator/Bi-PAP use, and health status will be 
recorded. 
2 Subjects may continue receiving study treatment injection every 4 months beyond Year 2 until commercial availability of the product.  If the study continues 
beyond Year 2 (i.e., beyond Day 715), then from Day 835 onwards, subjects will maintain evaluations for study treatment injection every 4 months with the 
assessments for those additional timepoints to alternate between the assessments done on Day 120 and those done on Day 239.  Day 120 assessments would be 
performed at Day 835 and Day 239 assessments would be performed at Day 954.  The alternating pattern would continue until the end of the study.  Part 2 
Final Follow-up Evaluation would then occur approximately 4 months after the last injection of study treatment. 
3 The Part 2 Final Follow-up Evaluation will occur 4 months after the last injection of study treatment, which will either be on Day 716, if the product is 
commercially available, or later, if Part 2 of the study continues beyond Year 2.  
4 Subjects who terminate early will be encouraged to complete the safety evaluations scheduled for the Part 2 Early Termination Evaluation. 
5 Inclusion/Exclusion Criteria, Informed Consent, and CSF PK must be performed on Part 2 Day 1.  
6 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each evaluation.  For subjects who are not receiving noninvasive ventilation, 
pulse oximetry will be measured overnight once a week at home. 
7 If Part 2 Day 1 study treatment injection is delayed more than 24 hours after the End of Part 1 visit, the following procedures must be done on Part 2 Day 1 
predose:  vital signs, weight, growth parameters, physical examination, ventilator use, neurological examination, and CSF PK.  If Part 2 Day 1 study treatment 
injection is delayed more than 24 hours after End of Part 1 due to an AE, SAE, or other safety concern, or if Part 2 Day 1 study treatment injection is delayed 
more than 30 days after End of Part 1 for any reason, the following procedures must be done on Part 2 Day 1 predose:  vital signs, weight, growth parameters, 
physical examination, ventilator use, neurological examination, ECG, CSF PK, and safety laboratory tests.  Immunogenicity testing must also be repeated 
predose if Part 2 Day 1 study treatment injection is delayed more than 30 days after End of Part 1 for any reason.  
8 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected 1 hour (±15 minutes) 
after the injection of study treatment.   
9 At the evaluations scheduled for injection of study treatment, subjects will be assessed for the following growth parameters:  body length, head circumference, 
chest circumference, and arm circumference.  Growth parameters and weight are to be collected at the same time. 
10 Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes. 
11 Neurological examinations will occur 1 hour after the injection of study treatment. 
12ECG will be performed on Days 239, 477, and 715, and at the Part 2 Final Follow-up Evaluation.  ECG must be performed before obtaining blood samples for 
safety laboratory tests. 
13Blood chemistry, hematology, and urinalysis panels. 
14Samples for safety laboratory tests will be collected before the injection of study treatment on the same days as ECG, plasma PK, and immunogenicity samples.  
15Blood samples for immunogenicity testing will be collected before the injection of study treatment on Days 239, 477, and 715. 


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16Refer to Table 6 for CSF PK sample schedule.  The CSF samples will be analyzed for ISIS 396443 concentrations.  The remaining CSF sample will be stored 
for optional future biomarker analyses. 
17Blood samples for PK assessment will be collected 4 hours (±1 hour) after the injection of study treatment only on Day 1.  Refer to Table 6 for the plasma PK 
sample schedule.  Plasma PK samples will be collected predose on Days 239, 477, and 715. 
18In addition to concomitant medications, ancillary procedures will be recorded. 
19AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2. 
 


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Table 4: 
Part 2 Schedule of Activities for Subjects Randomized to Receive Sham Procedure in Part 1 
Study Period 
Part 2 Treatment/Follow-Up 
Study Day 
Day 1 
Day 
21 
Day 15 (±1 day) 
Day 161 
Day 29 (±1 day) 
Day 
301  
Days 64, 183, 302, 
421, 540, 659, 778 
(±7 days)2  
Days 
65, 184, 
303, 
422, 
541, 
660, 
7791 
Part 2 Final 
Follow-Up 
(Day 897 
[±7 days])3 or 
Part 2 Early 
Termination4 
 
Predose5 LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
Informed Consent 
X5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs6 
X7 
 
X8 
X9 
X 
 
X8 
 
X 
 
X8 
 
X 
 
X8 
 
X 
Weight 
X7 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Growth 
Parameters10 
X7 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical 
Examination 
X7 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Ventilator Use 
X7 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Neurological 
Examination11 
X7 
 
X12 
X 
X 
 
X12 
 
X 
 
X12 
 
X 
 
X12 
 
X 
ECG 
X7 
 
 
X 
 
 
 
 
 
 
X 
 
X13 
 
 
 
X13 
Safety Laboratory 
Tests14 
X7 
 
 
 
 
 
 
 
 
 
 
 
X15 
 
 
 
X 
Coagulation 
Laboratory Tests 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
Sample 
X7 
 
 
 
 
 
 
 
 
 
 
 
X16 
 
 
 
X 
CSF PK17 
X5, 7 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Plasma PK18 
 
 
X18 
 
 
 
 
 
 
 
 
 
X18 
 
 
 
X 
Study Treatment 
Injection  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Inpatient Stay19 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone Contact 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 


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Study Period 
Part 2 Treatment/Follow-Up 
Study Day 
Day 1 
Day 
21 
Day 15 (±1 day) 
Day 161 
Day 29 (±1 day) 
Day 
301  
Days 64, 183, 302, 
421, 540, 659, 778 
(±7 days)2  
Days 
65, 184, 
303, 
422, 
541, 
660, 
7791 
Part 2 Final 
Follow-Up 
(Day 897 
[±7 days])3 or 
Part 2 Early 
Termination4 
 
Predose5 LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
for Safety 
Monitoring 
HINE Motor 
Milestone 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical Global 
Impression of 
Change 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Con Med 
Recording20 
X-------------------------------------------------------------------------------------------------------------------X 
Adverse Event 
Collection21 
X-------------------------------------------------------------------------------------------------------------------X 
AE = adverse event; Bi-PAP = bilevel positive airway pressure; Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; 
HINE = Hammersmith Infant Neurological Examination; LP = lumbar puncture; PK = pharmacokinetic(s); SAE = serious adverse event. 
1 After the injection of study treatment on Day 1, subjects will remain at the study site for at least 24 hours (Day 2) for safety monitoring.  There will be safety 
monitoring through telephone contact on the day following the injection of study treatment (i.e., Days 16, 30, 65, 184, 303, 422, 541, 660, and 779).  During 
that telephone contact, changes in concomitant medications and AEs, information on the subject’s daily ventilator/Bi-PAP use, and health status will be 
recorded. 
2 Subjects may continue receiving study treatment injection every 4 months beyond Year 2 until commercial availability of the product.  If the study continues 
beyond Year 2 (i.e., beyond Day 778), then from Day 897 onwards, subjects will maintain evaluations for study treatment injection every 4 months with the 
schedule of events for those additional timepoints to alternate between the assessments done on Day 183 and those done on Day 302.  Day 302 assessments 
would be performed at Day 897 and Day 183 assessments would be performed at Day 1016.  That pattern would continue until the end of the study.  Part 2 
Final Follow-up Evaluation would then occur approximately 4 months after the last injection of study treatment. 
3 The Part 2 Final Follow-up Evaluation will occur 4 months after the last injection of study treatment, which will either be on Day 778, if the product is 
commercially available, or later, if Part 2 of the study continues beyond Year 2. 
4 Subjects who terminate early will be encouraged to complete the safety evaluations scheduled for the Part 2 Early Termination Evaluation. 
5 Inclusion/Exclusion Criteria, Informed Consent, CSF PK, and coagulation laboratory tests must be performed on Part 2 Day 1 predose.  Coagulation laboratory 
tests will be performed locally.  
6 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each evaluation.  For subjects who are not receiving noninvasive ventilation, 
pulse oximetry will be measured overnight once a week at home. 
7 If Part 2 Day 1 study treatment injection is delayed more than 24 hours after the End of Part 1 visit, the following procedures must be done on Part 2 Day 1 
predose:  vital signs, weight, growth parameters, physical examination, ventilator use, neurological examination, and CSF PK.  If Part 2 Day 1 study treatment 


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injection is delayed more than 24 hours after End of Part 1 due to an AE, SAE, or other safety concern, or if Part 2 Day 1 study treatment injection is delayed 
more than 30 days after End of Part 1 for any reason, the following procedures must be done on Part 2 Day 1 predose:  vital signs, weight, growth parameters, 
physical examination, ventilator use, neurological examination, ECG, CSF PK, and safety laboratory tests.  Immunogenicity testing must also be repeated if 
Part 2 Day 1 study treatment injection is delayed more than 30 days after End of Part 1 for any reason. 
8 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected at 4 timepoints:  1, 2, 4, 
and 6 hours (all ±15 minutes) after the injection of study treatment only on Part 2 Day 1.  On subsequent study days, vital signs will be collected 1 hour after 
the injection of study treatment. 
9 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected on Day 2 within 20 to 
24 hours after the injection of study treatment only. 
10 At the evaluations scheduled for injection of study treatment, subjects will be assessed for the following growth parameters:  body length, head circumference, 
chest circumference, and arm circumference.  Growth parameters and weight are to be collected at the same time. 
11 Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes. 
12 Neurological examinations will occur 1 hour after the injection of study treatment. 
13ECG will be performed at Days 64, 183, 540, and 778, and at the Part 2 Final Follow-up Evaluation.  ECG must be performed before obtaining blood samples 
for safety laboratory tests. 
14Blood chemistry, hematology, and urinalysis panels. 
15Samples for safety laboratory tests will be collected before the injection of study treatment on the same days as ECG, plasma PK, and immunogenicity sample. 
16Blood samples for immunogenicity testing will be collected before the injection of study treatment on Days 64, 183, 540, and 778. 
17Refer to Table 7 for CSF PK sample schedule.  The CSF samples will be analyzed for ISIS 396443 concentrations.  The remaining CSF sample will be stored 
for optional future biomarker analyses. 
18Blood samples for PK assessment will be collected 4 hours (±1 hour) after the injection of study treatment only on Day 1.  Refer to Table 7 for the plasma PK 
sample schedule.  Plasma PK samples will be collected predose on Days 64, 183, 540, and 778. 
19Overnight stay (at least 24 hours) is required after the first injection of study treatment.  Following all subsequent injections, a stay of at least 1 hour at the study 
site is required; overnight stays are optional on these days. 
20In addition to concomitant medications, ancillary procedures will be recorded. 
21AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2. 
 


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Table 5 
Part 1 Pharmacokinetic Sampling Schedule1  
Treatment Period 
Part 1 Study Day 
Timepoints 
Blood 
Collection 
(mL) 
CSF Collection 
(mL)2 
Multiple Dose: 
LP Injection  
 
Day 1 
Predose 
NA 
0.5 
4 h (±1 h) postdose  
0.5 
NA 
Day 15 
Predose 
NA 
0.5 
Day 29 
Predose 
NA 
0.5 
Day 64 
Predose 
0.5 
0.5 
Day 183 
Predose 
0.5 
0.5 
Day 302 
Predose 
NA 
0.5 
End of Part 1 
NA 
0.5 
NA 
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy. 
1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual. 
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of ISIS 396443 with plasma and CSF constituents. 
 
Table 6 
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive ISIS 396443 in Part 11 
Treatment Period 
Part 2 Study Day 
Timepoints 
Blood 
Collection 
(mL) 
CSF Collection 
(mL)2 
Multiple Dose: 
LP Injection  
 
Day 1 
Predose 
NA 
0.5 
4 h (±1 h) postdose  
0.5 
NA 
Day 120 
Predose 
NA 
0.5 
Day 239 
Predose 
0.5 
0.5 
Day 358 
Predose 
NA 
0.5 
Day 477 
Predose 
0.5 
0.5 
Day 596 
Predose 
NA 
0.5 
Day 715 
Predose 
0.5 
0.5 
Part 2 Final 
Follow-Up 
NA 
0.5 
NA 
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy. 


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1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual. 
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of ISIS 396443 with plasma and CSF constituents. 
 
Table 7 
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive Sham Procedure in Part 11  
Treatment Period 
Part 2 Study Day 
Timepoints 
Blood 
Collection 
(mL) 
CSF Collection 
(mL)2 
Multiple Dose: 
LP Injection  
Day 1 
Predose 
NA 
0.5 
4 h (±1 h) postdose  
0.5 
NA 
Day 15 
Predose 
NA 
0.5 
Day 29 
Predose 
NA 
0.5 
Day 64 
Predose 
0.5 
0.5 
Day 183 
Predose 
0.5 
0.5 
Day 302 
Predose 
NA 
0.5 
Day 421 
Predose 
NA 
0.5 
Day 540 
Predose 
0.5 
0.5 
Day 659 
Predose 
NA 
0.5 
Day 778 
Predose 
0.5 
0.5 
Part 2 Final 
Follow-Up 
NA 
0.5 
NA 
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy. 
1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual. 
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of ISIS 396443 with plasma and CSF constituents. 


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5. 
INTRODUCTION  
ISIS 396443 is a uniformly modified, 2′-O-(2-methoxyethyl) (2′-MOE), antisense 
oligonucleotide (ASO) drug in development for the treatment of spinal muscular atrophy (SMA) 
due to genetic defects in the survival motor neuron 1 (SMN1) gene. 
ASOs are short synthetic strings of nucleotides designed to alter the expression of a targeted 
protein by selectively binding to the ribonucleic acid (RNA) that encodes the targeted protein.  In 
patients with SMA, the number of survival motor neuron 2 (SMN2) gene copies and the resulting 
amount of survival motor neuron (SMN) protein are correlated with disease onset and severity.  
A therapeutic approach predicted to benefit patients with SMA is to increase the levels of 
full-length SMN2 pre-messenger ribonucleic acid (mRNA) by restoring the splicing pattern that 
gives rise to full-length SMN2 mRNA, thus increasing full-length SMN protein levels and SMN 
protein activity.  ISIS 396443 is designed to bind to intron 7 of the SMN2 pre-mRNA, restoring 
the splicing pattern that gives rise to full-length SMN2 mRNA and thus increases full-length 
SMN protein levels (Figure 2). 
Figure 2: 
Antisense Oligonucleotide Therapeutic Approach for Treatment of Spinal 
Muscular Atrophy 
 
ASO = antisense oligonucleotide; FL = full-length; mRNA = messenger ribonucleic acid; SMA = spinal muscular 
atrophy; SMN = survival motor neuron; SMN1 = survival motor neuron 1; SMN2 = survival motor neuron 2. 


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5.1. 
Overview of Spinal Muscular Atrophy 
SMA is an autosomal recessive neuromuscular disease characterized by degeneration of the 
motor neurons in the anterior horn of the spinal cord, resulting in atrophy of the voluntary 
muscles of the limbs and trunk.  With an incidence of 1:6000 to 1:10,000 live births, SMA is the 
most common genetic cause of infant mortality, and a major cause of childhood morbidity due to 
weakness, in developed countries.  The natural history of SMA includes 4 major recognized 
phenotypes that are dependent on age of onset and achieved motor abilities.  The most severe 
form, Type I SMA, has a disease onset within the first few months of life; these children are 
never able to sit or walk and usually die from respiratory failure by the age of 2 years.  Patients 
with Type II SMA are able to sit but never walk unaided, with symptoms typically presenting 
between 6 and 18 months of age.  Patients with Type III SMA are able to sit and walk but may 
become severely and increasingly disabled.  Patients with Type IV or adult-onset SMA have an 
age of onset over 18 years and have normal life expectancies. 
SMA is caused by loss of SMN protein due to a homozygous deletion or mutation or compound 
heterozygous mutation in the SMN1 gene on chromosome 5q11-q13.  Humans have a duplication 
of the chromosome region where SMN1 is found, resulting in a second copy of the gene, SMN2.  
In SMN2, a C to T nucleotide substitution in exon 7 results in an alternative splicing event such 
that the majority of transcripts produced (~90%) lack exon 7, and a defective truncated protein is 
produced.  The remainder, SMN2 transcripts containing exon 7, produces a full-length protein 
product identical to the SMN1 protein, since the C to T substitution is silent.  Humans have a 
variable copy number of the SMN2 gene (0 to 8 copies) [Wirth 2006].  The number of SMN2 
copies and the resulting amount of full-length SMN protein expressed in patients with SMA 
(10% to 40% of normal SMN protein levels) correlate with SMA disease severity; thus, SMN2 is 
a key modifier of disease phenotype [Coovert 1997; Feldkötter 2002; Lefebvre 1997; Prior 
2004]. 
5.2. 
Current Therapies for Spinal Muscular Atrophy 
There are currently no approved therapies for SMA.  Current medical care is supportive and 
focused on respiratory support, nutritional support, and management of resulting 
musculotendinous contractures and neuromuscular scoliosis through bracing, physical therapy, 
and surgery [Wang 2007]. 
5.3. 
Profile of Previous Experience With ISIS 396443 
5.3.1. 
Nonclinical Experience 
ISIS 396443 was identified after an extensive screen of greater than 500 2′-MOE 
oligonucleotides in reporter gene assays, in vitro splicing assays, and SMA patient fibroblasts 
[Hua 2007; Hua 2008].  Data have shown that ISIS 396443 promotes a concentration-dependent 
increase in full-length transcripts (including exon 7) in patient fibroblast cells, achieving >90% 
full-length SMN2 transcripts, and forms nuclear structures called gems, known to contain SMN 
protein [Liu and Dreyfuss 1996].  In a mild mouse model of SMA, ISIS 396443 promoted 
inclusion of exon 7 in the SMN2 transgene in a variety of peripheral tissues when dosed 
systemically [Hua 2008] and in central nervous system (CNS) tissue, including the spinal cord, 


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when injected into the lateral ventricle [Hua 2010].  ISIS 396443 produced >90% exon 7 
inclusion in the transgenic mice and increased SMN protein production in motor neurons, 
resulting in the appearance of gems in motor neurons.  These studies were extended to a more 
severe mouse model of SMA (SMA Δ7) [Le 2005], where the CNS delivery of drug produced a 
dose-dependent effect on SMN2 exon 7 inclusion, SMN protein production, and survival.  These 
mice treated with ISIS 396443 demonstrated improved weight gain; improvements in muscle 
morphology, muscle strength, and motor coordination; and improved morphology of the motor 
neuron junctions [Passini 2011].  Furthermore, ISIS 396443 was shown to distribute widely in 
the CNS after intrathecal administration in monkeys [Passini 2011].  
The pharmacokinetics (PK) and toxicity of ISIS 396443 were assessed after a single intrathecal 
lumbar bolus injection (1 to 7 mg) in adult monkeys; after 14 weeks of repeated intrathecal 
lumbar bolus injections (0.3 mg/week to 3 mg/week or every other week) in juvenile monkeys 
(with a 4-week interim sacrifice); and after 53 weeks of repeated intrathecal lumbar bolus 
injections in juvenile monkeys.  In addition, a dedicated multiple-dose PK study in adult 
monkeys (3-week dosing period) was performed to assess the half-life of ISIS 396443 in 
cerebrospinal fluid (CSF), tissues, and plasma.  
In the single-dose study, following intrathecal dose administration, ISIS 396443 distributed from 
the CSF into the spinal cord, brain, and systemic circulation via CSF turnover.  Plasma 
concentrations of ISIS 396443 were relatively low compared to CSF concentrations. 
In the multiple-dose PK study, concentrations of ISIS 396443 in both CSF and plasma exhibited 
multiphasic disposition following intrathecal administration.  The terminal elimination half-life 
of ISIS 396443 in CSF was 102 days.  CSF concentrations peaked 1 hour after intrathecal 
injection, while plasma concentrations peaked 4 hours after the intrathecal injection.  Animals 
were sacrificed at multiple times after intrathecal administration, and analysis demonstrated that 
ISIS 396443 was slowly cleared from CNS tissues with terminal elimination half-lives between 
various brain and spinal cord regions ranging from 74 to 275 days (median:  116 days).  
In the 14-week and 53-week repeat-dose studies, concentrations of ISIS 396443 in CSF, plasma, 
and tissue were consistent with the pattern established in the 4-week multiple dose PK study.  
CSF and plasma concentrations increased in a dose-dependent manner in both studies.  
Consistent with previous studies, the time to reach maximum observed concentration (Tmax) in 
the plasma occurred approximately 2 to 5 hours after intrathecal bolus administration.  Tissue 
concentrations were measured for CNS tissues, and consistent values were obtained between the 
14- and 53-week studies after adjusting for the difference in dosing regimens. 
In both repeat-dose toxicology studies, dose-dependent increases in tissue concentrations of 
ISIS 396443 were seen in the brain, spinal cord, and liver.  In the 53-week study, during which 
ISIS 396443 was administered every 6 weeks, tissue concentrations were lower compared to the 
14-week study, as expected.  CNS tissues had half-lives of 117 to 195 days (median:  174 days), 
which is consistent with the range of elimination half-lives determined from the multiple-dose 
PK study. 
See the Investigator’s Brochure for detailed information on nonclinical studies. 


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5.3.2. 
Clinical Experience 
Completed studies in subjects with SMA 
ISIS 396443 has been evaluated in 3 completed open-label studies in subjects with SMA 
diagnosed during childhood:  ISIS 396443-CS1, ISIS 396443-CS2, and ISIS 396443-CS10. 
Study ISIS 396443-CS1 was a single-ascending dose Phase 1 study designed to assess the safety, 
tolerability, and PK of ISIS 396443 in subjects with later-onset SMA.  A single dose of 
ISIS 396443 was administered by intrathecal injection to subjects with SMA who were 2 to 
14 years of age.  Four doses (1, 3, 6, and 9 mg) were evaluated sequentially.  Each dose was 
studied in a cohort of 6 or 10 subjects.  All subjects received study treatment.  Twenty-eight 
subjects were dosed in the clinical trial, and all subjects completed dosing and follow-up visits 
per protocol.  ISIS 396443 was well tolerated, and no safety concerns were reported when 
administered as a single dose up to 9 mg.  Mild adverse events (AEs) of headache were the most 
commonly reported events.  The 2 events related to ISIS 396443 (palpitations and paresthesia) 
were mild in severity, were not dose related, and had resolved.  No serious AEs (SAEs) and no 
discontinuations due to AEs were reported.  There were no clinically significant changes in vital 
signs or safety laboratory parameters related to ISIS 396443.  CSF and plasma drug 
concentrations of ISIS 396443 were dose dependent and consistent with the nonclinical data. 
Study ISIS 396443-CS2 was an open-label, multiple-ascending dose, Phase 1/2a study designed 
to assess the safety, tolerability, and PK of ISIS 396443 in subjects with later-onset SMA.  
Multiple doses of ISIS 396443 were administered by intrathecal injection to subjects with SMA 
who were 2 to 15 years of age.  Four dose levels (3, 6, 9, and 12 mg) were evaluated 
sequentially.  Each dose level was studied in a cohort of 8 or 9 subjects, where all subjects 
received study treatment.  The 6 subjects who participated in Cohort 1 of ISIS 396443-CS1 were 
eligible to enroll in ISIS 396443-CS2; 3 of these subjects enrolled in ISIS 396443-CS2 Cohort 1 
and the other 3 enrolled in ISIS 396443-CS2 Cohort 2.  Thirty-four subjects were enrolled, and 
all but 1 subject completed the study.  One subject in the 12-mg ISIS 396443 dose cohort 
discontinued treatment early because of the Investigator’s decision.  The Investigator concluded 
that the subject and the parents could not tolerate the study procedures associated with dosing 
and PK draws, and thus, the subject was withdrawn.  ISIS 396443 was well tolerated, and no 
safety concerns were reported when ISIS 396443 was administered as multiple doses up to 
12 mg.  Post lumbar puncture (LP) syndrome was the most commonly reported AE.  None of the 
AEs reported during the study were considered related to ISIS 396443 or resulted in 
discontinuation from the study or of the study treatment.  Three SAEs were reported during the 
study; all were assessed as unrelated to ISIS 396443.  There were no clinically significant 
changes in vital signs, neurological or physical examination findings, or safety laboratory 
parameters related to ISIS 396443.  There were no dose-related safety concerns. 
Study ISIS 396443-CS10 was a single-dose open-label study to assess the safety and tolerability 
of a single intrathecal dose in subjects with later-onset SMA who participated in 
ISIS 396443-CS1 Cohorts 2, 3, and 4 (3, 6, or 9 mg).  Eighteen subjects (4 subjects at 6-mg dose 
and 14 subjects at 9-mg dose) were enrolled and received study treatment.  All 18 subjects 
completed the study.  


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Ongoing studies in subjects with SMA 
ISIS 396443 is also being evaluated in 7ongoing studies:  ISIS 396443-CS3B, 
ISIS 396443-CS3A, 232SM201, ISIS 396443-CS4, ISIS 396443-CS12, ISIS 396443-CS11, and 
232SM202 (the present study). 
Studies in subjects with SMA diagnosed during infancy 
Study ISIS 396443-CS3B is an ongoing, pivotal, randomized, double-blind, sham 
procedure-controlled, Phase 3, multicenter study to assess the clinical efficacy and safety of 
ISIS 396443 in infants with SMA (onset of clinical signs and symptoms consistent with SMA at 
≤6 months of age) who have 2 SMN2 copies.  Approximately 111 subjects are expected to be 
enrolled.  Subjects are to be randomized in a 2:1 ratio to receive either a scaled equivalent 12-mg 
dose of ISIS 396443 or a sham procedure control, respectively. 
Study ISIS 396443-CS3A is an ongoing, open-label, Phase 2 study to assess the efficacy, safety, 
tolerability, and PK of multiple doses of ISIS 396443.  Enrollment has been completed with 
21 subjects enrolled.  Two loading dose levels (scaled by infant age to be equivalent to either 
6 or 12 mg dose for children >2 years of age based on CSF volume) were evaluated sequentially 
in symptomatic infants with SMA who were between ≥21 and ≤7 months of age at screening.  
Loading doses were administered on Days 1, 15, and 85.  Maintenance dosing commenced 
24 weeks following Day 85 and at 18-week intervals thereafter. 
Study 232SM201 is an open-label, multicenter, global, single-arm study to assess the efficacy, 
safety, tolerability, and PK of multiple doses of ISIS 396443 in presymptomatic subjects with 
genetically diagnosed SMA.  The study is being conducted in subjects ≤6 weeks of age with 
genetic documentation of 5q SMA homozygous gene deletion or mutation or compound 
heterozygous mutation, genetic documentation of 2 or 3 copies of the SMN2 gene, 
CMAP ≥1 mV, and the absence of signs or symptoms of SMA.  Up to 25 subjects are planned to 
be treated in the study.  All subjects will receive a scaled equivalent 12-mg dose of ISIS 396443.   
Studies in subjects with SMA diagnosed during childhood 
Study ISIS 396443-CS4 is an ongoing, pivotal, randomized, multicenter, double-blind, sham 
procedure-controlled, Phase 3 study in subjects with later-onset SMA (onset of clinical signs and 
symptoms consistent with SMA at >6 months of age) being conducted to assess the clinical 
efficacy and safety of ISIS 396443.  Enrollment has been completed with 126 subjects enrolled.  
Subjects are randomized in a 2:1 ratio to receive either a scaled equivalent 12 mg dose of 
ISIS 396443 or a sham procedure control, respectively. 
Study ISIS 396443-CS12 is an ongoing open-label study to assess the safety, tolerability, and PK 
of ISIS 396443 (12 mg) administered intrathecally to subjects with later-onset SMA who 
previously participated in either ISIS 396443-CS2 or ISIS 396443-CS10.  
Studies in subjects with SMA diagnosed during infancy or childhood 
Study ISIS 396443-CS11 is an ongoing OLE study being conducted to evaluate the long-term 
safety, tolerability, and efficacy of ISIS 396443 administered intrathecally to subjects with SMA 
who previously participated in investigational studies of ISIS 396443.  Up to 274 subjects are 
planned to be treated in the study.  


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5.4. 
Study Rationale 
There is reasonably high genotype-phenotype correlation such that the SMN2 copy number can 
be used to predict the severity of disease (moderate or severe) with approximately 80% to 
85% accuracy [Burghes and Beattie 2009; Prior 2010; Swoboda 2005].  Evaluation of 
relationship between categories of functional status and number of SMN2 copies have indicated 
that as SMN2 copy number increases so does functional status [Feldkötter 2002; Swoboda 2005].  
However, assessment of various outcome measures over time have indicated that there is overlap 
among SMA types, and values vary widely with age and gross motor functional status with an 
overall age dependent decline [Swoboda 2005].  
5.4.1. 
Rationale for Part 1 
The intent of Part 1 of this study is to assess safety, tolerability, and explore the utility of selected 
efficacy endpoints in subjects who have onset of clinical signs and symptoms that are consistent 
with SMA at age ≤6 months or >6 months.  These subjects have either 2 or 3 SMN2 copies and 
are not eligible to participate in the 2 pivotal clinical studies, ISIS 396443-CS3B and 
ISIS 396443-CS4.  ISIS 396443-CS3B is a randomized, double-blind, sham 
procedure-controlled study investigating the therapeutic benefit of ISIS 396443 in subjects with 
2 SMN2 copies who have onset of clinical signs and symptoms of SMA at ≤6 months of age.  
ISIS 396443-CS4 is a randomized, double-blind, sham procedure-controlled study investigating 
the therapeutic benefit of ISIS 396443 in subjects who have onset of clinical signs and symptoms 
of SMA at >6 months of age.  To be consistent with the study design of the 2 pivotal clinical 
studies and to understand the safety and tolerability of ISIS 396443 compared with natural 
history, the present study is designed to include sham procedure control for an unbiased 
assessment of safety, tolerability, and selected efficacy endpoints in the study population that is 
not eligible to participate in the studies ISIS 396443-CS3B or ISIS 396443-CS4.  The design of 
the present study will also allow exploration of the safety and tolerability of a higher dose 
regimen in subjects who have onset of clinical signs and symptoms at >6 months of age, but who 
are not eligible for Study ISIS 396443-CS4. 
5.4.2. 
Rationale for Part 2:  Open-Label Extension Phase 
The rationale for Part 2 of this study is to assess the long-term safety and tolerability of 
ISIS 396443 in subjects with SMA who participated in Part 1 and completed their End of Part 1 
Evaluation assessments. 
5.5. 
Rationale for Dose and Schedule Selection 
The ISIS 396443 dose and dose interval for this study were selected based on nonclinical 
toxicology and PK observations from monkey studies using single-dose and repeat-dosing 
intrathecal administration, consideration of the target tissue concentration anticipated for drug 
pharmacology, and safety data in the completed and ongoing clinical studies of ISIS 396443.  
Based on pharmacology and PK results in SMA transgenic mice, it is estimated that a target 
spinal cord tissue concentration between 1 and 10 μg/g will produce 50% to 90% 
SMN2 exon 7 inclusion.  Nonclinical studies in juvenile monkeys receiving intrathecal doses of 
ISIS 396443 showed a resulting gradient of distribution of ISIS 396443 along the spinal cord, 
with mean lumbar spinal cord concentrations ranging from 1.6- to 2.3-fold and 2.0- to 3.5-fold 


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higher than thoracic and cervical spinal cord levels, respectively.  The dose selected for this 
multiple-dose clinical study (equivalent to 12 mg of ISIS 396443) is predicted to achieve levels 
at the high end of this range (approximately 10 μg/g lumbar and 3 μg/g cervical spinal cord 
tissue concentrations) after the first dose.  The loading dose interval (i.e., doses on Days 1, 15, 
29, and 64) was selected based on the nonclinical PK and pharmacology data in order to achieve 
and maintain ISIS 396443 spinal cord tissue levels that are predicted to be above or within the 
upper end of the pharmacologically active range by Day 64 (approximately 30 μg/g lumbar and 
10 μg/g cervical tissue concentration), while at the same time considering subject safety and 
convenience for repeated intrathecal injections by LP.  The higher number of loading doses 
would allow for the evaluation of safety and tolerability and preliminary exploratory efficacy 
endpoints in a broader population of subjects with SMA, including those who have onset of 
clinical signs and symptoms at >6 months of age but who are not eligible for Study 
ISIS 396443-CS4.  The maintenance dose interval (once every 4 months ) was selected based on 
the estimated spinal tissue and CSF drug half-life (4 to 6 months) and was selected to maintain 
spinal cord tissue levels of ISIS 396443 at a steady-state level within the estimated 
pharmacologically active range.  In Part 1, maintenance doses will be given on Day 183 and 
Day 302, for a total of 6 doses over approximately 10 months.  Subjects who were receiving 
ISIS 396443 in Part 1 will continue receiving maintenance doses in Part 2 every 4 months.  
Subjects who were receiving sham in Part 1, will receive maintenance doses starting on Day 183 
of Part 2. 
ISIS 396443 will be administered as an intrathecal injection.  The volume of the injection, and 
thus the dose, will be adjusted based on the subject’s age on the day of dosing as shown in 
Table 1, such that each subject will receive a 12-mg scaled equivalent dose based on CSF 
volume scaling.  Thus, younger subjects will be given a lower dose of drug, achieved by 
injecting a smaller volume that is proportional to the estimated CSF volume for age, such that the 
dose volume will be equivalent to 5 mL for a 2-year-old child to adult.  Dosing instructions and 
details regarding administration will be provided in the Directions for Handling and 
Administration (DHA). 
6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objectives and Endpoints 
Part 1 
The primary objective of Part 1 of this study is: 
 To assess the safety and tolerability of ISIS 396443 in subjects with SMA who are 
not eligible to participate in the clinical studies ISIS 396443-CS3B or 
ISIS 396443-CS4. 


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The endpoints that relate to this objective are: 
 Incidence of AEs and SAEs 
 Change from baseline (see Section 16.1) in clinical laboratory parameters, 
electrocardiograms (ECGs), and vital signs  
 Change from baseline (see Section 16.1) in neurological examination outcomes 
Part 2 
The primary objective of Part 2 of this study is: 
 To assess the long-term safety and tolerability of ISIS 396443 in subjects with SMA 
who participated in Part 1 and completed their End of Part 1 Evaluation assessments. 
The endpoints that relate to this objective are: 
 Incidence of AEs and SAEs 
 Change from baseline (see Section 16.1) in clinical laboratory parameters, ECGs, and 
vital signs  
 Change from baseline (see Section 16.1) in neurological examination outcomes 
6.2. 
Secondary Objectives and Endpoints 
Part 1 
The secondary objective of Part 1 of this study is: 
 To examine the PK of ISIS 396443 in subjects with SMA who are not eligible to 
participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4 
The endpoint that relates to this objective is:  
 ISIS 396443 concentrations in plasma and CSF 
Part 2 
The secondary objective of Part 2 of this study is: 
 To examine the PK of ISIS 396443 in subjects with SMA who participated in Part 1 
and completed their End of Part 1 Evaluation assessments 
The endpoint that relates to this objective is:  
 ISIS 396443 concentrations in plasma and CSF 
6.3. 
Exploratory Objectives and Endpoints 
Part 1 
The exploratory objective of Part 1 of this study is: 
 To explore the efficacy of ISIS 396443 in subjects with SMA who are not eligible to 
participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4. 


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The endpoints that relate to this objective are: 
 Change from baseline in ventilator use  
 Attainment of motor milestones assessed by Section 2 of the Hammersmith Infant 
Neurological Examination (HINE)  
 Change from baseline in growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for length, and head to 
chest circumference ratio) through final safety follow-up evaluation  
 Clinical Global Impression of Change (physician and caregiver assessment) through 
final safety follow-up evaluation 
The exploratory immunogenicity endpoint is as follows: 
 Plasma antibodies to ISIS 396443 
Part 2 
The exploratory objective of Part 2 of this study is: 
 To explore the efficacy of ISIS 396443 in subjects with SMA who participated in 
Part 1 and completed their End of Part 1 Evaluation assessments. 
The endpoints that relate to this objective are: 
 Change from baseline in ventilator use  
 Attainment of motor milestones assessed by Section 2 of the HINE  
 Change from baseline in growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for length, and head to 
chest circumference ratio) through Part 2 Final Follow-up Evaluation  
 Clinical Global Impression of Change (physician and caregiver assessment) through 
Part 2 Final Follow-up Evaluation 
The exploratory immunogenicity endpoint is as follows: 
 Plasma antibodies to ISIS 396443 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is a Phase 2 multicenter study conducted in 2 parts.  The study was originally designed as a 
randomized, double-blind, sham-procedure controlled study to assess the safety and tolerability 
and explore the efficacy of intrathecally administered ISIS 396443 up to approximately 
14 months (from the first dose until End of Part 1 Evaluation).  Based on emergent data from the 
ISIS 396443 clinical development program, the Sponsor may decide to terminate Part 1 early, 
and all subjects may then be offered the opportunity to be unblinded and transition to Part 2 prior 
to completion of all Part 1 evaluations.  Part 2 is an OLE phase that will assess long-term safety 
and tolerability and explore the efficacy of intrathecally administered ISIS 396443 for 
approximately 24 additional months (or until availability of commercial product).  In Part 1 of 
the study, up to 21 subjects will be randomized in a ratio of 2:1 to receive ISIS 396443 by 
intrathecal LP injection (n = 14) or to a sham procedure-control (n = 7).  Randomization will be 
stratified based on age at onset of clinical signs and symptoms consistent with SMA:  >6 months 
versus ≤6 months.  In Part 2 of the study, all subjects who participated in Part 1, who completed 
their End of Part 1 Evaluation assessments, and who elected to enroll in Part 2 will receive 
ISIS 396443 by intrathecal injection. 
Subjects who withdraw early from Part 1 will be encouraged to complete the End of Part 1 
Evaluation assessments at the time of withdrawal.  Subjects who withdraw early from Part 2 will 
be encouraged to complete the Part 2 Early Termination Evaluation assessments at the time of 
withdrawal.  
See Section 4.1 for a schematic of the study design. 
7.2. 
Overall Study Duration and Follow-Up 
Part 1 of the study will consist of a Screening Period, Treatment Period, and post-treatment End 
of Part 1 Evaluation.  For subjects who meet eligibility criteria and enroll in Part 1, the duration 
of Part 1 will be approximately 15 months (450 days) and will include a Screening Period of no 
greater than 28 days, a 302-day Treatment Period, and an End of Part 1 Evaluation 
approximately 4 months after the last dose.  Based on emergent data from the ISIS 396443 
clinical development program, the Sponsor may decide to terminate Part 1 early, and all subjects 
may be offered the opportunity to transition to Part 2 prior to completion of all Part 1 
evaluations. 
Part 2 will consist of a Treatment Period and a post-treatment Final Follow-up Evaluation.  For 
subjects who meet eligibility criteria and enroll in Part 2, the duration of Part 2 will be 
approximately 28 months and will include an open-label Treatment Period of approximately 
24 months (or until availability of commercial product) and a Part 2 Final Follow-up Evaluation 
approximately 4 months after the last dose of study treatment in Part 2. 
Total study duration for subjects who participate in both Part 1 and Part 2 will be approximately 
43 months. 


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7.2.1. 
Screening 
Subject eligibility for Part 1 of the study will be determined within 4 weeks (Day -28 to Day -1) 
prior to the first injection of ISIS 396443 or administration of sham procedure and will be 
confirmed before randomization.  If a subject initially fails any of the screening criteria, they will 
be allowed to be rescreened 1 time during the Screening Period at the discretion of the 
Investigator.  End of Part 1 Evaluation assessments will be used to confirm subjects’ eligibility 
for Part 2.  
7.2.2. 
Treatment 
Part 1 
Eligible subjects will be admitted to the study site on Part 1 Day 1, undergo predose evaluations, 
and then receive an LP injection of ISIS 396443 or a sham procedure.  After the injection on 
Day 1, subjects will remain at the study site for at least 24 hours after the procedure for safety 
monitoring. 
Subjects will return to the study site on Days 15, 29, 64, 183, and 302 (±1 day for Days 15 and 
29 and ±7 days for all other days) for follow-up evaluations and subsequent injections of study 
treatment or sham procedure, for a total of 6 injections or sham procedures over a dosing period 
of 10 months.  During these 5 evaluations, all subjects will remain at the study site for at least 
6 hours postdose for safety monitoring.  An overnight stay is optional, at the discretion of the 
Investigator.  Safety monitoring by telephone contact will occur on the day after injection of 
study treatment or sham procedure.  In addition, the study site will monitor the subject’s 
condition through telephone contact every other week (excluding weeks with study visit) 
throughout the study period. 
After completing the End of Part 1 Evaluation assessments, all eligible subjects may elect to 
enroll in Part 2. 
Based on emergent data from the ISIS 396443 clinical development program, the Sponsor may 
decide to terminate Part 1 early, and all subjects may be offered the opportunity to transition to 
Part 2 prior to completion of all Part 1 Evaluation assessments.  All subjects enrolled in the study 
at the time of Sponsor termination will be considered Part 1 completers.  The next study 
evaluation for those subjects will serve as an End of Part 1 Evaluation, which may occur at any 
time prior to the next scheduled Part 1 study evaluation.  
Unblinding will occur in order for the subjects to transition from Part 1 to Part 2. 
End of Part 1 Evaluation assessments are required to be done prior to the transition to Part 2.  
After performing the End of Part 1 Evaluation assessments, the subject may immediately 
transition to Part 2. 
Part 2 
Part 2 study procedures and schedules will be determined based on the subject’s treatment 
assignment in Part 1. 


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Subjects who were randomized to receive ISIS 396443 in Part 1 
End of Part 1 Evaluation assessments will be used to determine subject eligibility for Part 2 of 
the study.  For subjects who were receiving ISIS 396443 in Part 1, Part 2 Day 1 will occur 
following the End of Part 1 Evaluation or approximately 4 months following the last injection of 
ISIS 396443 in Part 1.  On Part 2 Day 1, these subjects will undergo predose evaluations 
according to the schedule of events (Table 3) and then receive their first dose of ISIS 396443 for 
Part 2 (next maintenance dose). 
Subjects will return to the study site on Days 120, 239, 358, 477, 596, and 715 (±7 days for all 
days) for follow-up evaluations and subsequent injections of ISIS 396443 over a dosing period of 
approximately 24 months (or until availability of commercial product).  Subjects will remain at 
the study site for at least 1 hour postdose for safety monitoring and can be discharged at the 
discretion of the site Investigator and in compliance with the institutional requirements once the 
subjects have adequately recovered from the dosing procedure.  An overnight stay is optional, at 
the discretion of the Investigator.  Safety monitoring by telephone contact will occur on the day 
after injection of study treatment.  In addition, the study site will monitor the subject’s condition 
through telephone contact every other week (excluding weeks with study visit) throughout the 
study period. 
Subjects who were randomized to receive sham procedure in Part 1 
End of Part 1 Evaluation assessments will be used to determine subject eligibility for Part 2 of 
the study.  For subjects who were receiving sham procedure in Part 1, Part 2 Day 1 will occur 
following the End of Part 1 Evaluation or as soon as possible following their End of Part 1 
Evaluation, in the event of early termination by the Sponsor due to emergent data from the 
ISIS 396443 clinical development program.  On Part 2 Day 1, these subjects will undergo 
predose evaluations according to the schedule of events (Table 4) and then receive their first 
injection of ISIS 396443 (first loading dose).  Subjects will remain at the study site for at least 
24 hours after the procedure for safety monitoring. 
Subjects will return to the study site on Days 15, 29, 64, 183, 302, 421, 540, 659, and 778 
(±1 day for Days 15 and 29 and ±7 days for all other days) for follow-up evaluations and 
subsequent injections of ISIS 396443 over a dosing period of approximately 24 months (or until 
availability of commercial product).  Subjects will remain at the study site for at least 1 hour 
postdose for safety monitoring and can be discharged at the discretion of the site Investigator and 
in compliance with the institutional requirements once the subjects have adequately recovered 
from the dosing procedure.  An overnight stay is optional, at the discretion of the Investigator.  
Safety monitoring by telephone contact will occur on the day after injection of study treatment.  
In addition, the study site will monitor the subject’s condition through telephone contact every 
other week (excluding weeks with study visit) throughout the study period.  
For both groups of subjects, Part 2 of the study will continue for approximately 24 months (or 
until availability of commercial product) and in accordance with applicable laws and regulations.  
Subjects may continue receiving treatment every 4 months beyond Year 2 until commercial 
availability of the product.  From Year 2 onwards, subjects will maintain evaluations for 
injection of study treatment every 4 months as indicated in Table 3 and Table 4. 


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7.2.3. 
Follow-Up 
Subjects who enroll in Part 1 but not Part 2 will return to the study site for an End of Part 1 
Evaluation approximately 4 months after the last dose of study treatment (End of Part 1 on 
Day 422 [±7 days]). 
In the event of a decision by the Sponsor to terminate the study earlier than the end of Part 1 
based on emergent data from the ISIS 396443 clinical development program, subjects who do 
not elect to participate in Part 2 will complete their next evaluation after Part 1 is terminated and 
that visit will be the End of Part 1 Evaluation. 
Subjects who enroll in Part 2 will have a Part 2 Final Follow-up Evaluation approximately 
4 months after the last open-label dose of ISIS 396443. 
Subjects who withdraw early from Part 1 will be encouraged to complete the End of Part 1 
Evaluation assessments at the time of withdrawal.  Subjects who withdraw early from Part 2 will 
be encouraged to complete the Part 2 Early Termination Evaluation assessments at the time of 
withdrawal. 
7.3. 
Study Stopping Rules 
For Part 1 and Part 2 of the study, the Sponsor may terminate the study at any time by informing 
Investigators (who will subsequently inform the corresponding ethics committees) and any other 
applicable regulatory agencies.  Investigators will be notified by the Sponsor if the study is 
placed on hold, completed, or closed.   
Conditions that may warrant termination of the study include, but are not limited to, the 
following: 
 The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study. 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product.   
7.4. 
End of Study 
The end of the study is the last subject’s completion of the last evaluation for Part 2. 
7.5. 
Safety Monitoring and Data and Safety Monitoring Board 
Safety data will be reviewed on an ongoing basis by the Sponsor and the Medical Monitor.  
Safety data will also be reviewed on a quarterly basis, throughout Part 1 of the study, by an 
independent Data and Safety Monitoring Board (DSMB; see Section 19.2).  


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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening or at the time point specified in the individual eligibility criterion listed: 
1. Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study 
and provide signed and dated informed consent and authorization to use confidential 
health information in accordance with national and local subject privacy regulations.   
2. Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound 
heterozygote. 
3. Onset of clinical signs and symptoms consistent with SMA at <6 months of age and have 
documentation of 3 SMN2 copies. 
OR 
Onset of clinical signs and symptoms consistent with SMA at <6 months of age, 
>7 months of age (211 days) at screening, and have documentation of 2 SMN2 copies. 
OR 
Onset of clinical signs and symptoms consistent with SMA at >6 months of age, are 
≤18 months of age at screening, and have documentation of 2 or 3 SMN2 copies. 
4. Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is 
planned for study procedures (as assessed by the Investigator and either the 
anesthesiologist or pulmonologist). 
5. Medical care, such as routine immunizations (including influenza vaccine, pneumococcus 
vaccine, and respiratory syncytial virus prophylaxis [palivizumab] if available), meets 
and is expected to continue to meet guidelines set out in the Consensus Statement for 
Standard of Care in SMA, in the opinion of the Investigator. 
6. Subjects with 2 SMN2 copies must reside within approximately 9 hours’ ground-travel 
distance from a participating study site for the duration of the study.  Residents who are 
>2 hours’ ground-travel distance from a study site must obtain clearance from the 
Investigator and the study Medical Monitor.  
7. Able to complete all study procedures, measurements, and visits, and parent or legal 
guardian/subject has adequately supportive psychosocial circumstances, in the opinion of 
the Investigator. 
For Part 2 only: 
To be eligible to participate in Part 2 of this study, candidates must meet the following eligibility 
criteria at the time of consent to participate in Part 2: 
1. Participation in Part 1 and completion of the End of Part 1 Evaluation assessments. 
2. Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study 
and to provide signed and dated informed consent on the Part 2 informed consent form 


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(ICF) and authorization to use confidential health information in accordance with 
national and local subject privacy regulations. 
3. Able to complete all study procedures, measurements, and visits, and parent or legal 
guardian/subject has adequately supportive psychosocial circumstances, in the opinion of 
the Investigator. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening or at the time point specified in the individual criterion listed: 
1. Any previous exposure to ISIS 396443; previous dosing in this study or previous studies 
with ISIS 396443. 
2. Signs or symptoms of SMA present at birth or within the first week after birth. 
3. Ventilation for ≥16 hours per day continuously for >21 days at screening. 
4. Permanent tracheostomy, implanted shunt for CSF drainage, or implanted CNS catheter 
at screening.  
5. History of brain or spinal cord disease that would interfere with the LP procedure, CSF 
circulation, or safety assessments. 
6. Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional 
support within 2 months prior to screening, or hospitalization for surgery planned during 
the study. 
7. Clinically significant abnormalities in hematology or clinical chemistry parameters or 
ECG, as assessed by the Investigator, at the Screening Visit that would render the subject 
unsuitable for inclusion. 
8. Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole, 
carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device 
within 30 days prior to screening.  Any history of gene therapy, prior ASO treatment, or 
cell transplantation. 
9. Ongoing medical condition that according to the Investigator would interfere with the 
conduct and assessments of the study.  Examples are medical disability (e.g., wasting or 
cachexia, severe anemia) that would interfere with the assessment of safety or would 
compromise the ability of the subject to undergo study procedures. 
10. The subject’s parent or legal guardian is unable to understand the nature, scope, and 
possible consequences of the study, or does not agree to comply with the protocol’s 
schedule of assessments. 
11. Subject’s parent or legal guardian is not willing to continue to meet standard of care 
guidelines for care (including vaccinations and respiratory syncytial virus prophylaxis if 
available), nor provide nutritional and respiratory support throughout the study. 
12. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the 
subject unsuitable for enrollment. 


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For Part 2 only: 
Candidates will be excluded from the Part 2 if they meet the following exclusion criterion at the 
time of consent into Part 2 of the study: 
1. Any significant change in clinical status, including laboratory tests that, in the opinion of 
the Investigator, would make them unsuitable to participate in Part 2.  The Investigator 
must reassess the subject’s medical fitness for participation and consider any diseases that 
would preclude treatment. 
Note that subjects who have been previously exposed to ISIS 396443 in Part 1 of the study 
(Exclusion criterion 1 for Part 1) may participate in Part 2. 
9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION  
9.1. 
Screening and Enrollment 
The subject’s legally authorized representative (e.g., parent or legal guardian) must provide 
informed consent for Part 1 before study-specific screening tests are performed and for Part 2 
before study-specific procedures are performed (see Section 17.3).  When a subject’s 
parent/guardian signs the ICF, that subject is assigned a unique subject identification number 
through the interactive response technology (IRT) system and is considered to be enrolled in the 
study.  Participating study sites are required to document all screened candidates initially 
considered for inclusion in this study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents, within the IRT system, and on 
the screening log.  If a subject initially fails any of the screening criteria, they will be allowed to 
be rescreened 1 time during the Screening Period, at the discretion of the Investigator.  
9.2. 
Registration and Randomization of Subjects 
In Part 1 of the study, subjects will be registered and randomized after all screening assessments 
have been completed and after the Investigator has verified that the subjects are eligible per 
criteria in Section 8.1 and Section 8.2   No subject may begin treatment until the subject is 
documented as registered (assigned a unique identification number) and is randomized for the 
study in the IRT system.  Any subject identification numbers that are assigned will not be reused 
even if the subject does not receive treatment.   
In Part 1 of the study, using an IRT system, eligible subjects will be randomized to receive 
ISIS 396443:sham procedure in a 2:1 ratio.  Randomization will be stratified based on age at 
onset of clinical signs and symptoms consistent with SMA:  >6 months versus <6 months.  
Subjects who withdraw from the study may be replaced. 
At the beginning of Part 2 of the study, the subject's treatment assignment will be unblinded via 
the IRT system.  Part 2 is the OLE phase of the study in which all subjects receive ISIS 396443. 
Refer to the Study Reference Guide for details on registration and randomization.  


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9.3. 
Blinding Procedures 
Part 1 of the study is a randomized, double-blind, sham-procedure controlled study.  The 
Sponsor, parents and/or legal guardians, and key study site personnel will be blinded throughout 
Part 1 of the study.  To maintain the study blind, it is imperative that subject treatment 
assignments are not shared with the subjects, their families, or any member of the study team, 
either at the study site or that of the Sponsor, except the unblinded site study staff (dedicated 
team) and the unblinded medical monitor or clinical research associate.  The DSMB may be 
unblinded as described in the DSMB charter.  
Before Part 2 Day 1, parents and/or legal guardians, key study site personnel, and the Sponsor 
will be unblinded to the treatment group to which the subjects were randomized in Part 1.  This 
will be performed according to the unblinding plan, which will be finalized prior to unblinding.  
Of note, in the event that the Sponsor decides to rollover subjects to Part 2 early, unblinding for 
key study site personnel will occur prior to the End of Part 1 Evaluation in order to facilitate 
bringing subjects who were randomized to receive sham in Part 1 as soon as possible and to 
maintain the 4-month dosing interval for subjects who were randomized to receive ISIS 396443 
in Part 2.  Treatment in Part 2 will be open-label, and all study subjects will receive ISIS 396443. 
9.3.1. 
Emergency Unblinding of Treatment Assignment  
In Part 1 of the study, if a subject has experienced an SAE (as defined in Section 15.1.2), and/or 
when knowledge of the treatment assignment will impact the clinical management of the subject, 
the Investigator will have the ability to unblind the treatment assignment for that subject using 
the IRT.  However, prior to unblinding, the Investigator should attempt to contact the blinded 
Medical Monitor to discuss the emergency.  The Sponsor or designee will be informed of the 
unblinding of a subject within 24 hours.  Every reasonable attempt should be made to complete 
the End of Part 1 Evaluation assessments prior to unblinding, as knowledge of the treatment arm 
could influence subject assessment.  The Investigator must document the reasons for unblinding 
in the subject’s source documents.  The Investigator is strongly advised not to divulge the 
subject’s treatment assignment to any individual not directly involved in managing the medical 
emergency, nor to personnel involved with the analysis and conduct of the study.  In cases where 
there are ethical reasons to have a subject whose treatment assignment was unblinded for safety 
reasons remain in the study, the Investigator must obtain specific approval from the Sponsor and 
the Medical Monitor for the subject to continue in the study.  
In addition, all suspected unexpected serious adverse reactions (SUSARs) will be unblinded by 
the Sponsor’s (or designee) Drug Safety and Quality Assurance personnel for the purpose of 
regulatory reporting (Section 15.3.4). 


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10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A subject must permanently discontinue study treatment for any of the following reasons: 
 The subject’s parent or legal guardian withdraws consent.   
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment. 
 At the discretion of the Investigator for medical reasons. 
 At the discretion of the Investigator or the Sponsor for noncompliance. 
The reason for discontinuation of study treatment must be recorded in the subject’s case report 
form (CRF). 
In Part 1 of the study, subjects who discontinue treatment will continue follow-up evaluations 
(i.e., predose evaluations at regular study evaluations) but with no postdose safety monitoring 
telephone contacts (Section 4.2, Table 2) unless either consent is withdrawn (Section 10.2) or the 
Sponsor terminates Part 1 early, in the case of emergent data from the ISIS 396443 clinical 
development program.  If a subject is unable to come for study evaluations, the minimum 
requirement for follow up will be telephone calls on a monthly basis.  At these evaluations or 
telephone contact, changes in concomitant medications and AEs, information on the subject’s 
daily ventilator use/bi-level positive airway pressure (Bi-PAP), and health status will be 
recorded.  The methods used to continue follow up (i.e., site evaluations or telephone calls to the 
subject’s parent, guardian, or caregiver) should be documented in the source document. 
In Part 2 of the study, subjects who discontinue treatment will continue follow-up evaluations 
unless consent is withdrawn (Section 10.2).  If a subject is unable to come for study evaluations, 
the minimum requirement for follow up will be telephone calls on a monthly basis.  The methods 
used to continue follow up (i.e., site evaluations or telephone calls to the subject’s parent, 
guardian, or caregiver) should be documented in the source document.  Follow-up evaluations 
for any subjects who discontinue treatment in Part 2 will continue through the end of Part 2. 
10.2. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any one of the following reasons: 
 The subject’s parent or legal guardian withdraws consent.   
 The subject’s parent or legal guardian is unwilling or unable to comply with the 
protocol. 
 The Sponsor terminates Part 1 early because of emergent data from the ISIS 396443 
clinical development program, and the subject elects not to enroll in Part 2. 
Subjects who withdraw early from Part 1 will be encouraged to complete the End of Part 1 
Evaluation assessments (see Section 4.2 [Table 2]) at the time of withdrawal.  Subjects who 
withdraw early from Part 2 will be encouraged to complete the Part 2 Early Termination 


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Evaluation assessments at the time of withdrawal (see Section 4.2 [Table 3, and Table 4]).  The 
reason for the subject’s withdrawal from the study must be recorded in the subject’s CRF. 
11. 
STUDY TREATMENT USE 
11.1. 
Regimen 
Refer to and follow the DHA for complete details. 
11.1.1. 
Study Treatment 
In Part 1 of the study, each subject will receive a single intrathecal bolus (1 to 3 minutes) LP 
injection of ISIS 396443 or sham procedure on Days 1, 15, 29, 64, 183, and 302 by dedicated 
study personnel who are unblinded to treatment group; this cannot be any of the key study site 
personnel (i.e., the Investigator, the study coordinator, or outcome assessors).  The study 
treatment administration will be performed in a dedicated room, and key study personnel and the 
parents will not be present during the procedure to ensure blinding.   
In Part 2 of the study, each subject will receive a single intrathecal bolus (1 to 3 minutes) LP 
injection of ISIS 396443 at the days determined by their Part 1 treatment assignment as specified 
in Table 3 and Table 4.  Treatment administration will not be blinded. 
ISIS 396443 will be administered using a “spinal anesthesia” needle and a 5-mL syringe.  A 22G 
to 25G spinal anesthesia needle is recommended based on subject size or clinical condition.  The 
target site for needle insertion is the L3/L4 space but may be 1 segment above or 1 to 2 segments 
below this level, if needed.  Depending on institutional guidelines, anesthesia may be used for 
the LP procedure or for the sham procedure, following institutional procedures.  Subjects will be 
encouraged to lie down flat for 1 hour following injection of the study treatment, if possible.  
Prior to each injection, 5 mL of CSF fluid will be collected for analyses.  CSF will be used for 
ISIS 396443 PK analyses.  Upon consent, extra CSF will be stored for optional future 
investigation of possible biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF 
microRNA panel) or for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, immunogenicity assessments (including 
assay development and validation purposes), or other actions of ISIS 396443 with CSF 
constituents.  CSF analyses and data presentation will be conducted in a blinded manner.   
The volume of the injection, and thus, the dose, will be adjusted for the subject’s age on the day 
of dosing, such that each subject will receive a 12-mg scaled equivalent dose based on CSF 
volume scaling (Table 1).  Thus, younger subjects will be given a lower dose of study treatment, 
achieved by injecting a smaller volume that is proportional to estimated CSF volume for age, 
such that dose volume will be equivalent to 5 mL for a 2-year-old child to adult.   
11.1.2. 
Sham Procedure 
In Part 1 of the study, subjects randomized to the sham procedure control group will undergo a 
sham procedure, rather than study treatment administration, on Study Days 1, 15, 29, 64, 183, 
and 302.  Details regarding the sham procedure will be provided in the DHA.  The sham 
procedure will be administered by dedicated study personnel who are unblinded to treatment 


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group; this cannot be any of the key study site personnel (i.e., the Investigator, study coordinator, 
or outcomes assessors).  The sham procedure will be performed in a dedicated room, and key 
study personnel and the parent or legal guardian will not be present during the procedure to 
ensure blinding.  
In general, the sham procedure will consist of a small needle prick on the lower back at the 
location where the LP injection is normally made.  The needle will break the skin, but no LP 
injection or needle insertion will occur.  The needle prick will be covered with the same bandage 
that is used to cover the LP injection normally, thus simulating the appearance of an LP 
injection.  If institutional guidelines require the use of anesthesia or sedation for an LP procedure 
in ISIS 396443-treated subjects, then in order to maintain the blind, minimal sedation (i.e., a low 
dose of an anxiolytic) should be used for the sham procedure, following institutional procedures.  
The study subject will be kept in the procedure room for the same amount of time that subjects 
administered study treatment are kept, thus simulating the time period of the study treatment 
administration procedure. 
Study treatment and sham kits will be packaged in a blinded fashion.  Blinded kits for the sham 
procedure contain artificial CSF (5.0 mL solution per 6 mL vial) that will not be injected but will 
be used to simulate CSF samples for that subject.  
11.2. 
Modification of Dose and/or Treatment Schedule 
No adjustment of dose is permitted.  In the event of a concurrent illness that would prevent the 
dosing procedure from being performed safely, an adjustment in the dose schedule may be 
permitted but must be approved by the Medical Monitor. 
11.3. 
Precautions 
There are no protocol-required treatment precautions. 
11.4. 
Compliance 
Compliance with treatment dosing is to be monitored and recorded by site staff. 
11.5. 
Concomitant Therapy and Procedures 
11.5.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between Screening and the Part 2 
Final Follow-up Evaluation/Telephone Call (or End of Part 1 Evaluation, if the subject does not 
enroll in Part 2). 
Allowed Concomitant Therapy 
Throughout the study, Investigators or designated licensed physicians involved in the study may 
prescribe concomitant medications or treatments deemed necessary for AEs or to provide 
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Disallowed Concomitant Therapy 
Subjects are prohibited from receiving other experimental agents, including gene therapy, during 
the study.  This includes marketed agents at experimental doses that are being tested for the 
treatment of SMA (e.g., albuterol/ salbutamol, riluzole, carnitine, sodium phenylbutyrate, 
valproate, hydroxyurea). 
11.5.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and the Part 2 Final Follow-up Evaluation/Telephone 
Call (or End of Part 1 Evaluation, if the subject does not enroll in Part 2). 
12. 
STUDY TREATMENT MANAGEMENT 
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol). 
Study treatment must be dispensed only by a pharmacist or medically qualified staff.  Study 
treatment is to be dispensed only for subjects enrolled in this study.  Once study treatment is 
prepared for a subject, it can be administered only to that subject.  Study treatment vials are for 
one-time use only; any study treatment remaining in the vial should not be used for another 
subject.   
12.1. 
Study Treatment 
ISIS 396443 is formulated as an isotonic solution at 2.4 mg/mL and is provided as a 5.0-mL fill 
volume in a 6-mL clear glass vial.  ISIS 396443 drug product contains the heptadecasodium salt 
of an 18-base residue phosphorothioate oligonucleotide. 
ISIS 396443 active drug is manufactured by Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. 
The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements.  At a minimum, the label will include a study reference code, drug identifier, and 
quantity of dosage units, lot number, and other pertinent information in accordance with local 
laws.  The expiry or use-by date is stored in the IRT system, and printable assignment reports are 
available to site personnel.  Study treatment should not be used after the expiration date.   
For Part 1 of the study, the study drug (ISIS 396443) and sham kits will be packaged in a blinded 
fashion.  Blinded kits for sham procedure contain artificial CSF provided as 5.0 mL solution per 
6 mL vial that will not be injected but will be used to simulate CSF samples for a subject.   
For Part 2 of the study, the study drug (ISIS 396443) kits will be packaged in an open-label 
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12.1.1. 
Study Treatment Preparation 
The individual preparing ISIS 396443 or artificial CSF should carefully review the instructions 
provided in the DHA.   
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or drug, do not use it.  The vials in question should be saved at the study site and the 
problem immediately reported to the Sponsor (or designee). 
12.1.2. 
Study Treatment Storage 
Study treatment must be stored in a secure location. 
ISIS 396443 is to be protected from light and stored long term at 2°C to 8°C in a locked 
refrigerator with limited access.  For additional information on storage requirements, follow the 
instructions provided in the DHA. 
12.1.3. 
Study Treatment Handling and Disposal 
The Investigator must return all used and unused vials of ISIS 396443 and artificial CSF as 
instructed by the Sponsor (or designee). 
If any used ISIS 396443 or artificial CSF supplies are to be destroyed at the study site, the 
institution or appropriate site personnel must obtain prior approval from the Sponsor (or 
designee), by providing, in writing, the destruction policy or details of the method of 
destruction.  After such destruction, the Sponsor (or designee) must be notified, in writing, of the 
details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the date of 
destruction, and proof of destruction. 
12.1.4. 
Study Treatment Accountability 
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), and accounts of any study treatment accidentally or 
deliberately destroyed.   
Unless otherwise notified, all vials, both used and unused, must be saved for study treatment 
accountability.  At the end of the study, reconciliation must be made between the amount of 
ISIS 396443 or artificial CSF supplied, dispensed, and subsequently destroyed or returned to the 
Sponsor (or designee).  A written explanation must be provided for any discrepancies. 


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13. 
EFFICACY, PHARMACOKINETIC, AND IMMUNOGENICITY 
ASSESSMENTS 
See Section 4.2 (Table 2, Table 3, and Table 4) for the timing of all efficacy assessments. 
13.1. 
Clinical Efficacy Assessments 
The following clinical assessments will be performed to evaluate the efficacy of ISIS 396443: 
 Ventilator use  
 HINE (Section 2) 
 Growth parameters (body length, head circumference, chest circumference, arm 
circumference, weight for age, weight for length, and head to chest circumference 
ratio) 
 Clinical Global Impression of Change (physician and caregiver assessment) 
13.2. 
Pharmacokinetic (ISIS 396443 Concentration) Assessments 
The following tests will be performed to assess the PK of ISIS 396443: 
 Plasma ISIS 396443 concentrations 
 CSF ISIS 396443 concentrations 
13.3. 
Immunogenicity Assessments 
The following test will be performed to assess the immunogenicity of ISIS 396443: 
 Anti-ISIS 396443 plasma antibody concentrations 


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14. 
SAFETY ASSESSMENTS 
See Section 4.2 (Table 2, Table 3, and Table 4) for the timing of all safety assessments. 
14.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to evaluate the safety profile of 
ISIS 396443: 
 Neurological examinations (assessment of mental status, level of consciousness, 
sensory motor function, cranial nerve function, and reflexes) 
 AEs, including SAEs 
 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, 
temperature, pulse oximetry, and transcutaneous carbon dioxide) 
 Weight 
 Physical examinations 
 Medical history 
 12-Lead ECGs 
 Use of concomitant medications 
14.2. 
Laboratory Safety Assessments 
The following laboratory tests will be performed to evaluate the safety profile of ISIS 396443: 
 Blood chemistry:  total protein, albumin, creatinine, cystatin C, creatine 
phosphokinase, blood urea nitrogen, total bilirubin (direct and indirect), alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, glucose, calcium, 
phosphorus, chloride, sodium, potassium 
 Hematology:  red blood cells, hemoglobin, hematocrit, platelets, white blood cells, 
white blood cell differential 
 Urinalysis:  specific gravity, pH, protein, glucose, ketones, bilirubin, red blood cells, 
white blood cells, epithelial cells, bacteria, casts, crystals 
 


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15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each subject’s legally authorized representative and/or main 
caregiver(s) must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies. 
15.1. 
Definitions 
15.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including a 
clinically significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator.  Abnormal laboratory findings that are considered by the Investigator 
as not clinically significant should not be reported as AEs.  Although abnormal laboratory values 
are typically not considered AEs, the following considerations may result in an abnormal 
laboratory value being considered an AE: 
 A laboratory test result that meets the criteria for an SAE 
 A laboratory test result that requires the subject to receive specific corrective therapy 
 A laboratory abnormality that the Investigator considers to be clinically significant 
15.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death 
 Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization is defined as an admission of >24 hours to a medical facility and does 
not qualify as an AE   
 Results in persistent or significant disability/incapacity 
 Results in a congenital anomaly/birth defect 


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An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the study site must document all of the following: 
 The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining consent from 
the subject’s parent or legal guardian to participate in the study. 
 The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s parent‘s or legal guardian‘s consent to participate 
in the study and the time of the procedure or treatment. 
 The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission. 
o If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless 
one of the requirements in Section 15.1.2 is met. 
15.2. 
Safety Classifications 
15.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.2 
 The relationship of the event to study treatment as defined in Section 15.2.2 
 The severity of the event as defined in Section 15.2.3 








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The Investigator must document the reasons for unblinding in the subject’s source documents.  
The Investigator is strongly advised not to divulge the subject’s treatment assignment to any 
individual not directly involved in managing the medical emergency or to personnel involved 
with the analysis and conduct of the study.   
15.5. 
Safety Responsibilities 
15.5.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
 Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment. 
 Determine the seriousness, relationship, and severity of each event. 
 Determine the onset and resolution dates of each event. 
 Complete an SAE form for each serious event and fax it as described in the Study 
Reference Guide within 24 hours of the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported as described in the Study Reference Guide within 24 hours of the 
study site staff becoming aware of new information. 
 Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records. 
 Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. 
 Report SAEs to local ethics committees, as required by local law. 
15.5.2. 
The Sponsor 
The Sponsor’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor (or designee) 
is responsible for reviewing with study site staff the definitions of AE and SAE, as 
well as the instructions for monitoring, recording, and reporting AEs and SAEs. 
 The Sponsor (or designee) is to notify all appropriate regulatory authorities, central 
ethics committees, and Investigators of SAEs, as required by local law, within 
required time frames. 


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16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
Part 1 and Part 2 will be analyzed separately.  For Part 1, in general, continuous variables will be 
summarized by descriptive statistics, including number, mean, median, standard deviation, 
minimum, and maximum.  Categorical variables will be presented with the number and 
percentage in each category.  For Part 2, no formal statistical analyses will be performed.  
Descriptive statistics will be presented for safety and efficacy data collected. 
For the Part 1 analysis, baseline is defined as the last nonmissing assessment prior to the first 
dose of study treatment in Part 1.  For the Part 2 analysis, baseline is defined as the last 
nonmissing assessment prior to the first dose of study treatment in Part 2.  In addition, a pooled 
analysis incorporating data from both Part 1 and Part 2 will be conducted to characterize the 
safety profile of ISIS 396443.  For subjects on active treatment in Part 1, safety data from both 
Part 1 and Part 2 will be included in the pooled analysis and the Part 1 baseline will used for 
those subjects in the pooled analysis.  For subjects on sham procedure in Part 1, only safety data 
from Part 2 will be included in the pooled analysis and the Part 2 baseline will be used for those 
subjects in the pooled analysis. 
Concomitant medication usage for each subject will be listed for review. 
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
16.1. 
Demographic and Baseline Characteristics  
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Subject disposition will be summarized by treatment group.  All subjects 
enrolled will be included in a summary of subject disposition.  
16.2. 
Safety and Tolerability 
Safety is the primary objective for the study.  All AEs, laboratory abnormalities, ECGs, and vital 
signs will be evaluated for safety.   
16.2.1. 
Analysis Population 
Safety analyses will be conducted in the safety population.  This safety set will include all 
subjects who are randomized and receive at least 1 dose of study treatment or sham procedure.  
Treatment duration and amount of study treatment received will be summarized by treatment 
group.   
16.2.2. 
Methods of Analysis 
16.2.2.1. Neurological Examinations 
Neurological examination findings will be listed for review, and as appropriate, results will be 
summarized descriptively for each treatment group.  The number and percentage of subjects with 
shifts from baseline normal to each of the categorical values denoting normal, abnormal, and 
abnormal (not AE) will be summarized.   


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16.2.2.2. Adverse Events 
All AEs will be analyzed based on the principle of treatment emergence.  An AE will be 
regarded as treatment emergent if it was present prior to the first dose of study treatment and 
subsequently worsened, or was not present prior to the first dose of study treatment but 
subsequently appeared.  The incidence of treatment-emergent AEs will be summarized overall, 
by severity, and by relationship to study treatment.  A subject having the same AE more than 
once will be counted only once in the incidence for that event.  The occurrence of the AE with 
the greatest severity will be used in the calculation of incidence by severity; the occurrence of the 
AE with the strongest relationship to study treatment will be used in the calculation of incidence 
by relationship to study treatment. 
All treatment-emergent AEs and SAEs will be summarized for each treatment group using the 
Medical Dictionary for Regulatory Activities (MedDRA) coding system, by system organ class, 
preferred term, relationship to study treatment, and severity.  Narratives of deaths, SAEs, early 
withdrawals from study treatment and from study due to AEs will be provided.  
16.2.2.3. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  The number and 
percentage of subjects with clinically relevant postbaseline abnormalities will be presented.  
Summary statistics for actual values and change from Baseline will also be presented. 
16.2.2.4. ECGs 
ECG results will be presented by subject, and as appropriate, results will be summarized 
descriptively for each treatment group.  The number and percentage of subjects with shifts from 
baseline normal to each of the categorical values denoting normal, abnormal clinically 
significant, and abnormal (not clinically significant) will be summarized. 
16.2.2.5. Clinical Laboratory Results 
Clinical laboratory evaluations including hematology, blood chemistry, and urinalysis will be 
summarized using study visit for each treatment group.  These safety variables will also be 
presented over time after study treatment administration, as appropriate.  Laboratory parameters 
will also be summarized using shift tables, as appropriate.  
16.3. 
Efficacy 
16.3.1. 
Analysis Population 
The exploratory analysis of efficacy will be performed on the intent-to-treat population.  The 
intent-to-treat population is defined as all subjects who are randomized and receive at least 
1 dose of study treatment or sham procedure.  
16.3.2. 
Methods of Analysis 
For continuous endpoints, the mean change from baseline will be estimated with 95% confidence 
limits.  For categorical outcomes, the proportion of subjects attaining a specified category will be 
estimated.  Selected endpoints may be pooled across subsets as appropriate.  


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16.4. 
Pharmacokinetics 
16.4.1. 
Analysis Population 
The PK population will include all subjects who are randomized and have at least 1 evaluable 
postdose or postsham-procedure PK sample. 
16.4.2. 
Methods of Analysis 
Plasma PK parameters, as applicable, and ISIS 396443 concentrations in plasma and CSF for the 
PK population will be summarized using descriptive statistics and, where warranted, presented 
graphically. 
16.5. 
Immunogenicity 
16.5.1. 
Analysis Population  
The analysis population for immunogenicity will include all subjects with available 
immunogenicity data. 
16.5.2. 
Methods of Analysis 
Results from the immunogenicity analyses for anti-ISIS 396443 plasma antibody status and titer 
will be summarized at the specified visits.   
16.6. 
Interim Analyses 
No formal interim analyses are planned.  However, if the Sponsor decides to terminate Part 1 
early, data prior to the unblinding of the first subject in Part 1 may be archived; no analyses are 
planned to be conducted based on the archived data.  Full analysis of Part 1 data will be done 
following database lock at the end of Part 1.  
16.7. 
Sample Size Considerations 
Since this study is exploratory, sample size determination will not be based on power 
consideration.  The sample size considered for this study will allow exploration of safety, 
tolerability, and selected efficacy endpoints in the selected study population.   


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17. 
ETHICAL REQUIREMENTS 
The Sponsor, 
 (the contract research organization [CRO] for this study), and the 
Investigator must comply with all instructions, regulations, and agreements in this protocol and 
applicable International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) 
guidelines and conduct the study according to local regulations. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. 
17.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
17.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  The Sponsor (or designee) will submit documents 
on behalf of the investigational sites in countries other than the US.   
If the Investigator makes any changes to the ICF, the Sponsor (or designee) must approve the 
changes before the ICF is submitted to the ethics committee.  A copy of the approved ICF must 
be provided to the Sponsor (or designee).  After approval, the ICF must not be altered without 
the agreement of the relevant ethics committee and the Sponsor (or designee). 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
The Sponsor (or designee) must receive a letter documenting ethics committee approval, which 
specifically identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  
Protocol amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. 
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and the Sponsor (or designee). 
17.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations.   
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 


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subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
Subjects will be informed that their race and ethnicity will not be collected for the purposes of 
data analysis during the study.  
In addition, subjects who have the capacity should provide their assent to participate in the study.  
The level of information provided to subjects should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines. 
A copy of the signed and dated ICF and assent, if applicable, must be given to the subject or the 
subject’s legally authorized representative.  The original signed and dated ICF will be retained 
with the study records.  Local regulations must be complied with in respect to the final 
disposition of the original (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent and assent, if applicable, must also be documented in the 
subject’s medical record. 
17.4. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America). 
During the study, subjects’ race and ethnicity will not be collected for the purposes of data 
analysis.  
Study reports will be used for research purposes only.  The subject will not be identified by name 
in CRFs, study-related forms, study reports, or any related publications.  Sponsor, its partners 
and designees, ethics committees, and various government health agencies may inspect the 
records of this study.  Every effort will be made to keep the subject’s personal medical data 
confidential. 
17.5. 
Compensation for Injury 
The Sponsor (or designee) maintains appropriate insurance coverage for clinical studies and will 
follow applicable local compensation laws. 
17.6. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor or Ionis with the subject before the subject makes a decision to participate in the study). 
17.7. 
Registration of Study and Disclosure of Study Results 
The Sponsor (or designee) will register the study and post study results regardless of outcome on 
a publicly accessible website in accordance with the applicable laws and regulations. 


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18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Study Site Initiation 
The Investigator must not screen any subjects prior to completion of a study initiation visit 
conducted by the Sponsor (or designee).  This initiation visit will include a detailed review of the 
protocol and study procedures. 
18.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will 
be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested. 
18.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. 
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate. 
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.  
CRFs will be not be used as source data.  Monitoring visits must be conducted according to the 
applicable ICH and GCP guidelines to ensure protocol adherence, quality of data, study 
treatment accountability, compliance with regulatory requirements, and continued adequacy of 
the investigational site and its facilities. 
18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and the Sponsor.  Ionis is the Sponsor 
of the study in the United States and Biogen Idec Research Limited is the Sponsor of the study in 
the Rest of World.  Biogen will be responsible for managing the study globally.  All financial 
details are provided in the separate contract(s) between the institution, Investigator, and the 
Sponsor.  
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 


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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
The Sponsor may transfer any or all of its study-related responsibilities to a CRO and other third 
parties; however, the Sponsor retains overall accountability for these activities. 
19.1.1. 
Contract Research Organization  
A CRO will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports and data management.  Before 
subjects are screened at each study site, the CRO will review study responsibilities with the 
Investigators and other study site staff, as appropriate. 
19.1.2. 
Interactive Response Technology 
IRT will be used in this study.  Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system. 
19.1.3. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool that is developed and supported by an electronic data 
capture vendor and configured by Sponsor or CRO. 
19.1.4. 
Central Laboratories for Laboratory Assessments 
A central laboratory will be selected by the Sponsor to analyze all hematology, blood chemistry, 
urine, and CSF samples collected at all study sites.  Local laboratories may be used to 
accommodate acute or urgent needs as discussed in in the Study Reference Guide. 
During the Part 1 Screening Period, a blood sample will be collected for SMN2 copy number 
analysis by the central laboratory only from those subjects without genetic documentation of 
SMN2 copy number.  For all other subjects, a blood sample will be collected at any time during 
the study for analysis of SMN2 copy number by the central laboratory. 
19.2. 
Study Committees 
Safety data will be reviewed on an ongoing quarterly basis throughout Part 1 of the study by an 
independent DSMB.  The DSMB will be assembled to review safety, tolerability, and efficacy 
(as needed) data collected on ISIS 396443 during the study.  Based on its ongoing assessment of 
the safety and tolerability of ISIS 396443, the DSMB will provide recommendations to the 
Sponsor for modifying, stopping, or continuing the study as planned. 
19.3. 
Changes to Final Study Protocol 
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 


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investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, the Sponsor (or designee) may, at any time, amend this protocol to eliminate an 
apparent immediate hazard to a subject.  In this case, the appropriate regulatory authorities will 
be notified subsequent to the modification. 
In the event of a protocol modification, the ICF may require similar modifications (see 
Sections 17.2 and 17.3). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify the Sponsor in writing and 
receive written authorization from the Sponsor to destroy study records.  In addition, the 
Investigator must notify the Sponsor of any changes in the archival arrangements including but 
not limited to archival at an offsite facility or transfer of ownership if the Investigator leaves the 
site. 
19.6. 
Study Report Signatory 
The Sponsor will follow all applicable local regulations pertaining to study report signatories. 
 


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20. 
REFERENCES 
Burghes AH, Beattie CE. Spinal muscular atrophy: why do low levels of survival motor neuron 
protein make motor neurons sick? Nat Rev Neurosci. 2009;10(8):597-609. 
Coovert DD, Le TT, McAndrew PE, et al. The survival motor neuron protein in spinal muscular 
atrophy. Hum Mol Genet. 1997;6(8):1205-14. 
Feldkötter M, Schwarzer V, Wirth R, et al. Quantitative analyses of SMN1 and SMN2 based on 
real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of 
spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358-68. 
Hua Y, Sahashi K, Hung G, et al. Antisense correction of SMN2 splicing in the CNS rescues 
necrosis in a type III SMA mouse model. Genes Dev. 2010;24(15):1634-44. 
Hua Y, Vickers TA, Baker BF, et al. Enhancement of SMN2 exon 7 inclusion by antisense 
oligonucleotides targeting the exon. PLoS Biol. 2007;5(4):e73. 
Hua Y, Vickers TA, Okunola HL, et al. Antisense masking of an hnRNP A1/A2 intronic splicing 
silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet. 2008;82(4):834-48. 
Le TT, Pham LT, Butchbach ME, et al. SMNDelta7, the major product of the centromeric 
survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and 
associates with full-length SMN. Hum Mol Genet. 2005;14(6):845-57. 
Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal 
muscular atrophy. Nat Genet. 1997;16(3):265-9. 
Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. 
EMBO J. 1996;15(14):3555-65. 
Matsuzawa J, Matsui M, Konishi T, et al. Age-related volumetric changes of brain gray and 
white matter in healthy infants and children. Cereb Cortex. 2001;11(4):335-42. 
Passini MA, Bu J, Richards AM, et al. Antisense oligonucleotides delivered to the mouse CNS 
ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011;3(72):72ra18. 
Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. 
2010;12(3):145-52. 
Prior TW, Swoboda KJ, Scott HD, et al. Homozygous SMN1 deletions in unaffected family 
members and modification of the phenotype by SMN2. Am J Med Genet A. 2004;130A(3):307-
10. 
Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to age, 
SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-12. 


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74 
Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal 
muscular atrophy. J Child Neurol. 2007;22(8):1027-49. 
Wirth B, Brichta L, Schrank B, et al. Mildly affected patients with spinal muscular atrophy are 
partially protected by an increased SMN2 copy number. Hum Genet. 2006;119(4):422-8. 
 


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21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A phase 2, randomized, double-blind, sham-procedure 
controlled study to assess the safety and tolerability and explore the efficacy of ISIS 396443 
(BIIB058) administered intrathecally in subjects with spinal muscular atrophy who are not 
eligible to participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4” and agree 
to conduct the study according to the protocol and the applicable ICH guidelines and GCP 
regulations, and to inform all who assist me in the conduct of this study of their responsibilities 
and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 








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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .....................................................................................10 
2. 
LIST OF ABBREVIATIONS.....................................................................................11 
3. 
SYNOPSIS .................................................................................................................12 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR 
STUDY 232SM202 ....................................................................................................23 
4.1. 
Study Schematic .........................................................................................................23 
4.2. 
Schedule of Events .....................................................................................................24 
4.2.1. 
Schedule of Events:  Part 1 .........................................................................................24 
4.2.2. 
Schedule of Events:  Part 2 .........................................................................................27 
5. 
INTRODUCTION ......................................................................................................35 
5.1. 
Overview of Spinal Muscular Atrophy .......................................................................36 
5.2. 
Current Therapies for Spinal Muscular Atrophy ........................................................36 
5.3. 
Profile of Previous Experience With ISIS 396443 .....................................................36 
5.3.1. 
Nonclinical Experience ...............................................................................................36 
5.3.2. 
Clinical Experience .....................................................................................................38 
5.4. 
Study Rationale ...........................................................................................................40 
5.4.1. 
Rationale for Part 1 .....................................................................................................40 
5.4.2. 
Rationale for Part 2:  Open-Label Extension Phase ...................................................40 
5.5. 
Rationale for Dose and Schedule Selection ................................................................40 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................41 
6.1. 
Primary Objectives and Endpoints .............................................................................41 
6.2. 
Secondary Objectives and Endpoints .........................................................................42 
6.3. 
Exploratory Objectives and Endpoints .......................................................................42 
7. 
STUDY DESIGN .......................................................................................................44 
7.1. 
Study Overview ..........................................................................................................44 
7.2. 
Overall Study Duration and Follow-Up .....................................................................44 
7.2.1. 
Screening ....................................................................................................................45 
7.2.2. 
Treatment ....................................................................................................................45 
7.2.3. 
Follow-Up ...................................................................................................................47 
7.3. 
Study Stopping Rules .................................................................................................47 
7.4. 
End of Study ...............................................................................................................47 


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7.5. 
Safety Monitoring and Data and Safety Monitoring Board ........................................47 
8. 
SELECTION OF SUBJECTS ....................................................................................48 
8.1. 
Inclusion Criteria ........................................................................................................48 
8.2. 
Exclusion Criteria .......................................................................................................49 
9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................50 
9.1. 
Screening and Enrollment ...........................................................................................50 
9.2. 
Registration and Randomization of Subjects ..............................................................50 
9.3. 
Blinding Procedures ....................................................................................................51 
9.3.1. 
Emergency Unblinding of Treatment Assignment .....................................................51 
10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................52 
10.1. 
Discontinuation of Study Treatment ...........................................................................52 
10.2. 
Withdrawal of Subjects From Study ...........................................................................52 
11. 
STUDY TREATMENT USE .....................................................................................53 
11.1. 
Regimen ......................................................................................................................53 
11.1.1. 
Study Treatment ..........................................................................................................53 
11.1.2. 
Sham Procedure ..........................................................................................................53 
11.2. 
Modification of Dose and/or Treatment Schedule ......................................................54 
11.3. 
Precautions ..................................................................................................................54 
11.4. 
Compliance .................................................................................................................54 
11.5. 
Concomitant Therapy and Procedures ........................................................................54 
11.5.1. 
Concomitant Therapy .................................................................................................54 
11.5.2. 
Concomitant Procedures .............................................................................................55 
12. 
STUDY TREATMENT MANAGEMENT ................................................................55 
12.1. 
Study Treatment ..........................................................................................................55 
12.1.1. 
Study Treatment Preparation ......................................................................................56 
12.1.2. 
Study Treatment Storage ............................................................................................56 
12.1.3. 
Study Treatment Handling and Disposal ....................................................................56 
12.1.4. 
Study Treatment Accountability .................................................................................56 
13. 
EFFICACY, PHARMACOKINETIC, AND IMMUNOGENICITY 
ASSESSMENTS.........................................................................................................57 
13.1. 
Clinical Efficacy Assessments ....................................................................................57 


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13.2. 
Pharmacokinetic (ISIS 396443 Concentration) Assessments .....................................57 
13.3. 
Immunogenicity Assessments ....................................................................................57 
14. 
SAFETY ASSESSMENTS ........................................................................................58 
14.1. 
Clinical Safety Assessments .......................................................................................58 
14.2. 
Laboratory Safety Assessments ..................................................................................58 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................59 
15.1. 
Definitions ..................................................................................................................59 
15.1.1. 
Adverse Event .............................................................................................................59 
15.1.2. 
Serious Adverse Event ................................................................................................59 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................60 
15.2. 
Safety Classifications ..................................................................................................60 
15.2.1. 
Investigator Assessment of Events .............................................................................60 
15.2.2. 
Relationship of Events to Study Treatment ................................................................61 
15.2.3. 
Severity of Events .......................................................................................................61 
15.2.4. 
Expectedness of Events ..............................................................................................61 
15.3. 
Monitoring and Recording Events ..............................................................................61 
15.3.1. 
Adverse Events ...........................................................................................................61 
15.3.2. 
Serious Adverse Events ..............................................................................................62 
15.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................62 
15.3.3.1. 
Deaths .........................................................................................................................63 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................63 
15.4. 
Procedures for Handling Special Situations ...............................................................63 
15.4.1. 
Overdose .....................................................................................................................63 
15.4.2. 
Medical Emergency ....................................................................................................63 
15.4.2.1. 
Unblinding for Medical Emergency ...........................................................................63 
15.5. 
Safety Responsibilities ................................................................................................64 
15.5.1. 
The Investigator ..........................................................................................................64 
15.5.2. 
The Sponsor ................................................................................................................64 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........65 
16.1. 
Demographic and Baseline Characteristics ................................................................65 
16.2. 
Safety and Tolerability ...............................................................................................65 


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16.2.1. 
Analysis Population ....................................................................................................65 
16.2.2. 
Methods of Analysis ...................................................................................................65 
16.2.2.1. 
Neurological Examinations ........................................................................................65 
16.2.2.2. 
Adverse Events ...........................................................................................................66 
16.2.2.3. 
Vital Signs ..................................................................................................................66 
16.2.2.4. 
ECGs ...........................................................................................................................66 
16.2.2.5. 
Clinical Laboratory Results ........................................................................................66 
16.3. 
Efficacy .......................................................................................................................66 
16.3.1. 
Analysis Population ....................................................................................................66 
16.3.2. 
Methods of Analysis ...................................................................................................67 
16.4. 
Pharmacokinetics ........................................................................................................67 
16.4.1. 
Analysis Population ....................................................................................................67 
16.4.2. 
Methods of Analysis ...................................................................................................67 
16.5. 
Immunogenicity ..........................................................................................................67 
16.5.1. 
Analysis Population ....................................................................................................67 
16.5.2. 
Methods of Analysis ...................................................................................................67 
16.6. 
Interim Analyses .........................................................................................................67 
16.7. 
Sample Size Considerations .......................................................................................67 
17. 
ETHICAL REQUIREMENTS ...................................................................................68 
17.1. 
Declaration of Helsinki ...............................................................................................68 
17.2. 
Ethics Committee ........................................................................................................68 
17.3. 
Subject Information and Consent ...............................................................................68 
17.4. 
Subject Data Protection ..............................................................................................69 
17.5. 
Compensation for Injury .............................................................................................69 
17.6. 
Conflict of Interest ......................................................................................................69 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................69 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................70 
18.1. 
Study Site Initiation ....................................................................................................70 
18.2. 
Quality Assurance .......................................................................................................70 
18.3. 
Monitoring of the Study..............................................................................................70 
18.4. 
Study Funding .............................................................................................................70 


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18.5. 
Publications .................................................................................................................70 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................71 
19.1. 
External Contract Organizations .................................................................................71 
19.1.1. 
Contract Research Organization .................................................................................71 
19.1.2. 
Interactive Response Technology ...............................................................................71 
19.1.3. 
Electronic Data Capture ..............................................................................................71 
19.1.4. 
Central Laboratories for Laboratory Assessments .....................................................71 
19.2. 
Study Committees .......................................................................................................71 
19.3. 
Changes to Final Study Protocol ................................................................................72 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................72 
19.5. 
Retention of Study Data ..............................................................................................72 
19.6. 
Study Report Signatory...............................................................................................72 
20. 
REFERENCES ...........................................................................................................73 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................75 
 
 
 


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LIST OF TABLES 
Table 1 
ISIS 396443 Dose Volume To Be Injected ................................................................18 
Table 2: 
Part 1 Schedule of Activities ......................................................................................24 
Table 3: 
Part 2 Schedule of Activities for Subjects Randomized to Receive ISIS 
396443 in Part 1 ..........................................................................................................27 
Table 4: 
Part 2 Schedule of Activities for Subjects Randomized to Receive Sham 
Procedure in Part 1 ......................................................................................................30 
Table 5 
Part 1 Pharmacokinetic Sampling Schedule1 ..............................................................33 
Table 6 
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive ISIS 396443 in Part 11 ..................................................................................33 
Table 7 
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive Sham Procedure in Part 11 ............................................................................34 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................23 
Figure 2: 
Antisense Oligonucleotide Therapeutic Approach for Treatment of Spinal 
Muscular Atrophy .......................................................................................................35 
 


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1. 
SPONSOR INFORMATION 
Ionis Pharmaceuticals, Inc. (Ionis) is the Sponsor of the study in the United States.  Biogen Idec 
Research Limited is the Sponsor of the study in the Rest of World.  Biogen Idec Research 
Limited (or designee) will be responsible for managing the study globally.  
 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA  02142 
United States 
 
Biogen Idec Research Limited  
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
USA 
 
 
Primary contact for urgent medical issues: 
 
:  
, MD 
 
 
 
 
 
 
Office
 
 
 
 
 
 
 
Mobile:
 
 
 
 
 
 
 
Fax: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 medical emergency: 
  
 
 
 
 
 
 
 
or 
 
 
Secondary contact for urgent medical issues: 
 
Biogen MA
: 
, MD 
 
 
 
 
 
 
Cell phone: 
 
 
Refer to the Study Reference Guide for complete contact information, including that for the 
unblinded Medical Monitor. 


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2. 
LIST OF ABBREVIATIONS 
 
2′ MOE 
2′ O (2 methoxyethyl) 
AE 
adverse event 
ASO 
antisense oligonucleotide 
Bi-PAP 
bi-level positive airway pressure  
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
DHA 
Directions for Handling and Administration 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
GCP 
Good Clinical Practice 
HINE 
Hammersmith Infant Neurological Examination 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRT 
interactive response technology 
LP 
lumbar puncture 
mRNA 
messenger ribonucleic acid 
OLE 
open-label extension 
PK 
pharmacokinetic(s) 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SMA 
spinal muscular atrophy 
SMN 
survival motor neuron 
SMN1 
survival motor neuron 1 
SMN2 
survival motor neuron 2 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time to reach maximum observed concentration 


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3. 
SYNOPSIS 
This is a brief summary.  For details, refer to the body of the protocol. 
Protocol Number: 
232SM202 
Protocol Title: 
A Phase 2, randomized, double-blind, sham-procedure controlled study 
to assess the safety and tolerability and explore the efficacy of 
ISIS 396443 (BIIB058) administered intrathecally in subjects with spinal 
muscular atrophy who are not eligible to participate in the clinical 
studies ISIS 396443-CS3B or ISIS 396443-CS4  
Version Number: 
2  
Name of Study 
Treatment: 
ISIS 396443 (BIIB058) 
Study Indication: 
Spinal muscular atrophy (SMA) 
Phase of 
Development: 
2 
Study Rationale: 
The rationale of Part 1 of the study is to assess the safety and tolerability 
and evaluate the utility of selected exploratory efficacy endpoints in 
subjects with SMA treated intrathecally with ISIS 396443 who are not 
eligible for the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4. 
Based on emergent data from the ISIS 396443 clinical development 
program, the Sponsor may decide to terminate Part 1 early, and all 
subjects may be offered the opportunity to transition to Part 2 (the open-
label extension phase) prior to completion of all Part 1 evaluations.  The 
rationale of Part 2 of the study is to assess the long-term safety and 
tolerability of ISIS 396443 in subjects with SMA who participated in 
Part 1 and completed their End of Part 1 Evaluation assessments. 
Study Objectives and 
Endpoints: 
Part 1 
Primary objective: 
The primary objective of Part 1 of this study is:  
 To assess the safety and tolerability of ISIS 396443 in 
subjects with SMA who are not eligible to participate in the 
clinical studies ISIS 396443-CS3B or ISIS 396443-CS4. 
The primary endpoints that relate to this objective are: 


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 Incidence of adverse events (AEs) and serious AEs (SAEs) 
 Change from baseline in clinical laboratory parameters, 
electrocardiograms (ECGs), and vital signs 
 Change from baseline in neurological examination outcomes 
Secondary objective: 
The secondary objective and endpoint of Part 1 of this study are as 
follows: 
 To examine the pharmacokinetics (PK) of ISIS 396443 in 
subjects with SMA who are not eligible to participate in the 
clinical studies ISIS 396443-CS3B or ISIS 396443-CS4 
 ISIS 396443 concentrations in plasma and cerebrospinal fluid 
(CSF) 
Part 2 
Primary objective: 
The primary objective of Part 2 of this study is: 
 To assess the long-term safety and tolerability of ISIS 396443 
in subjects with SMA who participated in Part 1 and 
completed their End of Part 1 Evaluation assessments. 
The primary endpoints that relate to this objective are: 
 Incidence of AEs and SAEs 
 Change from baseline in clinical laboratory parameters, 
ECGs, and vital signs 
 Change from baseline in neurological examination outcomes 
Secondary objective: 
The secondary objective and endpoint of Part 2 of this study are as 
follows: 
 To examine the PK of ISIS 396443 in subjects with SMA 
who participated in Part 1 and completed their End of Part 1 
Evaluation assessments 
 ISIS 396443 concentrations in plasma and CSF 
Exploratory objectives and endpoints are listed in Section 6.3. 
Study Design: 
This is a Phase 2 multicenter study conducted in 2 parts: 
Part 1 was originally designed as a randomized, double-blind, 
sham-procedure controlled study to assess the safety and tolerability and 
explore the efficacy of intrathecally administered ISIS 396443 over a 


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period of approximately 14 months (from the first dose until the End of 
Part 1 Evaluation).  Up to 21 subjects will be randomized in a ratio of 
2:1 to receive ISIS 396443 by intrathecal lumbar puncture (LP) injection 
or a sham-procedure control.  Randomization will be stratified based on 
age at onset of clinical signs and symptoms consistent with SMA:  
>6 months versus <6 months. 
After informed consent is obtained, subjects will undergo a screening 
evaluation no greater than 28 days prior to administration of the first 
dose of study treatment.  Subjects who meet the eligibility criteria will be 
randomized to receive ISIS 396443 or sham procedure.  Subjects will be 
admitted to the study site on Part 1 Day 1, undergo predose evaluations, 
and then receive an LP injection of study treatment or sham procedure.  
Subjects will return to the study site on Days 15, 29, 64, 183, and 302 for 
follow-up evaluations and subsequent injections or sham procedures.  
For subjects receiving ISIS 396443 or sham procedure, a CSF sample 
will be taken predose on each injection day in a manner that maintains 
the blind. 
After the study treatment dosing or sham procedure on Day 1, subjects 
will remain at the study site for at least 24 hours for safety monitoring.  
Following all subsequent injections, all subjects will remain at the study 
site for at least 6 hours postdose for safety monitoring.  
Safety monitoring will occur on the day following each injection of 
study treatment or sham procedure.  Subjects receiving the dosing or 
sham procedure on Days 15, 29, 64, 183, and 302 will be monitored by 
telephone contact on Days 16, 30, 65, 184, and 303. 
In addition, subjects will also be monitored through telephone contact 
throughout the duration of the study. 
An End of Part 1 Evaluation will occur up to 4 months after the last dose 
of ISIS 396443 or sham procedure, or sooner (if the Sponsor decides to 
terminate Part 1 early based on emergent data from the ISIS 396443 
clinical development program, as described below).  Subjects who 
terminate early from Part 1 of the study will be encouraged to complete 
the End of Part 1 Evaluation assessments at the time of withdrawal. 
After completing End of Part 1 Evaluation assessments according to the 
study schedule or sooner, if emergent data from the ISIS 396443 clinical 
development program necessitate the early termination of Part 1 by the 
Sponsor, all eligible subjects may elect to enroll in Part 2.  All subjects 
enrolled in the study at the time that the Sponsor terminates Part 1 will 
be considered Part 1 completers.  The next study evaluation for those 
subjects will serve as an End of Part 1 Evaluation, which may occur at 
any time prior to the next scheduled Part 1 study evaluation.  


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Based on emergent data from the ISIS 396443 clinical development 
program, the Sponsor may decide to terminate Part 1 early, and all 
subjects may then be offered the opportunity to be unblinded and 
transition to Part 2 prior to completion of all Part 1 evaluations.  Part 2 is 
an open-label extension (OLE) phase that will assess long-term safety 
and tolerability and explore the efficacy of intrathecally administered 
ISIS 396443 for approximately 24 additional months (or until 
availability of commercial product). 
Part 2 study procedures will be determined based on the treatment 
assignment in Part 1. 
Subjects who were randomized to receive ISIS 396443 in Part 1 
End of Part 1 Evaluation assessments will be used to determine subject 
eligibility for Part 2 of the study.  For subjects who were receiving 
ISIS 396443 in Part 1, Part 2 Day 1 will occur following the End of 
Part 1 Evaluation or approximately 4 months following the last injection 
of ISIS 396443 in Part 1.  On Part 2 Day 1, subjects will undergo 
predose evaluations according to the schedule of events and then receive 
their first dose of ISIS 396443 for Part 2 (next maintenance dose).  
Subjects will return to the study site on Days 120, 239, 358, 477, 596, 
and 715 for follow-up evaluations and subsequent maintenance dose 
injections.  All subjects will remain at the study site for at least 1 hour 
postdose for safety monitoring and can be discharged at the discretion of 
the site Investigator and in compliance with the institutional 
requirements once the subjects have adequately recovered from the 
dosing procedure.  
Safety monitoring by telephone contact will occur on the day after 
injection of study treatment.  Subjects will be monitored by telephone 
contact on Days 2, 121, 240, 359, 478, 597, and 716. 
In addition, subjects will be monitored through telephone contact 
throughout the duration of the study. 
A Part 2 Final Follow-up Evaluation will occur approximately 4 months 
after the last dose in Part 2.  Subjects who terminate early from Part 2 of 
the study will be encouraged to complete the Part 2 Early Termination 
Evaluation assessments at the time of withdrawal.  
Subjects who were randomized to receive sham procedure in Part 1 
End of Part 1 Evaluation assessments will be used to determine 
eligibility for Part 2 of the study.  For subjects who were receiving sham 
procedure in Part 1, Part 2 Day 1 will occur following the End of Part 1 
Evaluation or as soon as possible following the End of Part 1 Evaluation, 
in the event of early termination due to emergent data from the 
ISIS 396443 clinical development program.  On Part 2 Day 1, subjects 


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will undergo predose evaluations according to the schedule of events and 
then receive their first dose of ISIS 396443 (first loading dose).  Subjects 
will return to the study site on Days 15, 29, 64, 183, 302, 421, 540, 659, 
and 778 for follow-up evaluations and subsequent injections.  Subjects 
will remain at the study site for at least 24 hours on Day 1.  Following all 
subsequent injections, all subjects will remain at the study site for at least 
1 hour postdose for safety monitoring and can be discharged at the 
discretion of the site Investigator and in compliance with the institutional 
requirements once the subjects have adequately recovered from the 
dosing procedure.  
Safety monitoring by telephone contact will occur on the day after 
injection of study treatment after Day 1.  Subjects will be monitored by 
telephone contact on Days 16, 30, 65, 184, 303, 422, 541, 660, and 779. 
In addition, subjects will be monitored through telephone contact 
throughout the duration of the study. 
A Part 2 Final Follow-up Evaluation will occur approximately 4 months 
after the last dose in Part 2.  Subjects who terminate early from Part 2 
will be encouraged to complete the Part 2 Early Termination Evaluation 
assessments at the time of withdrawal. 
 
 


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Rationale for Dose 
and Schedule 
Selection: 
 
In Part 1, a scaled equivalent dose of 12 mg ISIS 396443 will be 
administered at each of the 6 doses (i.e., on Study Days 1, 15, 29, 64, 
183, and 302) over a dosing period of approximately 10 months to 
subjects randomized to receive active treatment. 
In Part 2, a scaled equivalent dose of 12 mg ISIS 396443 will be 
administered at each dose over a dosing period of approximately 
24 months (or until availability of the commercial product). 
The volume of the injection will be adjusted based on the subject’s age 
on the day of dosing as shown in Table 1, such that each subject will 
receive a 12-mg scaled equivalent dose based on CSF volume scaling.  
Thus, younger subjects will be given a lower absolute mg dose of study 
treatment, achieved by injecting a smaller volume that is proportional to 
estimated CSF volume for age, such that dose volume will be equivalent 
to 5 mL for 2 years of age to adult. 
The dose regimen and the dose interval for this study were selected 
based on nonclinical toxicology and PK observations from monkey 
studies using single-dose and repeat-dose intrathecal administration, 
consideration of the target tissue concentration anticipated for drug 
pharmacology, and safety data in the completed and ongoing clinical 
studies of ISIS 396443 to date.  Based on pharmacology and PK results 
in SMA transgenic mice, it is estimated that a target spinal cord tissue 
concentration between 1 and 10 μg/g will produce 50% to 90% SMN2 
exon 7 inclusion.  Nonclinical studies in juvenile monkeys receiving 
intrathecal doses of ISIS 396443 showed a resulting gradient of 
distribution of ISIS 396443 along the spinal cord, with mean lumbar 
spinal cord concentrations ranging from 1.6- to 2.3-fold and 2.0- to 
3.5-fold higher than thoracic and cervical spinal cord levels, 
respectively.  The dose selected for this multiple-dose clinical study 
(equivalent to 12 mg of ISIS 396443) is predicted to achieve levels at the 
high end of this range (approximately 10 μg/g lumbar and 3 μg/g 
cervical spinal cord tissue concentrations) after the first dose.  The 
loading dose interval (i.e., doses on Days 1, 15, 29, and 64) was selected 
based on the nonclinical PK and pharmacology data in order to achieve 
and maintain ISIS 396443 spinal cord tissue levels that are predicted to 
be above or within the upper end of the pharmacologically active range 
by Day 64 (approximately 30 μg/g lumbar and 10 μg/g cervical tissue 
concentration), while at the same time considering subject safety and 
convenience for repeated intrathecal injections by LP.  The higher 
number of loading doses would allow for the evaluation of safety and 
tolerability and preliminary exploratory efficacy endpoints in a broader 
population of subjects with SMA, including those who have onset of 
clinical signs and symptoms at >6 months of age but who are not eligible 


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for Study ISIS 396443-CS4.  The maintenance dose interval (once every 
4 months) was selected based on the estimated spinal tissue and CSF 
drug half-life (4 to 6 months) and was selected to maintain spinal cord 
tissue levels of ISIS 396443 at a steady-state level within the estimated 
pharmacologically active range.  In Part 1, maintenance doses will be 
given on Day 183 and Day 302, for a total of 6 doses over approximately 
10 months.  Subjects who were receiving ISIS 396443 in Part 1 will 
continue receiving maintenance doses in Part 2 every 4 months.  
Subjects who were receiving sham in Part 1 will receive maintenance 
doses starting on Day 183 of Part 2. 
 
Table 1 
ISIS 396443 Dose Volume To Be Injected 
Age 
Estimated 
CSF Volume 
(mL) 
Injection 
Volume (mL) 
Dose (mg) 
0-3 months 
(0-90 days) 
120 
4 
9.6 
3-6 months 
(91-182 days) 
130 
4.3 
10.3 
6-12 months 
(183-365 days) 
135 
4.5 
10.8 
12-24 months 
(366-730 days) 
140 
4.7 
11.3 
>24 months 
(>730 days) 
150 
5.0 
12.0 
Source: [Matsuzawa 2001] 
CSF = cerebrospinal fluid. 
Study Location: 
Global, multicenter 
Number of Planned 
Subjects: 
In Part 1, up to 21 subjects are planned (14 ISIS 396443; 7 sham 
procedure). 
In Part 2, up to 21 subjects are planned (21 ISIS 396443). 
Study Population: 
Part 1 of this study will be conducted in subjects who have clinical signs 
and symptoms of SMA at ≤6 months of age or at >6 months of age and 
who are not eligible for the clinical studies ISIS 396443-CS3B or 
ISIS 396443-CS4.  
Part 2 will include only subjects who participated in Part 1 and 
completed their End of Part 1 Evaluation assessments.  Subjects 


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enrolling in Part 2 must meet the Part 2-specific criteria. 
Detailed eligibility criteria are described in Section 8. 
Treatment Groups: 
In Part 1, subjects will receive either ISIS 396443 intrathecally or 
sham-procedure control in a 2:1 ratio.  Randomization will be balanced 
for the stratification factor (age of symptom onset >6 months versus 
<6 months).  A single dose level of 12 mg ISIS 396443 will be scaled by 
age at the time of dosing for each subject. 
In Part 2, all subjects will receive open-label ISIS 396443.  A single dose 
level of 12 mg ISIS 396443 will be scaled by age at the time of dosing 
for each subject. 
Duration of 
Treatment and 
Follow-up: 
For subjects who meet the eligibility criteria and enroll in Part 1 of the 
study, the duration of Part 1 will be approximately 15 months (450 days) 
and will include a Screening Period of no greater than 28 days, a 
302-day Treatment Period, and an End of Part 1 Evaluation 
approximately 4 months after the last dose.  Based on emergent data 
from the ISIS 396443 clinical development program, the Sponsor may 
decide to terminate Part 1 early, and all subjects may be offered the 
opportunity to transition to Part 2 prior to completion of all Part 1 
evaluations. 
For subjects who meet the eligibility criteria and enroll in Part 2 of the 
study, the duration of Part 2 will be approximately 28 months and will 
include an open-label Treatment Period of approximately 24 months (or 
until availability of commercial product) and a Part 2 Final Follow-up 
Evaluation approximately 4 months after the last dose of study treatment. 
Total study duration for subjects who participate in both Part 1 and 
Part 2 will be approximately 43 months. 
Criteria for 
Evaluation: 
The criteria for evaluation for Part 1 and Part 2 are as follows: 
Safety: 
 Neurological examinations (assessment of mental status, level of 
consciousness, sensory motor function, cranial nerve function, 
and reflexes)  
 AEs, including SAEs 
 Vital signs (resting systolic and diastolic blood pressure, pulse 
rate, respiratory rate, temperature, pulse oximetry, and 
transcutaneous carbon dioxide) 
 Weight 
 Physical examinations 


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 Medical history 
 12-Lead ECGs 
 Use of concomitant medications 
 Clinical laboratory tests (blood chemistry, hematology, and 
urinalysis) 
Pharmacokinetics: 
 Plasma ISIS 396443 concentrations 
 CSF ISIS 396443 concentrations 
Efficacy: 
 Ventilator use  
 Hammersmith Infant Neurological Examination (HINE, 
Section 2) 
 Growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for 
length, and head to chest circumference ratio) 
 Clinical Global Impression of Change (physician and caregiver 
assessment) 
Immunogenicity: 
 Anti-ISIS 396443 plasma antibody concentrations 


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Statistical Methods: 
 
Analysis Population 
The intent-to-treat population is defined as all subjects who are 
randomized and receive at least 1 dose of study treatment or sham 
procedure. 
The safety population will include all subjects who are randomized and 
receive at least 1 dose of study treatment or sham procedure.  
The PK population will include all subjects who are randomized and 
have at least 1 evaluable postdose or postsham-procedure PK sample.  
Part 1 
Safety Analysis 
The analysis of safety will be performed on the safety population.  The 
incidence of treatment-emergent AEs and SAEs will be tabulated.  
Changes from baseline in clinical laboratory parameters, vital signs, and 
ECG parameters will be summarized.  Incidence of clinically relevant 
changes from baseline in vital signs and ECGs will be summarized.  
Laboratory parameters will also be summarized using shift tables, as 
appropriate. 
PK Analysis 
Summary statistics for plasma and CSF concentrations of ISIS 396443 
will be provided.   
Exploratory Analysis 
For continuous endpoints, the mean change from baseline will be 
estimated with 95% confidence limits.  For categorical outcomes, the 
proportion of subjects attaining a specified category will be estimated.  
Selected endpoints may be pooled across subsets as appropriate.  
Part 2 
No formal statistical analyses will be performed.  Descriptive statistics 
will be presented for safety and efficacy data collected. 
Interim Analysis:  
No formal interim analyses are planned.  However, if the Sponsor 
decides to terminate Part 1 early, data prior to the unblinding of the first 
subject in Part 1 may be archived; no analyses are planned to be 
conducted based on the archived data.  Full analysis of Part 1 data will 
be done following database lock at the end of Part 1.  
Sample Size 
Determination: 
 
Since this study is exploratory, sample size determination will not be 
based on power consideration.  The sample size considered for this study 
will allow exploration of safety, tolerability, and selected efficacy 


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endpoints in the selected study population. 
Study Stopping 
Rules: 
The Sponsor may terminate this study at any time, after informing 
Investigators.  Investigators will be notified by the Sponsor if the study is 
placed on hold, completed, or closed. 


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4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR STUDY 232SM202 
4.1. 
Study Schematic 
Figure 1: 
Study Schematic 
 
1Study visits may continue every 4 months beyond Year 2 if commercial product is not yet available. 


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4.2. 
Schedule of Events 
4.2.1. 
Schedule of Events:  Part 1 
Table 2: 
Part 1 Schedule of Activities  
Study Period 
Screen1 
Part 1 Treatment/Follow-Up 
Study Day 
Days -28 
to -1 
Day 1 
Day 22 
Day 15 (±1 day) 
Day 
162  
Day 29 (±1 day) 
Day 
302  
Days 64, 183, 302 
(±7 days) 
Days 
65, 
184, 
3032  
End of 
Part 13, 4, 5 
 
 
Predose LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs6 
X 
X 
 
4X7 
X8 
X 
 
4X7 
 
X 
 
4X7 
 
X 
 
4X7 
 
X 
Weight 
X 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Growth Parameters9 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Ventilator Use 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Neurological 
Examination10 
X 
X 
 
X11 
X 
X 
 
X11 
 
X 
 
X11 
 
X 
 
X11 
 
X 
ECG  
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Safety Laboratory 
Tests12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
 
 
 
X14 
Coagulation 
Laboratory Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X14 
Immunogenicity 
Sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
CSF PK15 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Plasma PK 
 
 
 
X16 
 
 
 
 
 
 
 
 
 
X17 
 
 
 
X 
Study Treatment 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 


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Study Period 
Screen1 
Part 1 Treatment/Follow-Up 
Study Day 
Days -28 
to -1 
Day 1 
Day 22 
Day 15 (±1 day) 
Day 
162  
Day 29 (±1 day) 
Day 
302  
Days 64, 183, 302 
(±7 days) 
Days 
65, 
184, 
3032  
End of 
Part 13, 4, 5 
 
 
Predose LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
Injection or Sham 
Procedure 
Inpatient Stay18  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone Contact for 
Safety Monitoring2 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
HINE Motor 
Milestone 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical Global 
Impression of Change 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Con Med Recording19 
X ----------------------------------------------------------------------------------------------------------------------- X 
Adverse Event 
Collection20 
X ----------------------------------------------------------------------------------------------------------------------- X 
AE = adverse event; Bi PAP = bi level positive airway pressure; Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; 
HINE = Hammersmith Infant Neurological Examination; LP = lumbar puncture; PK = pharmacokinetic(s); SAE = serious adverse event; SMA = spinal 
muscular atrophy; SMN2 = survival motor neuron 2 
1 A blood sample will be collected at Screening for SMN2 copy number only from those subjects without genetic documentation of SMN2 copy number.  For all 
other subjects, a blood sample will be collected at any time during the study for analysis of SMN2 copy number by the central laboratory. 
2 After the injection of study treatment or sham procedure on Day 1, subjects will remain at the study site for at least 24 hours (Day 2) for safety monitoring.  On 
the day following the injection of study treatment or sham procedure on Days 15, 29, 64, 183, and 302, there will be safety monitoring through telephone 
contact.  During that telephone contact (i.e., Days 16, 30, 65, 184 and 303), changes in concomitant medications and AEs, information on the subject’s daily 
ventilator/Bi-PAP use, and health status will be recorded.   
3 End of Part 1 is one of the following:  Part 1 Final Follow-up Evaluation (Day 422 [±7 days]) according to the study schedule, early Part 1 Final Follow-up 
Evaluation to allow for rollover into Part 2, or Early Termination Evaluation for subjects who withdraw from the study during Part 1. 
4 For subjects not transitioning into Part 2, the date of the End of Part 1 Evaluation assessments will be the End of study.  For subjects who transition to Part 2, 
the date of the End of Part 1 will be the date of first dose in Part 2. 
, 5 
At the End of Part 1 evaluation, in order to allow transition to Part 2, subjects will be unblinded.  
6 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each evaluation.  For subjects who are not receiving noninvasive ventilation, 
pulse oximetry will be measured overnight once a week at home.   
7 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected at 4 timepoints:  1, 2, 4, 
and 6 hours (all ±15 minutes) after the injection of study treatment. 


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8 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected within 20 to 24 hours 
after the injection of study treatment or sham procedure. 
9 At the evaluations scheduled for injection of study treatment or sham procedure, subjects will be assessed for the following growth parameters:  body length, 
head circumference, chest circumference, and arm circumference.  Growth parameters and weight are to be collected at the same time. 
10 Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes. 
11 Neurological examinations will occur between 4 to 6 hours after the injection of study treatment or sham procedure. 
12 Blood chemistry, hematology, and urinalysis panels.  
13 Samples for safety laboratory tests will be collected before the injection of study treatment or sham procedure on Days 64 and 183 only.  
14 End of Part 1 safety laboratory tests and coagulation laboratory tests to be performed at the local laboratory in parallel with the central laboratory. 
15Refer to Table 5 for CSF PK sample schedule.  The CSF samples will be analyzed for ISIS 396443 concentrations.  The remaining CSF sample will be stored 
for optional future biomarker analyses.   
16Blood samples for PK assessment will be collected 4 hours (±1 hour) after the injection of study treatment or sham procedure only on Day 1.  Refer to Table 5 
for the plasma PK sample schedule. 
17Blood samples for PK assessment will be collected before the injection of study treatment or sham procedure on Days 64 and 183 only.  Refer to Table 5 for the 
plasma PK sample schedule. 
18Overnight stay (at least 24 hours) is required after the first injection of study treatment or sham procedure.  Following all subsequent injections or sham 
procedures, a stay of at least 6 hours at the study site is required; overnight stays are optional on these days. 
19In addition to concomitant medications, ancillary procedures will be recorded. 
20AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2. 
 


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4.2.2. 
Schedule of Events:  Part 2 
Table 3: 
Part 2 Schedule of Activities for Subjects Randomized to Receive ISIS 396443 in Part 1  
Study Period 
Part 2 Treatment/Follow-Up 
Study Day 
Day 1 
Day 21 
Days 120, 239, 358, 477, 596, 715 (±7 days)2 
Days 121, 240, 
359, 478, 597, 
7161 
Part 2 Final Follow-Up 
(Day 835 [±7 days])3or Part 2 
Early Termination4 
 
 
Predose5 
LP 
Postdose 
Predose 
LP 
 
Postdose 
Informed Consent 
X5 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
Criteria 
X5 
 
 
 
 
 
 
 
 
Vital Signs6 
X7,12 
 
X8 
X 
X 
 
X8 
 
X 
Weight 
X7,12 
 
 
 
X 
 
 
 
X 
Growth Parameters9 
X7,12 
 
 
 
X 
 
 
 
X 
Physical Examination 
X7,12 
 
 
 
X 
 
 
 
X 
Ventilator Use 
X7,12 
 
 
X 
X 
 
 
X 
X 
Neurological 
Examination10 
X7,12 
 
X11 
 
X 
 
X11 
 
X 
ECG 
X12 
 
 
 
X13 
 
 
 
X 
Safety Laboratory 
Tests14 
X12 
 
 
 
X15 
 
 
 
X 
Immunogenicity 
Sample  
X12 
 
 
 
X16 
 
 
 
X 
CSF PK17 
X5 
 
 
 
X 
 
 
 
 
Plasma PK 
 
 
X18 
 
X18 
 
 
 
X 
Study Treatment 
Injection  
 
X 
 
 
 
X 
 
 
 
Telephone Contact for 
Safety Monitoring 
 
 
 
X 
 
 
 
X 
 
HINE Motor 
Milestone 
X12 
 
 
 
X 
 
 
 
X 
Clinical Global 
Impression of Change 
X12 
 
 
 
X 
 
 
 
X 


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Study Period 
Part 2 Treatment/Follow-Up 
Study Day 
Day 1 
Day 21 
Days 120, 239, 358, 477, 596, 715 (±7 days)2 
Days 121, 240, 
359, 478, 597, 
7161 
Part 2 Final Follow-Up 
(Day 835 [±7 days])3or Part 2 
Early Termination4 
 
 
Predose5 
LP 
Postdose 
Predose 
LP 
 
Postdose 
Con Med Recording19 
X---------------------------------------------------------------------------------------------------------------------------------X 
Adverse Event 
Collection20 
X---------------------------------------------------------------------------------------------------------------------------------X 
AE = adverse event; Bi PAP = bi level positive airway pressure; Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; 
HINE = Hammersmith Infant Neurological Examination; LP = lumbar puncture; PK = pharmacokinetic(s); SAE = serious adverse event. 
1 There will be safety monitoring through telephone contact on the day following the injection of study treatment (i.e., Days 2, 121, 240, 359, 478, 597, and 716).  
During that telephone contact, changes in concomitant medications and AEs, information on the subject’s daily ventilator/Bi PAP use, and health status will be 
recorded. 
2 Subjects may continue receiving study treatment injection every 4 months beyond Year 2 until commercial availability of the product.  If the study continues 
beyond Year 2 (i.e., beyond Day 715), then from Day 835 onwards, subjects will maintain evaluations for study treatment injection every 4 months with the 
assessments for those additional timepoints to alternate between the assessments done on Day 120 and those done on Day 239.  Day 120 assessments would be 
performed at Day 835 and Day 239 assessments would be performed at Day 954.  The alternating pattern would continue until the end of the study.  Part 2 
Final Follow-up Evaluation would then occur approximately 4 months after the last injection of study treatment. 
3 The Part 2 Final Follow-up Evaluation will occur 4 months after the last injection of study treatment, which will either be on Day 716, if the product is 
commercially available, or later, if Part 2 of the study continues beyond Year 2.  
4 Subjects who terminate early will be encouraged to complete the safety evaluations scheduled for the Part 2 Early Termination Evaluation. 
5 Inclusion/Exclusion Criteria, Informed Consent, and CSF PK must be performed on Part 2 Day 1.  
6 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each evaluation.  For subjects who are not receiving noninvasive ventilation, 
pulse oximetry will be measured overnight once a week at home. 
7 The indicated predose assessments will be repeated on Part 2 Day 1 if the study treatment injection will occur more than 24 hours after End of Part 1 
Evaluation. 
8 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected 1 hour (±15 minutes) 
after the injection of study treatment.  Note that on Part 2 Day 1, this group of patients must have a plasma PK blood sample 4 hours after injection of study 
treatment. 
9 At the evaluations scheduled for injection of study treatment, subjects will be assessed for the following growth parameters:  body length, head circumference, 
chest circumference, and arm circumference.  Growth parameters and weight are to be collected at the same time. 
10 Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes. 
11 Neurological examinations will occur 1 hour after the injection of study treatment. 
12 If Part 2 Day 1 study treatment injection is delayed more than 24 hours after End of Part 1 due to an AE, SAE, or other safety concern, safety laboratory testing 
and ECG must be performed in addition to the indicated predose assessments.  If Part 2 Day 1 study treatment injection is delayed more than 30 days after End 
of Part 1 for any reason, safety laboratory testing, ECG, and immunogenicity testing must be performed in addition to the indicated predose assessments. 
13 ECG will be performed on Days 239, 477, and 715, and at the Part 2 Final Follow-up Evaluation.  ECG must be performed before obtaining blood samples for 
safety laboratory tests. 
14 Blood chemistry, hematology, and urinalysis panels. 
15 Blood samples for safety laboratory tests will be collected before the injection of study treatment on Days 239, 477, and 715, and at the Part 2 Final Follow-up 
Evaluation on the same day as ECG, plasma PK, and immunogenicity sample.  


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16 Blood samples for immunogenicity samples will be collected before the injection of study treatment on Days 239, 477, and 715, and at the Part 2 Final 
Follow-up Evaluation. 
17 Refer to Table 6 for CSF PK sample schedule.  The CSF samples will be analyzed for ISIS 396443 concentrations.  The remaining CSF sample will be stored 
for optional future biomarker analyses. 
18 Blood samples for PK assessment will be collected 4 hours (±1 hour) after the injection of study treatment only on Day 1.  Refer to Table 6 for the plasma PK 
sample schedule.  Plasma PK to be performed predose on Days 239, 477, and 715. 
19 In addition to concomitant medications, ancillary procedures will be recorded. 
20 AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2. 
 


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Table 4: 
Part 2 Schedule of Activities for Subjects Randomized to Receive Sham Procedure in Part 1 
Study Period 
Part 2 Treatment/Follow-Up 
Study Day 
Day 1 
Day 
21 
Day 15 (±1 day) 
Day 161 
Day 29 (±1 day) 
Day 301  
Days 64, 183, 302, 
421, 540, 659, 778 
(±7 days)2  
Days 
65, 184, 
303, 
422, 
541, 
660, 
7791 
Part 2 Final 
Follow-Up 
(Day 897 
[±7 days])3 or 
Part 2 Early 
Termination4 
 
Predose5 LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
Informed Consent 
X5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs6 
X7, 13 
 
4X8 
X9 
X 
 
X8 
 
X 
 
X8 
 
X 
 
X8 
 
X 
Weight 
X7, 13 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Growth Parameters10 
X7, 13 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical Examination 
X7, 13 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Ventilator Use 
X7, 13 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Neurological 
Examination11 
X7, 13 
 
X12 
X 
X 
 
X12 
 
X 
 
X12 
 
X 
 
X12 
 
X 
ECG 
X13 
 
 
X 
 
 
 
 
 
 
X 
 
X14 
 
 
 
X 
Safety Laboratory 
Tests15 
X13 
 
 
 
 
 
 
 
 
 
 
 
X16 
 
 
 
X 
Coagulation 
Laboratory Tests 
X5 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
Sample 
X13 
 
 
 
 
 
 
 
 
 
 
 
X17 
 
 
 
X 
CSF PK18 
X5 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Plasma PK19 
 
 
X19 
 
 
 
 
 
 
 
 
 
X19 
 
 
 
X 
Study Treatment 
Injection  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Inpatient Stay20 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone Contact 
for Safety Monitoring 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 


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Study Period 
Part 2 Treatment/Follow-Up 
Study Day 
Day 1 
Day 
21 
Day 15 (±1 day) 
Day 161 
Day 29 (±1 day) 
Day 301  
Days 64, 183, 302, 
421, 540, 659, 778 
(±7 days)2  
Days 
65, 184, 
303, 
422, 
541, 
660, 
7791 
Part 2 Final 
Follow-Up 
(Day 897 
[±7 days])3 or 
Part 2 Early 
Termination4 
 
Predose5 LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
HINE Motor 
Milestone 
X13 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical Global 
Impression of Change 
X13 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Con Med Recording21 
X-------------------------------------------------------------------------------------------------------------------X 
Adverse Event 
Collection22 
X-------------------------------------------------------------------------------------------------------------------X 
AE = adverse event; Bi PAP = bi level positive airway pressure; Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; 
HINE = Hammersmith Infant Neurological Examination; LP = lumbar puncture; PK = pharmacokinetic(s); SAE = serious adverse event. 
1 After the injection of study treatment on Day 1, subjects will remain at the study site for at least 24 hours (Day 2) for safety monitoring.  There will be safety 
monitoring through telephone contact on the day following the injection of study treatment (i.e., Days 16, 30, 65, 184, 303, 422, 541, 660, and 779).  During 
that telephone contact, changes in concomitant medications and AEs, information on the subject’s daily ventilator/Bi PAP use, and health status will be 
recorded. 
2 Subjects may continue receiving study treatment injection every 4 months beyond Year 2 until commercial availability of the product.  If the study continues 
beyond Year 2 (i.e., beyond Day 778), then from Day 897 onwards, subjects will maintain evaluations for study treatment injection every 4 months with the 
schedule of events for those additional timepoints to alternate between the assessments done on Day 183 and those done on Day 302.  Day 302 assessments 
would be performed at Day 897 and Day 183 assessments would be performed at Day 1016.  That pattern would continue until the end of the study.  Part 2 
Final Follow-up Evaluation would then occur approximately 4 months after the last injection of study treatment. 
3 The Part 2 Final Follow-up Evaluation will occur 4 months after the last injection of study treatment, which will either be on Day 778, if the product is 
commercially available, or later, if Part 2 of the study continues beyond Year 2. 
4 Subjects who terminate early will be encouraged to complete the safety evaluations scheduled for the Part 2 Early Termination Evaluation. 
5 Inclusion/Exclusion Criteria, Informed Consent, CSF PK, and coagulation laboratory tests must be performed on Part 2 Day 1. 
6 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each evaluation.  For subjects who are not receiving noninvasive ventilation, 
pulse oximetry will be measured overnight once a week at home. 
7 The indicated predose assessments will only repeated on Part 2 Day 1 if the study treatment injection will occur more than 24 hours after End of Part 1 
Evaluation. 
8 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected at 4 timepoints:  1, 2, 4, 
and 6 hours (all ±15 minutes) after the injection of study treatment only on Part 2 Day 1.  On subsequent study days, vital signs will be collected 1 hour after 
the injection of study treatment. 
9 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected on Day 2 within 20 to 
24 hours after the injection of study treatment only. 


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10 At the evaluations scheduled for injection of study treatment, subjects will be assessed for the following growth parameters:  body length, head circumference, 
chest circumference, and arm circumference.  Growth parameters and weight are to be collected at the same time. 
11 Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes. 
12 Neurological examinations will occur 1 hour after the injection of study treatment. 
13If Part 2 Day 1 study treatment injection is delayed more than 24 hours after End of Part 1 due to an AE, SAE, or other safety concern, safety laboratory testing 
and ECG must be performed in addition to the indicated predose assessments.  If Part 2 Day 1 study treatment injection is delayed more than 30 days after End 
of Part 1 for any reason, safety laboratory testing, ECG, and immunogenicity testing must be performed, in addition to the indicated predose assessments. 
14 ECG will be performed at Days 64, 183, 540, and 778, and at the Part 2 Final Follow-up Evaluation.  ECG must be performed before obtaining blood samples 
for safety laboratory tests. 
15 Blood chemistry, hematology, and urinalysis panels. 
16 Blood samples for safety laboratory tests will be collected before the injection of study treatment on same days as ECG, plasma PK, and immunogenicity 
sample. 
17 Blood samples for immunogenicity testing will be collected before the injection of study treatment on Days 64, 183, 540, and 778, and at the Part 2 Final 
Follow-up Evaluation. 
18 Refer to Table 7 for CSF PK sample schedule.  The CSF samples will be analyzed for ISIS 396443 concentrations.  The remaining CSF sample will be stored 
for optional future biomarker analyses. 
19 Blood samples for PK assessment will be collected 4 hours (±1 hour) after the injection of study treatment only on Day 1.  Refer to Table 7 for the plasma PK 
sample schedule.  Plasma PK will be collected predose on Days 64, 183, 540, and 778, and at the Part 2 Final Follow-up Evaluation. 
20 Overnight stay (at least 24 hours) is required after the first injection of study treatment.  Following all subsequent injections, a stay of at least 1 hour at the 
study site is required; overnight stays are optional on these days. 
21 In addition to concomitant medications, ancillary procedures will be recorded. 
22 AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2. 
 


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Table 5 
Part 1 Pharmacokinetic Sampling Schedule1  
Treatment Period 
Part 1 Study Day 
Timepoints 
Blood 
Collection 
(mL) 
CSF Collection 
(mL)2 
Multiple Dose: 
LP Injection  
 
Day 1 
Predose 
NA 
0.5 
4 h (±1 h) postdose  
0.5 
NA 
Day 15 
Predose 
NA 
0.5 
Day 29 
Predose 
NA 
0.5 
Day 64 
Predose 
0.5 
0.5 
Day 183 
Predose 
0.5 
0.5 
Day 302 
Predose 
NA 
0.5 
End of Part 1 
NA 
0.5 
NA 
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy. 
1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual. 
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of ISIS 396443 with plasma and CSF constituents. 
 
Table 6 
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive ISIS 396443 in Part 11 
Treatment Period 
Part 2 Study Day 
Timepoints 
Blood 
Collection 
(mL) 
CSF Collection 
(mL)2 
Multiple Dose: 
LP Injection  
 
Day 1 
Predose 
NA 
0.5 
4 h (±1 h) postdose  
0.5 
NA 
Day 120 
Predose 
NA 
0.5 
Day 239 
Predose 
0.5 
0.5 
Day 358 
Predose 
NA 
0.5 
Day 477 
Predose 
0.5 
0.5 
Day 596 
Predose 
NA 
0.5 
Day 715 
Predose 
0.5 
0.5 
Part 2 Final 
Follow-Up 
NA 
0.5 
NA 
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy. 


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1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual. 
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of ISIS 396443 with plasma and CSF constituents. 
 
Table 7 
Part 2 Pharmacokinetic Sampling Schedule for Subjects Randomized to 
Receive Sham Procedure in Part 11  
Treatment Period 
Part 2 Study Day 
Timepoints 
Blood 
Collection 
(mL) 
CSF Collection 
(mL)2 
Multiple Dose: 
LP Injection  
Day 1 
Predose 
NA 
0.5 
4 h (±1 h) postdose  
0.5 
NA 
Day 15 
Predose 
NA 
0.5 
Day 29 
Predose 
NA 
0.5 
Day 64 
Predose 
0.5 
0.5 
Day 183 
Predose 
0.5 
0.5 
Day 302 
Predose 
NA 
0.5 
Day 421 
Predose 
NA 
0.5 
Day 540 
Predose 
0.5 
0.5 
Day 659 
Predose 
NA 
0.5 
Day 778 
Predose 
0.5 
0.5 
Part 2 Final 
Follow-Up 
NA 
0.5 
NA 
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy. 
1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual. 
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of ISIS 396443 with plasma and CSF constituents. 


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5. 
INTRODUCTION  
ISIS 396443 is a uniformly modified, 2′-O-(2-methoxyethyl) (2′-MOE), antisense 
oligonucleotide (ASO) drug in development for the treatment of spinal muscular atrophy (SMA) 
due to genetic defects in the survival motor neuron 1 (SMN1) gene. 
ASOs are short synthetic strings of nucleotides designed to alter the expression of a targeted 
protein by selectively binding to the ribonucleic acid (RNA) that encodes the targeted protein.  In 
patients with SMA, the number of survival motor neuron 2 (SMN2) gene copies and the resulting 
amount of survival motor neuron (SMN) protein are correlated with disease onset and severity.  
A therapeutic approach predicted to benefit patients with SMA is to increase the levels of 
full-length SMN2 pre-messenger ribonucleic acid (mRNA) by restoring the splicing pattern that 
gives rise to full-length SMN2 mRNA, thus increasing full-length SMN protein levels and SMN 
protein activity.  ISIS 396443 is designed to bind to intron 7 of the SMN2 pre-mRNA, restoring 
the splicing pattern that gives rise to full-length SMN2 mRNA and thus increases full-length 
SMN protein levels (Figure 2). 
Figure 2: 
Antisense Oligonucleotide Therapeutic Approach for Treatment of Spinal 
Muscular Atrophy 
 
ASO = antisense oligonucleotide; FL = full-length; mRNA = messenger ribonucleic acid; SMA = spinal muscular 
atrophy; SMN = survival motor neuron; SMN1 = survival motor neuron 1; SMN2 = survival motor neuron 2. 


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5.1. 
Overview of Spinal Muscular Atrophy 
SMA is an autosomal recessive neuromuscular disease characterized by degeneration of the 
motor neurons in the anterior horn of the spinal cord, resulting in atrophy of the voluntary 
muscles of the limbs and trunk.  With an incidence of 1:6000 to 1:10,000 live births, SMA is the 
most common genetic cause of infant mortality, and a major cause of childhood morbidity due to 
weakness, in developed countries.  The natural history of SMA includes 4 major recognized 
phenotypes that are dependent on age of onset and achieved motor abilities.  The most severe 
form, Type I SMA, has a disease onset within the first few months of life; these children are 
never able to sit or walk and usually die from respiratory failure by the age of 2 years.  Patients 
with Type II SMA are able to sit but never walk unaided, with symptoms typically presenting 
between 6 and 18 months of age.  Patients with Type III SMA are able to sit and walk but may 
become severely and increasingly disabled.  Patients with Type IV or adult-onset SMA have an 
age of onset over 18 years and have normal life expectancies. 
SMA is caused by loss of SMN protein due to a homozygous deletion or mutation or compound 
heterozygous mutation in the SMN1 gene on chromosome 5q11-q13.  Humans have a duplication 
of the chromosome region where SMN1 is found, resulting in a second copy of the gene, SMN2.  
In SMN2, a C to T nucleotide substitution in exon 7 results in an alternative splicing event such 
that the majority of transcripts produced (~90%) lack exon 7, and a defective truncated protein is 
produced.  The remainder, SMN2 transcripts containing exon 7, produces a full-length protein 
product identical to the SMN1 protein, since the C to T substitution is silent.  Humans have a 
variable copy number of the SMN2 gene (0 to 8 copies) [Wirth 2006].  The number of SMN2 
copies and the resulting amount of full-length SMN protein expressed in patients with SMA 
(10% to 40% of normal SMN protein levels) correlate with SMA disease severity; thus, SMN2 is 
a key modifier of disease phenotype [Coovert 1997; Feldkötter 2002; Lefebvre 1997; Prior 
2004]. 
5.2. 
Current Therapies for Spinal Muscular Atrophy 
There are currently no approved therapies for SMA.  Current medical care is supportive and 
focused on respiratory support, nutritional support, and management of resulting 
musculotendinous contractures and neuromuscular scoliosis through bracing, physical therapy, 
and surgery [Wang 2007]. 
5.3. 
Profile of Previous Experience With ISIS 396443 
5.3.1. 
Nonclinical Experience 
ISIS 396443 was identified after an extensive screen of greater than 500 2′-MOE 
oligonucleotides in reporter gene assays, in vitro splicing assays, and SMA patient fibroblasts 
[Hua 2007; Hua 2008].  Data have shown that ISIS 396443 promotes a concentration-dependent 
increase in full-length transcripts (including exon 7) in patient fibroblast cells, achieving >90% 
full-length SMN2 transcripts, and forms nuclear structures called gems, known to contain SMN 
protein [Liu and Dreyfuss 1996].  In a mild mouse model of SMA, ISIS 396443 promoted 
inclusion of exon 7 in the SMN2 transgene in a variety of peripheral tissues when dosed 


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systemically [Hua 2008] and in central nervous system (CNS) tissue, including the spinal cord, 
when injected into the lateral ventricle [Hua 2010].  ISIS 396443 produced >90% exon 7 
inclusion in the transgenic mice and increased SMN protein production in motor neurons, 
resulting in the appearance of gems in motor neurons.  These studies were extended to a more 
severe mouse model of SMA (SMA Δ7) [Le 2005], where the CNS delivery of drug produced a 
dose-dependent effect on SMN2 exon 7 inclusion, SMN protein production, and survival.  These 
mice treated with ISIS 396443 demonstrated improved weight gain; improvements in muscle 
morphology, muscle strength, and motor coordination; and improved morphology of the motor 
neuron junctions [Passini 2011].  Furthermore, ISIS 396443 was shown to distribute widely in 
the CNS after intrathecal administration in monkeys [Passini 2011].  
The pharmacokinetics (PK) and toxicity of ISIS 396443 were assessed after a single intrathecal 
lumbar bolus injection (1 to 7 mg) in adult monkeys; after 14 weeks of repeated intrathecal 
lumbar bolus injections (0.3 mg/week to 3 mg/week or every other week) in juvenile monkeys 
(with a 4-week interim sacrifice); and after 53 weeks of repeated intrathecal lumbar bolus 
injections in juvenile monkeys.  In addition, a dedicated multiple-dose PK study in adult 
monkeys (3-week dosing period) was performed to assess the half-life of ISIS 396443 in 
cerebrospinal fluid (CSF), tissues, and plasma.  
In the single-dose study, following intrathecal dose administration, ISIS 396443 distributed from 
the CSF into the spinal cord, brain, and systemic circulation via CSF turnover.  Plasma 
concentrations of ISIS 396443 were relatively low compared to CSF concentrations. 
In the multiple-dose PK study, concentrations of ISIS 396443 in both CSF and plasma exhibited 
multiphasic disposition following intrathecal administration.  The terminal elimination half-life 
of ISIS 396443 in CSF was 102 days.  CSF concentrations peaked 1 hour after intrathecal 
injection, while plasma concentrations peaked 4 hours after the intrathecal injection.  Animals 
were sacrificed at multiple times after intrathecal administration, and analysis demonstrated that 
ISIS 396443 was slowly cleared from CNS tissues with terminal elimination half-lives between 
various brain and spinal cord regions ranging from 74 to 275 days (median:  116 days).  
In the 14-week and 53-week repeat-dose studies, concentrations of ISIS 396443 in CSF, plasma, 
and tissue were consistent with the pattern established in the 4-week multiple dose PK study.  
CSF and plasma concentrations increased in a dose-dependent manner in both studies.  
Consistent with previous studies, the time to reach maximum observed concentration (Tmax) in 
the plasma occurred approximately 2 to 5 hours after intrathecal bolus administration.  Tissue 
concentrations were measured for CNS tissues, and consistent values were obtained between the 
14- and 53-week studies after adjusting for the difference in dosing regimens. 
In both repeat-dose toxicology studies, dose-dependent increases in tissue concentrations of 
ISIS 396443 were seen in the brain, spinal cord, and liver.  In the 53-week study, during which 
ISIS 396443 was administered every 6 weeks, tissue concentrations were lower compared to the 
14-week study, as expected.  CNS tissues had half-lives of 117 to 195 days (median:  174 days), 
which is consistent with the range of elimination half-lives determined from the multiple-dose 
PK study. 
See the Investigator’s Brochure for detailed information on nonclinical studies. 


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5.3.2. 
Clinical Experience 
Completed studies in subjects with SMA 
ISIS 396443 has been evaluated in 3 completed open-label studies in subjects with SMA 
diagnosed during childhood:  ISIS 396443-CS1, ISIS 396443-CS2, and ISIS 396443-CS10. 
Study ISIS 396443-CS1 was a single-ascending dose Phase 1 study designed to assess the safety, 
tolerability, and PK of ISIS 396443 in subjects with later-onset SMA.  A single dose of 
ISIS 396443 was administered by intrathecal injection to subjects with SMA who were 2 to 
14 years of age.  Four doses (1, 3, 6, and 9 mg) were evaluated sequentially.  Each dose was 
studied in a cohort of 6 or 10 subjects.  All subjects received study treatment.  Twenty-eight 
subjects were dosed in the clinical trial, and all subjects completed dosing and follow-up visits 
per protocol.  ISIS 396443 was well tolerated, and no safety concerns were reported when 
administered as a single dose up to 9 mg.  Mild adverse events (AEs) of headache were the most 
commonly reported events.  The 2 events related to ISIS 396443 (palpitations and paresthesia) 
were mild in severity, were not dose related, and had resolved.  No serious AEs (SAEs) and no 
discontinuations due to AEs were reported.  There were no clinically significant changes in vital 
signs or safety laboratory parameters related to ISIS 396443.  CSF and plasma drug 
concentrations of ISIS 396443 were dose dependent and consistent with the nonclinical data. 
Study ISIS 396443-CS2 was an open-label, multiple-ascending dose, Phase 1/2a study designed 
to assess the safety, tolerability, and PK of ISIS 396443 in subjects with later-onset SMA.  
Multiple doses of ISIS 396443 were administered by intrathecal injection to subjects with SMA 
who were 2 to 15 years of age.  Four dose levels (3, 6, 9, and 12 mg) were evaluated 
sequentially.  Each dose level was studied in a cohort of 8 or 9 subjects, where all subjects 
received study treatment.  The 6 subjects who participated in Cohort 1 of ISIS 396443-CS1 were 
eligible to enroll in ISIS 396443-CS2; 3 of these subjects enrolled in ISIS 396443-CS2 Cohort 1 
and the other 3 enrolled in ISIS 396443-CS2 Cohort 2.  Thirty-four subjects were enrolled, and 
all but 1 subject completed the study.  One subject in the 12-mg ISIS 396443 dose cohort 
discontinued treatment early because of the Investigator’s decision.  The Investigator concluded 
that the subject and the parents could not tolerate the study procedures associated with dosing 
and PK draws, and thus, the subject was withdrawn.  ISIS 396443 was well tolerated, and no 
safety concerns were reported when ISIS 396443 was administered as multiple doses up to 
12 mg.  Post lumbar puncture (LP) syndrome was the most commonly reported AE.  None of the 
AEs reported during the study were considered related to ISIS 396443 or resulted in 
discontinuation from the study or of the study treatment.  Three SAEs were reported during the 
study; all were assessed as unrelated to ISIS 396443.  There were no clinically significant 
changes in vital signs, neurological or physical examination findings, or safety laboratory 
parameters related to ISIS 396443.  There were no dose-related safety concerns. 
Study ISIS 396443-CS10 was a single-dose open-label study to assess the safety and tolerability 
of a single intrathecal dose in subjects with later-onset SMA who participated in 
ISIS 396443-CS1 Cohorts 2, 3, and 4 (3, 6, or 9 mg).  Eighteen subjects (4 subjects at 6-mg dose 
and 14 subjects at 9-mg dose) were enrolled and received study treatment.  All 18 subjects 
completed the study.  


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Ongoing studies in subjects with SMA 
ISIS 396443 is also being evaluated in 7ongoing studies:  ISIS 396443-CS3B, 
ISIS 396443-CS3A, 232SM201, ISIS 396443-CS4, ISIS 396443-CS12, ISIS 396443-CS11, and 
232SM202 (the present study). 
Studies in subjects with SMA diagnosed during infancy 
Study ISIS 396443-CS3B is an ongoing, pivotal, randomized, double-blind, sham 
procedure-controlled, Phase 3, multicenter study to assess the clinical efficacy and safety of 
ISIS 396443 in infants with SMA (onset of clinical signs and symptoms consistent with SMA at 
≤6 months of age) who have 2 SMN2 copies.  Approximately 111 subjects are expected to be 
enrolled.  Subjects are to be randomized in a 2:1 ratio to receive either a scaled equivalent 12-mg 
dose of ISIS 396443 or a sham procedure control, respectively. 
Study ISIS 396443-CS3A is an ongoing, open-label, Phase 2 study to assess the efficacy, safety, 
tolerability, and PK of multiple doses of ISIS 396443.  Enrollment has been completed with 
21 subjects enrolled.  Two loading dose levels (scaled by infant age to be equivalent to either 
6 or 12 mg dose for children >2 years of age based on CSF volume) were evaluated sequentially 
in symptomatic infants with SMA who were between ≥21 and ≤7 months of age at screening.  
Loading doses were administered on Days 1, 15, and 85.  Maintenance dosing commenced 
24 weeks following Day 85 and at 18-week intervals thereafter. 
Study 232SM201 is an open-label, multicenter, global, single-arm study to assess the efficacy, 
safety, tolerability, and PK of multiple doses of ISIS 396443 in presymptomatic subjects with 
genetically diagnosed SMA.  The study is being conducted in subjects ≤6 weeks of age with 
genetic documentation of 5q SMA homozygous gene deletion or mutation or compound 
heterozygous mutation, genetic documentation of 2 or 3 copies of the SMN2 gene, 
CMAP ≥1 mV, and the absence of signs or symptoms of SMA.  Up to 25 subjects are planned to 
be treated in the study.  All subjects will receive a scaled equivalent 12-mg dose of ISIS 396443.   
Studies in subjects with SMA diagnosed during childhood 
Study ISIS 396443-CS4 is an ongoing, pivotal, randomized, multicenter, double-blind, sham 
procedure-controlled, Phase 3 study in subjects with later-onset SMA (onset of clinical signs and 
symptoms consistent with SMA at >6 months of age) being conducted to assess the clinical 
efficacy and safety of ISIS 396443.  Enrollment has been completed with 126 subjects enrolled.  
Subjects are randomized in a 2:1 ratio to receive either a scaled equivalent 12 mg dose of 
ISIS 396443 or a sham procedure control, respectively. 
Study ISIS 396443-CS12 is an ongoing open-label study to assess the safety, tolerability, and PK 
of ISIS 396443 (12 mg) administered intrathecally to subjects with later-onset SMA who 
previously participated in either ISIS 396443-CS2 or ISIS 396443-CS10.  
Studies in subjects with SMA diagnosed during infancy or childhood 
Study ISIS 396443-CS11 is an ongoing OLE study being conducted to evaluate the long-term 
safety, tolerability, and efficacy of ISIS 396443 administered intrathecally to subjects with SMA 
who previously participated in investigational studies of ISIS 396443.  Up to 274 subjects are 
planned to be treated in the study.  


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5.4. 
Study Rationale 
There is reasonably high genotype-phenotype correlation such that the SMN2 copy number can 
be used to predict the severity of disease (moderate or severe) with approximately 80% to 
85% accuracy [Burghes and Beattie 2009; Prior 2010; Swoboda 2005].  Evaluation of 
relationship between categories of functional status and number of SMN2 copies have indicated 
that as SMN2 copy number increases so does functional status [Feldkötter 2002; Swoboda 2005].  
However, assessment of various outcome measures over time have indicated that there is overlap 
among SMA types, and values vary widely with age and gross motor functional status with an 
overall age dependent decline [Swoboda 2005].  
5.4.1. 
Rationale for Part 1 
The intent of Part 1 of this study is to assess safety, tolerability, and explore the utility of selected 
efficacy endpoints in subjects who have onset of clinical signs and symptoms that are consistent 
with SMA at age ≤6 months or >6 months.  These subjects have either 2 or 3 SMN2 copies and 
are not eligible to participate in the 2 pivotal clinical studies, ISIS 396443-CS3B and 
ISIS 396443-CS4.  ISIS 396443-CS3B is a randomized, double-blind, sham 
procedure-controlled study investigating the therapeutic benefit of ISIS 396443 in subjects with 
2 SMN2 copies who have onset of clinical signs and symptoms of SMA at ≤6 months of age.  
ISIS 396443-CS4 is a randomized, double-blind, sham procedure-controlled study investigating 
the therapeutic benefit of ISIS 396443 in subjects who have onset of clinical signs and symptoms 
of SMA at >6 months of age.  To be consistent with the study design of the 2 pivotal clinical 
studies and to understand the safety and tolerability of ISIS 396443 compared with natural 
history, the present study is designed to include sham procedure control for an unbiased 
assessment of safety, tolerability, and selected efficacy endpoints in the study population that is 
not eligible to participate in the studies ISIS 396443-CS3B or ISIS 396443-CS4.  The design of 
the present study will also allow exploration of the safety and tolerability of a higher dose 
regimen in subjects who have onset of clinical signs and symptoms at >6 months of age, but who 
are not eligible for Study ISIS 396443-CS4. 
5.4.2. 
Rationale for Part 2:  Open-Label Extension Phase 
The rationale for Part 2 of this study is to assess the long-term safety and tolerability of 
ISIS 396443 in subjects with SMA who participated in Part 1 and completed their End of Part 1 
Evaluation assessments. 
5.5. 
Rationale for Dose and Schedule Selection 
The ISIS 396443 dose and dose interval for this study were selected based on nonclinical 
toxicology and PK observations from monkey studies using single-dose and repeat-dosing 
intrathecal administration, consideration of the target tissue concentration anticipated for drug 
pharmacology, and safety data in the completed and ongoing clinical studies of ISIS 396443.  
Based on pharmacology and PK results in SMA transgenic mice, it is estimated that a target 
spinal cord tissue concentration between 1 and 10 μg/g will produce 50% to 90% 
SMN2 exon 7 inclusion.  Nonclinical studies in juvenile monkeys receiving intrathecal doses of 
ISIS 396443 showed a resulting gradient of distribution of ISIS 396443 along the spinal cord, 


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with mean lumbar spinal cord concentrations ranging from 1.6- to 2.3-fold and 2.0- to 3.5-fold 
higher than thoracic and cervical spinal cord levels, respectively.  The dose selected for this 
multiple-dose clinical study (equivalent to 12 mg of ISIS 396443) is predicted to achieve levels 
at the high end of this range (approximately 10 μg/g lumbar and 3 μg/g cervical spinal cord 
tissue concentrations) after the first dose.  The loading dose interval (i.e., doses on Days 1, 15, 
29, and 64) was selected based on the nonclinical PK and pharmacology data in order to achieve 
and maintain ISIS 396443 spinal cord tissue levels that are predicted to be above or within the 
upper end of the pharmacologically active range by Day 64 (approximately 30 μg/g lumbar and 
10 μg/g cervical tissue concentration), while at the same time considering subject safety and 
convenience for repeated intrathecal injections by LP.  The higher number of loading doses 
would allow for the evaluation of safety and tolerability and preliminary exploratory efficacy 
endpoints in a broader population of subjects with SMA, including those who have onset of 
clinical signs and symptoms at >6 months of age but who are not eligible for Study 
ISIS 396443-CS4.  The maintenance dose interval (once every 4 months ) was selected based on 
the estimated spinal tissue and CSF drug half-life (4 to 6 months) and was selected to maintain 
spinal cord tissue levels of ISIS 396443 at a steady-state level within the estimated 
pharmacologically active range.  In Part 1, maintenance doses will be given on Day 183 and 
Day 302, for a total of 6 doses over approximately 10 months.  Subjects who were receiving 
ISIS 396443 in Part 1 will continue receiving maintenance doses in Part 2 every 4 months.  
Subjects who were receiving sham in Part 1, will receive maintenance doses starting on Day 183 
of Part 2. 
ISIS 396443 will be administered as an intrathecal injection.  The volume of the injection, and 
thus the dose, will be adjusted based on the subject’s age on the day of dosing as shown in 
Table 1, such that each subject will receive a 12-mg scaled equivalent dose based on CSF 
volume scaling.  Thus, younger subjects will be given a lower dose of drug, achieved by 
injecting a smaller volume that is proportional to the estimated CSF volume for age, such that the 
dose volume will be equivalent to 5 mL for a 2-year-old child to adult.  Dosing instructions and 
details regarding administration will be provided in the Directions for Handling and 
Administration (DHA). 
6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objectives and Endpoints 
Part 1 
The primary objective of Part 1 of this study is: 
 To assess the safety and tolerability of ISIS 396443 in subjects with SMA who are 
not eligible to participate in the clinical studies ISIS 396443-CS3B or 
ISIS 396443-CS4. 


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The endpoints that relate to this objective are: 
 Incidence of AEs and SAEs 
 Change from baseline (see Section 16.1) in clinical laboratory parameters, 
electrocardiograms (ECGs), and vital signs  
 Change from baseline (see Section 16.1) in neurological examination outcomes 
Part 2 
The primary objective of Part 2 of this study is: 
 To assess the long-term safety and tolerability of ISIS 396443 in subjects with SMA 
who participated in Part 1 and completed their End of Part 1 Evaluation assessments. 
The endpoints that relate to this objective are: 
 Incidence of AEs and SAEs 
 Change from baseline (see Section 16.1) in clinical laboratory parameters, ECGs, and 
vital signs  
 Change from baseline (see Section 16.1) in neurological examination outcomes 
6.2. 
Secondary Objectives and Endpoints 
Part 1 
The secondary objective of Part 1 of this study is: 
 To examine the PK of ISIS 396443 in subjects with SMA who are not eligible to 
participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4 
The endpoint that relates to this objective is:  
 ISIS 396443 concentrations in plasma and CSF 
Part 2 
The secondary objective of Part 2 of this study is: 
 To examine the PK of ISIS 396443 in subjects with SMA who participated in Part 1 
and completed their End of Part 1 Evaluation assessments 
The endpoint that relates to this objective is:  
 ISIS 396443 concentrations in plasma and CSF 
6.3. 
Exploratory Objectives and Endpoints 
Part 1 
The exploratory objective of Part 1 of this study is: 
 To explore the efficacy of ISIS 396443 in subjects with SMA who are not eligible to 
participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4. 


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The endpoints that relate to this objective are: 
 Change from baseline in ventilator use  
 Attainment of motor milestones assessed by Section 2 of the Hammersmith Infant 
Neurological Examination (HINE)  
 Change from baseline in growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for length, and head to 
chest circumference ratio) through final safety follow-up evaluation  
 Clinical Global Impression of Change (physician and caregiver assessment) through 
final safety follow-up evaluation 
The exploratory immunogenicity endpoint is as follows: 
 Plasma antibodies to ISIS 396443 
Part 2 
The exploratory objective of Part 2 of this study is: 
 To explore the efficacy of ISIS 396443 in subjects with SMA who participated in 
Part 1 and completed their End of Part 1 Evaluation assessments. 
The endpoints that relate to this objective are: 
 Change from baseline in ventilator use  
 Attainment of motor milestones assessed by Section 2 of the HINE  
 Change from baseline in growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for length, and head to 
chest circumference ratio) through Part 2 Final Follow-up Evaluation  
 Clinical Global Impression of Change (physician and caregiver assessment) through 
Part 2 Final Follow-up Evaluation 
The exploratory immunogenicity endpoint is as follows: 
 Plasma antibodies to ISIS 396443 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is a Phase 2 multicenter study conducted in 2 parts.  The study was originally designed as a 
randomized, double-blind, sham-procedure controlled study to assess the safety and tolerability 
and explore the efficacy of intrathecally administered ISIS 396443 up to approximately 
14 months (from the first dose until End of Part 1 Evaluation).  Based on emergent data from the 
ISIS 396443 clinical development program, the Sponsor may decide to terminate Part 1 early, 
and all subjects may then be offered the opportunity to be unblinded and transition to Part 2 prior 
to completion of all Part 1 evaluations.  Part 2 is an OLE phase that will assess long-term safety 
and tolerability and explore the efficacy of intrathecally administered ISIS 396443 for 
approximately 24 additional months (or until availability of commercial product).  In Part 1 of 
the study, up to 21 subjects will be randomized in a ratio of 2:1 to receive ISIS 396443 by 
intrathecal LP injection (n = 14) or to a sham procedure-control (n = 7).  Randomization will be 
stratified based on age at onset of clinical signs and symptoms consistent with SMA:  >6 months 
versus ≤6 months.  In Part 2 of the study, all subjects who participated in Part 1, who completed 
their End of Part 1 Evaluation assessments, and who elected to enroll in Part 2 will receive 
ISIS 396443 by intrathecal injection. 
Subjects who withdraw early from Part 1 will be encouraged to complete the End of Part 1 
Evaluation assessments at the time of withdrawal.  Subjects who withdraw early from Part 2 will 
be encouraged to complete the Part 2 Early Termination Evaluation assessments at the time of 
withdrawal.  
See Section 4.1 for a schematic of the study design. 
7.2. 
Overall Study Duration and Follow-Up 
Part 1 of the study will consist of a Screening Period, Treatment Period, and post-treatment End 
of Part 1 Evaluation.  For subjects who meet eligibility criteria and enroll in Part 1, the duration 
of Part 1 will be approximately 15 months (450 days) and will include a Screening Period of no 
greater than 28 days, a 302-day Treatment Period, and an End of Part 1 Evaluation 
approximately 4 months after the last dose.  Based on emergent data from the ISIS 396443 
clinical development program, the Sponsor may decide to terminate Part 1 early, and all subjects 
may be offered the opportunity to transition to Part 2 prior to completion of all Part 1 
evaluations. 
Part 2 will consist of a Treatment Period and a post-treatment Final Follow-up Evaluation.  For 
subjects who meet eligibility criteria and enroll in Part 2, the duration of Part 2 will be 
approximately 28 months and will include an open-label Treatment Period of approximately 
24 months (or until availability of commercial product) and a Part 2 Final Follow-up Evaluation 
approximately 4 months after the last dose of study treatment in Part 2. 
Total study duration for subjects who participate in both Part 1 and Part 2 will be approximately 
43 months. 


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7.2.1. 
Screening 
Subject eligibility for Part 1 of the study will be determined within 4 weeks (Day -28 to Day -1) 
prior to the first injection of ISIS 396443 or administration of sham procedure and will be 
confirmed before randomization.  If a subject initially fails any of the screening criteria, they will 
be allowed to be rescreened 1 time during the Screening Period at the discretion of the 
Investigator.  End of Part 1 Evaluation assessments will be used to confirm subjects’ eligibility 
for Part 2.  
7.2.2. 
Treatment 
Part 1 
Eligible subjects will be admitted to the study site on Part 1 Day 1, undergo predose evaluations, 
and then receive an LP injection of ISIS 396443 or a sham procedure.  After the injection on 
Day 1, subjects will remain at the study site for at least 24 hours after the procedure for safety 
monitoring. 
Subjects will return to the study site on Days 15, 29, 64, 183, and 302 (±1 day for Days 15 and 
29 and ±7 days for all other days) for follow-up evaluations and subsequent injections of study 
treatment or sham procedure, for a total of 6 injections or sham procedures over a dosing period 
of 10 months.  During these 5 evaluations, all subjects will remain at the study site for at least 
6 hours postdose for safety monitoring.  An overnight stay is optional, at the discretion of the 
Investigator.  Safety monitoring by telephone contact will occur on the day after injection of 
study treatment or sham procedure.  In addition, the study site will monitor the subject’s 
condition through telephone contact every other week (excluding weeks with study visit) 
throughout the study period. 
After completing the End of Part 1 Evaluation assessments, all eligible subjects may elect to 
enroll in Part 2. 
Based on emergent data from the ISIS 396443 clinical development program, the Sponsor may 
decide to terminate Part 1 early, and all subjects may be offered the opportunity to transition to 
Part 2 prior to completion of all Part 1 Evaluation assessments.  All subjects enrolled in the study 
at the time of Sponsor termination will be considered Part 1 completers.  The next study 
evaluation for those subjects will serve as an End of Part 1 Evaluation, which may occur at any 
time prior to the next scheduled Part 1 study evaluation.  
Unblinding will occur in order for the subjects to transition from Part 1 to Part 2. 
End of Part 1 Evaluation assessments are required to be done prior to the transition to Part 2.  
After performing the End of Part 1 Evaluation assessments, the subject may immediately 
transition to Part 2. 
Part 2 
Part 2 study procedures and schedules will be determined based on the subject’s treatment 
assignment in Part 1. 


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Subjects who were randomized to receive ISIS 396443 in Part 1 
End of Part 1 Evaluation assessments will be used to determine subject eligibility for Part 2 of 
the study.  For subjects who were receiving ISIS 396443 in Part 1, Part 2 Day 1 will occur 
following the End of Part 1 Evaluation or approximately 4 months following the last injection of 
ISIS 396443 in Part 1.  On Part 2 Day 1, these subjects will undergo predose evaluations 
according to the schedule of events (Table 3) and then receive their first dose of ISIS 396443 for 
Part 2 (next maintenance dose). 
Subjects will return to the study site on Days 120, 239, 358, 477, 596, and 715 (±7 days for all 
days) for follow-up evaluations and subsequent injections of ISIS 396443 over a dosing period of 
approximately 24 months (or until availability of commercial product).  Subjects will remain at 
the study site for at least 1 hour postdose for safety monitoring and can be discharged at the 
discretion of the site Investigator and in compliance with the institutional requirements once the 
subjects have adequately recovered from the dosing procedure.  An overnight stay is optional, at 
the discretion of the Investigator.  Safety monitoring by telephone contact will occur on the day 
after injection of study treatment.  In addition, the study site will monitor the subject’s condition 
through telephone contact every other week (excluding weeks with study visit) throughout the 
study period. 
Subjects who were randomized to receive sham procedure in Part 1 
End of Part 1 Evaluation assessments will be used to determine subject eligibility for Part 2 of 
the study.  For subjects who were receiving sham procedure in Part 1, Part 2 Day 1 will occur 
following the End of Part 1 Evaluation or as soon as possible following their End of Part 1 
Evaluation, in the event of early termination by the Sponsor due to emergent data from the 
ISIS 396443 clinical development program.  On Part 2 Day 1, these subjects will undergo 
predose evaluations according to the schedule of events (Table 4) and then receive their first 
injection of ISIS 396443 (first loading dose).  Subjects will remain at the study site for at least 
24 hours after the procedure for safety monitoring. 
Subjects will return to the study site on Days 15, 29, 64, 183, 302, 421, 540, 659, and 778 
(±1 day for Days 15 and 29 and ±7 days for all other days) for follow-up evaluations and 
subsequent injections of ISIS 396443 over a dosing period of approximately 24 months (or until 
availability of commercial product).  Subjects will remain at the study site for at least 1 hour 
postdose for safety monitoring and can be discharged at the discretion of the site Investigator and 
in compliance with the institutional requirements once the subjects have adequately recovered 
from the dosing procedure.  An overnight stay is optional, at the discretion of the Investigator.  
Safety monitoring by telephone contact will occur on the day after injection of study treatment.  
In addition, the study site will monitor the subject’s condition through telephone contact every 
other week (excluding weeks with study visit) throughout the study period.  
For both groups of subjects, Part 2 of the study will continue for approximately 24 months (or 
until availability of commercial product) and in accordance with applicable laws and regulations.  
Subjects may continue receiving treatment every 4 months beyond Year 2 until commercial 
availability of the product.  From Year 2 onwards, subjects will maintain evaluations for 
injection of study treatment every 4 months as indicated in Table 3 and Table 4. 


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7.2.3. 
Follow-Up 
Subjects who enroll in Part 1 but not Part 2 will return to the study site for an End of Part 1 
Evaluation approximately 4 months after the last dose of study treatment (End of Part 1 on 
Day 422 [±7 days]). 
In the event of a decision by the Sponsor to terminate the study earlier than the end of Part 1 
based on emergent data from the ISIS 396443 clinical development program, subjects who do 
not elect to participate in Part 2 will complete their next evaluation after Part 1 is terminated and 
that visit will be the End of Part 1 Evaluation. 
Subjects who enroll in Part 2 will have a Part 2 Final Follow-up Evaluation approximately 
4 months after the last open-label dose of ISIS 396443. 
Subjects who withdraw early from Part 1 will be encouraged to complete the End of Part 1 
Evaluation assessments at the time of withdrawal.  Subjects who withdraw early from Part 2 will 
be encouraged to complete the Part 2 Early Termination Evaluation assessments at the time of 
withdrawal. 
7.3. 
Study Stopping Rules 
For Part 1 and Part 2 of the study, the Sponsor may terminate the study at any time by informing 
Investigators (who will subsequently inform the corresponding ethics committees) and any other 
applicable regulatory agencies.  Investigators will be notified by the Sponsor if the study is 
placed on hold, completed, or closed.   
Conditions that may warrant termination of the study include, but are not limited to, the 
following: 
 The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study. 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product.   
7.4. 
End of Study 
The end of the study is the last subject’s completion of the last evaluation for Part 2. 
7.5. 
Safety Monitoring and Data and Safety Monitoring Board 
Safety data will be reviewed on an ongoing basis by the Sponsor and the Medical Monitor.  
Safety data will also be reviewed on a quarterly basis, throughout Part 1 of the study, by an 
independent Data and Safety Monitoring Board (DSMB; see Section 19.2).  


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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening or at the time point specified in the individual eligibility criterion listed: 
1. Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study 
and provide signed and dated informed consent and authorization to use confidential 
health information in accordance with national and local subject privacy regulations.   
2. Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound 
heterozygote. 
3. Onset of clinical signs and symptoms consistent with SMA at <6 months of age and have 
documentation of 3 SMN2 copies. 
OR 
Onset of clinical signs and symptoms consistent with SMA at <6 months of age, 
>7 months of age (211 days) at screening, and have documentation of 2 SMN2 copies. 
OR 
Onset of clinical signs and symptoms consistent with SMA at >6 months of age, are 
≤18 months of age at screening, and have documentation of 2 or 3 SMN2 copies. 
4. Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is 
planned for study procedures (as assessed by the Investigator and either the 
anesthesiologist or pulmonologist). 
5. Medical care, such as routine immunizations (including influenza vaccine, pneumococcus 
vaccine, and respiratory syncytial virus prophylaxis [palivizumab] if available), meets 
and is expected to continue to meet guidelines set out in the Consensus Statement for 
Standard of Care in SMA, in the opinion of the Investigator. 
6. Subjects with 2 SMN2 copies must reside within approximately 9 hours’ ground-travel 
distance from a participating study site for the duration of the study.  Residents who are 
>2 hours’ ground-travel distance from a study site must obtain clearance from the 
Investigator and the study Medical Monitor.  
7. Able to complete all study procedures, measurements, and visits, and parent or legal 
guardian/subject has adequately supportive psychosocial circumstances, in the opinion of 
the Investigator. 
For Part 2 only: 
To be eligible to participate in Part 2 of this study, candidates must meet the following eligibility 
criteria at the time of consent to participate in Part 2: 
1. Participation in Part 1 and completion of the End of Part 1 Evaluation assessments. 


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2. Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study 
and to provide signed and dated informed consent on the Part 2 informed consent form 
(ICF) and authorization to use confidential health information in accordance with 
national and local subject privacy regulations. 
3. Able to complete all study procedures, measurements, and visits, and parent or legal 
guardian/subject has adequately supportive psychosocial circumstances, in the opinion of 
the Investigator. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening or at the time point specified in the individual criterion listed: 
1. Any previous exposure to ISIS 396443; previous dosing in this study or previous studies 
with ISIS 396443. 
2. Signs or symptoms of SMA present at birth or within the first week after birth. 
3. Ventilation for ≥16 hours per day continuously for >21 days at screening. 
4. Permanent tracheostomy, implanted shunt for CSF drainage, or implanted CNS catheter 
at screening.  
5. History of brain or spinal cord disease that would interfere with the LP procedure, CSF 
circulation, or safety assessments. 
6. Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional 
support within 2 months prior to screening, or hospitalization for surgery planned during 
the study. 
7. Clinically significant abnormalities in hematology or clinical chemistry parameters or 
ECG, as assessed by the Investigator, at the Screening Visit that would render the subject 
unsuitable for inclusion. 
8. Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole, 
carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device 
within 30 days prior to screening.  Any history of gene therapy, prior ASO treatment, or 
cell transplantation. 
9. Ongoing medical condition that according to the Investigator would interfere with the 
conduct and assessments of the study.  Examples are medical disability (e.g., wasting or 
cachexia, severe anemia) that would interfere with the assessment of safety or would 
compromise the ability of the subject to undergo study procedures. 
10. The subject’s parent or legal guardian is unable to understand the nature, scope, and 
possible consequences of the study, or does not agree to comply with the protocol’s 
schedule of assessments. 
11. Subject’s parent or legal guardian is not willing to continue to meet standard of care 
guidelines for care (including vaccinations and respiratory syncytial virus prophylaxis if 
available), nor provide nutritional and respiratory support throughout the study. 


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12. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the 
subject unsuitable for enrollment. 
For Part 2 only: 
Candidates will be excluded from the Part 2 if they meet the following exclusion criterion at the 
time of consent into Part 2 of the study: 
1. Any significant change in clinical status, including laboratory tests that, in the opinion of 
the Investigator, would make them unsuitable to participate in Part 2.  The Investigator 
must reassess the subject’s medical fitness for participation and consider any diseases that 
would preclude treatment. 
Note that subjects who have been previously exposed to ISIS 396443 in Part 1 of the study 
(Exclusion criterion 1 for Part 1) may participate in Part 2. 
9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION  
9.1. 
Screening and Enrollment 
The subject’s legally authorized representative (e.g., parent or legal guardian) must provide 
informed consent for Part 1 before study-specific screening tests are performed and for Part 2 
before study-specific procedures are performed (see Section 17.3).  When a subject’s 
parent/guardian signs the ICF, that subject is assigned a unique subject identification number 
through the interactive response technology (IRT) system and is considered to be enrolled in the 
study.  Participating study sites are required to document all screened candidates initially 
considered for inclusion in this study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents, within the IRT system, and on 
the screening log.  If a subject initially fails any of the screening criteria, they will be allowed to 
be rescreened 1 time during the Screening Period, at the discretion of the Investigator.  
9.2. 
Registration and Randomization of Subjects 
In Part 1 of the study, subjects will be registered and randomized after all screening assessments 
have been completed and after the Investigator has verified that the subjects are eligible per 
criteria in Section 8.1 and Section 8.2   No subject may begin treatment until the subject is 
documented as registered (assigned a unique identification number) and is randomized for the 
study in the IRT system.  Any subject identification numbers that are assigned will not be reused 
even if the subject does not receive treatment.   
In Part 1 of the study, using an IRT system, eligible subjects will be randomized to receive 
ISIS 396443:sham procedure in a 2:1 ratio.  Randomization will be stratified based on age at 
onset of clinical signs and symptoms consistent with SMA:  >6 months versus <6 months.  
Subjects who withdraw from the study may be replaced. 
At the beginning of Part 2 of the study, the subject's treatment assignment will be unblinded via 
the IRT system.  Part 2 is the OLE phase of the study in which all subjects receive ISIS 396443. 


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Refer to the Study Reference Guide for details on registration and randomization.  
9.3. 
Blinding Procedures 
Part 1 of the study is a randomized, double-blind, sham-procedure controlled study.  The 
Sponsor, parents and/or legal guardians, and key study site personnel will be blinded throughout 
Part 1 of the study.  To maintain the study blind, it is imperative that subject treatment 
assignments are not shared with the subjects, their families, or any member of the study team, 
either at the study site or that of the Sponsor, except the unblinded site study staff (dedicated 
team) and the unblinded medical monitor or clinical research associate.  The DSMB may be 
unblinded as described in the DSMB charter.  
Before Part 2 Day 1, parents and/or legal guardians, key study site personnel, and the Sponsor 
will be unblinded to the treatment group to which the subjects were randomized in Part 1.  This 
will be performed according to the unblinding plan, which will be finalized prior to unblinding.  
Of note, in the event that the Sponsor decides to rollover subjects to Part 2 early, unblinding for 
key study site personnel will occur prior to the End of Part 1 Evaluation in order to facilitate 
bringing subjects who were randomized to receive sham in Part 1 as soon as possible and to 
maintain the 4-month dosing interval for subjects who were randomized to receive ISIS 396443 
in Part 2.  Treatment in Part 2 will be open-label, and all study subjects will receive ISIS 396443. 
9.3.1. 
Emergency Unblinding of Treatment Assignment  
In Part 1 of the study, if a subject has experienced an SAE (as defined in Section 15.1.2), and/or 
when knowledge of the treatment assignment will impact the clinical management of the subject, 
the Investigator will have the ability to unblind the treatment assignment for that subject using 
the IRT.  However, prior to unblinding, the Investigator should attempt to contact the blinded 
Medical Monitor to discuss the emergency.  The Sponsor or designee will be informed of the 
unblinding of a subject within 24 hours.  Every reasonable attempt should be made to complete 
the End of Part 1 Evaluation assessments prior to unblinding, as knowledge of the treatment arm 
could influence subject assessment.  The Investigator must document the reasons for unblinding 
in the subject’s source documents.  The Investigator is strongly advised not to divulge the 
subject’s treatment assignment to any individual not directly involved in managing the medical 
emergency, nor to personnel involved with the analysis and conduct of the study.  In cases where 
there are ethical reasons to have a subject whose treatment assignment was unblinded for safety 
reasons remain in the study, the Investigator must obtain specific approval from the Sponsor and 
the Medical Monitor for the subject to continue in the study.  
In addition, all suspected unexpected serious adverse reactions (SUSARs) will be unblinded by 
the Sponsor’s (or designee) Drug Safety and Quality Assurance personnel for the purpose of 
regulatory reporting (Section 15.3.4). 


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10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A subject must permanently discontinue study treatment for any of the following reasons: 
 The subject’s parent or legal guardian withdraws consent.   
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment. 
 At the discretion of the Investigator for medical reasons. 
 At the discretion of the Investigator or the Sponsor for noncompliance. 
The reason for discontinuation of study treatment must be recorded in the subject’s case report 
form (CRF). 
In Part 1 of the study, subjects who discontinue treatment will continue follow-up evaluations 
(i.e., predose evaluations at regular study evaluations) but with no postdose safety monitoring 
telephone contacts (Section 4.2, Table 2) unless either consent is withdrawn (Section 10.2) or the 
Sponsor terminates Part 1 early, in the case of emergent data from the ISIS 396443 clinical 
development program.  If a subject is unable to come for study evaluations, the minimum 
requirement for follow up will be telephone calls on a monthly basis.  At these evaluations or 
telephone contact, changes in concomitant medications and AEs, information on the subject’s 
daily ventilator use/bi-level positive airway pressure (Bi-PAP), and health status will be 
recorded.  The methods used to continue follow up (i.e., site evaluations or telephone calls to the 
subject’s parent, guardian, or caregiver) should be documented in the source document. 
In Part 2 of the study, subjects who discontinue treatment will continue follow-up evaluations 
unless consent is withdrawn (Section 10.2).  If a subject is unable to come for study evaluations, 
the minimum requirement for follow up will be telephone calls on a monthly basis.  The methods 
used to continue follow up (i.e., site evaluations or telephone calls to the subject’s parent, 
guardian, or caregiver) should be documented in the source document.  Follow-up evaluations 
for any subjects who discontinue treatment in Part 2 will continue through the end of Part 2. 
10.2. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any one of the following reasons: 
 The subject’s parent or legal guardian withdraws consent.   
 The subject’s parent or legal guardian is unwilling or unable to comply with the 
protocol. 
 The Sponsor terminates Part 1 early because of emergent data from the ISIS 396443 
clinical development program, and the subject elects not to enroll in Part 2. 
Subjects who withdraw early from Part 1 will be encouraged to complete the End of Part 1 
Evaluation assessments (see Section 4.2 [Table 2) at the time of withdrawal.  Subjects who 


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withdraw early from Part 2 will be encouraged to complete the Part 2 Early Termination 
Evaluation assessments at the time of withdrawal (see Section 4.2 [Table 3, and Table 4]).  The 
reason for the subject’s withdrawal from the study must be recorded in the subject’s CRF. 
11. 
STUDY TREATMENT USE 
11.1. 
Regimen 
Refer to and follow the DHA for complete details. 
11.1.1. 
Study Treatment 
In Part 1 of the study, each subject will receive a single intrathecal bolus (1 to 3 minutes) LP 
injection of ISIS 396443 or sham procedure on Days 1, 15, 29, 64, 183, and 302 by dedicated 
study personnel who are unblinded to treatment group; this cannot be any of the key study site 
personnel (i.e., the Investigator, the study coordinator, or outcome assessors).  The study 
treatment administration will be performed in a dedicated room, and key study personnel and the 
parents will not be present during the procedure to ensure blinding.   
In Part 2 of the study, each subject will receive a single intrathecal bolus (1 to 3 minutes) LP 
injection of ISIS 396443 at the days determined by their Part 1 treatment assignment as specified 
in Table 3 and Table 4.  Treatment administration will not be blinded. 
ISIS 396443 will be administered using a “spinal anesthesia” needle and a 5-mL syringe.  A 22G 
to 25G spinal anesthesia needle is recommended based on subject size or clinical condition.  The 
target site for needle insertion is the L3/L4 space but may be 1 segment above or 1 to 2 segments 
below this level, if needed.  Depending on institutional guidelines, anesthesia may be used for 
the LP procedure or for the sham procedure, following institutional procedures.  Subjects will be 
encouraged to lie down flat for 1 hour following injection of the study treatment, if possible.  
Prior to each injection, 5 mL of CSF fluid will be collected for analyses.  CSF will be used for 
ISIS 396443 PK analyses.  Upon consent, extra CSF will be stored for optional future 
investigation of possible biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF 
microRNA panel) or for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, immunogenicity assessments (including 
assay development and validation purposes), or other actions of ISIS 396443 with CSF 
constituents.  CSF analyses and data presentation will be conducted in a blinded manner.   
The volume of the injection, and thus, the dose, will be adjusted for the subject’s age on the day 
of dosing, such that each subject will receive a 12-mg scaled equivalent dose based on CSF 
volume scaling (Table 1).  Thus, younger subjects will be given a lower dose of study treatment, 
achieved by injecting a smaller volume that is proportional to estimated CSF volume for age, 
such that dose volume will be equivalent to 5 mL for a 2-year-old child to adult.   
11.1.2. 
Sham Procedure 
In Part 1 of the study, subjects randomized to the sham procedure control group will undergo a 
sham procedure, rather than study treatment administration, on Study Days 1, 15, 29, 64, 183, 


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and 302.  Details regarding the sham procedure will be provided in the DHA.  The sham 
procedure will be administered by dedicated study personnel who are unblinded to treatment 
group; this cannot be any of the key study site personnel (i.e., the Investigator, study coordinator, 
or outcomes assessors).  The sham procedure will be performed in a dedicated room, and key 
study personnel and the parent or legal guardian will not be present during the procedure to 
ensure blinding.  
In general, the sham procedure will consist of a small needle prick on the lower back at the 
location where the LP injection is normally made.  The needle will break the skin, but no LP 
injection or needle insertion will occur.  The needle prick will be covered with the same bandage 
that is used to cover the LP injection normally, thus simulating the appearance of an LP 
injection.  If institutional guidelines require the use of anesthesia or sedation for an LP procedure 
in ISIS 396443-treated subjects, then in order to maintain the blind, minimal sedation (i.e., a low 
dose of an anxiolytic) should be used for the sham procedure, following institutional procedures.  
The study subject will be kept in the procedure room for the same amount of time that subjects 
administered study treatment are kept, thus simulating the time period of the study treatment 
administration procedure. 
Study treatment and sham kits will be packaged in a blinded fashion.  Blinded kits for the sham 
procedure contain artificial CSF (5.0 mL solution per 6 mL vial) that will not be injected but will 
be used to simulate CSF samples for that subject.  
11.2. 
Modification of Dose and/or Treatment Schedule 
No adjustment of dose is permitted.  In the event of a concurrent illness that would prevent the 
dosing procedure from being performed safely, an adjustment in the dose schedule may be 
permitted but must be approved by the Medical Monitor. 
11.3. 
Precautions 
There are no protocol-required treatment precautions. 
11.4. 
Compliance 
Compliance with treatment dosing is to be monitored and recorded by site staff. 
11.5. 
Concomitant Therapy and Procedures 
11.5.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between Screening and the Part 2 
Final Follow-up Evaluation/Telephone Call (or End of Part 1 Evaluation, if the subject does not 
enroll in Part 2). 
Allowed Concomitant Therapy 
Throughout the study, Investigators or designated licensed physicians involved in the study may 
prescribe concomitant medications or treatments deemed necessary for AEs or to provide 
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Disallowed Concomitant Therapy 
Subjects are prohibited from receiving other experimental agents, including gene therapy, during 
the study.  This includes marketed agents at experimental doses that are being tested for the 
treatment of SMA (e.g., albuterol/ salbutamol, riluzole, carnitine, sodium phenylbutyrate, 
valproate, hydroxyurea). 
11.5.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and the Part 2 Final Follow-up Evaluation/Telephone 
Call (or End of Part 1 Evaluation, if the subject does not enroll in Part 2). 
12. 
STUDY TREATMENT MANAGEMENT 
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol). 
Study treatment must be dispensed only by a pharmacist or medically qualified staff.  Study 
treatment is to be dispensed only for subjects enrolled in this study.  Once study treatment is 
prepared for a subject, it can be administered only to that subject.  Study treatment vials are for 
one-time use only; any study treatment remaining in the vial should not be used for another 
subject.   
12.1. 
Study Treatment 
ISIS 396443 is formulated as an isotonic solution at 2.4 mg/mL and is provided as a 5.0-mL fill 
volume in a 6-mL clear glass vial.  ISIS 396443 drug product contains the heptadecasodium salt 
of an 18-base residue phosphorothioate oligonucleotide. 
ISIS 396443 active drug is manufactured by Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. 
The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements.  At a minimum, the label will include a study reference code, drug identifier, and 
quantity of dosage units, lot number, and other pertinent information in accordance with local 
laws.  The expiry or use-by date is stored in the IRT system, and printable assignment reports are 
available to site personnel.  Study treatment should not be used after the expiration date.   
For Part 1 of the study, the study drug (ISIS 396443) and sham kits will be packaged in a blinded 
fashion.  Blinded kits for sham procedure contain artificial CSF provided as 5.0 mL solution per 
6 mL vial that will not be injected but will be used to simulate CSF samples for a subject.   
For Part 2 of the study, the study drug (ISIS 396443) kits will be packaged in an open-label 
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12.1.1. 
Study Treatment Preparation 
The individual preparing ISIS 396443 or artificial CSF should carefully review the instructions 
provided in the DHA.   
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or drug, do not use it.  The vials in question should be saved at the study site and the 
problem immediately reported to the Sponsor (or designee). 
12.1.2. 
Study Treatment Storage 
Study treatment must be stored in a secure location. 
ISIS 396443 is to be protected from light and stored long term at 2°C to 8°C in a locked 
refrigerator with limited access.  For additional information on storage requirements, follow the 
instructions provided in the DHA. 
12.1.3. 
Study Treatment Handling and Disposal 
The Investigator must return all used and unused vials of ISIS 396443 and artificial CSF as 
instructed by the Sponsor (or designee). 
If any used ISIS 396443 or artificial CSF supplies are to be destroyed at the study site, the 
institution or appropriate site personnel must obtain prior approval from the Sponsor (or 
designee), by providing, in writing, the destruction policy or details of the method of 
destruction.  After such destruction, the Sponsor (or designee) must be notified, in writing, of the 
details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the date of 
destruction, and proof of destruction. 
12.1.4. 
Study Treatment Accountability 
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), and accounts of any study treatment accidentally or 
deliberately destroyed.   
Unless otherwise notified, all vials, both used and unused, must be saved for study treatment 
accountability.  At the end of the study, reconciliation must be made between the amount of 
ISIS 396443 or artificial CSF supplied, dispensed, and subsequently destroyed or returned to the 
Sponsor (or designee).  A written explanation must be provided for any discrepancies. 


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13. 
EFFICACY, PHARMACOKINETIC, AND IMMUNOGENICITY 
ASSESSMENTS 
See Section 4.2 (Table 2, Table 3, and Table 4) for the timing of all efficacy assessments. 
13.1. 
Clinical Efficacy Assessments 
The following clinical assessments will be performed to evaluate the efficacy of ISIS 396443: 
 Ventilator use  
 HINE (Section 2) 
 Growth parameters (body length, head circumference, chest circumference, arm 
circumference, weight for age, weight for length, and head to chest circumference 
ratio) 
 Clinical Global Impression of Change (physician and caregiver assessment) 
13.2. 
Pharmacokinetic (ISIS 396443 Concentration) Assessments 
The following tests will be performed to assess the PK of ISIS 396443: 
 Plasma ISIS 396443 concentrations 
 CSF ISIS 396443 concentrations 
13.3. 
Immunogenicity Assessments 
The following test will be performed to assess the immunogenicity of ISIS 396443: 
 Anti-ISIS 396443 plasma antibody concentrations 


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14. 
SAFETY ASSESSMENTS 
See Section 4.2 (Table 2, Table 3, and Table 4) for the timing of all safety assessments. 
14.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to evaluate the safety profile of 
ISIS 396443: 
 Neurological examinations (assessment of mental status, level of consciousness, 
sensory motor function, cranial nerve function, and reflexes) 
 AEs, including SAEs 
 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, 
temperature, pulse oximetry, and transcutaneous carbon dioxide) 
 Weight 
 Physical examinations 
 Medical history 
 12-Lead ECGs 
 Use of concomitant medications 
14.2. 
Laboratory Safety Assessments 
The following laboratory tests will be performed to evaluate the safety profile of ISIS 396443: 
 Blood chemistry:  total protein, albumin, creatinine, cystatin C, creatine 
phosphokinase, blood urea nitrogen, total bilirubin (direct and indirect), alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, glucose, calcium, 
phosphorus, chloride, sodium, potassium 
 Hematology:  red blood cells, hemoglobin, hematocrit, platelets, white blood cells, 
white blood cell differential 
 Urinalysis:  specific gravity, pH, protein, glucose, ketones, bilirubin, red blood cells, 
white blood cells, epithelial cells, bacteria, casts, crystals 
 


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15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each subject’s legally authorized representative and/or main 
caregiver(s) must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies. 
15.1. 
Definitions 
15.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including a 
clinically significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator.  Abnormal laboratory findings that are considered by the Investigator 
as not clinically significant should not be reported as AEs.  Although abnormal laboratory values 
are typically not considered AEs, the following considerations may result in an abnormal 
laboratory value being considered an AE: 
 A laboratory test result that meets the criteria for an SAE 
 A laboratory test result that requires the subject to receive specific corrective therapy 
 A laboratory abnormality that the Investigator considers to be clinically significant 
15.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death 
 Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization is defined as an admission of >24 hours to a medical facility and does 
not qualify as an AE   
 Results in persistent or significant disability/incapacity 


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 Results in a congenital anomaly/birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the study site must document all of the following: 
 The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining consent from 
the subject’s parent or legal guardian to participate in the study. 
 The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s parent‘s or legal guardian‘s consent to participate 
in the study and the time of the procedure or treatment. 
 The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission. 
o If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless 
one of the requirements in Section 15.1.2 is met. 
15.2. 
Safety Classifications 
15.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.2 
 The relationship of the event to study treatment as defined in Section 15.2.2 
 The severity of the event as defined in Section 15.2.3 






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To report initial or follow-up information on an SAE, fax or email a completed SAE form as 
described in the Study Reference Guide. 
15.3.3.1. Deaths 
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate CRF.  All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event.  The Investigator should make every effort to obtain and send 
death certificates and autopsy reports as described in the Study Reference Guide.  The term death 
should be reported as an SAE only if the cause of death is not known and cannot be determined. 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions 
SUSARs are SAEs that are unexpected and judged by the Investigator or the Sponsor (or 
designee) to be related to the study treatment administered. 
The Sponsor (or designee) will report SUSARs to the appropriate regulatory authorities and to 
Investigators as required, according to local law. 
15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Overdose 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol; an overdose must be documented as a protocol deviation.  A 
brief description should be provided in the deviation form, including whether the subject was 
symptomatic (with a list of symptoms) or asymptomatic.  Overdoses are not considered AEs and 
should not be recorded as an AE on the CRF; however, all overdoses must be reported to the 
Medical Monitor within 24 hours of the site becoming aware of the overdose.  An overdose must 
be reported to the Medical Monitor even if the overdose does not result in an AE.  If an overdose 
results in an AE, then the AE must be recorded.  If an overdose results in an SAE, then the SAE 
form must be completed and faxed as described in the Study Reference Guide.  All study 
treatment-related dosing information must be recorded on the dosing CRF. 
15.4.2. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator or designee should 
contact 
, MD, Office:
, Mobile:  
, 
Fax:
, 
 (or 
 medical emergency:  
 or 
) or 
, MD at 
. 
15.4.2.1. Unblinding for Medical Emergency 
In a medical emergency when knowledge of the subject’s treatment assignment may influence 
the subject’s clinical care, the Investigator (or designee) should attempt to contact the blinded 
Biogen MA Medical Director or blinded 
 Medical Monitor to discuss the emergency 


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within 24 hours.  In these instances, the Investigator (or designee) may access the subject's 
treatment assignment by IRT.   
The Investigator must document the reasons for unblinding in the subject’s source documents.  
The Investigator is strongly advised not to divulge the subject’s treatment assignment to any 
individual not directly involved in managing the medical emergency or to personnel involved 
with the analysis and conduct of the study.   
15.5. 
Safety Responsibilities 
15.5.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
 Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment. 
 Determine the seriousness, relationship, and severity of each event. 
 Determine the onset and resolution dates of each event. 
 Complete an SAE form for each serious event and fax it as described in the Study 
Reference Guide within 24 hours of the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported as described in the Study Reference Guide within 24 hours of the 
study site staff becoming aware of new information. 
 Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records. 
 Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. 
 Report SAEs to local ethics committees, as required by local law. 
15.5.2. 
The Sponsor 
The Sponsor’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor (or designee) 
is responsible for reviewing with study site staff the definitions of AE and SAE, as 
well as the instructions for monitoring, recording, and reporting AEs and SAEs. 
 The Sponsor (or designee) is to notify all appropriate regulatory authorities, central 
ethics committees, and Investigators of SAEs, as required by local law, within 
required time frames. 


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16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
Part 1 and Part 2 will be analyzed separately.  For Part 1, in general, continuous variables will be 
summarized by descriptive statistics, including number, mean, median, standard deviation, 
minimum, and maximum.  Categorical variables will be presented with the number and 
percentage in each category.  For Part 2, no formal statistical analyses will be performed.  
Descriptive statistics will be presented for safety and efficacy data collected. 
For the Part 1 analysis, baseline is defined as the last nonmissing assessment prior to the first 
dose of study treatment in Part 1.  For the Part 2 analysis, baseline is defined as the last 
nonmissing assessment prior to the first dose of study treatment in Part 2.  In addition, a pooled 
analysis incorporating data from both Part 1 and Part 2 will be conducted to characterize the 
safety profile of ISIS 396443.  For subjects on active treatment in Part 1, safety data from both 
Part 1 and Part 2 will be included in the pooled analysis and the Part 1 baseline will used for 
those subjects in the pooled analysis.  For subjects on sham procedure in Part 1, only safety data 
from Part 2 will be included in the pooled analysis and the Part 2 baseline will be used for those 
subjects in the pooled analysis. 
Concomitant medication usage for each subject will be listed for review. 
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
16.1. 
Demographic and Baseline Characteristics  
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Subject disposition will be summarized by treatment group.  All subjects 
enrolled will be included in a summary of subject disposition.  
16.2. 
Safety and Tolerability 
Safety is the primary objective for the study.  All AEs, laboratory abnormalities, ECGs, and vital 
signs will be evaluated for safety.   
16.2.1. 
Analysis Population 
Safety analyses will be conducted in the safety population.  This safety set will include all 
subjects who are randomized and receive at least 1 dose of study treatment or sham procedure.  
Treatment duration and amount of study treatment received will be summarized by treatment 
group.   
16.2.2. 
Methods of Analysis 
16.2.2.1. Neurological Examinations 
Neurological examination findings will be listed for review, and as appropriate, results will be 
summarized descriptively for each treatment group.  The number and percentage of subjects with 


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shifts from baseline normal to each of the categorical values denoting normal, abnormal, and 
abnormal (not AE) will be summarized.   
16.2.2.2. Adverse Events 
All AEs will be analyzed based on the principle of treatment emergence.  An AE will be 
regarded as treatment emergent if it was present prior to the first dose of study treatment and 
subsequently worsened, or was not present prior to the first dose of study treatment but 
subsequently appeared.  The incidence of treatment-emergent AEs will be summarized overall, 
by severity, and by relationship to study treatment.  A subject having the same AE more than 
once will be counted only once in the incidence for that event.  The occurrence of the AE with 
the greatest severity will be used in the calculation of incidence by severity; the occurrence of the 
AE with the strongest relationship to study treatment will be used in the calculation of incidence 
by relationship to study treatment. 
All treatment-emergent AEs and SAEs will be summarized for each treatment group using the 
Medical Dictionary for Regulatory Activities (MedDRA) coding system, by system organ class, 
preferred term, relationship to study treatment, and severity.  Narratives of deaths, SAEs, early 
withdrawals from study treatment and from study due to AEs will be provided.  
16.2.2.3. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  The number and 
percentage of subjects with clinically relevant postbaseline abnormalities will be presented.  
Summary statistics for actual values and change from Baseline will also be presented. 
16.2.2.4. ECGs 
ECG results will be presented by subject, and as appropriate, results will be summarized 
descriptively for each treatment group.  The number and percentage of subjects with shifts from 
baseline normal to each of the categorical values denoting normal, abnormal clinically 
significant, and abnormal (not clinically significant) will be summarized. 
16.2.2.5. Clinical Laboratory Results 
Clinical laboratory evaluations including hematology, blood chemistry, and urinalysis will be 
summarized using study visit for each treatment group.  These safety variables will also be 
presented over time after study treatment administration, as appropriate.  Laboratory parameters 
will also be summarized using shift tables, as appropriate.  
16.3. 
Efficacy 
16.3.1. 
Analysis Population 
The exploratory analysis of efficacy will be performed on the intent-to-treat population.  The 
intent-to-treat population is defined as all subjects who are randomized and receive at least 
1 dose of study treatment or sham procedure.  


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16.3.2. 
Methods of Analysis 
For continuous endpoints, the mean change from baseline will be estimated with 95% confidence 
limits.  For categorical outcomes, the proportion of subjects attaining a specified category will be 
estimated.  Selected endpoints may be pooled across subsets as appropriate.  
16.4. 
Pharmacokinetics 
16.4.1. 
Analysis Population 
The PK population will include all subjects who are randomized and have at least 1 evaluable 
postdose or postsham-procedure PK sample. 
16.4.2. 
Methods of Analysis 
Plasma PK parameters, as applicable, and ISIS 396443 concentrations in plasma and CSF for the 
PK population will be summarized using descriptive statistics and, where warranted, presented 
graphically. 
16.5. 
Immunogenicity 
16.5.1. 
Analysis Population  
The analysis population for immunogenicity will include all subjects with available 
immunogenicity data. 
16.5.2. 
Methods of Analysis 
Results from the immunogenicity analyses for anti-ISIS 396443 plasma antibody status and titer 
will be summarized at the specified visits.   
16.6. 
Interim Analyses 
No formal interim analyses are planned.  However, if the Sponsor decides to terminate Part 1 
early, data prior to the unblinding of the first subject in Part 1 may be archived; no analyses are 
planned to be conducted based on the archived data.  Full analysis of Part 1 data will be done 
following database lock at the end of Part 1.  
16.7. 
Sample Size Considerations 
Since this study is exploratory, sample size determination will not be based on power 
consideration.  The sample size considered for this study will allow exploration of safety, 
tolerability, and selected efficacy endpoints in the selected study population.   


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17. 
ETHICAL REQUIREMENTS 
The Sponsor, 
 (the contract research organization [CRO] for this study), and the 
Investigator must comply with all instructions, regulations, and agreements in this protocol and 
applicable International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) 
guidelines and conduct the study according to local regulations. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. 
17.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
17.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  The Sponsor (or designee) will submit documents 
on behalf of the investigational sites in countries other than the US.   
If the Investigator makes any changes to the ICF, the Sponsor (or designee) must approve the 
changes before the ICF is submitted to the ethics committee.  A copy of the approved ICF must 
be provided to the Sponsor (or designee).  After approval, the ICF must not be altered without 
the agreement of the relevant ethics committee and the Sponsor (or designee). 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
The Sponsor (or designee) must receive a letter documenting ethics committee approval, which 
specifically identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  
Protocol amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. 
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and the Sponsor (or designee). 
17.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations.   


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The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
Subjects will be informed that their race and ethnicity will not be collected for the purposes of 
data analysis during the study.  
In addition, subjects who have the capacity should provide their assent to participate in the study.  
The level of information provided to subjects should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines. 
A copy of the signed and dated ICF and assent, if applicable, must be given to the subject or the 
subject’s legally authorized representative.  The original signed and dated ICF will be retained 
with the study records.  Local regulations must be complied with in respect to the final 
disposition of the original (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent and assent, if applicable, must also be documented in the 
subject’s medical record. 
17.4. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America). 
During the study, subjects’ race and ethnicity will not be collected for the purposes of data 
analysis.  
Study reports will be used for research purposes only.  The subject will not be identified by name 
in CRFs, study-related forms, study reports, or any related publications.  Sponsor, its partners 
and designees, ethics committees, and various government health agencies may inspect the 
records of this study.  Every effort will be made to keep the subject’s personal medical data 
confidential. 
17.5. 
Compensation for Injury 
The Sponsor (or designee) maintains appropriate insurance coverage for clinical studies and will 
follow applicable local compensation laws. 
17.6. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor or Ionis with the subject before the subject makes a decision to participate in the study). 
17.7. 
Registration of Study and Disclosure of Study Results 
The Sponsor (or designee) will register the study and post study results regardless of outcome on 
a publicly accessible website in accordance with the applicable laws and regulations. 


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18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Study Site Initiation 
The Investigator must not screen any subjects prior to completion of a study initiation visit 
conducted by the Sponsor (or designee).  This initiation visit will include a detailed review of the 
protocol and study procedures. 
18.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will 
be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested. 
18.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. 
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate. 
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.  
CRFs will be not be used as source data.  Monitoring visits must be conducted according to the 
applicable ICH and GCP guidelines to ensure protocol adherence, quality of data, study 
treatment accountability, compliance with regulatory requirements, and continued adequacy of 
the investigational site and its facilities. 
18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and the Sponsor.  Ionis is the Sponsor 
of the study in the United States and Biogen Idec Research Limited is the Sponsor of the study in 
the Rest of World.  Biogen will be responsible for managing the study globally.  All financial 
details are provided in the separate contract(s) between the institution, Investigator, and the 
Sponsor.  
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 


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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
The Sponsor may transfer any or all of its study-related responsibilities to a CRO and other third 
parties; however, the Sponsor retains overall accountability for these activities. 
19.1.1. 
Contract Research Organization  
A CRO will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports and data management.  Before 
subjects are screened at each study site, the CRO will review study responsibilities with the 
Investigators and other study site staff, as appropriate. 
19.1.2. 
Interactive Response Technology 
IRT will be used in this study.  Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system. 
19.1.3. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool that is developed and supported by an electronic data 
capture vendor and configured by Sponsor or CRO. 
19.1.4. 
Central Laboratories for Laboratory Assessments 
A central laboratory will be selected by the Sponsor to analyze all hematology, blood chemistry, 
urine, and CSF samples collected at all study sites.  Local laboratories may be used to 
accommodate acute or urgent needs as discussed in in the Study Reference Guide. 
During the Part 1 Screening Period, a blood sample will be collected for SMN2 copy number 
analysis by the central laboratory only from those subjects without genetic documentation of 
SMN2 copy number.  For all other subjects, a blood sample will be collected at any time during 
the study for analysis of SMN2 copy number by the central laboratory. 
19.2. 
Study Committees 
Safety data will be reviewed on an ongoing quarterly basis throughout Part 1 of the study by an 
independent DSMB.  The DSMB will be assembled to review safety, tolerability, and efficacy 
(as needed) data collected on ISIS 396443 during the study.  Based on its ongoing assessment of 
the safety and tolerability of ISIS 396443, the DSMB will provide recommendations to the 
Sponsor for modifying, stopping, or continuing the study as planned. 


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19.3. 
Changes to Final Study Protocol 
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, the Sponsor (or designee) may, at any time, amend this protocol to eliminate an 
apparent immediate hazard to a subject.  In this case, the appropriate regulatory authorities will 
be notified subsequent to the modification. 
In the event of a protocol modification, the ICF may require similar modifications (see 
Sections 17.2 and 17.3). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify the Sponsor in writing and 
receive written authorization from the Sponsor to destroy study records.  In addition, the 
Investigator must notify the Sponsor of any changes in the archival arrangements including but 
not limited to archival at an offsite facility or transfer of ownership if the Investigator leaves the 
site. 
19.6. 
Study Report Signatory 
The Sponsor will follow all applicable local regulations pertaining to study report signatories. 
 


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20. 
REFERENCES 
Burghes AH, Beattie CE. Spinal muscular atrophy: why do low levels of survival motor neuron 
protein make motor neurons sick? Nat Rev Neurosci. 2009;10(8):597-609. 
Coovert DD, Le TT, McAndrew PE, et al. The survival motor neuron protein in spinal muscular 
atrophy. Hum Mol Genet. 1997;6(8):1205-14. 
Feldkötter M, Schwarzer V, Wirth R, et al. Quantitative analyses of SMN1 and SMN2 based on 
real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of 
spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358-68. 
Hua Y, Sahashi K, Hung G, et al. Antisense correction of SMN2 splicing in the CNS rescues 
necrosis in a type III SMA mouse model. Genes Dev. 2010;24(15):1634-44. 
Hua Y, Vickers TA, Baker BF, et al. Enhancement of SMN2 exon 7 inclusion by antisense 
oligonucleotides targeting the exon. PLoS Biol. 2007;5(4):e73. 
Hua Y, Vickers TA, Okunola HL, et al. Antisense masking of an hnRNP A1/A2 intronic splicing 
silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet. 2008;82(4):834-48. 
Le TT, Pham LT, Butchbach ME, et al. SMNDelta7, the major product of the centromeric 
survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and 
associates with full-length SMN. Hum Mol Genet. 2005;14(6):845-57. 
Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal 
muscular atrophy. Nat Genet. 1997;16(3):265-9. 
Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. 
EMBO J. 1996;15(14):3555-65. 
Matsuzawa J, Matsui M, Konishi T, et al. Age-related volumetric changes of brain gray and 
white matter in healthy infants and children. Cereb Cortex. 2001;11(4):335-42. 
Passini MA, Bu J, Richards AM, et al. Antisense oligonucleotides delivered to the mouse CNS 
ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011;3(72):72ra18. 
Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. 
2010;12(3):145-52. 
Prior TW, Swoboda KJ, Scott HD, et al. Homozygous SMN1 deletions in unaffected family 
members and modification of the phenotype by SMN2. Am J Med Genet A. 2004;130A(3):307-
10. 
Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to age, 
SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-12. 


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Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal 
muscular atrophy. J Child Neurol. 2007;22(8):1027-49. 
Wirth B, Brichta L, Schrank B, et al. Mildly affected patients with spinal muscular atrophy are 
partially protected by an increased SMN2 copy number. Hum Genet. 2006;119(4):422-8. 
 
 


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21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A phase 2, randomized, double-blind, sham-procedure 
controlled study to assess the safety and tolerability and explore the efficacy of ISIS 396443 
(BIIB058) administered intrathecally in subjects with spinal muscular atrophy who are not 
eligible to participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4” and agree 
to conduct the study according to the protocol and the applicable ICH guidelines and GCP 
regulations, and to inform all who assist me in the conduct of this study of their responsibilities 
and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 










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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .....................................................................................10 
2. 
LIST OF ABBREVIATIONS.....................................................................................11 
3. 
SYNOPSIS .................................................................................................................12 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR 
STUDY 232SM202 ....................................................................................................19 
4.1. 
Study Schematic .........................................................................................................19 
4.2. 
Schedule of Events .....................................................................................................20 
5. 
INTRODUCTION ......................................................................................................24 
5.1. 
Profile of Previous Experience With ISIS 396443 .....................................................25 
5.2. 
Study Rationale ...........................................................................................................27 
5.3. 
Rationale for Dose and Schedule Selection ................................................................28 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................29 
6.1. 
Objectives ...................................................................................................................29 
6.1.1. 
Primary Objective .......................................................................................................29 
6.1.2. 
Secondary Objectives .................................................................................................29 
6.1.3. 
Exploratory Objectives ...............................................................................................29 
6.2. 
Endpoints ....................................................................................................................29 
6.2.1. 
Primary Endpoint ........................................................................................................29 
6.2.2. 
Secondary Endpoints ..................................................................................................30 
6.2.3. 
Exploratory Endpoints ................................................................................................30 
7. 
STUDY DESIGN .......................................................................................................30 
7.1. 
Study Overview ..........................................................................................................30 
7.2. 
Overall Study Duration and Follow-Up .....................................................................31 
7.2.1. 
Screening ....................................................................................................................31 
7.2.2. 
Treatment ....................................................................................................................31 
7.2.3. 
Follow-Up ...................................................................................................................31 
7.3. 
Study Stopping Rules .................................................................................................31 
7.4. 
End of Study ...............................................................................................................32 
7.5. 
Safety Monitoring and Data and Safety Monitoring Board ........................................32 
8. 
SELECTION OF SUBJECTS ....................................................................................32 
8.1. 
Inclusion Criteria ........................................................................................................32 


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8.2. 
Exclusion Criteria .......................................................................................................33 
9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................34 
9.1. 
Screening and Enrollment ...........................................................................................34 
9.2. 
Registration and Randomization of Subjects ..............................................................34 
9.3. 
Blinding Procedures ....................................................................................................35 
9.3.1. 
Unblinding of Treatment Assignment ........................................................................35 
10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................35 
10.1. 
Discontinuation of Study Treatment ...........................................................................35 
10.2. 
Withdrawal of Subjects From Study ...........................................................................36 
11. 
STUDY TREATMENT USE .....................................................................................36 
11.1. 
Regimen ......................................................................................................................36 
11.1.1. 
Study Treatment ..........................................................................................................36 
11.1.2. 
Sham Procedure ..........................................................................................................37 
11.2. 
Modification of Dose and/or Treatment Schedule ......................................................37 
11.3. 
Precautions ..................................................................................................................37 
11.4. 
Compliance .................................................................................................................38 
11.5. 
Concomitant Therapy and Procedures ........................................................................38 
11.5.1. 
Concomitant Therapy .................................................................................................38 
11.5.2. 
Concomitant Procedures .............................................................................................38 
12. 
STUDY TREATMENT MANAGEMENT ................................................................38 
12.1. 
Study Treatment ..........................................................................................................38 
12.1.1. 
Study Treatment Preparation ......................................................................................39 
12.1.2. 
Study Treatment Storage ............................................................................................39 
12.1.3. 
Study Treatment Handling and Disposal ....................................................................39 
12.1.4. 
Study Treatment Accountability .................................................................................39 
13. 
EFFICACY, PHARMACOKINETIC, AND 
IMMUNOGENICITYASSESSMENTS.....................................................................40 
13.1. 
Clinical Efficacy Assessments ....................................................................................40 
13.2. 
Pharmacokinetic (ISIS 396443 Concentration) Assessments .....................................40 
13.3. 
Immunogenicity Assessments ....................................................................................40 
14. 
SAFETY ASSESSMENTS ........................................................................................41 


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14.1. 
Clinical Safety Assessments .......................................................................................41 
14.2. 
Laboratory Safety Assessments ..................................................................................41 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................42 
15.1. 
Definitions ..................................................................................................................42 
15.1.1. 
Adverse Event .............................................................................................................42 
15.1.2. 
Serious Adverse Event ................................................................................................42 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................43 
15.2. 
Safety Classifications ..................................................................................................43 
15.2.1. 
Investigator Assessment of Events .............................................................................43 
15.2.2. 
Relationship of Events to Study Treatment ................................................................43 
15.2.3. 
Severity of Events .......................................................................................................44 
15.2.4. 
Expectedness of Events ..............................................................................................44 
15.3. 
Monitoring and Recording Events ..............................................................................44 
15.3.1. 
Adverse Events ...........................................................................................................44 
15.3.2. 
Serious Adverse Events ..............................................................................................45 
15.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................45 
15.3.3.1. 
Deaths .........................................................................................................................46 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................46 
15.4. 
Procedures for Handling Special Situations ...............................................................46 
15.4.1. 
Overdose .....................................................................................................................46 
15.4.2. 
Medical Emergency ....................................................................................................46 
15.4.2.1. 
Unblinding for Medical Emergency ...........................................................................46 
15.5. 
Safety Responsibilities ................................................................................................47 
15.5.1. 
The Investigator ..........................................................................................................47 
15.5.2. 
The Sponsor ................................................................................................................47 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........48 
16.1. 
Demographic and Baseline Characteristics ................................................................48 
16.2. 
Safety and Tolerability ...............................................................................................48 
16.2.1. 
Analysis Population ....................................................................................................48 
16.2.2. 
Methods of Analysis ...................................................................................................48 
16.2.2.1. 
Neurological Examinations ........................................................................................48 


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16.2.2.2. 
Adverse Events ...........................................................................................................48 
16.2.2.3. 
Vital Signs ..................................................................................................................49 
16.2.2.4. 
ECGs ...........................................................................................................................49 
16.2.2.5. 
Clinical Laboratory Results ........................................................................................49 
16.3. 
Efficacy .......................................................................................................................49 
16.3.1. 
Analysis Population ....................................................................................................49 
16.3.2. 
Methods of Analysis ...................................................................................................49 
16.4. 
Pharmacokinetics ........................................................................................................50 
16.4.1. 
Analysis Population ....................................................................................................50 
16.4.2. 
Methods of Analysis ...................................................................................................50 
16.5. 
Immunogenicity ..........................................................................................................50 
16.5.1. 
Analysis Population ....................................................................................................50 
16.5.2. 
Methods of Analysis ...................................................................................................50 
16.6. 
Interim Analyses .........................................................................................................50 
16.7. 
Sample Size Considerations .......................................................................................50 
17. 
ETHICAL REQUIREMENTS ...................................................................................51 
17.1. 
Declaration of Helsinki ...............................................................................................51 
17.2. 
Ethics Committee ........................................................................................................51 
17.3. 
Subject Information and Consent ...............................................................................51 
17.4. 
Subject Data Protection ..............................................................................................52 
17.5. 
Compensation for Injury .............................................................................................52 
17.6. 
Conflict of Interest ......................................................................................................52 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................52 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................53 
18.1. 
Study Site Initiation ....................................................................................................53 
18.2. 
Quality Assurance .......................................................................................................53 
18.3. 
Monitoring of the Study..............................................................................................53 
18.4. 
Study Funding .............................................................................................................53 
18.5. 
Publications .................................................................................................................53 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................54 
19.1. 
External Contract Organizations .................................................................................54 


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19.1.1. 
Contract Research Organization .................................................................................54 
19.1.2. 
Interactive Response Technology ...............................................................................54 
19.1.3. 
Electronic Data Capture ..............................................................................................54 
19.1.4. 
Central Laboratories for Laboratory Assessments .....................................................54 
19.2. 
Study Committees .......................................................................................................54 
19.3. 
Changes to Final Study Protocol ................................................................................55 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................55 
19.5. 
Retention of Study Data ..............................................................................................55 
19.6. 
Study Report Signatory...............................................................................................55 
20. 
REFERENCES ...........................................................................................................56 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................57 
 
 
LIST OF TABLES 
Table 1 
ISIS 396443 Dose Volume To Be Injected ................................................................15 
Table 2: 
Schedule of Activities .................................................................................................20 
Table 3 
Pharmacokinetic Sampling Schedule1 ........................................................................23 
Table 4 
ISIS 396443 Dose Volume To Be Injected ................................................................29 
 
 
LIST OF FIGURES 
Figure 1: 
Antisense Oligonucleotide Therapeutic Approach for Treatment of Spinal 
Muscular Atrophy .......................................................................................................24 
 
 


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1. 
SPONSOR INFORMATION 
Isis Pharmaceuticals, Inc. (Isis) is the Sponsor of the study in the United States.  Biogen Idec Inc. 
(Biogen Idec) is the Sponsor of the study in the Rest of World.  Biogen Idec (or designee) will be 
responsible for managing the study globally.   
Biogen Idec MA Inc. 
14 Cambridge Center 
Cambridge, MA  02142 
USA 
 
Biogen Idec Research Limited  
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
Isis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
USA 
 
Biogen Idec Australia Pty Ltd 
Suite 1, Level 5 
123 Epping Road 
North Ryde, NSW 2113 
Australia 
 
Primary contact for urgent medical issues: 
 
: 
, MD 
 
 
Cell phone: 
 
 
 
 medical emergency: 
 
 
 
or 
 
Secondary contact for urgent medical issues: 
 
Biogen Idec 
: 
, MD, MPH 
 
 
 
 
 
 
Cell phone: 
 
 
Refer to the Study Reference Guide for complete contact information, including that for the 
unblinded Medical Monitor. 


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2. 
LIST OF ABBREVIATIONS 
 
2′-MOE 
2′-O-(2-methoxyethyl) 
AE 
adverse event 
ASO 
antisense oligonucleotide 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
DHA 
Directions for Handling and Administration 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
HINE 
Hammersmith Infant Neurological Examination 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRT 
interactive response technology 
LP 
lumbar puncture 
mRNA 
messenger ribonucleic acid 
PK 
pharmacokinetic(s) 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SMA 
spinal muscular atrophy 
SMN 
survival motor neuron 
SMN1 
survival motor neuron 1 
SMN2 
survival motor neuron 2 
SUSAR 
suspected unexpected serious adverse reaction 


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3. 
SYNOPSIS 
This is a brief summary.  For details, refer to the body of the protocol. 
Protocol Number: 
232SM202 
Protocol Title: 
A phase 2, randomized, double-blind, sham-procedure controlled study 
to assess the safety and tolerability and explore the efficacy of 
ISIS 396443 (BIIB058) administered intrathecally in subjects with spinal 
muscular atrophy who are not eligible to participate in the clinical 
studies ISIS 396443-CS3B or ISIS 396443-CS4 
Version Number: 
1 
Name of Study 
Treatment: 
ISIS 396443 (BIIB058) 
Study Indication: 
Spinal muscular atrophy (SMA) 
Phase of 
Development: 
2 
Rationale for the 
Study: 
The rationale is to assess the safety and tolerability and evaluate the 
utility of selected exploratory efficacy endpoints in subjects with SMA 
treated intrathecally with ISIS 396443 who are not eligible for the 
clinical studies ISIS 396443-CS3B or ISIS 396443-CS4.  
Study Objectives and 
Endpoints: 
Objectives 
Primary objective:   
 To assess the safety and tolerability of ISIS 396443 in 
subjects with SMA who are not eligible to participate in the 
clinical studies ISIS 396443-CS3B or ISIS 396443-CS4 
Secondary objective:   
 To examine the pharmacokinetics (PK) of ISIS 396443 in 
subjects with SMA who are not eligible to participate in the 
clinical studies ISIS 396443-CS3B or ISIS 396443-CS4 
Exploratory objective: 
 To explore the efficacy of ISIS 396443 in subjects with SMA 
who are not eligible to participate in the clinical studies ISIS 
396443-CS3B or ISIS 396443-CS4 


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Endpoints 
Primary endpoints: 
The primary safety and tolerability endpoints of this study are as 
follows: 
 Incidence of adverse events (AEs) and serious AEs (SAEs) 
 Change from baseline in clinical laboratory parameters, 
electrocardiograms (ECGs), and vital signs  
 Change from baseline in neurological examination outcomes 
Secondary endpoint: 
The secondary endpoint is as follows: 
 ISIS 396443 concentrations in plasma and cerebrospinal fluid 
(CSF) 
Exploratory endpoints: 
The exploratory efficacy endpoints of this study are as follows: 
 Change from baseline in ventilator use  
 Attainment of motor milestones assessed by Section 2 of the 
Hammersmith Infant Neurological Examination (HINE)  
 Change from baseline in growth parameters through final 
safety follow-up visit  
 Clinical Global Impression of Change (physician and 
caregiver assessment) through final safety follow-up visit 
The exploratory immunogenicity endpoint is as follows: 
 Plasma antibodies to ISIS 396443 
Study Design: 
This randomized, double-blind, sham-procedure controlled study will 
assess the safety and tolerability and explore the efficacy of intrathecally 
administered ISIS 396443 over a period of 14 months (from the first 
dose until the last safety follow-up visit).  Up to 21 subjects will be 
randomized in a ratio of 2:1 to receive ISIS 396443 by intrathecal 
lumbar puncture (LP) injection or a sham-procedure control.  
Randomization will be stratified based on age at onset of clinical signs 
and symptoms consistent with SMA:  >6 months versus <6 months. 
After informed consent is obtained, subjects will undergo a screening 
evaluation no greater than 28 days prior to administration of the first 
dose.  Subjects who meet the eligibility criteria will be randomized to 
study treatment.  Subjects will be admitted to the study site on Study 
Day 1, undergo predose evaluations, and then receive an LP injection of 


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study treatment or sham procedure.  Subjects will return to the study site 
on Days 15, 29, 64, 183, and 302 for follow-up evaluations and 
subsequent injections or sham procedures.  For subjects receiving 
ISIS396443, a CSF sample will be taken predose on each injection day 
in a manner that maintains the blind.   
After the dosing or sham procedure on Day 1, subjects will remain at the 
study site for at least 24 hours for safety monitoring.  Following all 
subsequent injections, the subjects will remain at the study site for at 
least 6 hours after the procedure for safety monitoring. 
Safety monitoring will occur on the day following each injection of 
study treatment or sham procedure.  Subjects receiving the dosing or 
sham procedure on Days 15, 29, 64, 183, and 302 will be monitored by 
telephone contact on Days 16, 30, 65, 184, and 303.   
In addition, subjects will also be monitored through telephone contact 
throughout the duration of the study.   
A final follow-up evaluation will occur approximately 4 months after the 
last dose or sham procedure.  Subjects who terminate early from the 
study will be encouraged to complete the early termination study 
procedures and assessments at the time of withdrawal.  After treatment 
and the final follow-up evaluation, all eligible subjects may elect to 
enroll in an open-label treatment extension study, pending study 
approval by the ethics committees and the appropriate regulatory 
authorities.  This will be done without unblinding the subject's treatment 
group.   
Rationale for Dose 
and Schedule 
Selection: 
A scaled equivalent dose of 12 mg, ISIS 396443 will be administered at 
each of the 6 doses (i.e., on Study Days 1, 15, 29, 64, 183, and 302) over 
a dosing period of approximately 10 months.   
The volume of the injection will be adjusted based on the subject’s age 
on the day of dosing as shown in Table 1, such that each subject will 
receive a 12 mg scaled equivalent dose based on CSF volume scaling. 
Thus, younger subjects will be given a lower absolute mg dose of study 
treatment, achieved by injecting a smaller volume that is proportional to 
estimated CSF volume for age, such that dose volume will be equivalent 
to 5 mL for 2 years of age to adult.  
The dose regimen and the dose interval for this study were selected 
based on nonclinical toxicology and PK observations from monkey 
studies using single-dose and repeat-dose intrathecal administration, 
consideration of the target tissue concentration anticipated for drug 
pharmacology, and safety data in the completed and ongoing clinical 
studies of ISIS 396443 to date.  Based on pharmacology and PK results 
in SMA transgenic mice, it is estimated that a target spinal cord tissue 


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concentration between 1 and 10 μg/g will produce 50% to 90% SMN2 
exon 7 inclusion.  Nonclinical studies in juvenile monkeys receiving 
intrathecal doses of ISIS 396443 showed a resulting gradient of 
distribution of ISIS 396443 along the spinal cord, with mean lumbar 
spinal cord concentrations ranging from 1.6- to 2.3-fold and 2.0- to 
3.5-fold higher than thoracic and cervical spinal cord levels, 
respectively.  The dose selected for this multiple-dose clinical study 
(equivalent to 12 mg of ISIS 396443) is predicted to achieve levels at the 
high end of this range (approximately 10 μg/g lumbar and 3 μg/g 
cervical spinal cord tissue concentrations) after the first dose.  The 
loading dose interval (i.e., doses on Days 1, 15, 29, and 64) was selected 
based on the nonclinical PK and pharmacology data in order to achieve 
and maintain ISIS 396443 spinal cord tissue levels that are predicted to 
be above or within the upper end of the pharmacologically active range 
by Day 64 (approximately 30 μg/g lumbar and 10 μg/g cervical tissue 
concentration), while at the same time considering subject safety and 
convenience for repeated intrathecal injections by LP.  The higher 
number of loading doses would allow for the evaluation of safety and 
tolerability and preliminary exploratory efficacy endpoints in a broader 
population of subjects with SMA, including those who have onset of 
clinical signs and symptoms at >6 months of age but who are not eligible 
for Study ISIS 396443-CS4.  The maintenance dose interval (once every 
4 months) was selected based on the estimated spinal tissue and CSF 
drug half-life (4 to 6 months) and was selected to maintain spinal cord 
tissue levels of ISIS 396443 at a steady-state level within the estimated 
pharmacologically active range.  Maintenance doses will be given on 
Day 183 and Day 302, for a total of 6 doses over approximately 
10 months.   
Table 1 
ISIS 396443 Dose Volume To Be Injected 
Age 
Estimated 
CSF Volume 
(mL) 
Injection 
Volume (mL) 
Dose (mg) 
0-3 months 
(0-90 days) 
120 
4 
9.6 
3-6 months 
(91-182 days) 
130 
4.3 
10.3 
6-12 months 
(183-365 days) 
135 
4.5 
10.8 
12-24 months 
(366-730 days) 
140 
4.7 
11.3 
>24 months 
(>730 days) 
150 
5.0 
12.0 


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Study Location: 
Global, multicenter 
Number of Planned 
Subjects: 
Up to 21 subjects are planned (14 ISIS 396443; 7 sham procedure) 
Study Population: 
This study will be conducted in subjects who have clinical signs and 
symptoms of SMA at ≤6 months of age or at >6 months of age and who 
are not eligible for the clinical studies ISIS 396443-CS3B or 
ISIS 396443-CS4. 
Detailed criteria are described in Section 8.   
Treatment Groups: 
Subjects will receive either ISIS 396443 or sham-procedure control 
intrathecally in a 2:1 ratio.  Randomization will be balanced for the 
stratification factor (age of symptom onset >6 months versus <6 
months).  A single dose level of 12 mg ISIS 396443 will be scaled by 
age at the time of dosing for each subject.   
Duration of 
Treatment and 
Follow-up: 
For subjects who meet the eligibility criteria and enroll in the study, the 
study duration will be approximately 15 months (450 days) and will 
include a Screening Period of no greater than 28 days, a 302-day 
Treatment Period, and a final follow-up evaluation approximately 
4 months after the last dose.   
Subjects who terminate early from the study will be encouraged to 
complete the early termination study procedures and assessments at the 
time of withdrawal.   
Criteria for 
Evaluation:  
The criteria for evaluation are as follows: 
Safety: 
 Neurological examinations (assessment of mental status, level of 
consciousness, sensory motor function, cranial nerve function, 
and reflexes)  
 AEs, including SAEs 
 Vital signs (resting systolic and diastolic blood pressure, pulse 
rate, respiratory rate, temperature, pulse oximetry, and 
transcutaneous carbon dioxide) 
 Weight 
 Physical examinations 
 Medical history 
 12-Lead ECGs 


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 Use of concomitant medications 
 Clinical laboratory tests (serum chemistry, hematology, and 
urinalysis) 
Pharmacokinetics: 
 Plasma ISIS 396443 concentrations 
 CSF ISIS 396443 concentrations 
Efficacy: 
 Ventilator use  
 HINE (Section 2) 
 Growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for 
length, and head to chest circumference ratio) 
 Clinical Global Impression of Change (physician and caregiver 
assessment) 
Immunogenicity: 
 Anti-ISIS 396443 plasma antibody concentrations 
Statistical Methods: 
Analysis Population 
The intent-to-treat population is defined as all subjects who are 
randomized, receive at least 1 dose of study treatment or sham 
procedure, and have at least 1 postbaseline evaluation.  
The safety population will include all subjects who are randomized and 
receive at least 1 dose of study treatment or sham procedure.   
The PK population will include all subjects who are randomized and 
have at least 1 evaluable postdose or postsham-procedure PK sample.  
Safety Analysis 
The analysis of safety will be performed on the safety population.  The 
incidence of treatment-emergent AEs and SAEs will be tabulated.  
Changes from baseline in clinical laboratory parameters, vital signs, and 
ECG parameters will be summarized.  Incidence of clinically relevant 
changes from baseline in vital signs and ECGs will be summarized.  
Laboratory parameters will also be summarized using shift tables.   
PK Analysis 
Summary statistics for plasma and CSF concentrations of ISIS 396443 
will be provided.   
Exploratory Analysis 
For continuous endpoints, the mean change from baseline will be 
estimated with 95% confidence limits.  For categorical outcomes, the 


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proportion of subjects attaining a specified category will be estimated.  
Selected endpoints may be pooled across subsets as appropriate.   
Interim Analysis: 
No interim analyses will be conducted. 
Sample Size 
Determination: 
Since this study is exploratory, sample size determination will not be 
based on power consideration.  The sample size considered for this study 
will allow exploration of safety, tolerability, and selected efficacy 
endpoints in the selected study population. 
Study Stopping 
Rules: 
The Sponsor may terminate this study at any time, after informing 
Investigators.  Investigators will be notified by the Sponsor if the study is 
placed on hold, completed, or closed. 


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4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR STUDY 232SM202 
4.1. 
Study Schematic 
 
 
 
 
Screening: 
-28 to -1 day 
Randomization 
(2:1 ISIS 396443: 
sham 
procedure); 
stratification 
based on age at 
onset of clinical 
signs and 
symptoms 
consistent with 
SMA:  >6 months 
versus <6 months 
 
Dosing or sham 
procedure: 
Days 1, 15, 29, 64, 
183, and 302 
 
 
Final 
follow-up: 
4 months after 
the last dose or 
sham procedure 
 
Safety 
evaluations by 
telephone 
contact the day 
after dosing or 
sham procedure: 
Days 16, 30, 65, 
184, and 303 
Additional 
safety 
evaluations by 
telephone 
contact every 
other week 
throughout the 
study 
(excluding 
weeks with 
study visit) 


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4.2. 
Schedule of Events 
Note:  After the first injection of study treatment or sham procedure, subjects will be monitored by phone every other week (excluding 
weeks in which there is a study visit) throughout the study.  At telephone contact, changes in concomitant medications and AEs will 
be recorded, as well as information on the subject’s daily ventilator/bi-level positive airway pressure (Bi-PAP) use, and health status.   
Table 2: 
Schedule of Activities 
Study Period 
Screen1 
Treatment/Follow-Up 
Study Day 
Days -28 
to -1 
Day 1 
Day 
22 
Day 15 (±1 day) 
Day 
162  
Day 29 (±1 day) 
Day 
302  
Days 64, 183, 302 (±7 
days) 
Days 
65, 184, 
3032  
Final 
Follow-Up 
(Day 422 
[±7 days])3 
or Early 
Termination
4 
 
 
Predose LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs5 
X 
X 
 
4X6 
X7 
X 
 
X 
 
X 
 
4X6 
 
X 
 
4X6 
 
X 
Weight 
X 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Growth Parameters8 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Ventilator Use 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Neurological 
Examination9 
X 
X 
 
X10 
X 
X 
 
X10 
 
X 
 
X10 
 
X 
 
X10 
 
X 
ECG 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Safety Laboratory 
Tests11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X12 
 
 
 
X 
Coagulation 
Laboratory Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Period 
Screen1 
Treatment/Follow-Up 
Study Day 
Days -28 
to -1 
Day 1 
Day 
22 
Day 15 (±1 day) 
Day 
162  
Day 29 (±1 day) 
Day 
302  
Days 64, 183, 302 (±7 
days) 
Days 
65, 184, 
3032  
Final 
Follow-Up 
(Day 422 
[±7 days])3 
or Early 
Termination
4 
 
 
Predose LP Postdose 
Predose LP 
 
Postdose 
 
Predose LP Postdose 
Predose LP Postdose 
 
 
Immunogenicity 
Sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
CSF PK13 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Plasma PK 
 
 
 
X14 
 
 
 
 
 
 
 
 
 
X15 
 
 
 
X 
Study Treatment 
Injection or Sham 
Procedure 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Inpatient Stay16  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone Contact for 
Safety Monitoring2 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
HINE Motor 
Milestone 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical Global 
Impression of Change 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Con Med Recording17 
   X ----------------------------------------------------------------------------------------------------------------------- X 
Adverse Event 
Collection18 
   X ----------------------------------------------------------------------------------------------------------------------- X 
AE = adverse event; Con Med = concomitant medication; CSF = cerebrospinal fluid; ECG = electrocardiogram; LP = lumbar puncture; 
PK = pharmacokinetic(s); SAE = serious adverse event; SMA = spinal muscular atrophy; SMN2 = survival motor neuron 2 
1 A blood sample will be collected at Screening for SMN2 copy number only from those subjects without genetic documentation of SMN2 copy number.  For all 
other subjects, a blood sample will be collected at any time during the study for analysis of SMN2 copy number by the central laboratory. 
2 After the injection of study treatment or sham procedure on Day 1, subjects will remain at the study site for at least 24 hours (Day 2) for safety monitoring.  On 
the day following the injection of study treatment or sham procedure on Days 15, 29, 64, 183, and 302, there will be safety monitoring through telephone 
contact.  During that telephone contact (i.e., Days 16, 30, 65, 184 and 303), changes in concomitant medications and AEs, information on the subject’s daily 
ventilator/Bi-PAP use, and health status will be recorded.   


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3 The final follow-up visit will occur 4 months (Day 422 [±7 days]) after the last injection of study treatment or sham procedure. 
4 Subjects who terminate early will be encouraged to complete the safety evaluations scheduled for the final follow-up visit. 
5 Vital signs include resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.  
Pulse oximetry and transcutaneous carbon dioxide will be measured predose at each visit.  For subjects who are not receiving noninvasive ventilation, pulse 
oximetry will be measured overnight once a week at home.   
6 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected at 4 timepoints: 1, 2, 4, 
and 6 hours (all ±15 minutes) after the injection of study treatment or sham procedure. 
7 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, and pulse oximetry) will be collected within 20-24 hours after 
the injection of study treatment or sham procedure. 
8 At the visits scheduled for injection of study treatment or sham procedure, subjects will be assessed for the following growth parameters:  body length, head 
circumference, chest circumference, and arm circumference. 
9 Neurological examinations include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes. 
10 Neurological examinations will occur between 4 to 6 hours after the injection of study treatment or sham procedure. 
11 Serum chemistry, hematology, and urinalysis panels.   
12 Samples for safety laboratory tests will be collected before the injection of study treatment or sham procedure on Days 64 and 183 only.   
13 Refer to Table 3 for CSF PK sample schedule.  The CSF samples will be analyzed for ISIS 396443 concentrations.  The remaining CSF sample will be stored 
for optional future biomarker analyses.   
14 Blood samples for PK assessment will be collected 4 hours (±1 h) after the injection of study treatment or sham procedure only on Day 1.  Refer to Table 3 for 
the plasma PK sample schedule. 
15Blood samples for PK assessment will be collected before the injection of study treatment or sham procedure on Days 64 and 183 only.  Refer to Table 3 for the 
plasma PK sample schedule. 
16 Overnight stay (at least 24 hours) is required after the first injection of study treatment or sham procedure.  Following all subsequent injections or sham 
procedures, a stay of at least 6 hours at the study site is required; overnight stays are optional on these days. 
17 In addition to concomitant medications, ancillary procedures will be recorded. 
18 AEs and SAEs will be collected in the case report form from the time of signing of the informed consent form as described in Section 15.3.1 and 
Section 15.3.2. 
 


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Table 3 
Pharmacokinetic Sampling Schedule1 
Treatment Period 
Study Day 
Timepoints 
Blood 
Collection 
(mL) 
CSF Collection 
(mL)2 
Multiple Dose: 
LP Injection  
 
Day 1 
Predose 
NA 
0.5 
4 h (±1 h) postdose  
0.5 
NA 
Day 15 
Predose 
NA 
0.5 
Day 29 
Predose 
NA 
0.5 
Day 64 
Predose 
0.5 
0.5 
Day 183 
Predose 
0.5 
0.5 
Day 302 
Predose 
NA 
0.5 
Final Follow-Up 
NA 
0.5 
NA 
CSF = cerebrospinal fluid; h = hour; min = minutes; LP = lumbar puncture; mRNA = messenger ribonucleic acid; 
NA = not applicable (no collection scheduled); SMA = spinal muscular atrophy. 
1 Details on sampling, preparation, and shipment are included in the Study Laboratory Manual. 
2 Upon consent, the collected CSF samples from the study subjects will be stored for future investigation of possible 
biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF microRNA panel), for profiling of study drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, and 
immunogenicity assessments (including assay development and validation purposes), or for assessing other actions 
of ISIS 396443 with plasma and CSF constituents. 
 


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5. 
INTRODUCTION  
ISIS 396443 is a uniformly modified, 2′-O-(2-methoxyethyl) (2′-MOE), antisense 
oligonucleotide (ASO) drug in development for the treatment of spinal muscular atrophy (SMA) 
due to genetic defects in the survival motor neuron 1 (SMN1) gene. 
ASOs are short synthetic strings of nucleotides designed to alter the expression of a targeted 
protein by selectively binding to the ribonucleic acid (RNA) that encodes the targeted protein.  In 
patients with SMA, the number of survival motor neuron 2 (SMN2) gene copies and the resulting 
amount of survival motor neuron (SMN) protein are correlated with disease onset and severity.  
A therapeutic approach predicted to benefit patients with SMA is to increase the levels of 
full-length SMN2 pre-messenger ribonucleic acid (mRNA) by restoring the splicing pattern that 
gives rise to full-length SMN2 mRNA, thus increasing full-length SMN protein levels and SMN 
protein activity.  ISIS 396443 is designed to bind to intron 7 of the SMN2 pre-mRNA, restoring 
the splicing pattern that gives rise to full-length SMN2 mRNA and thus increases full-length 
SMN protein levels (Figure 1). 
Figure 1: 
Antisense Oligonucleotide Therapeutic Approach for Treatment of Spinal 
Muscular Atrophy 
 
ASO = antisense oligonucleotide; FL = full-length; mRNA = messenger ribonucleic acid; SMA = spinal muscular 
atrophy; SMN = survival motor neuron; SMN1 = survival motor neuron 1; SMN2 = survival motor neuron 2. 


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Overview of Spinal Muscular Atrophy 
SMA is an autosomal recessive neuromuscular disease characterized by degeneration of the 
motor neurons in the anterior horn of the spinal cord, resulting in atrophy of the voluntary 
muscles of the limbs and trunk.  With an incidence of 1:6000 to 1:10,000 live births, SMA is the 
most common genetic cause of infant mortality, and a major cause of childhood morbidity due to 
weakness, in developed countries.  The natural history of SMA includes 4 major recognized 
phenotypes that are dependent on age of onset and achieved motor abilities.  The most severe 
form, Type I SMA, has a disease onset within the first few months of life; these children are 
never able to sit or walk and usually die from respiratory failure by the age of 2 years.  Patients 
with Type II SMA are able to sit but never walk unaided, with symptoms typically presenting 
between 6 and 18 months of age.  Patients with Type III SMA are able to sit and walk but may 
become severely and increasingly disabled.  Patients with Type IV or adult-onset SMA have an 
age of onset over 18 years and have normal life expectancies. 
SMA is caused by loss of SMN protein due to a homozygous deletion or mutation or compound 
heterozygous mutation in the SMN1 gene on chromosome 5q11-q13.  Humans have a duplication 
of the chromosome region where SMN1 is found, resulting in a second copy of the gene, SMN2.  
In SMN2, a C to T nucleotide substitution in exon 7 results in an alternative splicing event such 
that the majority of transcripts produced (~90%) lack exon 7, and a defective truncated protein is 
produced.  The remainder, SMN2 transcripts containing exon 7, produces a full-length protein 
product identical to the SMN1 protein, since the C to T substitution is silent.  Humans have a 
variable copy number of the SMN2 gene (0 to 8 copies).  The number of SMN2 copies and the 
resulting amount of full-length SMN protein expressed in patients with SMA (10% to 40% of 
normal SMN protein levels) correlate with SMA disease severity; thus, SMN2 is a key modifier 
of disease phenotype [Coovert 1997], [Lefebvre 1997], [Feldkötter 2002], [Prior 2004]. 
Current Therapies for Spinal Muscular Atrophy 
There are currently no approved therapies for SMA.  Current medical care is supportive and 
focused on respiratory support, nutritional support, and management of resulting 
musculotendinous contractures and neuromuscular scoliosis through bracing, physical therapy, 
and surgery [Wang 2007]. 
5.1. 
Profile of Previous Experience With ISIS 396443 
Nonclinical Experience 
ISIS 396443 was identified after an extensive screen of greater than 500 2′-MOE 
oligonucleotides in reporter gene assays, in vitro splicing assays, and SMA patient fibroblasts 
[Hua 2007], [Hua 2008].  Data have shown that ISIS 396443 promotes a 
concentration-dependent increase in full-length transcripts (including exon 7) in patient 
fibroblast cells, achieving >90% full-length SMN2 transcripts, and forms nuclear structures 
called gems, known to contain SMN protein [Liu and Dreyfuss 1996].  In a mild mouse model of 
SMA, ISIS 396443 promoted inclusion of exon 7 in the SMN2 transgene in a variety of 
peripheral tissues when dosed systemically [Hua 2008] and in central nervous system (CNS) 
tissue, including the spinal cord, when injected into the lateral ventricle [Hua 2010].  
ISIS 396443 produced >90% exon 7 inclusion in the transgenic mice and increased SMN protein 


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production in motor neurons, resulting in the appearance of gems in motor neurons.  These 
studies were extended to a more severe mouse model of SMA (SMA Δ7) [Le 2005], where the 
CNS delivery of drug produced a dose-dependent effect on SMN2 exon 7 inclusion, SMN 
protein production, and survival.  These mice treated with ISIS 396443 demonstrated improved 
weight gain; improvements in muscle morphology, muscle strength, and motor coordination; and 
improved morphology of the motor neuron junctions [Passini 2011].  Furthermore, ISIS 396443 
was shown to distribute widely in the CNS after intrathecal administration in monkeys [Passini 
2011]. 
The pharmacokinetics (PK) and toxicity of ISIS 396443 were assessed after a single intrathecal 
lumbar bolus injection (1 to 7 mg) in adult monkeys, after 14 weeks (with a 4-week interim 
sacrifice) of repeated intrathecal lumbar bolus injections (0.3 to 3 mg/week or every other week) 
in juvenile monkeys, and after 53 weeks of repeated intrathecal lumbar bolus injections in 
juvenile monkeys.  In addition, a dedicated PK study in adult monkeys was performed to assess 
the half-life of ISIS 396443 in cerebrospinal fluid (CSF), tissues, and plasma.  
See the Investigator’s Brochure for detailed information on nonclinical studies. 
Clinical Experience 
ISIS 396443 has been evaluated in 2 completed open-label studies:  ISIS 396443-CS1 and 
ISIS 396443-CS10. 
ISIS 396443-CS1 is a single-ascending-dose, phase 1 study designed to assess the safety, 
tolerability, and PK of ISIS 396443 in subjects with SMA.  A single dose of ISIS 396443 was 
administered by intrathecal injection to subjects with SMA who were 2 to 14 years of age.  Four 
doses (1, 3, 6, and 9 mg) were evaluated sequentially.  Each dose was studied in a cohort of 6 or 
10 subjects, where all subjects received study treatment.  In this study, all subjects completed 
dosing and follow-up visits per protocol.  Overall, ISIS 396443 was well tolerated, and no safety 
concerns were identified up to the 9-mg dose.  No serious adverse events (SAEs) or 
dose-limiting toxicities were reported in ISIS 396443-CS1.  Adverse events (AEs) were mild or 
moderate in severity, and there was no relationship with ISIS 396443 dose.  In addition, no 
ISIS 396443-related adverse changes in neurological examinations were reported despite 
intensive monitoring during the immediate postdosing period.  CSF and plasma drug 
concentrations observed were generally consistent with predictions made from nonclinical 
monkey studies.   
ISIS 396443-CS10 was a single-dose, phase 1 redosing study to assess the safety, tolerability, 
and PK of ISIS 396443 in subjects with SMA who previously participated in Cohorts 2, 3, and 4 
of ISIS 396443-CS1.   
ISIS 396443 is also being evaluated in 5 ongoing studies:  ISIS 396443-CS2, ISIS 396443-CS12, 
ISIS 396443-CS3A, ISIS 396443-CS3B, and ISIS 396443-CS4.  
ISIS 396443-CS2 is an open-label, multiple-ascending-dose, phase 1/2a study designed to assess 
the safety, tolerability, and PK of ISIS 396443 in subjects with SMA.  Multiple doses of ISIS 
396443, ranging from 3 to 12 mg, are being administered by intrathecal injection to 2- to 
15-year-old subjects with SMA.   


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ISIS 396443-CS12 is an open-label, multiple-dose, phase 1 study to assess the safety and 
tolerability of a single intrathecal dose of ISIS 396443 (12 mg) in subjects with SMA who 
previously participated in either ISIS 396443-CS2 or ISIS 396443-CS10.  
ISIS 396443-CS3A is an open-label, multiple-dose, phase 2 study designed to assess the safety, 
tolerability, and PK of ISIS 396443 in subjects with infantile-onset SMA.  Multiple doses of 
ISIS 396443 are being administered by intrathecal injection to symptomatic infants with SMA 
≤7 months of age.  Two doses (6- and 12-mg dose equivalent scaled by CSF volume) are being 
evaluated sequentially.  
ISIS 396443-CS3B is a randomized, double-blind, sham-procedure controlled, phase 3 study to 
assess the clinical efficacy and safety of ISIS 396443 in subjects with infantile-onset SMA (onset 
of clinical signs and symptoms consistent with SMA at ≤6 months of age) who have 2 SMN2 
copies.  A dose level of 12 mg ISIS 396443 (scaled to equivalent dose by age) or sham procedure 
will be administered at each of 6 doses over a dosing period of 10 months. 
ISIS 396443-CS4, is a randomized, double-blind, sham-procedure controlled, phase 3 study to 
assess the clinical efficacy and safety of ISIS 396443 administered intrathecally in subjects with 
later-onset (onset of clinical signs and symptoms consistent with SMA at >6 months of age).  A 
dose of 12 mg ISIS 396443 or sham procedure will be administered at each of 4 doses over 
15 months to 2-to 12 year old subjects with SMA. 
5.2. 
Study Rationale 
There is reasonably high genotype-phenotype correlation such that the SMN2 copy number can 
be used to predict the severity of disease (moderate or severe) with approximately 80% to 85% 
accuracy [Burghes and Beattie 2009; Prior 2010; Swoboda 2005].  Evaluation of relationship 
between categories of functional status and number of SMN2 copies have indicated that as SMN2 
copy number increases so does functional status [Feldkötter 2002; Swoboda 2005].  However, 
assessment of various outcome measures over time have indicated that there is overlap among 
SMA types, and values vary widely with age and gross motor functional status with an overall 
age dependent decline [Swoboda 2005].  
The intent of this study is to assess safety, tolerability, and explore the utility of selected efficacy 
endpoints in subjects who have onset of clinical signs and symptoms that are consistent with 
SMA at age ≤6 months or >6 months.  These subjects have either 2 or 3 SMN2 copies and are not 
eligible to participate in the 2 pivotal clinical studies, ISIS 396443-CS3B and ISIS 396443-CS4.  
ISIS 396443-CS3B is a randomized, double-blind, sham-procedure controlled study 
investigating the therapeutic benefit of ISIS 396443 in subjects with 2 SMN2 copies who have 
onset of clinical signs and symptoms of SMA at ≤6 months of age.  ISIS 396443-CS4 is a 
randomized, double-blind, sham-procedure controlled study investigating the therapeutic benefit 
of ISIS 396443 in subjects who have onset of clinical and signs and symptoms of SMA at 
>6 months of age.  To be consistent with the study design of the 2 pivotal clinical studies and to 
understand the safety and tolerability of ISIS 396443 compared with natural history, the present 
study is designed to include sham-procedure control for an unbiased assessment of safety, 
tolerability, and selected efficacy endpoints in the study population that is not eligible to 
participate in the studies ISIS 396443 CS3B or ISIS 396443 CS4.  The design of the present 


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study will also allow exploration of the safety and tolerability of a higher dose regimen in 
subjects who have onset of clinical signs and symptoms at >6 months of age, but who are not 
eligible for Study ISIS 396443-CS4.   
5.3. 
Rationale for Dose and Schedule Selection 
The ISIS 396443 dose and dose interval for this study were selected based on nonclinical 
toxicology and PK observations from monkey studies using single-dose and repeat-dosing 
intrathecal administration, consideration of the target tissue concentration anticipated for drug 
pharmacology, and safety data in the completed and ongoing clinical studies of ISIS 396443.  
Based on pharmacology and PK results in SMA transgenic mice, it is estimated that a target 
spinal cord tissue concentration between 1 and 10 μg/g will produce 50% to 90% 
SMN2 exon 7 inclusion.  Nonclinical studies in juvenile monkeys receiving intrathecal doses of 
ISIS 396443 showed a resulting gradient of distribution of ISIS 396443 along the spinal cord, 
with mean lumbar spinal cord concentrations ranging from 1.6- to 2.3-fold and 2.0- to 3.5-fold 
higher than thoracic and cervical spinal cord levels, respectively.  The dose selected for this 
multiple-dose clinical study (equivalent to 12 mg of ISIS 396443) is predicted to achieve levels 
at the high end of this range (approximately 10 μg/g lumbar and 3 μg/g cervical spinal cord 
tissue concentrations) after the first dose.  The loading dose interval (i.e., doses on Days 1, 15, 
29, and 64) was selected based on the nonclinical PK and pharmacology data in order to achieve 
and maintain ISIS 396443 spinal cord tissue levels that are predicted to be above or within the 
upper end of the pharmacologically active range by Day 64 (approximately 30 μg/g lumbar and 
10 μg/g cervical tissue concentration), while at the same time considering subject safety and 
convenience for repeated intrathecal injections by lumbar puncture (LP).  The higher number of 
loading doses would allow for the evaluation of safety and tolerability and preliminary 
exploratory efficacy endpoints in a broader population of subjects with SMA, including those 
who have onset of clinical signs and symptoms at >6 months of age but who are not eligible for 
Study ISIS 396443-CS4.  The maintenance dose interval (once every 4 months ) was selected 
based on the estimated spinal tissue and CSF drug half-life (4 to 6 months) and was selected to 
maintain spinal cord tissue levels of ISIS 396443 at a steady-state level within the estimated 
pharmacologically active range.  Maintenance doses will be given on Day 183 and Day 302, for 
a total of 6 doses over approximately 10 months. 
ISIS 396443 will be administered as an intrathecal injection.  The volume of the injection, and 
thus the dose, will be adjusted based on the subject’s age on the day of dosing as shown in 
Table 4 , such that each subject will receive a 12-mg scaled equivalent dose based on CSF 
volume scaling.  Thus, younger subjects will be given a lower dose of drug, achieved by 
injecting a smaller volume that is proportional to the estimated CSF volume for age, such that the 
dose volume will be equivalent to 5 mL for a 2-year-old child to adult.  Dosing instructions and 
details regarding administration will be provided in the Directions for Handling and 
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Table 4 
ISIS 396443 Dose Volume To Be Injected 
Age 
Estimated CSF 
Volume 
(mL) 
Injection Volume 
(mL) 
Dose 
(mg) 
0-3 months 
(0-90 days) 
120 
4 
9.6 
3-6 months 
(91-182 days) 
130 
4.3 
10.3 
6-12 months 
(183-365 days) 
135 
4.5 
10.8 
12-24 months 
(366-730 days) 
140 
4.7 
11.3 
>24 months 
(>730 days) 
150 
5.0 
12.0 
 Source:  [Matsuzawa 2001] 
CSF = cerebrospinal fluid. 
6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives  
6.1.1. 
Primary Objective 
The primary objective of the study is: 
 To assess the safety and tolerability of ISIS 396443 in subjects with SMA who are not 
eligible to participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4 
6.1.2. 
Secondary Objectives 
The secondary objective of this study is: 
 To examine the PK of ISIS 396443 in subjects with SMA who are not eligible to 
participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4 
6.1.3. 
Exploratory Objectives 
The exploratory objective of this study is: 
 To explore the efficacy of ISIS 396443 in subjects with SMA who are not eligible to 
participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary safety and tolerability endpoints of this study are as follows: 


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 Incidence of AEs and SAEs 
 Change from baseline in clinical laboratory parameters, electrocardiograms (ECGs), 
and vital signs  
 Change from baseline in neurological examination outcomes 
6.2.2. 
Secondary Endpoints 
The secondary endpoint of this study is as follows: 
 ISIS 396443 concentrations in plasma and CSF 
6.2.3. 
Exploratory Endpoints 
The exploratory efficacy endpoints of this study are as follows: 
 Change from baseline in ventilator use  
 Attainment of motor milestones assessed by Section 2 of the Hammersmith Infant 
Neurological Examination (HINE)  
 Change from baseline in growth parameters (body length, head circumference, chest 
circumference, arm circumference, weight for age, weight for length, and head to 
chest circumference ratio) through final safety follow-up visit  
 Clinical Global Impression of Change (physician and caregiver assessment) through 
final safety follow-up visit 
The exploratory immunogenicity endpoint is as follows: 
 Plasma antibodies to ISIS 396443 
7. 
STUDY DESIGN 
7.1. 
Study Overview 
This phase 2, multicenter, randomized, double-blind, sham-procedure controlled study will 
assess the safety and tolerability and explore the efficacy of intrathecally administered ISIS 
396443 over 14 months (from the first dose until the last safety follow-up visit).  Up to 
21 subjects will be randomized in a ratio of 2:1 to receive ISIS 396443 by intrathecal (LP 
injection (n=14) or to a sham-procedure control (n=7).  Randomization will be stratified based on 
age at onset of clinical signs and symptoms consistent with SMA:  >6 months versus ≤6 months.   
If a subject terminates early from the study, they will be encouraged to complete safety 
assessments as per the final follow-up visit.   
See Section 4.1 (Table 2) for a schematic of the study design. 


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7.2. 
Overall Study Duration and Follow-Up 
The study period will consist of a Screening Period, Treatment Period, and post-treatment 
follow-up evaluation.   
7.2.1. 
Screening 
Subject eligibility for the study will be determined within 4 weeks (Day -28 to Day -1) prior to 
the administration of the first dose or sham procedure and will be confirmed before 
randomization.  If a subject initially fails any of the screening criteria, they will be allowed to be 
rescreened 1 time during the Screening Period, at the discretion of the Investigator.   
7.2.2. 
Treatment 
Eligible subjects will be admitted to the study site on Study Day 1, undergo predose evaluations, 
and then receive an LP injection of ISIS 396443 or a sham procedure.  After the injection on 
Day 1, subjects will remain at the study site for at least 24 hours after the procedure for safety 
monitoring.   
Subjects will return to the study site on Days 15, 29, 64, 183, and 302 for follow-up evaluations 
and subsequent injections of study treatment or sham procedure, for a total of 6 injections or 
sham procedures over a dosing period of 10 months.  During these 5 visits, subjects will remain 
at the study site for at least 6 hours after the procedure for safety monitoring.  An overnight stay 
is optional, at the discretion of the Investigator.  Safety monitoring by telephone contact will 
occur on the day after injection of study treatment or sham procedure.  In addition, the study site 
will monitor the subject’s condition through telephone contact every other week (excluding 
weeks with study visit), throughout the study period.   
A CSF sample for PK analysis and for optional future analyses of biomarkers will be taken 
before the injection of study treatment or sham procedure on Days 1, 15, 29, 64, 183, and 302 in 
a manner that protects the blind.   
7.2.3. 
Follow-Up 
Subjects will return to the study site for a final follow-up evaluation approximately 4 months 
(Final Study Visit on Day 422 [±7 days]) after the last dose of study treatment.   
Following treatment and the final follow-up evaluation, all eligible subjects may elect to enroll in 
an open-label treatment extension study, pending study approval by the ethics committees and 
the appropriate regulatory authorities.  This will be done without unblinding the subject's 
treatment group.   
Subjects who prematurely withdraw from the study are to complete the early termination study 
procedures and assessments at the time of withdrawal.   
7.3. 
Study Stopping Rules 
The sponsor may terminate the study at any time by informing Investigators (who will 
subsequently inform the corresponding ethics committees), and any other applicable regulatory 


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agencies.  Investigators will be notified by the Sponsor if the study is placed on hold, completed, 
or closed.   
Conditions that may warrant termination of the study include, but are not limited to, the 
following: 
 The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study. 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product.   
7.4. 
End of Study 
The end of study is last subject, last visit.   
7.5. 
Safety Monitoring and Data and Safety Monitoring Board 
Safety data will be reviewed on an ongoing basis by the Sponsor and the Medical Monitor.  
Safety data will also be reviewed on an ongoing basis by an independent Data and Safety 
Monitoring Board ([DSMB]; see Section 19.2).   
8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening or at the time point specified in the individual eligibility criterion listed: 
1. Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study 
and provide signed and dated informed consent and authorization to use confidential 
health information in accordance with national and local subject privacy regulations.   
2. Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound 
heterozygote. 
3. Onset of clinical signs and symptoms consistent with SMA at <6 months of age and have 
documentation of 3 SMN2 copies.  
OR 
Onset of clinical signs and symptoms consistent with SMA at <6 months of age, >7 
months of age (211 days) at screening, and have documentation of 2 SMN2 copies. 
OR 
Onset of clinical signs and symptoms consistent with SMA at >6 months of age, are ≤18 
months of age at screening, and have documentation of 2 or 3 SMN2 copies. 


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4. Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is 
planned for study procedures (as assessed by the Investigator and either the 
anesthesiologist or pulmonologist). 
5. Medical care, such as routine immunizations (including influenza vaccine, pneumococcus 
vaccine, and respiratory syncytial virus prophylaxis [palivizumab] if available), meets 
and is expected to continue to meet guidelines set out in the Consensus Statement for 
Standard of Care in SMA, in the opinion of the Investigator. 
6. Subjects with 2 SMN2 copies must reside within approximately 9 hours’ ground-travel 
distance from a participating study site for the duration of the study.  Residents who are 
>2 hours’ ground-travel distance from a study site must obtain clearance from the 
Investigator and the study Medical Monitor.  
7. Able to complete all study procedures, measurements, and visits, and parent or legal 
guardian/subject has adequately supportive psychosocial circumstances, in the opinion of 
the Investigator. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening or at the time point specified in the individual criterion listed: 
1. Any previous exposure to ISIS 396443; previous dosing in this study or previous studies 
with ISIS 396443. 
2. Signs or symptoms of SMA present at birth or within the first week after birth. 
3. Ventilation for ≥16 hours per day continuously for >21 days at screening. 
4. Permanent tracheostomy, implanted shunt for CSF drainage, or implanted CNS catheter 
at screening.  
5. History of brain or spinal cord disease that would interfere with the LP procedure, CSF 
circulation, or safety assessments. 
6. Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional 
support within 2 months prior to screening, or hospitalization for surgery planned during 
the study. 
7. Clinically significant abnormalities in hematology or clinical chemistry parameters or 
ECG, as assessed by the Investigator, at the Screening Visit that would render the subject 
unsuitable for inclusion. 
8. Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole, 
carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device 
within 30 days prior to screening.  Any history of gene therapy, prior ASO treatment, or 
cell transplantation. 
9. Ongoing medical condition that according to the Investigator would interfere with the 
conduct and assessments of the study.  Examples are medical disability (e.g., wasting or 


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cachexia, severe anemia) that would interfere with the assessment of safety or would 
compromise the ability of the subject to undergo study procedures. 
10. The subject’s parent or legal guardian is unable to understand the nature, scope, and 
possible consequences of the study, or does not agree to comply with the protocol’s 
schedule of assessments. 
11. Subject’s parent or legal guardian is not willing to continue to meet standard of care 
guidelines for care (including vaccinations and respiratory syncytial virus prophylaxis if 
available), nor provide nutritional and respiratory support throughout the study. 
12. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the 
subject unsuitable for enrollment. 
9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION  
9.1. 
Screening and Enrollment 
The subject’s legally authorized representative (e.g., parent or legal guardian) must provide 
informed consent before any study-specific screening tests are performed (see Section 17.3).  
When a subject’s parent/guardian signs the informed consent form (ICF), that subject is assigned 
a unique subject identification number through the interactive response technology (IRT) system 
and is considered to be enrolled in the study.  Participating study sites are required to document 
all screened candidates initially considered for inclusion in this study.  If a subject is excluded 
from the study, the reasons for exclusion will be documented in the subject’s source documents, 
within the IRT system, and on the screening log.  If a subject initially fails any of the screening 
criteria, they will be allowed to be rescreened 1 time during the Screening Period, at the 
discretion of the Investigator.   
9.2. 
Registration and Randomization of Subjects 
Subjects will be registered and randomized after all screening assessments have been completed 
and after the Investigator has verified that the subjects are eligible per criteria in Sections 8.1 
and 8.2.  No subject may begin treatment until the subject is documented as registered (assigned 
a unique identification number) and is randomized for the study in the IRT system.  Any subject 
identification numbers that are assigned will not be reused even if the subject does not receive 
treatment.   
Using an IRT system, eligible subjects will be randomized to receive ISIS 396443: sham 
procedure in a 2:1 ratio.  Randomization will be stratified based on age at onset of clinical signs 
and symptoms consistent with SMA:  >6 months versus <6 months.  Subjects who withdraw 
from the study may be replaced.   
Refer to the Study Reference Guide for details on registration and randomization.   


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9.3. 
Blinding Procedures  
This is a randomized, double-blind, sham-procedure controlled study.  The sponsor, parents 
and/or legal guardians, and key study site personnel will be blinded throughout the study.  To 
maintain the study blind, it is imperative that subject treatment assignments are not shared with 
the subjects, their families, or any member of the study team, either at the study site or that of the 
Sponsor, except the unblinded site study staff (dedicated team) and the unblinded medical 
monitor or clinical research associate.  The DSMB may be unblinded as described in the DSMB 
charter.  
9.3.1. 
Unblinding of Treatment Assignment 
If a subject has experienced an SAE (as defined in Section 15.1.2), and/or when knowledge of 
the treatment assignment will impact the clinical management of the subject, the Investigator will 
have the ability to unblind the treatment assignment for that subject using the IRT.  However, 
prior to unblinding, the Investigator should attempt to contact the blinded Medical Monitor to 
discuss the emergency.  The Sponsor or designee will be informed of the unblinding of a subject 
within 24 hours.  Every reasonable attempt should be made to complete the final follow-up visit 
(approximately 4 months after the last dose of study treatment) early termination procedures and 
assessments prior to unblinding, as knowledge of the treatment arm could influence subject 
assessment.  The Investigator must document the reasons for unblinding in the subject’s source 
documents.  The Investigator is strongly advised not to divulge the subject’s treatment 
assignment to any individual not directly involved in managing the medical emergency, nor to 
personnel involved with the analysis and conduct of the study.  In cases where there are ethical 
reasons to have a subject whose treatment assignment was unblinded for safety reasons remain in 
the study, the Investigator must obtain specific approval from the Sponsor and the Medical 
Monitor for the subject to continue in the study.  
In addition, all suspected unexpected serious adverse reactions (SUSARs) will be unblinded by 
the Sponsor’s (or designee) Drug Safety and Quality Assurance personnel for the purpose of 
regulatory reporting (Section 15.3.4). 
10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A subject must permanently discontinue study treatment for any of the following reasons: 
 The subject’s parent or legal guardian withdraws consent.   
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment. 
 At the discretion of the Investigator for medical reasons. 
 At the discretion of the Investigator or Sponsor for noncompliance. 


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The reason for discontinuation of study treatment must be recorded in the subject’s case report 
form (CRF). 
Subjects who discontinue treatment will continue follow-up (i.e., predose evaluations at regular 
study visits [Days 15, 29, 64, 183, and 302] but with no postdose safety monitoring telephone 
contacts [Days 16, 30, 65, 184, and 303]) unless consent is withdrawn.  If a subject is unable to 
come for study visits, the minimum requirement for follow-up will be telephone calls on a 
monthly basis.  At these visits or telephone contact, changes in concomitant medications and 
AEs, information on the subject’s daily ventilator use/ bi-level positive airway pressure 
(Bi-PAP), and health status will be recorded.  The methods used to continue follow-up (i.e., site 
visits or telephone calls to the subject’s parent or guardian or caregiver) should be documented in 
the source document.   
10.2. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any one of the following reasons: 
 The subject’s parent or legal guardian withdraws consent.   
 The subject’s parent or legal guardian is unwilling or unable to comply with the 
protocol. 
Subjects who prematurely withdraw from the study are to complete the early termination study 
procedures and observations at the time of withdrawal (see Section 4.2 [Table 2 ]).  The reason 
for the subject’s withdrawal from the study must be recorded in the subject’s CRF. 
11. 
STUDY TREATMENT USE 
11.1. 
Regimen 
Refer to and follow the DHA for complete details. 
11.1.1. 
Study Treatment 
Each subject will receive a single intrathecal bolus (1 to 3 minutes) LP injection of ISIS 396443 
or sham procedure on Days 1, 15, 29, 64, 183, and 302 by dedicated study personnel who are 
unblinded to treatment group; this cannot be any of the key study site personnel (i.e., the 
Investigator, the study coordinator, or outcome assessors).  The study treatment administration 
will be performed in a dedicated room, and key study personnel and the parents will not be 
present during the procedure to ensure blinding.   
ISIS 396443 will be administered using a “spinal anesthesia” needle and a 5-mL syringe.  A 22G 
to 25G spinal anesthesia needle is recommended based on subject size or clinical condition.  The 
target site for needle insertion is the L3/L4 space but may be 1 segment above or 1 to 2 segments 
below this level, if needed.  Depending on institutional guidelines, anesthesia may be used for 
the LP procedure or for the sham procedure, following institutional procedures.  Subjects will be 
encouraged to lie down flat for 1 hour following injection of the study treatment, if possible.  
Prior to each injection, 5 mL of CSF fluid will be collected for analyses.  CSF will be used for 


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ISIS 396443 PK analyses.  Upon consent, extra CSF will be stored for optional future 
investigation of possible biomarkers of SMA disease (e.g., CSF mRNA, CSF protein, CSF 
microRNA panel) or for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, immunogenicity assessments (including 
assay development and validation purposes), or other actions of ISIS 396443 with CSF 
constituents.  CSF analyses and data presentation will be conducted in a blinded manner.   
The volume of the injection, and thus, the dose, will be adjusted for the subject’s age on the day 
of dosing, such that each subject will receive a 12-mg scaled equivalent dose based on CSF 
volume scaling (Table 4).  Thus, younger subjects will be given a lower dose of study treatment, 
achieved by injecting a smaller volume that is proportional to estimated CSF volume for age, 
such that dose volume will be equivalent to 5 mL for a 2-year-old child to adult.   
11.1.2. 
Sham Procedure 
Subjects randomized to the sham-procedure control group will undergo a sham procedure, rather 
than study treatment administration, on Study Days 1, 15, 29, 64, 183, and 302.  Details 
regarding the sham procedure will be provided in the DHA.  The sham procedure will be 
administered by dedicated study personnel who are unblinded to treatment group; this cannot be 
any of the key study site personnel (i.e., the Investigator, study coordinator, or outcomes 
assessors).  The sham procedure will be performed in a dedicated room, and key study personnel 
and the parent or legal guardian will not be present during the procedure to ensure blinding.  
In general, the sham procedure will consist of a small needle prick on the lower back at the 
location where the LP injection is normally made.  The needle will break the skin, but no LP 
injection or needle insertion will occur.  The needle prick will be covered with the same bandage 
that is used to cover the LP injection normally, thus simulating the appearance of an LP 
injection.  If institutional guidelines require the use of anesthesia or sedation for an LP procedure 
in ISIS 396443-treated subjects, then in order to maintain the blind, minimal sedation (i.e., a low 
dose of an anxiolytic) should be used for the sham procedure, following institutional procedures.  
The study subject will be kept in the procedure room for the same amount of time that subjects 
administered study treatment are kept, thus simulating the time period of the study treatment 
administration procedure. 
Study treatment and sham kits will be packaged in a blinded fashion.  Blinded kits for the sham 
procedure contain artificial CSF (5.0 mL solution per 6 mL vial) that will not be injected but will 
be used to simulate CSF samples for that subject.  
11.2. 
Modification of Dose and/or Treatment Schedule 
No adjustment of dose is permitted.  In the event of a concurrent illness that would prevent the 
dosing procedure from being performed safely, an adjustment in the dose schedule may be 
permitted but must be approved by the Medical Monitor. 
11.3. 
Precautions 
There are no protocol-required treatment precautions. 


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11.4. 
Compliance 
Compliance with treatment dosing is to be monitored and recorded by site staff. 
11.5. 
Concomitant Therapy and Procedures 
11.5.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between Screening and Final Study 
Visit/Telephone Call. 
Allowed Concomitant Therapy 
Throughout the study, Investigators or designated licensed physicians involved in the study may 
prescribe concomitant medications or treatments deemed necessary for AEs or to provide 
adequate supportive care. 
Disallowed Concomitant Therapy 
Subjects are prohibited from receiving other experimental agents, including gene therapy, during 
the study. This includes marketed agents at experimental doses that are being tested for the 
treatment of SMA (albuterol/ salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, 
hydroxyurea, etc.). 
11.5.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and Final Study Visit/Telephone Call. 
12. 
STUDY TREATMENT MANAGEMENT 
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol). 
Study treatment must be dispensed only by a pharmacist or medically qualified staff.  Study 
treatment is to be dispensed only for subjects enrolled in this study.  Once study treatment is 
prepared for a subject, it can be administered only to that subject.  Study treatment vials are for 
one-time use only; any study treatment remaining in the vial should not be used for another 
subject.   
12.1. 
Study Treatment 
ISIS 396443 is formulated as an isotonic solution at 2.4 mg/mL and is provided as a 5.0-mL fill 
volume in a 6-mL clear glass vial.  ISIS 396443 drug product contains the heptadecasodium salt 
of an 18-base residue phosphorothioate oligonucleotide. 
ISIS 396443 active drug is manufactured by Isis Pharmaceuticals, Inc., Carlsbad, CA, USA. 


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The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements.  At a minimum, the label will include a study reference code, drug identifier, and 
quantity of dosage units, lot number, and other pertinent information in accordance with local 
laws.  The expiry or use-by date is stored in the IRT system, and printable assignment reports are 
available to site personnel.  Study treatment should not be used after the expiration date.   
The study drug (ISIS 396443) and sham kits will be packaged in a blinded fashion.  Blinded kits 
for sham procedure contain artificial CSF provided as 5.0 mL solution per 6 mL vial that will not 
be injected but will be used to simulate CSF samples for a subject.   
12.1.1. 
Study Treatment Preparation 
The individual preparing ISIS 396443 or artificial CSF should carefully review the instructions 
provided in the DHA.   
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or drug, do not use it.  The vials in question should be saved at the study site and the 
problem immediately reported to the Sponsor (or designee). 
12.1.2. 
Study Treatment Storage 
Study treatment must be stored in a secure location. 
ISIS 396443 is to be protected from light and stored long term at 2°C to 8°C in a locked 
refrigerator with limited access.  For additional information on storage requirements, follow the 
instructions provided in the DHA. 
12.1.3. 
Study Treatment Handling and Disposal 
The Investigator must return all used and unused vials of ISIS 396443 and artificial CSF as 
instructed by the Sponsor (or designee). 
If any used ISIS 396443 or artificial CSF supplies are to be destroyed at the study site, the 
institution or appropriate site personnel must obtain prior approval from the Sponsor (or 
designee), by providing, in writing, the destruction policy or details of the method of 
destruction.  After such destruction, the Sponsor (or designee) must be notified, in writing, of the 
details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the date of 
destruction, and proof of destruction. 
12.1.4. 
Study Treatment Accountability 
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), and accounts of any study treatment accidentally or 
deliberately destroyed.   
Unless otherwise notified, all vials, both used and unused, must be saved for study treatment 
accountability.  At the end of the study, reconciliation must be made between the amount of 
ISIS 396443 or artificial CSF supplied, dispensed, and subsequently destroyed or returned to the 
Sponsor (or designee).  A written explanation must be provided for any discrepancies. 


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13. 
EFFICACY, PHARMACOKINETIC, AND 
IMMUNOGENICITYASSESSMENTS 
See Section 4.2 (Table 2) for the timing of all assessments. 
13.1. 
Clinical Efficacy Assessments 
The following clinical assessments will be performed to evaluate the efficacy of ISIS 396443: 
 Ventilator use  
 HINE (Section 2) 
 Growth parameters (body length, head circumference, chest circumference, arm 
circumference, weight for age, weight for length, and head to chest circumference 
ratio) 
 Clinical Global Impression of Change (physician and caregiver assessment) 
13.2. 
Pharmacokinetic (ISIS 396443 Concentration) Assessments 
The following tests will be performed to assess the PK of ISIS 396443: 
 Plasma ISIS 396443 concentrations 
 CSF ISIS 396443 concentrations 
13.3. 
Immunogenicity Assessments 
The following test will be performed to assess the immunogenicity of ISIS 396443: 
 Anti-ISIS 396443 plasma antibody concentrations 


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14. 
SAFETY ASSESSMENTS 
See Section 4.2 (Table 2) for the timing of all safety assessments. 
14.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to evaluate the safety profile of 
ISIS 396443: 
 Neurological examinations (assessment of mental status, level of consciousness, 
sensory motor function, cranial nerve function, and reflexes) 
 AEs, including SAEs 
 Vital signs (resting systolic and diastolic blood pressure, pulse rate, respiratory rate, 
temperature, pulse oximetry, and transcutaneous carbon dioxide) 
 Weight 
 Physical examinations 
 Medical history 
 12-Lead ECGs 
 Use of concomitant medications 
14.2. 
Laboratory Safety Assessments 
The following laboratory tests will be performed to evaluate the safety profile of ISIS 396443: 
 Blood chemistry:  total protein, albumin, creatinine, cystatin C, creatine 
phosphokinase, blood urea nitrogen, total bilirubin (direct and indirect), alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, glucose, calcium, 
phosphorus, chloride, sodium, potassium 
 Hematology:  red blood cells, hemoglobin, hematocrit, platelets, white blood cells, 
white blood cell differential 
 Urinalysis:  specific gravity, pH, protein, glucose, ketones, bilirubin, red blood cells, 
white blood cells, epithelial cells, bacteria, casts, crystals 


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15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each subject’s legally authorized representative and/or main 
caregiver(s) must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies. 
15.1. 
Definitions 
15.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including a 
clinically significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator.  Abnormal laboratory findings that are considered by the Investigator 
as not clinically significant should not be reported as AEs.  Although abnormal laboratory values 
are typically not considered AEs, the following considerations may result in an abnormal 
laboratory value being considered an AE: 
 A laboratory test result that meets the criteria for an SAE 
 A laboratory test result that requires the subject to receive specific corrective therapy 
 A laboratory abnormality that the Investigator considers to be clinically significant 
15.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death 
 Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization is defined as an admission of >24 hours to a medical facility and does 
not qualify as an AE   
 Results in persistent or significant disability/incapacity 


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 Results in a congenital anomaly/birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the study site must document all of the following: 
 The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining consent from 
the subject’s parent or legal guardian to participate in the study. 
 The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s parent‘s or legal guardian‘s consent to participate 
in the study and the time of the procedure or treatment. 
 The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission. 
o If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless 
one of the requirements in Section 15.1.2 is met. 
15.2. 
Safety Classifications 
15.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.2 
 The relationship of the event to study treatment as defined in Section 15.2.2 
 The severity of the event as defined in Section 15.2.3 
15.2.2. 
Relationship of Events to Study Treatment  
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment: 






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15.3.3.1. Deaths 
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate CRF.  All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event.  The Investigator should make every effort to obtain and send 
death certificates and autopsy reports to 
 Safety.  The term death should be 
reported as an SAE only if the cause of death is not known and cannot be determined. 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions 
SUSARs are SAEs that are unexpected and judged by the Investigator or Sponsor (or designee) 
to be related to the study treatment administered. 
The Sponsor (or designee) will report SUSARs to the appropriate regulatory authorities and to 
Investigators as required, according to local law. 
15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Overdose 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol; an overdose must be documented as a protocol deviation.  A 
brief description should be provided in the deviation form, including whether the subject was 
symptomatic (with a list of symptoms) or asymptomatic.  Overdoses are not considered AEs and 
should not be recorded as an AE on the CRF; however, all overdoses must be reported to the 
Medical Monitor within 24 hours of the site becoming aware of the overdose.  An overdose must 
be reported to the Medical Monitor even if the overdose does not result in an AE.  If an overdose 
results in an AE, then the AE must be recorded.  If an overdose results in an SAE, then the SAE 
form must be completed and faxed to 
 Safety.  All study treatment-related dosing 
information must be recorded on the dosing CRF. 
15.4.2. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator or designee should 
contact 
 at 
 (or 
 medical emergency: 
 or 
) or 
 at 
.   
15.4.2.1. Unblinding for Medical Emergency 
In a medical emergency when knowledge of the subject’s treatment assignment may influence 
the subject’s clinical care, the Investigator (or designee) should attempt to contact the blinded 
Biogen Idec Medical Director or blinded 
 Medical Monitor to discuss the emergency 
within 24 hours.  In these instances, the Investigator (or designee) may access the subject's 
treatment assignment by IRT.   
The Investigator must document the reasons for unblinding in the subject’s source documents.  
The Investigator is strongly advised not to divulge the subject’s treatment assignment to any 


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individual not directly involved in managing the medical emergency or to personnel involved 
with the analysis and conduct of the study.   
15.5. 
Safety Responsibilities 
15.5.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
 Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment. 
 Determine the seriousness, relationship, and severity of each event. 
 Determine the onset and resolution dates of each event. 
 Complete an SAE form for each serious event and fax it to 
 Safety 
within 24 hours of the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to 
 Safety within 24 hours of the study site staff 
becoming aware of new information. 
 Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records. 
 Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. 
 Report SAEs to local ethics committees, as required by local law. 
15.5.2. 
The Sponsor 
The Sponsor’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor (or designee) 
is responsible for reviewing with study site staff the definitions of AE and SAE, as 
well as the instructions for monitoring, recording, and reporting AEs and SAEs. 
 The Sponsor (or designee) is to notify all appropriate regulatory authorities, central 
ethics committees, and Investigators of SAEs, as required by local law, within 
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16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
In general, continuous variables will be summarized by descriptive statistics, including number, 
mean, median, standard deviation, minimum, and maximum.  Categorical variables will be 
presented with the number and percentage in each category. 
Baseline is defined as the average of 2 assessments taken during the screening/baseline period.  
The baseline for other assessments is defined as the last nonmissing assessment prior to the first 
dose of study treatment. 
Concomitant medication usage for each subject will be listed for review. 
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
16.1. 
Demographic and Baseline Characteristics  
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Subject disposition will be summarized by treatment group.  All subjects 
enrolled will be included in a summary of subject disposition.  
16.2. 
Safety and Tolerability 
Safety is the primary objective for the study.  All AEs, laboratory abnormalities, ECGs, and vital 
signs will be evaluated for safety.   
16.2.1. 
Analysis Population 
Safety analyses will be conducted in the safety population.  This safety set will include all 
subjects who are randomized and receive at least 1 dose of study treatment or sham procedure.  
Treatment duration and amount of study treatment received will be summarized by treatment 
group.   
16.2.2. 
Methods of Analysis 
16.2.2.1. Neurological Examinations 
Neurological examination findings will be listed for review, and as appropriate, results will be 
summarized descriptively for each treatment group.  The number and percentage of subjects with 
shifts from baseline normal to each of the categorical values denoting normal, abnormal, and 
abnormal (not AE) will be summarized.   
16.2.2.2. Adverse Events 
All AEs will be analyzed based on the principle of treatment emergence.  An AE will be 
regarded as treatment emergent if it was present prior to the first dose of study treatment and 
subsequently worsened, or was not present prior to the first dose of study treatment but 
subsequently appeared.  The incidence of treatment-emergent AEs will be summarized overall, 


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by severity, and by relationship to study treatment.  A subject having the same AE more than 
once will be counted only once in the incidence for that event.  The occurrence of the AE with 
the greatest severity will be used in the calculation of incidence by severity; the occurrence of the 
AE with the strongest relationship to study treatment will be used in the calculation of incidence 
by relationship to study treatment. 
All treatment-emergent AEs and SAEs will be summarized for each treatment group using the 
Medical Dictionary for Regulatory Activities (MedDRA) coding system, by system organ class, 
preferred term, relationship to study treatment, and severity.  Narratives of deaths, SAEs, early 
withdrawals from study treatment and from study due to AEs will be provided.  
16.2.2.3. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  The number and 
percentage of subjects with clinically relevant postbaseline abnormalities will be presented.  
Summary statistics for actual values and change from Baseline will also be presented. 
16.2.2.4. ECGs 
ECG results will be presented by subject, and as appropriate, results will be summarized 
descriptively for each treatment group.  The number and percentage of subjects with shifts from 
baseline normal to each of the categorical values denoting normal, abnormal clinically 
significant, and abnormal (not clinically significant) will be summarized. 
16.2.2.5. Clinical Laboratory Results 
Clinical laboratory evaluations including hematology, blood chemistry, and urinalysis will be 
summarized using study visit for each treatment group.  These safety variables will also be 
presented over time after study treatment administration, as appropriate. 
16.3. 
Efficacy 
16.3.1. 
Analysis Population 
The exploratory analysis of efficacy will be performed on the intent-to-treat population.  The 
intent-to-treat population is defined as all subjects who are randomized, receive at least 1 dose of 
study treatment or sham procedure, and have at least 1 postbaseline evaluation.  
16.3.2. 
Methods of Analysis 
For continuous endpoints, the mean change from baseline will be estimated with 95% confidence 
limits.  For categorical outcomes, the proportion of subjects attaining a specified category will be 
estimated.  Selected endpoints may be pooled across subsets as appropriate.  


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16.4. 
Pharmacokinetics 
16.4.1. 
Analysis Population 
The PK population will include all subjects who are randomized and have at least 1 evaluable 
postdose or postsham-procedure PK sample.   
16.4.2. 
Methods of Analysis 
Plasma PK parameters, as applicable, and ISIS 396443 concentrations in plasma and CSF for the 
PK population will be summarized using descriptive statistics and, where warranted, presented 
graphically.   
16.5. 
Immunogenicity 
16.5.1. 
Analysis Population  
The analysis population for immunogenicity will include all subjects with available 
immunogenicity data. 
16.5.2. 
Methods of Analysis 
Results from the immunogenicity analyses for anti-ISIS 396443 plasma antibody status and titer 
will be summarized at the specified visits.   
16.6. 
Interim Analyses 
No formal interim analyses will be conducted. 
16.7. 
Sample Size Considerations 
Since this study is exploratory, sample size determination will not be based on power 
consideration.  The sample size considered for this study will allow exploration of safety, 
tolerability, and selected efficacy endpoints in the selected study population.   


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17. 
ETHICAL REQUIREMENTS 
The Sponsor and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and applicable International Conference on Harmonisation (ICH) and Good 
Clinical Practice (GCP) guidelines and conduct the study according to local regulations. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. 
17.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
17.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  The Sponsor (or designee) will submit documents 
on behalf of the investigational sites in countries other than the United States.  
If the Investigator makes any changes to the ICF, the Sponsor (or designee) must approve the 
changes before the ICF is submitted to the ethics committee.  A copy of the approved ICF must 
be provided to the Sponsor (or designee).  After approval, the ICF must not be altered without 
the agreement of the relevant ethics committee and the Sponsor (or designee). 
It is the responsibility of the Investigator(s) to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
The Sponsor (or designee) must receive a letter documenting ethics committee approval, which 
specifically identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  
Protocol amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. 
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and the Sponsor (or designee). 
17.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the 
subject’s legally authorized representative (e.g., parent or legal guardian) in accordance with 
local practice and regulations.   
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject’s legally 


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authorized representative.  The subject’s legally authorized representative must be given 
sufficient time to consider whether the subject will participate in the study.   
A copy of the signed and dated ICF must be given to the subject’s legally authorized 
representative.  The signed and dated ICF will be retained with the study records.  Local 
regulations must be complied with in respect to the final disposition of the original (wet 
signature) and copies of the signed and dated ICFs.   
Confirmation of informed consent must also be documented in the subject’s medical record. 
17.4. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, the subject’s 
legally authorized representative must also provide all authorizations required by local law (e.g., 
Protected Health Information authorization in North America). 
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  The Sponsor, its partner(s) and designee(s), ethics 
committees, and various government health agencies may inspect the records of this study.  
Every effort will be made to keep the subject’s personal medical data confidential. 
17.5. 
Compensation for Injury 
The Sponsor (or designee) maintains appropriate insurance coverage for clinical trials and will 
follow applicable local compensation laws. 
17.6. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor or its partners) with the subject’s legally authorized representative before the subject’s 
legally authorized representative makes a decision for the subject to participate in the study. 
17.7. 
Registration of Study and Disclosure of Study Results 
The Sponsor (or designee) will register the study and post study results regardless of outcome on 
a publicly accessible website in accordance with the applicable laws and regulations. 


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18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Study Site Initiation 
The Investigator must not screen any subjects prior to completion of a study initiation visit 
conducted by the Sponsor (or designee).  This initiation visit will include a detailed review of the 
protocol and study procedures. 
18.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits.  The Investigator will be expected 
to cooperate with any audit and to provide assistance and documentation (including source data) 
as requested. 
18.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. 
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the study and 
after the study has completed, as appropriate. 
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved. 
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
18.4. 
Study Funding 
Biogen Idec is funding the study.  Isis is the Sponsor of the study in the United States and Biogen 
Idec is the Sponsor of the study in the Rest of World. Biogen Idec (or designee) will be 
responsible for managing the study globally.  All financial details are provided in the separate 
contract(s) between the institution, Investigator, and Biogen Idec.  
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 
 


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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
The Sponsor may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, the Sponsor retains overall accountability 
for these activities. 
19.1.1. 
Contract Research Organization  
A CRO will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports and data management.  Before 
subjects are screened at each study site, the CRO will review study responsibilities with the 
Investigators and other study site staff, as appropriate. 
19.1.2. 
Interactive Response Technology 
IRT will be used in this study.  Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system. 
19.1.3. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool that is supported by a vendor and configured by the 
Sponsor or CRO. 
19.1.4. 
Central Laboratories for Laboratory Assessments 
A central laboratory will be selected by the Sponsor to analyze all hematology, blood chemistry, 
urine, and CSF samples collected at all study sites.  Local laboratories may be used to 
accommodate acute or urgent needs as discussed in in the Study Reference Manual. 
During the Screening Period, a blood sample will be collected for SMN2 copy number analysis 
by the central laboratory only from those subjects without genetic documentation of SMN2 copy 
number.  For all other subjects, a blood sample will be collected at any time during the study for 
analysis of SMN2 copy number by the central laboratory. 
19.2. 
Study Committees 
Safety data will be reviewed on an ongoing basis by an independent DSMB.  The DSMB will be 
assembled to review safety, tolerability, and efficacy (as needed) data collected on ISIS 396443 
during the study.  Based on its ongoing assessment of the safety and tolerability of ISIS 396443, 
the DSMB will provide recommendations to the Sponsor for modifying, stopping, or continuing 
the study as planned. 


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19.3. 
Changes to Final Study Protocol 
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, the Sponsor (or designee) may, at any time, amend this protocol to eliminate an 
apparent immediate hazard to a subject.  In this case, the appropriate regulatory authorities will 
be notified subsequent to the modification. 
In the event of a protocol modification, the ICF may require similar modifications (see 
Sections 17.2 and 17.3). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify the Sponsor in writing and 
receive written authorization from the Sponsor to destroy study records.  In addition, the 
Investigator must notify the Sponsor of any changes in the archival arrangements including but 
not limited to archival at an offsite facility or transfer of ownership if the Investigator leaves the 
site. 
19.6. 
Study Report Signatory 
The Sponsor will follow all applicable local regulations pertaining to study report signatories. 
 


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20. 
REFERENCES 
Burghes AH, Beattie CE. Spinal muscular atrophy: why do low levels of survival motor neuron 
protein make motor neurons sick? Nat Rev Neurosci. 2009;10(8):597-609. 
Coovert DD, Le TT, McAndrew PE, et al. The survival motor neuron protein in spinal muscular 
atrophy. Hum Mol Genet. 1997;6(8):1205-14. 
Feldkötter M, Schwarzer V, Wirth R, et al. Quantitative analyses of SMN1 and SMN2 based on 
real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of 
spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358-68. 
Hua Y, Sahashi K, Hung G, et al. Antisense correction of SMN2 splicing in the CNS rescues 
necrosis in a type III SMA mouse model. Genes Dev. 2010;24(15):1634-44. 
Hua Y, Vickers TA, Baker BF, et al. Enhancement of SMN2 exon 7 inclusion by antisense 
oligonucleotides targeting the exon. PLoS Biol. 2007;5(4):e73. 
Hua Y, Vickers TA, Okunola HL, et al. Antisense masking of an hnRNP A1/A2 intronic splicing 
silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet. 2008;82(4):834-48. 
Le TT, Pham LT, Butchbach ME, et al. SMNDelta7, the major product of the centromeric 
survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and 
associates with full-length SMN. Hum Mol Genet. 2005;14(6):845-57. 
Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal 
muscular atrophy. Nat Genet. 1997;16(3):265-9. 
Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. 
EMBO J. 1996;15(14):3555-65. 
Matsuzawa J, Matsui M, Konishi T, et al. Age-related volumetric changes of brain gray and 
white matter in healthy infants and children. Cereb Cortex. 2001;11(4):335-42. 
Passini MA, Bu J, Richards AM, et al. Antisense oligonucleotides delivered to the mouse CNS 
ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011;3(72):72ra18. 
Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. 
2010;12(3):145-52. 
Prior TW, Swoboda KJ, Scott HD, et al. Homozygous SMN1 deletions in unaffected family 
members and modification of the phenotype by SMN2. Am J Med Genet A. 2004;130A(3):307-
10. 
Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to age, 
SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-12. 
Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal 
muscular atrophy. J Child Neurol. 2007;22(8):1027-49. 
 


Protocol 232SM202 
Version 1 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
57 
 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A phase 2, randomized, double-blind, sham-procedure 
controlled study to assess the safety and tolerability and explore the efficacy of ISIS 396443 
(BIIB058) administered intrathecally in subjects with spinal muscular atrophy who are not 
eligible to participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4” and agree 
to conduct the study according to the protocol and the applicable ICH guidelines and GCP 
regulations, and to inform all who assist me in the conduct of this study of their responsibilities 
and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 

SAP_000.pdf: 
  
  
 
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St atistic al A n al ysis Pl a n 
Versi o n N o.: Fi nal V 1. 0  
 St u d y Title: A p hase 2, ra n d o mize d, d o u ble- bli n d, s ha m- pr oce d ure c o ntr olle d st u d y t o assess 
t he safet y a n d t olera bilit y a n d e x pl ore t he efficac y of I SI S 3 9 6 4 4 3 ( BII B 0 5 8) a d mi nistere d 
i ntrat hecall y i n s u bjects wit h s pi nal m usc ular atr o p h y w h o are n ot eli gi ble t o par tici pate i n t he 
cli nical st u dies I SI S 3 9 6 4 4 3- C S 3 B or I SI S 3 9 6 4 4 3- C S 4  
Part 2 a n d i nte grate d Part 1 a n d 2 a nal yses 
Na me of St u d y Treat me nt: I SI S 3 9 6 4 4 3 
Pr ot oc ol N o.:  2 3 2 S M 2 0 2  / N C T 0 2 4 6 2 7 5 9. 
St u d y P hase: P hase 2  




  
  
 
 
 
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T A B L E O F C O N T E N T S 
1  
S T U D Y D E SI G N ................................................................................................................ 8  
1. 1  
Scree ni n g......................................................................................................................  8 
1. 2  
St u d y treat me nt ............................................................................................................ 9  
1. 3  
F oll o w- U p .................................................................................................................... 9  
1. 4  
Sc he matic of e ve nts ................................................................................................... 1 0  
D E S C RI P TI O N O F O BJ E C TI V E S A N D E N D P OI N T S ............................................................. 2 7  
1. 1  
Pri mar y O bjecti ves a n d E n d p oi nts ............................................................................. 2 7  
1. 2  
Sec o n dar y O bjecti ves a n d E n d p oi nt .......................................................................... 2 8  
1. 3  
E x pl orat or y e n d p oi nts ................................................................................................ 2 8  
2  
S T A TI S TI C A L M E T H O D S: G E N E R A L C O N SI D E R A TI O N S ..................................... 2 9  
3  
S T U D Y S U BJ E C T S ......................................................................................................... 3 1  
3. 1  
S u bject Acc o u nta bilit y ............................................................................................... 3 1  
3. 2  
De m o gra p h y a n d Baseli ne Di sease C haracteristics ................................................... 3 1 
3. 3  
E xte nt of E x p os ure ..................................................................................................... 3 2  
3. 4  
C o nc o mita nt t hera p y .................................................................................................. 3 2  
3. 5  
Pr ot oc ol de viati o ns ..................................................................................................... 3 3  
4  
E F FI C A C Y D A T A ( E X P L O R A T O R Y) .......................................................................... 3 4  
4. 1  
Visit Wi n d o wi n g ........................................................................................................ 3 4  
4. 2  
Ve ntilati o n data .......................................................................................................... 3 5  
4. 2. 1   C ha n ge i n Ve ntilat or use ................................................................................................... 3 6  
4. 2. 2   Ti me t o Deat h or Per ma ne nt Ve ntilati o n .......................................................................... 3 6  
4. 2. 3   S ur vi val ...................................................................................................................... ....... 3 7 
4. 3  
Gr o wt h para meters ..................................................................................................... 3 7  
4. 4  
N u m ber of H os pitalizati o ns ....................................................................................... 3 7  


  
  
 
 
 
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4. 5  
M ot or milest o nes ....................................................................................................... 3 7  
4. 5. 1   HI N E m ot or milest o nes..................................................................................................... 3 8  
4. 5. 2   W H O m ot or milest o nes..................................................................................................... 4 1  
4. 6  
Cli nical Gl o bal I m pressi o n of C ha n ge (I n ve sti gat or a n d Care gi ver assess me nts) .... 4 2 
4. 7  
A C E N D ......................................................................................................................  4 3  
4. 8  
Bi o mar kers .................................................................................................................  4 3  
4. 8. 1   p Nf- H c o nce ntrati o n a n d c ha n ge i n p Nf- H ....................................................................... 4 3  
4. 8. 2   C ha n ge i n C S F S M N pr otei n c o nce ntrati o n ..................................................................... 4 4  
4. 9  
Si bli n g S M A Data C ollecti o n .................................................................................... 4 4  
4. 1 0  
I nteri m A nal yses ........................................................................................................ 4 4 
5  
S A F E T Y D A T A ............................................................................................................... 4 4  
5. 1  
Cli nical a d verse e ve nts .............................................................................................. 4 4  
5. 1. 1   A d verse e ve nts b y se verit y ............................................................................................... 4 6  
5. 1. 2   A d verse e ve nts b y relati o ns hi p t o st u d y treat me nt ........................................................... 4 6  
5. 1. 3   Seri o us a d verse e ve nts ...................................................................................................... 4 6  
5. 1. 4   A d verse e ve nts t hat le d t o disc o nti n uati o n fr o m treat me nt a n d/ or wit h dra wal fr o m st u d y 4 6  
5. 1. 5   Deat hs ........................................................................................................................ ........ 4 7 
5. 1. 6   Prese ntati o ns ................................................................................................................. .... 4 7 
5. 1. 7   S u b gr o u p a nal ysis .............................................................................................................  4 8 
5. 2  
Cli nical la b orat or y data .............................................................................................. 4 8  
5. 3  
E C G............................................................................................................................  5 0 
5. 4  
Vital si g ns .................................................................................................................. 5 0  
5. 5  
Ne ur ol o gical e xa mi nati o ns ........................................................................................ 5 0  
5. 6  
I nteri m safet y a nal yses ............................................................................................... 5 1 
6  
P H A R M A C O KI N E TI C D A T A ........................................................................................ 5 1  


  
  
 
 
 
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6. 1  
C S F c o nce ntrati o n data .............................................................................................. 5 1  
6. 2  
Plas ma c o nce ntrati o n data .......................................................................................... 5 2  
7  
I M M U N O G E NI CI T Y D A T A ........................................................................................... 5 2 
8  
S A M P L E SI Z E J U S TI FI C A TI O N ................................................................................... 5 3  
9  
R E F E R E N C E S ..................................................................................................................  5 3  
 
  
 
 


  
  
 
 
 
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LI S T O F A B B R E VI A TI O N S 
 A C E N D  
 assess me nt of Care gi ver E x perie nce wit h Ne ur o m usc ular Disease 
A E
 a d verse
 
e ve nt
 
A L T/ S G P T
 ala ni ne
 
a mi n otra nsferase/ser u m gl uta mic p yr u vic tra nsa mi nase 
a P T T 
acti vate d partial t hr o m b o plasti n ti me 
 A S T/ S G O T    
as partate a mi n otra nsferase/ser u m gl uta mic- o xal oacetic tra nsa mi nase 
 A T C    
  
a nat o mical t hera pe utic class  
 B L Q    
  
bel o w t he l o wer li mit of q ua ntificati o n 
 B U N    
  
bl o o d urea nitr o ge n 
 
C P K
  
 creati ne
 
p h os p h o ki nase
 
 C R F    
  
case re p ort f or m 
 
C S F
  
 cere br os pi nal
 
fl ui d
 
 C V  
  
  
c oefficie nt of variati o n 
 D S M B  
  
data safet y m o nit ori n g b oar d 
 HI N E    
  
ha m mers mit h i nfa nt ne ur ol o gical e xa mi nati o n 
 
I M
 
 
 i m m u n o ge nicit y
 
I N R 
i nter nati o nal n or malize d rati o 
 
I T
 
 
 i ntrat hecal
 
 L L N    
  
l o wer li mit of n or mal 
 L L O Q  
  
l o wer li mit of q ua ntificati o n 
 
L P
 
 
 l u m bar- p u nct ure
 
 Me d D R A  
  
me dical dicti o nar y f or re g ulat or y acti vities 
p Nf- H
  
 p h os p h or ylate d
 
ne ur ofila me nt hea v y c hai n s u b u nit 


  
  
 
 
 
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P K
 
 
 p har mac o ki netics
 
P T
 
 
 preferre d
 
ter m
 
P T T 
partial t hr o m b o plasti n ti me 
 R B C    
  
re d bl o o d cell 
 
S A E
  
 seri o us
 
a d verse
 
e ve nt
 
 
S D
 
 
 sta n dar d
 
de viati o n
 
 S M A    
  
s pi nal m usc ular atr o p h y 
 S O C    
  
s yste m or ga n class 
 U L N    
  
u p per li mit of n or mal 
 
W B C
  
 w hite
 
bl o o d
 
cell
 
 
W H O
  
 w orl d
 
healt h
 
or ga nizati o n
 
 W H O Dr u g    
w orl d healt h orga nizati o n dr u g dicti o nar y 
 
 


  
  
 
 
 
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1  
St u d y Desi g n 
 
T his is a P hase 2 m ultice nter st u d y c o n d ucte d i n 2 parts. 
Part 1 was ori gi nall y desi g ne d as a ra n d o mize d, d o u ble- bli n d, s ha m- pr oce d ure c o ntr olle d st u d y t o 
assess t he safet y a n d t olera bilit y a n d e x pl ore t he e fficac y of i ntrat hecall y a d mi nistere d N usi nerse n 
(als o k n o w n as I SI S 3 9 6 4 4 3 a n d BII B 0 5 8) o ver a perio d of a p pr o xi matel y 1 4 m o nt hs (fr o m t he first 
d ose u ntil t he E n d of Part 1 E val uati o n). U p t o 2 1 s u bjects were ra n d o mize d i n a rati o of 2: 1 t o recei ve 
N usi nerse n b y i ntrat hecal l u m bar p u nct ure ( L P) i n jecti o n or a s ha m- pr oce d ure c o ntr ol. Ra n d o mizati o n 
was stratifie d base d o n a ge at o nset of cli nical si g n s a n d s y m pt o ms c o nsiste nt wit h S M A: > 6 m o nt hs 
vers us < = 6 m o nt hs. Part 1 of t he st u d y was st o p pe d earl y d ue t o t he efficac y res ults see n i n t he I SI S 
3 9 6 4 4 3- C S 3 B st u d y a n d t he pla n ne d a nal ysis of Part 1 is  descri be d i n a se parate Statistical A nal ysis 
Pla n a n d c orres p o n di n g C S R. 
Part 2 st u d y pr oce d ures will be deter mi ne d ba se d o n t he treat me nt assi g n me nt i n Part 1.  
F or s u bjects w h o were ra n d o mize d t o recei ve N usi ne rse n i n Part 1, Part 2 Da y 1 will occ ur f oll o wi n g 
t he E n d of Part 1 E val uati o n or a p pr o xi matel y 4 m o nths f oll o wi n g t he last i njecti o n of N usi nerse n i n 
Part 1. O n Part 2 Da y 1, s u bjec ts will u n der g o pre d ose e val uati o ns acc or di n g t o t he sc he d ule of e ve nts 
a n d t he n recei ve t heir first d ose of N usi nerse n f or Part 2 ( ne xt mai nte na nce d ose). S u bjects will ret ur n 
t o t he st u d y site o n Da ys 1 2 0, 2 3 9, 3 5 8, 4 7 7, 5 9 6, a n d 7 1 5 f or f oll o w- u p e val uati o ns a n d s u bse q ue nt 
mai nte na nce d ose i njecti o ns. F or s u bjects w h o were r ecei vi n g s ha m pr oce d ure i n Part 1, Part 2 Da y 1 
will occ ur f oll o wi n g t he E n d of Part 1 E val uati o n or  as s o o n as p ossi ble f oll o wi n g t he E n d of Part 1 
E val uati o n. At Da y 1, s u bjects will u n der g o pre d os e e val uati o ns acc or di n g t o t he sc he d ule of e ve nts 
a n d t he n recei ve t heir first d ose of N usi nerse n (first l oa di n g d ose). S u bjects will ret ur n t o t he st u d y 
site o n Da ys 1 5, 2 9, 6 4, 1 8 3, 3 0 2, 4 2 1, 5 4 0, 6 5 9, a n d 7 7 8 f or f oll o w- u p e val uati o ns a n d s u bse q ue nt 
i njecti o ns. All s u bjects will ter mi nate earl y Part 2 f or e nr oll me nt i n o pe n-la bel e xte nsi o n st u d y, 
I SI S 3 9 6 4 4 3- C S 1 1. 
 
T his statistical a nal ysis pla n ( S A P) descri bes t he a n al yses pla n ne d f or t he e ntire st u d y (i nte grati o n of 
Part 1 a n d Part 2) a n d a d diti o nall y s o me s u m maries of Part 2 data o nl y. 
1. 1  
Scree ni n g  
After i nf or me d c o nse nt is o btai ne d, s u bjects u n der g o a Scree ni n g e val uati o n n o greater t ha n 2 8 da ys 
pri or t o a d mi nistrati o n of t he first d ose or first s ha m pr oce d ure at w hic h ti me t heir eli gi bilit y f or t he 
st u d y will be e xa mi ne d. 


  
  
 
 
 
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1. 2  
St u d y tre at me nt 
I n Part 1 of t he st u d y, eac h s u bject was a d mi nistere d a si n gle i ntrat hecal b ol us ( 1 t o 3 mi n utes) L P 
i njecti o n of N usi nerse n or s ha m pr oce d ure o n Days 1, 1 5, 2 9, 6 4, 1 8 3, a n d 3 0 2 b y de dicate d st u d y 
pers o n nel w h o were u n bli n de d t o treat me nt. T he st u d y treat me nt a d mi nistrati o n was perf or me d i n a 
de dicate d r o o m, a n d ke y st u d y pers o n nel a n d t he pare nts were n ot prese nt d uri n g t he pr oce d ure t o 
e ns ure bli n di n g.  
I n Part 2 of t he st u d y, all s u bjects recei ve d N usi nerse n. S u bjects ra n d o mize d t o recei ve s ha m i n Part 1 
of t he st u d y recei ve d l oa di n g d oses i n Part 2 a n d after t hat a mai nte na nce d ose (e ver y 1 2 0 da ys) a n d 
s u bjects ra n d o mize d t o recei ve N usi nerse n i n Part 1 of t he st u d y c o nti n ue d o n mai nte na nce d oses. 
Treat me nt a d mi nistrati o n was n ot bli n de d. 
 
1. 3  
F oll o w- U p 
Part  1  was  ter mi nate d  earl y  after  a n  i nteri m  a nal ysis  of  a  p hase  3  st u d y  i n  i nfa nts  wit h  S M A  
(I SI S 3 9 6 4 4 3- C S 3 B) de m o nstrate d a p ositi ve be nefit-ris k pr ofile f or N usi nerse n. S u bjects ret ur ne d t o 
t he st u d y site f or a f oll o w- u p e val uati o n ( Fi nal St u d y Visit) a p pr o xi matel y 4 m o nths after t he last d ose 
of st u d y treat me nt i n Part 1 a n d all eli gi ble were e nr o lle d i n Part 2. Part 2 will ter mi nate earl y as well 
t o all o w s u bjects t o e nr oll i n a n ot her l o n g ter m P hase 3 o pe n-la bel e xte nsi o n st u d y, I SI S 3 9 6 4 4 3- C S 1 1. 
S u bjects w h o ter mi nate earl y fr o m Part 2 of t he st u d y will be e nc o ura ge d t o c o m plete t he Part 2 Earl y 
Ter mi nati o n E val uati o n assess me nts  at t he ti me of wit h dra wal.  
 
 


  
  
 
 
 
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1. 4  
Sc he m atic of e ve nts 
T he sc he d ule of eve nts is as f oll o ws  
 
Fi g ure 1: St u d y Sc he m atic 1 
 
 
 
 
 
 






  
  
 
 
 
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A E = a d verse e ve nt; Bi- P A P = bile vel p ositi v e air wa y press ure; C o n Me d = c o nc o mita nt me dicati o n; C S F = cere br os pi nal fl ui d; E C G  = electr ocar di o gra m; 
HI N E = Ha m mers mit h I nfa nt Ne ur ol o gical E xa mi nati o n; L P = l u m b ar p u nct ure; P K = p har mac o ki netic(s); S A E = seri o us a d verse e ve nt;  S M A = s pi nal 
m usc ular atr o p h y; S M N 2  = s ur vi val m ot or ne ur o n 2 
1  A bl o o d sa m ple will be c ollecte d at Scree ni n g f or S M N 2  c o p y n u m ber o nl y fr o m t h ose s u bjects wit h o ut ge netic d oc u me ntati o n of S M N 2  c o p y n u m ber. F or all 
ot her s u bjects, a bl o o d sa m ple will be c ollecte d at a n y ti me d uri n g t he st u d y f or a nal ysis of S M N 2  c o p y n u m ber b y t he ce ntral la b orat or y. 
2  After t he i njecti o n of st u d y treat me nt or s ha m pr oce dure o n Da y 1, s u bjects will re mai n at  t he st u d y site f or at least 2 4 h o urs ( Da y 2) f or safet y m o nit ori n g. O n 
t he da y f oll o wi n g t he i njecti o n of st u d y treatme nt or s ha m pr oce d ure o n Da ys 1 5, 2 9, 6 4, 1 8 3, a n d 3 0 2, t her e will be safet y m o n it ori n g t hr o u g h tele p h o ne 
c o ntact. D uri n g t hat tele p h o ne c o ntact (i.e., Da ys 1 6, 3 0, 6 5, 1 8 4 a n d 3 0 3), c ha n ges i n c o nc o mita nt me dicati o ns a n d A Es, i nf or m ati o n o n t he s u bject’s dail y 
ve ntilat or/ Bi- P A P use, a n d hea lt h stat us will be rec or de d.  
3 E n d of Part 1 is o ne of t he f oll o wi n g: Pa rt 1 Fi nal F oll o w- u p E val uati o n ( Da y 4 2 2 [ ±7 da ys]) acc or di n g t o t he st u d y sc he d ule, e arl y Part 1 Fi nal F oll o w- u p 
E val uati o n t o all o w f or r oll o ver i nt o Part 2, or Earl y Ter mi na ti o n E val uati o n f or s u bjects w h o wit h dra w fr o m t he st u d y d uri n g Part 1. 
4  F or s u bjects n ot tra nsiti o ni n g i nt o Part 2, t he date of t he E n d of Part 1 E valuati o n assess me nts will be t he e n d of st u d y. F or s u bjects w h o tra nsiti on t o Part 2, t he 
date of t he E n d of Part 1 will be t h e date of first d ose i n Part 2. 
5 At t he E n d of Part 1 e val uati o n, i n  or der t o all o w tra nsiti o n t o Part 2, s u bjects will be u n bli n de d.  
6  Vital si g ns i ncl u de resti n g s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y rate, te m perat ure, p ulse o xi metr y, a n d tra nsc uta ne o us car b o n di o xi de. 
P ulse o xi metr y a n d tra nsc uta ne o us car b o n di o xi de will be meas ur e d pre d ose at eac h e val uati o n. F or s u bjects w h o are n ot recei vi n g n o ni n vasi ve ve ntilati o n, 
p ulse o xi metr y will be meas ure d o ver ni g ht o nce a wee k at h o me.  
7  Vital si g ns (resti n g s yst olic a nd diast olic bl o o d press ure, p ulse rate, res pirat or y rate, te m perat ure, a n d p ulse o xi metr y) wil l be c ollecte d at 4 ti me p oi nts: 1, 2, 4, 
a n d 6 h o urs (all ± 1 5 mi n utes) after t he i njecti o n of st u d y treat me nt. 
8  Vital si g ns (resti n g s yst olic a nd diast olic bl o o d press ure, p ulse rate, res pirat or y rate, te m perat ure, a n d p ulse o xi metr y) wil l be c ollecte d wit hi n 2 0 t o 2 4 h o urs 
after t he i njecti o n of st u d y tr eat me nt or s ha m pr oce d ure. 
9  At t he e val uati o ns sc he d ule d f or i njecti o n of st u d y treat me nt or s ha m pr oce d ure, s u bjects will be assess e d f or t he f oll o wi n g g r o wt h para meters: b o d y le n gt h, 
hea d circ u mfere nce, c hest circ u mfe re nce, a n d ar m circ u mfere nce.  
1 0 Ne ur ol o gical e xa mi nati o ns i ncl u de assess me nt of me ntal stat us, le vel of c o nsci o us ness, se ns or y f u ncti o n, m ot or f u ncti o n, cra nial ner ve f u ncti o n, a n d refle xes. 
1 1Ne ur ol o gical e xa mi nati o ns will occ ur bet w ee n 4 t o 6 h o urs after t he i njecti o n of  st u d y treat me nt or s ha m pr oce d ure. 
1 2Bl o o d c he mistr y, he mat ol o g y , a n d uri nal ysis pa nels.  
1 3 Sa m ples f or safet y la b orat or y tests will be c ollecte d bef ore t he i njecti on of st u d y treat me nt or s ha m  pr oce d ure o n Da ys 6 4 a n d 1 8 3 o nl y.  
1 4E n d of Part 1 safet y la b orat or y tests ma y be perf or me d l ocall y i n a d diti o n t o ce ntrall y t o acc o m m o date t he Part 2 Da y 1 d osi n g.   


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 02  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 1 4 of 5 4 
 
1 5Refer t o Err or! Refere nce s o urce n ot f o u n d.  f or C S F P K sa m ple sc he d ule. T he C S F sa m ples will be a nal yze d f or N usi nerse n c o nce ntrati o ns. T he re mai ni n g 
C S F sa m ple will be st ore d f or o pti o nal f ut ure bi o mar ker a nal yses.  
1 6Bl o o d sa m ples f or P K assess me nt will be c ollecte d 4 h o urs ( ± 1 h o u r) after t he i njecti on of st u d y treat me nt or s ha m pr oce d ure o n l y o n Da y 1. Refer t o Err or! 
Refere nce s o urce n ot f o u n d.  f or t he plas ma P K sa m ple sc he d ule. 
1 7Bl o o d sa m ples f or P K assess me nt will be c ollecte d bef ore t he i njecti o n of st u d y treat me nt  or s ha m pr oce d ure o n Da ys 6 4 a n d 1 8 3 o nl y. Refer t o Err or! 
Refere nce s o urce n ot f o u n d.  f or t he plas ma P K sa m ple sc he d ule. 
1 8O ver ni g ht sta y (at least 2 4 h o urs) is re q u ire d after t he first i njecti o n of st u d y treatme nt or s ha m pr oce d ure. F oll o wi n g all s u bse q ue nt i njecti o ns or s ha m 
pr oce d ures, a sta y of at least 6 h o urs at t he st u d y site  is re q uire d; o ver ni g ht sta ys are o pti o nal o n t hese da ys. 
1 9I n a d diti o n t o c o nc o mita nt me dicati o ns, a ncillar y pr oce d ures  will be rec or de d. 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 02  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 1 5 of 5 4 
 
2 0A Es a n d S A Es will be c ollecte d i n t he case re p ort f or m fr o m t he ti me of si g ni n g of t h e i nf or me d c o nse nt f or m as descri be d i n Secti o n a n d Secti o n 1 5. 3. 2  of t he 
pr ot oc ol. 






  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 02  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 1 8 of 5 4 
 
2 If t he st u d y c o nti n ues be y o n d Year 2 (i.e., be y o n d Da y 7 1 5), t he n fr o m Da y 8 3 5 o n war ds, s u bjects will mai ntai n e val uati o ns f or st u d y treat me nt i njecti o n e ver y 
4 m o nt hs wit h t he assess me nts f or t h ose a d diti o nal ti me p oi nts t o alter nate bet wee n t he assess me nts d o ne o n Da y 1 2 0 a n d t h ose d o ne o n Da y 2 3 9. Da y 1 2 0 
assess me nts w o ul d be perf or me d at Da y 8 3 5 a n d Da y 2 3 9 assess me nts  w o ul d be perf or me d at Da y 9 5 4. T he alter nati n g patter n w o ul d c o nti n ue u ntil t he e n d of 
t he st u d y. Part 2 Fi nal F oll o w- u p E val uati o n w o ul d t he n occ ur a ppr o xi matel y 4 m o nt hs after t he last i njecti o n of st u d y treat me n t. 
3 T he Part 2 Fi nal F oll o w- u p E val uati o n will o cc ur 4 m o nt hs after t he last i njecti o n of st u d y treat me nt, w hic h will eit her be o n Da y 7 1 6 or later, if Part 2 of t he 
st u d y c o nti n ues be y o n d Year 2.  
4  S u bjects w h o ter mi nate earl y will be e nc o ura ge d t o c o m plete t he safet y e val uati o ns sc he d ule d f or t he Part 2 Earl y Ter mi nati o n E val uati o n. 
5  I ncl usi o n/ E xcl usi o n Criteria, I nf or me d C o nse nt, a n d C S F P K m ust be perf or me d o n Part 2 Da y 1. 
6 Vital si g ns i ncl u de resti n g s yst olic a n d diast olic bl o o d press ure , p ulse rate, res pirat or y rate, te m perat ure, p ulse o xi metr y, an d tra nsc uta ne o us car b o n di o xi de. 
P ulse o xi metr y a n d tra nsc uta ne o us car b o n di o xi de  will be meas ure d pre dose at eac h e val uati o n. 
7 If Part 2 Da y 1 st u d y treat me nt i njecti o n is dela ye d m ore t ha n 2 4 h o urs after t he E n d of Part 1 visit, t he f oll o wi n g pr oce d ures m ust be d o ne o n Part 2 Da y 1 
pre d ose: vital si g ns, wei g ht, gr o w t h para meters, p h ysical e xa mi nati o n, ve ntilat or use, ne ur ol o gical e xa mi na ti o n, a n d C S F P K. If Part 2 Da y 1 st u d y treat me nt 
i njecti o n is dela ye d m ore t ha n 2 4 h o urs after E n d of Part 1 d ue t o a n A E, S A E, or ot her safet y c o ncer n, or if Part 2 Da y 1 st u dy treat me nt i njecti o n is dela ye d 
m ore t ha n 3 0 da ys after E n d of Part 1 f or a n y reas o n, t he f oll o w i n g pr oce d ures m ust be d o ne o n Part 2 Da y 1 pre d ose: vital si g ns, wei g ht, gr o wt h para meters, 
p h ysical e xa mi nati o n, ve ntilat or use, ne ur ol o gical e xa mi nati o n, E C G, C S F P K, a n d safet y  la b orat or y tests. I m m u n o ge nicit y testi ng m ust als o be re peate d 
pre d ose if Part 2 Da y 1 st u d y treat me nt i njecti o n is dela ye d m ore t ha n 3 0 da ys after E n d of Part 1 f or a n y reas o n.  
8 Vital si g ns (resti n g s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y rate, te m perat ure, a n d p ulse o xi metr y) will  be c ollecte d 1 h o ur ( ± 1 5 mi n utes) 
after t he i njecti o n of st u d y treat me nt.  
9 At t he e val uati o ns sc he d ule d f o r i njecti o n of st u d y treat me nt, s u bjects will be assesse d f or t he f oll o wi n g  gr o wt h para meters: bo d y le n gt h, hea d circ u mfere nce, 
c hest circ u mfere nce, a n d ar m circ u mfere nce. Gr o wt h para me ters a n d wei g ht are t o be c ollecte d at t he sa me ti me. 
1 0 Ne ur ol o gical e xa mi nati o ns i ncl u de assess me n t of me ntal stat us, le vel of c o nsci o us ness, se ns or y f u ncti o n, m ot or f u ncti o n, cra nial ner ve f u ncti o n, a n d refle xes. 
If se dati o n was use d, please all o w s ufficie nt rec o ver y ti me f or t he s u bject t o be f ull y e n ga ge d i n t he e xa mi nati o n beca use it is i m p orta nt t hat t he data c ollecte d 
tr ul y reflect t he s u bject’s ne ur ol o gical perf or ma nce. 
1 1 Pre d ose a n d p ost d ose. 
1 2E C G will be perf or me d o n Da ys 2 3 9, 4 7 7, a n d 7 1 5, a n d at t he Part 2 Fi nal F oll o w- u p E val uati o n. E C G m ust be perf or me d bef ore o bt ai ni n g bl o o d sa m ples f or 
safet y la b orat or y tests. 
1 3Bl o o d c he mistr y, he mat ol o g y, uri nal ysis, uri ne t otal pr otei n pa nels, a n d c oa g ulati o n para meters . Uri ne t otal pr otei n a n d c oa g ulati o n para meters will be assesse d 
b y l ocal la b orat ories. 
1 4Sa m ples f or safet y la b orat or y tests will be c ollecte d bef ore  t he i njecti o n of st u d y treatme nt at eac h d osi n g visit.  
1 5Bl o o d sa m ples f or i m m u n o ge nicit y testi n g will be c ollecte d bef ore  t he i njecti o n of st u d y treat ment o n Da ys 2 3 9, 4 7 7, a n d 7 1 5. 
1 6Refer t o Err or! Refere nce s o urce n ot f o u n d.  f or C S F P K sa m ple sc he d ule. T he C S F sa m ples will be a nal yze d f or N usi nerse n c o nce ntrati o ns. T he re mai ni n g 
C S F sa m ple will be st ore d f or o p ti o nal f ut ure bi o mar ker a nal yses. 
1 7Bl o o d sa m ples f or P K assess me nt will be c ollecte d 4 h o urs ( ± 1 h o u r) after t he i njecti o n of st u d y treat me nt o nl y o n Da y 1. Refer t o Err or! Refere nce s o urce 
n ot f o u n d.  f or t he plas ma P K sa m ple sc he d ule. Plas ma P K sa m ples will be c ollecte d pre d ose o n Da ys 2 3 9, 4 7 7, a n d 7 1 5. 
1 8T he o pti o nal assess me nt of si bli n g S M A data c ollecti o n will be perf or me d o nl y after o btai ni n g c o nse nt. 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 02  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 1 9 of 5 4 
 
1 9I n a d diti o n t o c o nc o mita nt me dicati o ns, a ncillar y pr oce d ures  will be rec or de d. 
2 0A Es a n d S A Es will be c ollecte d i n t he case re p ort f or m fr o m t he ti me of si g ni n g of t h e i nf or me d c o nse nt f or m as descri be d i n Secti o n a n d Secti o n 1 5. 3. 2  of t he 
pr ot oc ol. 
 








  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 02  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 2 3 of 5 4 
 
3 T he Part 2 Fi nal F oll o w- u p E val uati o n will o cc ur 4 m o nt hs after t he last i njecti o n of st u d y treat me nt, w hic h will eit her be o n Da y 7 7 8 or later, if Part 2 of t he 
st u d y c o nti n ues be y o n d Year 2. 
4 S u bjects w h o ter mi nate earl y will be e nc o ura g e d t o c o m plete t he safet y e val uati o ns sche d ule d f or t he Part 2 Earl y Ter mi nati o n E val uati o n. 
5 I ncl usi o n/ E xcl usi o n Criteria, I nf or me d C o nse nt, a n d C SF P K m ust be perf or me d o n Part 2 Da y 1 pre d ose. 
6 Vital si g ns i ncl u de resti n g s yst olic a n d diast olic bl o o d press ure , p ulse rate, res pirat or y rate, te m perat ure, p ulse o xi metr y, an d tra nsc uta ne o us car b o n di o xi de. 
P ulse o xi metr y a n d tra nsc uta ne o us car b o n di o xi de  will be meas ure d pre dose at eac h e val uati o n. 
7 If Part 2 Da y 1 st u d y treat me nt i njecti o n is dela ye d m ore t ha n 2 4 h o urs after t he E n d of Part 1 visit, t he f oll o wi n g pr oce d ures m ust be d o ne o n Part 2 Da y 1 
pre d ose: vital si g ns, wei g ht, gr o w t h para meters, p h ysical e xa mi nati o n, ve ntilat or use, ne ur ol o gical e xa mi na ti o n, a n d C S F P K. If Part 2 Da y 1 st u d y treat me nt 
i njecti o n is dela ye d m ore t ha n 2 4 h o urs after E n d of Part 1 d ue t o a n A E, S A E, or ot her safet y c o ncer n, or if Part 2 Da y 1 st u dy treat me nt i njecti o n is dela ye d 
m ore t ha n 3 0 da ys after E n d of Part 1 f or a n y reas o n, t he f oll o w i n g pr oce d ures m ust be d o ne o n Part 2 Da y 1 pre d ose: vital si g ns, wei g ht, gr o wt h para meters, 
p h ysical e xa mi nati o n, ve ntilat or use, ne ur ol o gical e xa mi nati o n, E C G, C S F P K, a n d safet y  la b orat or y tests. I m m u n o ge nicit y testi ng m ust als o be re peate d if 
Part 2 Da y 1 st u d y treat me nt i njecti o n is dela ye d m ore  t ha n 3 0 da ys after E n d of Part 1 f or a n y reas o n. 
8  Vital si g ns (resti n g s yst olic a nd diast olic bl o o d press ure, p ulse rate, res pirat or y rate, te m perat ure, a n d p ulse o xi metr y) wil l be c ollecte d at 4 ti me p oi nts: 1, 2, 4, 
a n d 6 h o urs (all ± 1 5 mi n utes) after t he i njecti o n of st u d y treat m e nt o nl y o n Part 2 Da y 1. O n s u bse q ue nt st u d y da ys, vital si g n s will be c ollecte d 1 h o ur after t he 
i njecti o n of st u d y treat me nt. 
9 Vital si g ns (resti n g s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y rate, te m perat ure, a n d p ulse o xi metr y) will  be c ollecte d o n Da y 2 wit hi n 2 0 t o 
2 4 h o urs after t he i njecti o n of st u d y treat me nt o nl y. 
1 0 At t he e val uati o ns sc he d ule d f o r i njecti o n of st u d y treat me nt, s u bjects will be assesse d f or t he f oll o wi n g  gr o wt h para meters: bo d y le n gt h, hea d circ u mfere nce, 
c hest circ u mfere nce, a n d ar m circ u mfere nce. Gr o wt h para me ters a n d wei g ht are t o be c ollecte d at t he sa me ti me. 
1 1 Ne ur ol o gical e xa mi nati o ns i ncl u de assess me n t of me ntal stat us, le vel of c o nsci o us ness, se ns or y f u ncti o n, m ot or f u ncti o n, cra nial ner ve f u ncti o n, a n d refle xes. 
If se dati o n was use d, please all o w s ufficie nt rec o ver y ti me f or t he s u bject t o be f ull y e n ga ge d i n t he e xa mi nati o n beca use it is i m p orta nt t hat t he data c ollecte d 
tr ul y reflect t he s u bject’s ne ur ol o gical perf or ma nce. 
1 2 Pre d ose a n d p ost d ose. 
1 3E C G will be perf or me d at Da ys 6 4, 1 8 3, 5 4 0,  a n d 7 7 8, a n d at t he Part 2 Fi nal F oll o w- u p E val uati o n. E C G m ust be perf or me d bef ore  o btai ni n g bl o o d sa m ples 
f or safet y la b orat or y tests. 
1 4Bl o o d c he mistr y, he mat ol o g y, uri nal ysis, uri ne t otal pr otei n pa nels, a n d c oa g ulati o n para meters . Uri ne t otal pr otei n a n d c oa g ulati o n para meters will be assesse d 
b y l ocal la b orat ories. 
1 5Sa m ples f or safet y la b orat or y tests will be c ollecte d bef o re t he i njecti o n of st u d y treat me nt at eac h d osi n g visit. 
1 6Bl o o d sa m ples f or i m m u n o ge nicit y testi n g will be c ollecte d bef ore t he i njecti o n of st u d y treat me nt o n Da ys 6 4, 1 8 3, 3 0 2, 4 2 1, 54 0, 6 5 9, a n d 7 7 8. 
1 7Refer t o Err or! Refere nce s o urce n ot f o u n d.  f or C S F P K sa m ple sc he d ule. T he C S F sa m ples will be a nal yze d f or N usi nerse n c o nce ntrati o ns. T he re mai ni n g 
C S F sa m ple will be st ore d f or o p ti o nal f ut ure bi o mar ker a nal yses. 
1 8Bl o o d sa m ples f or P K assess me nt will be c ollecte d 4 h o urs ( ± 1 h o u r) after t he i njecti o n of st u d y treat me nt o nl y o n Da y 1. Refer t o Err or! Refere nce s o urce 
n ot f o u n d.  f or t he plas ma P K sa m ple sc he d ule. Plas ma P K sa m ples will be c ollecte d pr e d ose o n Da ys 6 4, 1 8 3, 5 4 0, a n d 7 7 8. 
1 9O ver ni g ht sta y (at least 2 4 h o urs) is re q u ire d after t he first i njecti o n of st u d y treat me nt. F oll o wi n g all s u bse q ue nt i njecti o ns, a sta y of at least 1 h o ur at t he st u d y 
site is re q uire d; o ver ni g ht sta ys are o pti o nal o n t hese da ys. 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 02  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 2 4 of 5 4 
 
2 0T he o pti o nal assess me nt of si bli n g S M A data c ollecti o n will be perf or me d o nl y after o btai ni n g c o nse nt. 
2 1I n a d diti o n t o c o nc o mita nt me dicati o ns, a ncillar y pr oce d ures  will be rec or de d. 
2 2A Es a n d S A Es will be c ollecte d i n t he case re p ort f or m fr o m t he ti me of si g ni n g of t h e i nf or me d c o nse nt f or m descri be d i n Secti o n a n d Secti o n 1 5. 3. 2  of t he 
pr ot oc ol. 
 






  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 2 7 of 5 4 
 
P K P art 2 
Da y 5 4 0 
Pre d ose 
0. 5 
0. 5 
Da y 6 5 9 
Pre d ose 
N A 
0. 5 
Da y 7 7 8 
Pre d ose 
0. 5 
0. 5 
Part 2 Fi nal 
F oll o w- U p 
N A
 0. 5
 
N A
 
C S F = cere br os pi nal fl ui d; h = h o ur; mi n = mi n utes; L P = l u m bar p u nct ure; m R N A = messe n ger ri b o n ucleic aci d; 
N A = n ot a p plica ble ( n o c ollecti o n sc he d ule d); S M A = s pi nal m usc ular atr o p h y. 
1  Details o n sa m pli n g, pre parati o n, a n d s hi p me nt are i ncl u de d i n t he St u d y La b orat or y Ma n ual. 
2  U p o n c o nse nt, t he c ollecte d C S F sa m ples fr o m t he st u d y s ubjects will be st ore d f or f ut ure i n vesti gati o n of p ossi ble 
bi o mar kers of S M A disease (e. g., C S F m R N A, C S F pr otei n, C S F micr o R N A pa nel), f or pr ofili n g of st u d y dr u g 
bi n di n g pr otei ns, bi oa nal ytical met h o d vali dati o n p ur p oses, sta bilit y assess me nts, meta b olite assess me nts, a n d 
i m m u n o ge nicit y assess me nts (i ncl u di n g assa y de vel o p me nt a nd vali dati o n p ur p oses), or f or assessi n g ot her acti o ns 
of N usi nerse n wit h plas ma a n d C S F c o nstit ue nts. 
 
 
Descri pti o n of O bjecti ves a n d E n d p oi nts 
1. 1  
Pri m ar y O bjecti ves a n d E n d p oi nts 
P art 1  
T he pri mar y o bjecti ve of Pa rt 1 of t his st u d y is:  
 T o assess t he safet y a n d t olera bilit y of N usi nerse n i n s u bjects wit h S M A w h o are n ot 
eli gi ble t o partici pate i n t he cli nical st u dies I SI S 3 9 6 4 4 3- C S 3 B or I SI S 3 9 6 4 4 3- C S 4.  
T he e n d p oi nts t hat relate t o  t his o bjecti ve are:  
 
I nci de nce of a d verse e ve nts ( A Es) a n d seri o us a d verse e ve nts ( S A Es)  
  C ha n ge fr o m baseli ne (see Secti o n 5 ) i n cli nical la b orat or y para meters, 
electr ocar di o gra ms ( E C Gs), vital si g ns, a n d gr o wt h para meters 
  C ha n ge fr o m baseli ne (see Secti o n 5 ) i n ne ur ol o gical e xa mi nati o n o utc o mes  
P art 2  
T he pri mar y o bjecti ve of Part 2 of t his st u d y is:   
 T o assess t he l o n g-ter m safet y a n d t olera bilit y  of N usi nerse n i n s u bjects wit h S M A w h o 
partici pate d i n Part 1 a n d c o m plete d t hei r E n d of Part 1 E val uati o n assess me nts.  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 2 8 of 5 4 
 
T he e n d p oi nts t hat relate t o  t his o bjecti ve are:  
 I nci de nce of A Es a n d S A Es  
 C ha n ge fr o m baseli ne (see Secti o n 5 ) i n cli nical la b orat or y para meters, E C Gs, a n d vital 
si g ns  
 C ha n ge fr o m baseli ne (see Secti o n 5 ) i n ne ur ol o gical e xa mi nati o n o utc o mes  
 C oa g ulati o n para meters (acti vate d part ial t hr o m b o plasti n ti me [a P T T], partial 
t hr o m b o plasti n ti me [ P T T], a n d i nter nati o nal n or malize d rati o [I N R]) a n d uri ne t otal 
pr otei n 
1. 2  
Sec o n d ar y O bjecti ves a n d E n d p oi nt 
T he sec o n dar y o bjecti ve a n d e n d p oi nt of Part 1 of t his st u d y are as f oll o ws: 
 
 T o e xa mi ne t he p har mac o ki netics ( P K) of N usi nerse n i n su bjects wit h S M A w h o are n ot 
eli gi ble t o partici pate i n  t he cli nical st u dies I SI S 3 9 6 4 4 3- C S 3 B or I SI S 3 9 6 4 4 3- C S 4 
 
N usi nerse n c o nce ntrati o ns i n plas ma a n d cere br os pi nal fl ui d ( C S F) 
T he sec o n dar y o bjecti ve a n d e n d p oi nt of Part 2 of t his st u d y are as f oll o ws: 
 T o e xa mi ne t he P K of N usi nerse n i n s u bjects  wit h S M A w h o partici pate d i n Part 1 a n d 
c o m plete d t heir E n d of Part 1 E val uati o n assess me nts 
 N usi nerse n c o nce ntrati o ns i n plas ma a n d C S F 
 Plas ma a nti b o dies t o N usi nerse n 
1. 3  
E x pl or at or y e n d p oi nts 
P art 1  
T he e x pl orat or y o bjecti ve of Part 1 of t his st u d y is:  
• T o e x pl ore t he efficac y of N usi nerse n i n s u bjects wit h S M A w h o are n ot eli gi ble t o partici pate 
i n t he cli nical stu dies I SI S 3 9 6 4 4 3- C S 3 B or I SI S 3 9 6 4 4 3- C S 4.  
T he e n d p oi nts t hat relate t o  t his o bjecti ve are:  
 C ha n ge fr o m baseli ne i n ve ntilat or use 
 Attai n me nt of m ot or milest o nes assesse d b y Secti o n 2 of t he Ha m mers mit h I nfa nt 
Ne ur ol o gical E xa mi nati o n ( HI N E) 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 2 9 of 5 4 
 
 C ha n ge fr o m baseli ne i n gr o wt h para meters  ( b o d y le n gt h, hea d circ u mfere nce, c hest 
circ u mfere nce, ar m circ u mfere nce, wei g ht f or a ge, wei g ht f or le n gt h, a n d hea d t o c hest 
circ u mfere nce rati o) t hr o u g h fi nal safet y f oll o w- u p e val uati o n  
 Cli nical Gl o bal I m pressi o n of C ha n ge ( p h ys icia n a n d care gi ver assess me nt) t hr o u g h fi nal 
safet y f oll o w- u p e val uati o n  
  Plas ma a nti b o dies t o N usi nerse n  
P art 2  
T he e x pl orat or y o bjecti ve of Part 2 of t his st u d y is:  
• T o e x pl ore t he efficac y of N usi nerse n i n s u bjects wit h S M A w h o partic i pate d i n Part 1 a n d 
c o m plete d t heir E n d of Part 1 E val uati o n assess me nts.  
T he e n d p oi nts t hat relate t o  t his o bjecti ve are:  
 C ha n ge fr o m baseli ne i n ve ntilat or use  
 Attai n me nt of m ot or milest o nes assesse d b y W orl d Healt h Or ga nizati o n ( W H O) m ot or 
milest o nes a n d Secti o n 2 of t he HI N E  
 C ha n ge fr o m baseli ne i n gr o wt h para meters  ( b o d y le n gt h, hea d circ u mfere nce, c hest 
circ u mfere nce, ar m circ u mfere nce, wei g ht f or a ge, wei g ht f or le n gt h, a n d hea d t o c hest 
circ u mfere nce rati o) t hr o u g h Part 2 Fi nal F oll o w- u p E val uati o n  
 
Cli nical Gl o bal I m pressi o n of C ha n ge ( p h ys icia n a n d care gi ver assess me nt) t hr o u g h Part 
2 Fi nal F oll o w- u p E val uati o n a n d Assess m e nt of Care gi ver E x perie nce wit h 
Ne ur o m usc ular Disease ( A C E N D)  
2  
St atistic al Met h o ds: Ge ner al C o nsi der ati o ns 
I n t his S A P, t he ter ms “c o ntr ol” a n d “ pre vi o us co ntr ol” refer t o t he set of s u bjects w h o were 
ra n d o mize d t o u n der g o t he s ha m pr oce d ure d uri n g t he Part 1. 
I n or der t o disti n g uis h n o mi nal visit na mes fr o m d urati o n defi ne d i n da ys, visit na mes will be 
referre d t o as “ Da y 1 5”, “ Da y 2 9”, etc., a n d “ 1 5 da ys” or “ 2 9 da ys” etc. will be use d t o defi ne ti me 
i nter vals. 
D ue t o e mer ge nt data fr o m t he N usi nerse n cli ni cal de vel o p me nt pr o gra m, t he s u bjects i n Part 1 
e n de d t he st u d y earl y as f oll o ws: s u bjects ra n d o mize d t o s ha m ter mi n ate d Part 1 first irres pecti ve 
of Part 1 pl a n ne d d osi n g da ys a n d s u bjects ra n d o mize d t o N usi nerse n tra nsiti o ne d t o Part 2 
acc or di n gl y t o t heir s pecific d ose sc he d ule . Part 2 was als o ter mi nate d earl y t o all o w s u bjects t o 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 0 of 5 4 
 
e nter t he I SI S 3 9 6 4 4 3- C S 1 1 st u d y. F or t hese reas o ns, t h e act ual st u d y da y ass o ciate d wit h visits 
Part 1 a n d Part 2 will var y wi del y a m o n gst s u bjects. T heref ore, a wi n d o wi n g sc he ma will be 
i m ple me nte d f or b y visit a nal yses (see secti o n 4. 1) 
 
T he safet y p o p ulati o n will i ncl u de all s u bjects w h o are ra n d o mize d a n d r ecei ve at least 1 d ose of 
st u d y treat me nt or s ha m pr oce d ure. S u bjects ra n d o mize d t o recei ve s ha m pr oce d ure b ut i nc orrectl y 
treate d wit h N usi nerse n will be c o u nte d i n t he I SI S 3 9 6 4 4 3 gr o u p fr o m t he first d ose of N usi nerse n 
recei ve d.  
T he Efficac y set at eac h visit will be defi ne d as t he s u bset of s u bjects i n t he Safet y set w h o has 
ha d t he o p p ort u nit y t o be assesse d at t hat visit (act ual visit f or Part 2 or wi n d o we d visit f or 
i nte grate d a nal ysis see secti o n 4. 1)  
T he P K p o p ulati o n will i ncl u de all s u bjects w h o ar e ra n d o mize d a n d ha ve at least 1 e val ua ble p ost 
d ose or p ost s ha m- pr oce d ure P K sa m ple.  
T he i m m u n o ge nicit y p o p ulati o n wi ll i ncl u de all s u bjects w h o are ra n d o mize d a n d ha ve at least 1 
e val ua ble p ost d ose or p ost s h a m- pr oce d ure i m m u n o ge nicit y data. 
F or all ti me-t o-e ve nt e n d p oi nts, (e. g., ti me t o deat h or per ma n e nt ve ntilati o n), t he date of first 
d ose/s ha m a d mi nistrati o n will be use d as t he refe re nce ti me p oi nt. If t he date of first d ose/s ha m 
pr oce d ure is i nc o m plete, t he date of ra n d o mizati o n will be use d . 
S u m mar y statistics will be prese nte d t hr o u g h o ut.  F or c o nti n u o us e n d p oi nts, s u m mar y statistics 
will ge nerall y i ncl u de n u m ber of s u bjects wit h da ta, mea n, sta n dar d de viati o n, me dia n, mi ni m u m 
a n d ma xi m u m. T he mea n c ha n ges fr o m baseli ne w ill be esti mate d wit h 9 5 % c o nfi de nce i nter vals. 
F or cate g orical e n d p oi nts, s u m mar y statistics w ill ge nerall y i ncl u de: n u mber of s u bjects d ose d, 
n u m ber of s u bjects wit h data, a n d t he perce nta ge of t h ose wit h data i n eac h cate g or y. Fre q ue nc y 
distri b uti o ns will be prese nte d as a p pr o priate. 
T he statistical s oft ware, S A S ® versi o n 9. 4 or a b o ve , will be use d f or all s u m maries a n d statistical 
a nal yses.  
F or Part 2, a li mite d n u m ber of s u m maries will be pr o d uce d. T he a p pr oac h will be t o preser ve t he 
Part 1 st u d y gr o u pi n gs as f oll o ws f o r Safet y a n d Efficac y p o p ulati o n: 
 Pre vi o us c o ntr ol. 
 Pre vi o us I SI S 3 9 6 4 4 3. 
 T otal ( pre vi o us c o ntr ol a n d pre vi o us I SI S 3 9 6 4 4 3).  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 1 of 5 4 
 
 
F or t he i nte grate d a nal yses, t he Safet y dis pla ys will be gr o u pe d as f oll o ws: 
 Pre vi o us c o ntr ol, Part 1, fr o m t hei r first s ha m pr oce d ure i n Part 1.  
 Pre vi o us c o ntr ol, Part 2, fr o m t hei r first I SI S 3 9 6 4 4 3 d ose i n Part 2.  
 Pre vi o us I SI S 3 9 6 4 4 3, Part 1 a n d 2, fr o m t heir first I SI S 3 9 6 4 4 3 d ose i n Part 1.  
 T otal ( Pre vi o us c o ntr ol Part 2 a n d pre vi o us I SI S 3 9 6 4 4 3 Part 1 a n d 2) 
F or t he i nte grate d a nal yses, t he Efficac y dis pla ys will be gr o u pe d as f oll o ws: 
 Pre vi o us c o ntr ol, Part 1, fr o m t hei r first s ha m pr oce d ure i n Part 1.  
 Pre vi o us c o ntr ol, Part 2, fr o m t hei r first I SI S 3 9 6 4 4 3 d ose i n Part 2.  
 Pre vi o us c o ntr ol, Part 1 a n d 2, fr o m t heir first s ha m pr oce d ure i n Part 1. 
 Pre vi o us I SI S 3 9 6 4 4 3, Part 1 a n d 2, fr o m t heir first I SI S 3 9 6 4 4 3 d ose i n Part 1.  
3  
St u d y S u bj ects 
3. 1  
S u bject Acc o u nt a bilit y 
T he n u m ber of s u bjects w h o were ra n d o mize d, s plit b y  stratificati o n fact or (a ge of s y m pt o m o nset: 
< 6 a n d > = 6 m o nt hs), w h o were d ose d, w h o c o m plete d Part 1 b ut n ot i n Part 2, w h o c o m plete d Part 
2,  w h o  disc o nti n ue d  treat me nt  al o n g  wit h  t he  reas o ns  wit h dra w i n g  fr o m  t he  st u d y,  will  be  
prese nte d. 
Listi n gs  of  t h ose  s u bjects  w h o  wit h dr e w  fr o m  t he  st u d y  a n d  t he  reas o ns  f or  
disc o nti n uati o n/ wit h dra wal will be prese nte d. S u bjects w h o die d d uri n g t he st u d y will be liste d 
se paratel y. 
3. 2  
De m o gr a p h y a n d B aseli ne Dise ase C h ar acteristics 
Baseli ne data ( de m o gra p h y, birt h c haracteristics a n d S M N hist or y, me dica l hist or y a n d baseli ne 
c haracteristics) will be s u m marize d. Me dical hist or y was c ollecte d o nl y at scree ni n g of Part 1. 
De m o gra p h y i ncl u des a ge at Part 1 first d ose ( < = 7, > 7 < = 1 8, > 1 8 m o nt hs t o 2 years, > = 2 t o < 3 
years, > = 3 t o < 4 years, > = 4 t o 5 years, a n d > 5 years) a n d a ge at Part 2 first d ose (si milar 
cate g ories), se x, et h nicit y, a n d race. S M A hist or y will i ncl u de a ge at S M A o nset ( m o nt hs), a ge at 
S M A dia g n osis ( m o nt hs), a n d disease d urati o n.  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 2 of 5 4 
 
Baseli ne disease c haracteristics will i ncl u de HI N E m ot or milest o nes a n d gr o wt h para meters – 
t hese assess me nts are f urt her descri be d i n Secti o n 4 .  
Baseli ne  will  ge nerall y  be  defi ne d  as  t he  cl osest  meas ure me nt  bef or e  t he  first  d ose/s ha m  
pr oce d ure. F or Part 2, t he baseli ne c o ul d be t he pr e d ose assess me nt of Da y 1, or t he last assess me nt 
i n Part 1, de pe n di n g o n t he act ual sc he d ule of e ve nts i n Part 2 see secti o n 1. 4. 
De m o gra p hic a n d baseli ne disease c h aracteristics will be prese nte d f or t he Safet y set as well as 
b ot h re peate d b y a ge of S M A o nset ( < 6 m o nt hs, > = 6 m o nt hs). 
3. 3  
E xte nt of E x p os ure 
T he n u m ber of d oses a n d or/ s ha m pr oce d ures will  be s u m marize d usi n g fre q ue nc y distri b uti o ns. 
T he a m o u nt of N usi nerse n recei ve d will be  s u m marize d usi n g s u m mar y statistics.  
O verall ti me o n st u d y will be defi ne d as t he t otal n u m ber of da ys a s u bject is k n o w n t o be f oll o we d 
o n st u d y a n d will be calc ulate d as f oll o ws: 
O verall ti me o n st u d y = ( Last date o n st u d y) – ( Date of  first d ose or first s ha m pr oce d ure) + 1. 
T he last date o n st u d y is defi ne d as  t he date of t he latest visit or e val uati o n or tele p h o ne c o ntact, 
or ti me of deat h fr o m all a vaila ble data f or a gi ve n s u bject.  
Gi ve n t he l o n g half-life of  N usi nerse n, s u bjects are c o nsi dere d t o be e x p ose d t o st u d y dr u g fr o m 
t he ti me t he first d ose was a d mi nistere d t o t he last da y of f oll o w- u p. Esse ntiall y, e x p os ure is 
e q ui vale nt t o ti me o n st u d y.  
T he d osi n g a n d ti me o n st u d y will be s u m mari ze d o nl y f or Part 2 a n d i nte grate d data. 
3. 4  
C o nc o mit a nt t her a p y 
A c o nc o mita nt t hera p y is a n y dr u g or s u bsta nce a d mi nistere d be t wee n Scree ni n g a n d or E n d of 
st u d y E val uati o n.  
T hr o u g h o ut t he st u d y, I n vesti gat ors or desi g nate d  lice nse d p h ysicia ns i nv ol ve d i n t he st u d y ma y 
prescri be c o nc o mita nt me dicati o ns or treat me nts dee me d necessar y f or treat me nt of A Es or t o 
pr o vi de  a de q uate  s u p p orti ve  care.  S u bjects  are  pr o hi bite d  fr o m  recei vi n g  ot her  e x peri me ntal  
a ge nts, i ncl u di n g ge ne t hera p y, d uri n g t he st u d y. T his i ncl u des mar kete d a g e nts at e x peri me ntal 
d oses t hat are bei n g teste d f or t he treat me nt of S M A (e. g., al b uter ol/ sal b uta m ol, ril uz ole, car niti ne, 
s o di u m p he n yl b ut yrate, val pr oate, h y dr o x y urea). All c o nc o mita nt me dicati o ns will be c o de d usi n g 
t he W orl d Healt h Or ga nizati o n dr u g dicti o nar y ( W H O Dr u g). 
A c o nc o mita nt pr oce d ure is a n y t hera pe utic i nter ve nti o n (e. g., s ur ger y/ bi o ps y, p h ysical t hera p y) 
or dia g n ostic assess me nt (e. g., bl o o d gas meas ure me nt, bacterial c ult ures) perf or me d bet wee n t he 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 3 of 5 4 
 
ti me t he s u bject is e nr olle d i n t he st u d y a n d E n d of Part 2. T hese will be c ollecte d o n t he a ncillar y 
pr oce d ure pa ge of t he e C R F a n d will be c o de d usi n g Me d D R A. 
F or t he p ur p oses of a nal ysis, a c o nc o mita nt t hera p y (i ncl u di n g me dicati o n or pr oce d ure) is defi ne d 
as a n y t hera p y t hat was ta ke n or a d mi nistere d o n or after t he first i njecti o n of N usi nerse n or s ha m 
pr oce d ure. F or s u bjects recei vi n g t he s ha m pr oce d ure i n Part 1 w h o s u bse q ue ntl y r oll o ver o nt o 
N usi nerse n i n Part 2, a n a d diti o nal defi niti o n will  be a p plie d a n d t hera pies will be c o nsi dere d t o 
be c o nc o mita nt me dicati o n if t he y were ta ke n o n or  after t he first d ose of N usi nerse n i n Part 2. 
T his defi niti o n i ncl u des t hera pies t hat were starte d pri or t o t he i nitiati o n of i njecti o n of N usi nerse n 
or s ha m pr oce d ure if t heir use c o nti n ue d o n or afte r t he first i njecti o n of N usi nerse n. I n or der t o 
defi ne c o nc o mita nt t hera pies wit h missi n g start or st o p dates, t he f oll o wi n g a d diti o nal criteria will 
be use d: 
 
 if b ot h t he start a n d st o p dates of a partic ular t hera p y were missi n g, t hat t hera p y is 
c o nsi dere d c o nc o mita nt; 
 if t he start date of a t hera p y was missi n g a n d t he st o p date of t hat t hera p y fell o n or after 
t he date of d osi n g, t hat t hera p y is c o nsi dere d c o nc o mita nt; 
 if t he start date of a t hera p y was pri or t o t he date of d osi n g a n d t he st o p date of t hat 
t hera p y was missi n g a n d t he t hera p y was liste d as c o nti n ui n g, t hat t hera p y is c o nsi dere d 
c o nc o mita nt;  
 if t he start date of a t hera p y was pri or t o t he date of d osi n g a n d t he st o p date of t hat 
t hera p y was missi n g a n d t he t hera p y was liste d as n ot  c o nti n ui n g, t hat t hera p y is 
c o nsi dere d c o nc o mita nt, or 
 if t he start or st o p date of a t hera p y is partial, it will be c o nsi dere d c o nc o mita nt w here it is 
n ot p ossi ble t o r ule o ut t hat it was n ot ta ke n c o nc o mita ntl y. 
T he n u m ber a n d perce nta ge of s u bjects w h o were ta ki n g eac h t y pe of c o nc o mita nt me dicati o n at 
baseli ne a n d d uri n g t he st u d y will be prese nte d. T he n u m ber a n d perce nta ge of s u bjects ta ki n g 
eac h t y pe of a ncillar y pr oce d ure will be prese nte d b y preferre d ter m.   
3. 5  
Pr ot oc ol de vi ati o ns 
Pr ot oc ol de viati o ns i de ntifie d d uri n g site m o nit ori n g will be ca pt ure d i n a pr ot oc ol de viati o n l o g 
a n d cate g orize d as maj or or mi n or de viati o ns. T h ese de viati o ns will be liste d. Maj or pr ot oc ol 
de viati o ns will be s u m marize d f or o nl y Part 2 as part of t his S A P.  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 4 of 5 4 
 
4  
Effic ac y d at a (e x pl or at or y)  
4. 1  
Visit Wi n d o wi n g  
P art 2 a n alysis  
Part 2 will ter mi nate earl y a n d t he e n d of st u d y vi sit will occ ur at differe nt ti me p oi nts, f or t his 
reas o n t he e n d of st u d y visit will be re-la bele d a n d wi n d o we d as f oll o w: 
 If t he act ual st u d y da y falls wit hi n +/- 7 da ys of a n y of Part 2 Da y x x visit, t he e n d of 
st u d y visit will be re-la belle d as t he c orres p o n di n g sc he d ule d visit. 
 Ot her wise, t he e n d of st u d y visit will be  re-la belle d as a n u nsc he d ule d visit. 
 
I nte gr ate d a n alysis  
T he HI N E m ot or milest o nes, gr o wt h para meters  a n d C GI, la b orat or y data, C S F a n d Plas ma 
c o nce ntrati o ns i nte grate d a nal yses will be wi n d o we d as f oll o ws: 
 
St u d y da ys < = 1 will be la belle d Baseli ne  
 St u d y da ys > 1 t o < = 2 2 will be la belle d Da y 1 5 
 St u d y da ys > 2 2 t o < = 4 7 will be la belle d Da y 2 9 
 St u d y da ys > 4 7 t o < = 1 2 3 will be la belle d Da y 6 4 
 St u d y da ys > 1 2 3 t o < = 2 4 2 will be la belle d Da y 1 8 3 
 St u d y da ys > 2 4 2 t o < = 3 6 2 will be la belle d Da y 3 0 2 
 St u d y da ys > 3 6 2 t o < = 4 8 2 will be la belle d Da y 4 2 2 
 St u d y da ys > 4 8 2 t o < = 6 0 0 will be la belle d Da y 5 4 0 
 St u d y da ys > 6 0 0 t o < = 7 1 9 will be la belle d Da y 6 5 9 
 St u d y da ys > 7 1 9 t o < = 8 3 8 will be la belle d Da y 7 7 8 
  St u d y da ys > 8 3 8 t o < = 9 5 8 will be la belle d Da y 8 9 8 
  St u d y da ys > 9 5 8 t o < = 1 0 7 8 will be la belle d Da y 1 0 1 8 
 St u d y da ys > 1 0 7 8 t o < = 1 1 9 8 will be la belle d Da y 1 1 3 8 
 
If m ulti ple res ults are all ocate d i nt o t he sa me wi n d o w t he n t he cl osest n o n- missi n g res ult t o t he 
tar get date will be c h ose n. 
I n  or der  t o  acc o u nt  f or  t he  de n o mi nat or  acr oss  t he  a nal ysis  visits,  a n  Efficac y  set  f or  eac h  
wi n d o we d a nal ysis visit ( Da y  X) will be defi ne d as: a s u bset of s u bjects i n t he Safet y set w h o ha ve 
t he o p p ort u nit y t o be assesse d at t he Da y X visit, w here t he l o wer b o u n d f or t he wi n d o we d a nal ysis 
visit are de n ote d: L = l o wer. S pecificall y, it will i ncl u de all s u bjects wit h a ti me differe nce of at 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 5 of 5 4 
 
least L da ys bet wee n t he date of first d ose a n d t he e n d of Part 2. A s u bject w h o has die d or 
wit h dra w n will be i ncl u de d pr o vi de d t hat t here is a differe nce of at least L da ys bet wee n t he date 
of first d ose a n d t he e n d of Part 2. I n a sit ua ti o n w here t he s u bject was k n o w n t o ha ve wit h dra w n 
fr o m t he st u d y at a date wit hi n t he wi n d o w d ue t o r olli n g o ver t o c o m mercial dr u g t he n t he y will 
be e xcl u de d fr o m t he c orres p o n di n g Efficac y set a n d s u bse q ue nt a nal ysis visit Efficac y sets.   
A n e val ua ble set will be defi ne d f or eac h a nal ysis visit as t he s u bset of s u bjects i n t he Efficac y set 
at t he a nal ysis visit w h o meet t he f oll o wi n g criteria:  
 Val ue assi g ne d fr o m t he wi n d o wi n g  
 S u bject w h o die d or disc o nti n ue d fr o m t he st u d y – n o i m p utati o n of efficac y data will be 
perf or me d f or s uc h s u bjects a n d t he y  will be c o nsi dere d n o n-res p o n ders. 
 N o val ue assi g ne d fr o m wi n d o wi n g, b ut o n g oi n g i n st u d y wit h a s u bse q ue nt assess me nt 
assi g ne d t o a later a nal ysis visit. I n t his si t uati o n, a val ue will be i m p ute d as t he val ue 
fr o m t he a nal ysis visit pri or t o t he missi n g visit. 
 
A c o u ple of c o nsi derati o n as part of t his fi nal criteri o n are as f oll o ws: 
 
 I n a sit uati o n w here a s u bject d oes n ot ha ve a wi n d o we d val ue at a nal ysis visit X a n d is 
k n o w n t o disc o nti n ue at t he ne xt visit, X + 1,  wit h o ut a n effi cac y assess me nt, t he s u bject 
w o ul d n ot be i ncl u de d wit hi n t he de n o mi nat or  f or t he res p o n der a nal ysis at visit X, b ut 
t he y w o ul d be i ncl u de d as a n o n-res p o n der at visit X + 1. 
 I n a sit uati o n w here a s u bject d oes n ot ha ve a wi n d o we d val ue at a nal ysis visit X a n d is 
k n o w n t o disc o nti n ue at t he ne xt visit, X + 1, wit h a n efficac y assess me nt pri or t o t he 
disc o nti n uati o n, t he s u bject w o ul d be i ncl u de d wit hi n t he de n o mi nat or f or t he res p o n der 
a nal ysis at visit X a n d t he last o bser ve d val ue will be utilize d, a n d t he n t he y w o ul d be 
i ncl u de d as a n o n-res p o n der at visit X + 1. 
 
4. 2  
Ve ntil ati o n d at a 
Ve ntilat or use d uri n g t he st u d y will be trac ke d at  st u d y visits, wit h details c ollecte d usi n g a 
ve ntilati o n diar y or ot her a vaila ble s o urces. Care gi vers will i niti ate c ollecti n g ve ntilati o n diar y 
data f or all s u bjects. N ote, o nce t he first e ntr y of  ve ntilati o n use has bee n rec or de d o n t he diar y, 
t he n t he diar y will t he n nee d t o be c o m plete d u ntil t he e n d of t he st u d y. If t he dail y n u m ber of 
h o urs of ve ntilati o n a n d t he t y pe is  t he sa me f or c o nsec uti ve da ys, t he n t he first a n d last da y date 
will be ca pt ure d, t o get her wit h t he dail y h o urs a n d t y pe of ve ntilati o n – in vasi ve/ n o n-i n vasi ve (f or 
pr o p h yla xis or treat me nt). F or da ys o n w hic h ve ntilat or use was n ot rec o r de d, t he n u m ber of h o urs 
of use will be i m p ute d usi n g t he greater of t he dail y val ues a m o n g t he da ys t hat fla n k t he missi n g 
da y(s).  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 6 of 5 4 
 
4. 2. 1  C h a n ge i n Ve ntil at or use 
I n t he statistical a nal ysis of Part 1, f or eac h s u bject t he mea n n u m ber of h o urs of ve ntilat or was 
calc ulate d a m o n gst t he peri o ds. T hes e peri o ds were create d fr o m t he first d ose of N usi nerse n or 
s ha m pr oce d ure t o t he n o mi nal visit.(e xa m ple Da y 1: > fr o m Da y 1 t o Da y 1 5 visit; Da y 1 5: fr o m 
Da y 1 5 i ncl usi ve t o Da y 2 9 visit). I n Part 2 f or eac h s u bject t he mea n n u m ber of h o urs will be 
calc ulate d f or a m o nt hl y i nter val ( 3 0 da ys) starti n g fr o m t he first d ose of N usi nerse n or s ha m 
pr oce d ure. T he i nter vals will be: m o nt h 1 fr o m Da y 1 i ncl usi ve t o Da y 3 0, M o nt h 2 fr o m Sa y 3 0 
i ncl usi ve t o Da y 6 0, a n d s o o n.  
T he c ha n ge fr o m baseli ne o ver ti me will be prese nte d a n d a pl ot of b ot h t otal a n d c ha n ge fr o m 
baseli ne will be prese nte d. 
F or eac h s u bject, t he t otal n u m ber of h o urs of ve n tilati o n s u p p ort re q uire d d uri n g t he st u d y will be 
calc ulate d a n d pr orate d acc or di n g t o n u m ber of da ys  o n st u d y. T he perce nta ge of ti me o n ve ntilat or 
s u p p ort i n t otal a n d b y t y pe eit her i n vasi ve pr o p h ylactic, i n vasi ve treat me nt, or n o n-i n vasi ve 
pr o p h ylactic a n d n ot i n vasi ve trea t me nt will be prese nte d.  
T he differe nt res pirat or y ai ds/t hera pies use d will be liste d  
4. 2. 2  Ti me t o De at h or Per m a ne nt Ve ntil ati o n 
Per ma ne nt ve ntilati o n is defi ne d as trac he ost o m y or ≥1 6 h o urs of ve ntilat or y s u p p ort per da y 
c o nti n u o usl y f or > 2 1 da ys i n t he a bse nce of a n ac ute re versi ble e ve nt. T his e n d p oi nt was n ot pre-
s pecifie d i n t he pr ot oc ol. 
Ti me t o per ma ne nt ve ntilati o n a n d ac ute re versi ble  e ve nts will be deter mi ne d b y me dical re vie w. 
F or all ti me-t o-e ve nt e n d p oi nts (e. g., ti me t o deat h or per ma ne nt ve ntilati o n), t he date of first 
d ose/s ha m a d mi nistrati o n will be use d as t he refe re nce ti me p oi nt. If t he date of first d ose/s ha m 
pr oce d ure is i nc o m plete, t he date of ra n d o mizati o n will be use d. O nl y e ve nts t hat were a dj u dicate d 
will be i ncl u de d i n t he a nal ysis. S u bjects w h o d o n ot meet t he e n d p oi nt defi niti o n will be ce ns ore d 
at t he last occasi o n t he s u bject wa s see n (eit her i n- pers o n visit or b y tele p h o ne c o ntact ), irres pecti ve 
of w het her t he s u bject has c o m plete d a f ull c o ur se of treat me nt a n d w het her t he s u bject has 
c o m plete d t he st u d y or wit h dra w n pre mat urel y. H o we ver, i n t he e ve nt t hat a s u bject has be g u n a 
ve ntilati o n diar y, t he latest e ntr y i n t he diar y will be use d as t he date of ce ns ori n g. Of n ote, o nce a 
ve ntilati o n diar y has bee n starte d, t he diar y will t he n nee d t o be c o m plete d e ver y da y u ntil t he e n d 
of t he st u d y. 
T he me dia n ti mes t o deat h or per ma ne nt ve ntilati o n a n d ass ociate d 9 5 % c o nfi de nce li mits will be 
esti mate d usi n g t he Ka pla n- Meier met h o d. T he pr o p orti o n of s u bjects w h o meet s uc h a n e ve nt 
will be esti mate d fr o m t he Ka pla n- Meier c ur ve. 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 7 of 5 4 
 
4. 2. 3  S ur vi v al 
S ur vi val rates o ver ti me will be esti mate d fr o m t he Ka pla n- Meier c ur ve f or ti me t o deat h base d 
o n t he Safet y set. 
4. 3  
Gr o wt h p ar a meters 
Gr o wt h para meters c o m prise le n gt h f or a ge, wei g ht  f or a ge, wei g ht f or le n gt h, hea d circ u mfere nce 
f or a ge, c hest circ u mfere nce, hea d t o c hest circu mfere nce rati o, a n d ar m circ u mfere nce are t o be 
assesse d t hr o u g h t he st u d y. 
  
T he W H O c hil d gr o wt h sta n dar ds ( W H O C hil d Gr o w t h Sta n dar ds, 2 0 0 6) will be use d t o deter mi ne 
t he perce ntiles f or eac h para meter. T he W H O pr o vi des a S A S macr o ( S A S i gr o w u p pac ka ge) w hic h 
ca n  be  d o w nl oa de d  fr o m  a  we bsite  [ W H O  A nt hr o ] a n d  t his  will  be  utilize d  t o  calc ulate  t he 
perce ntiles f or eac h c hil d. 
T he c ha n ge fr o m bas eli ne t o e ac h wi n d o we d a n al ysis visit will be  s u m marize d usi n g descri pti ve 
statistics f or t he f oll o wi n g gr o wt h para m eters: wei g ht f or a ge, w ei g ht f or le n gt h/ hei g ht, hea d 
circ u mfere nce, c h est circ u mfere n ce, hea d  t o c hest circ u mfere nce r ati o n a n d ar m 
circ u mf er e nce. Prese ntati o ns will be ma de f or all gr o u ps. 
 
T w o a d diti o nal a nal yses will be perf or me d e x a mi ni n g t he c h a n ge bet wee n W H O perce ntiles 
( S pr o ule 2 0 1 2). I n t he first a nal ysis, s u bjects wit h wei g ht bel o w t h e 5t h perce ntile base d o n 
W H O gr o wt h c harts, i n t he s ec o n d, s u bjects wit h decr ease d gr o wt h vel ocit y res ulti n g i n falli n g 
m ore t ha n maj or perce ntiles ( 3 r d, 5t h, 1 0t h, 2 5t h, 5 0t h, 7 5t h, 9 0t h, 9 5t h, 9 7t h) o ver a 6- m o nt h 
peri o d will be use d. B ot h a n al yses will be prese nt e d b y wi n d o w e d a nal ysis visit b y i n de x 
treat me nt gr o u p a n d o ver all. 
 
Gr o wt h para meters will als o be s u m marize d b y a ge of S M A o nset ( < = 6 m o nt hs, > 6 m o nt hs). 
Missi n g v al ues 
N o i m p utati o n will be perf or me d f or missi n g data. 
 
4. 4  
N u m ber of H os pit aliz ati o ns  
T he n u m ber a n d reas o n f or h os pitalizati o ns  per s u bject will be s u m marize d.  
 
4. 5  
M ot or milest o nes 
M ot or milest o nes assess me nts are ma de usi n g HI N E, Secti o n 2 a n d W H O m ot or milest o nes (after 
V 4 of t he pr ot oc ol). Eac h assess me nt is  descri be d i n f urt her detail bel o w.  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 8 of 5 4 
 
4. 5. 1  HI N E m ot or milest o nes 
HI N E Secti o n 2 c o m prises ei g ht tests f or m ot or mile st o nes: hea d c o ntr ol, sitti n g, v ol u ntar y gras p, 
a bilit y t o kic k i n s u pi ne p ositi o n, r o lli n g, cra wli n g, sta n di n g, a n d wal ki n g. 
T here are 2 6 p ossi ble m ot or milest o nes t hat ca n be ac hie ve d usi n g t his sc he ma ( prese nte d bel o w). 
A s u bject w h ose res ults all a p pear i n t he first c ol u m n ( u na ble t o mai ntai n hea d u pri g ht, ca n n ot sit, 
n o gras p, etc.) has n ot ac hie ve d a n y m ot or milest o ne. A s u bject w h ose res ults all a p pear i n t he 
sec o n d c ol u m n ( hea d w o b bles, sits wit h s u p p ort at hi ps, uses t he w h ole ha n d f or a v ol u ntar y gras p, 
etc.) has ac hie ve d 8 m ot or milest o ne s. A s u bject w h ose res ults all a p pear i n t he t hir d c ol u m n ( hea d 
mai ntai ne d u pri g ht all t he ti me, pr o ps w he n sitti n g, i n de x fi n ger a n d t h u m b b ut i m mat ure gras p, 
etc.) has ac hie ve d 1 6 m ot or milest o nes. 
Att ai n me nt of m ot or milest o nes assesse d by Se cti o n 2 of t he H a m mers mit h  I nf a nt Ne ur ol o gic al 
Ex a mi n ati o n ( HI N E) 
F or t he i nte grate d a nal ysis, t he HI N E m ot or milest o nes a nal yses will be prese nte d b y wi n d o we d 
a nal ysis visits (see secti o n 4. 1).  
 
T he defi niti o n of a m ot or milest o ne res p o n der is  base d u p o n t he m ot or milest o nes cate g ories i n 
Secti o n 2 of t he HI N E, wit h t he e xcl usi o n of v ol u ntar y gras p as f oll o ws: 
 S u bject de m o nstrates at least a 2- p oi nt i ncr ease i n t he cate g or y of a bilit y t o kic k or 
i ncrease t o t he ma xi mal sc ore o n t hat cate g ory (t o uc hi n g t oes), or a 1 – p oi nt i ncrease i n 
t he m ot or milest o nes cate g or y of hea d c o ntr ol, r olli n g, sitti n g, cra wli n g, sta n di n g, or 
wal ki n g A N D 
 A m o n g t he m ot or milest o ne cate g ories, wit h t h e e xcl usi o n of v ol u ntar y gras p, t here are 
m ore cate g ories w here t here is i m pr o ve me nt, as defi ne d i n (i) be l o w, t ha n t here are 
cate g ories w here t here is w orse ni n g (as defi ne d bel o w).  
 S u bjects w h o die or wit h dra w fr o m t he st u d y o n  or pri or t o t he visit will be c o u nte d as 
n o n-res p o n ders a n d will be i n cl u de d i n t he de n o mi nat or 
I m pr o ve me nt i n m ot or milest o nes is defi ne d as a 2- p oi nt i ncrease i n t he t otal m ot or milest o nes 
sc ore, w here v ol u ntar y gras p is e xcl u de d. F or e xa m ple, (i) a 1- p oi nt i ncrease i n hea d c o ntr ol 
a n d a 1- p oi nt i ncrease i n r olli n g is c o nsi dere d a res p o nse, (ii) a 2- p oi nt i ncrease i n r olli n g is 
c o nsi dere d a res p o nse, (iii) a 2- p oi nt i ncrease i n  r olli n g wit h a 1- p oi nt decrease i n hea d c o ntr ol 
is c o nsi dere d a n o n-res p o nse. W orse ni n g is defi ned as at least a 2- p oi nt decrease or a decrease 
t o t he l o west p ossi ble sc ore of n o kic ki n g. F or t he ot her 6 cate g ories, w ors e ni n g is defi ne d as 
at least 1- p oi nt decrease. 
T o ill ustrate t his res p o n der defi niti o n, e xa m ples are pr o vi de d bel o w. I n t hese e xa m ples, it is 
ass u me d t hat t here are n o c ha n ges i n m ot or milest o ne cate g ories ot her t ha n t h ose state d. 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 3 9 of 5 4 
 
 A s u bject wit h a 2- p oi nt i ncrease of a bilit y t o kic k, a 1- p oi nt i ncrease i n r olli n g, a n d a 
1- p oi nt decrease i n hea d c o ntr ol is a res p o n der.  
 A s u bject wit h a 1- p oi nt i ncrease of a bilit y t o kic k fr o m “t o uc hes le gs” t o “t o uc hes t oes” 
is a res p o n der.  
 A s u bject wit h a 1- p oi nt i ncrease of hea d c o ntr ol a n d a 1- p oi nt d ecrease r olli n g is a n o n-
res p o n der.  
 A s u bject wit h a 1- p oi nt i ncrease of r olli n g a n d a 2- p oi nt decrease i n a bilit y t o kic k is a 
n o n-res p o n der.  
 A s u bject wit h a 1- p oi nt i ncrease of r olli n g a n d a 1- p oi nt decrease of a bilit y t o kic k fr o m 
“ u p war d verticall y” t o “ kic ks h oriz o nta l, le gs d o n ot lift” is a res p o n der.  
 A s u bject wit h a 1- p oi nt i ncrease of r olli n g a n d a 1- p oi nt decrease of a bilit y t o kic k fr o m 
“ kic ks h oriz o ntal, le gs d o n ot lift” t o “ n o kic ki n g” is a n o n-res p o n der.  
 A s u bject wit h a 2- p oi nt i ncrease of  v ol u ntar y gras p is a n o n-res p o n der.  
 A s u bject wit h a 1- p oi nt i ncrease of r olli n g a n d a 2- p oi nt decrease of v ol u ntar y gras p is a 
res p o n der.  
 
T he res p o nse will be c o n d ucte d o n data fr o m eac h vi sit a n d wi n d o we d visit se paratel y f or Part 2 
a n d i nte grate d a nal ysis res pecti vel y (see se cti o n 4. 1 f or details a b o ut t he wi n d o wi n g).  
 
A d diti o n al prese nt ati o ns of HI N E m ot or milest o nes  
  T he a b o ve res p o n der a nal ysis will be re peate d f or t he s u bjects t hat are res p o n der at 
last a vaila ble assess me nt. F or t h ose s u bjects t hat are resp o n ders, t he a nal ysis visits 
w he n first res p o n d occ urre d will be als o dis pla ye d. 
 T he pr o p orti o n of s u bjects w h o ha ve  ac hie ve d t he f oll o w milest o nes: 
 F ull hea d c o ntr ol, 
 Sta ble sit or pi v ots, 
 Sta n d u nai de d, 
 Wal k i n de pe n de ntl y 
will be prese nte d b y visit a n d at t he last a vaila ble assess me nt (f or t he i nte grate d 
a nal ysis)  
 T he pr o p orti o n of s u bjects w h o ha ve ac hie ve d i n di vi d ual milest o nes will be prese nte d 
b y visit.  
T he s hift fr o m baseli ne t o last a vaila ble a ssess me nt (f or t he i nte grate d a nal ysis).  
 T he t otal m ot or milest o nes sc ore ac hie ve d o ver ti me will be prese nte d (f or Part 2 o nl y 
a n d t he i nte grate d a nal ysis) .                                                                                                                     


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 0 of 5 4 
 
 T he c ha n ge fr o m baseli ne o ver ti me will be prese nte d a n d a pl ot of b ot h t otal a n d 
c ha n ge fr o m baseli ne will be prese nte d (f or Part 2 o nl y a n d t he i nte grate d a nal ysis) .                            
 
T he a nal ysis of m ot or milest o nes res p o n ders a n d s u m maries of t otal m ot or milest o nes sc ore will 
als o be c o n d ucte d b y a ge of S M A o nset ( < = 6 m o nt hs, > 6 m o nt hs). 
 
 
Missi n g data  
P art 2 a n alysis  
F or Part 2 HI N E m ot or milest o nes, Baseli ne will be  retrie ve d fr o m Part 1 a n d it will be t he last 
assess me nt i n Part 1.  
S o me ge neral r ules f or t he a p pr oac hes t o i m p uta ti o n of missi n g data are descri be d i n t he f oll o wi n g 
secti o ns. 
1)  If a s u bject has a n y milest o nes missi n g at baseli ne t he n t he missi n g milest o ne will be 
i m p ute d usi n g t he me dia n baseli ne val ue wit hi n t he a ge of S M A o nset ( < = 6 m o nt hs, > 6 
m o nt hs). f or t he c orres p o n de nt milest o ne le vel 
2)  If a s u bject has a n y missi n g milest o nes at a n y visit t hat is n ot last visit, t he n t he missi n g 
milest o ne will be i m p ute d usi n g a li near i nter p olati o n at t he milest o ne le vel f or a n y act ual 
sc he d ule d st u d y visits. 
3)  If a s u bject has a n y missi n g milest o nes at last visit, t he n t he missi n g milest o ne will be 
i m p ute d usi n g t he l o west o bser ve d val ue f or milest o ne assi g ne d wit hi n t he a ge of S M A 
o nset ( < = 6 m o nt hs, > 6 m o nt hs) a n d gr o u p t o w hic h t he s u bject bel o n gs at t hat visit (e. g., if 
a pre vi o us c o ntr ol s u bject’s last  visit is Da y 1 2 0, t he n t he at l o west o bser ve d val ue f or t he 
pre vi o us c o ntr ol gr o u p at Da y 1 2 0 is use d f or t he n o n- missi n g val ues f or t he s pecific m ot or 
milest o ne). 
 
I nte gr ate d a n alysis  
F or t he i nte grate d a nal ysis, t h ese r ules will be a p plie d:  
F or s u bjects ra n d o mize d t o N usi nerse n i n Part 1 t he n  Part 1 a n d Part 2 will be c o nsi dere d as a o ne 
peri o d a n d a n y data a vaila ble will be use d f or a n y i m p utati o n. H o we ver, f or s u bjects w h o were 
ra n d o mize d t o recei ve S ha m i n Part 1 t he n t he t w o peri o ds ( Part 1 a n d 2) will be c o nsi dere d 
se paratel y a n d n o i m p ut ati o n will be all o we d i.e., n o i nter p ola ti o n bet wee n t he 2 peri o ds.  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 1 of 5 4 
 
T he i m p utati o n of missi n g data will f oll o w t hese r ules: 
1)  If a s u bject has a n y milest o nes missi n g at baseli ne t he n t he missi n g milest o ne will be 
i m p ute d usi n g t he me dia n baseli ne val ue wit hi n t he a ge of S M A o nset ( < = 6 m o nt hs, > 6 
m o nt hs). f or t he c orres p o n de nt milest o ne le vel 
2)  If a s u bject has a n y missi n g milest o nes at a n y ot her visit t hat is n ot last visit t he n t he missi n g 
milest o ne will be i m p ute d usi n g a li near i nter p olati o n at t he milest o ne le vel f or a n y act ual 
sc he d ule d st u d y visits (f or last visit, please see b ullet p oi nt 4). 
3)  Perf or m wi n d o wi n g selecti n g t he cl osest n o n- missi n g milest o ne t o t he tar get date  
4)  If a s u bject has a least o ne milest o ne o bser ved b ut s o me milest o nes are missi n g, t he n a n y 
missi n g milest o nes at t he last visit will be i m p ute d usi n g t he l o west o bser ve d val ue f or t hat 
milest o ne, assi g ne d wit hi n t he a ge of S M A o nset ( < = 6 m o nt hs, > 6 m o nt hs) t o w hic h t he 
s u bject bel o n gs, at t hat wi n d o we d a nal ysis visit. If o nl y a date  is a vaila ble a n d all of t he 
milest o nes are missi n g, t he n n o i m p utati o n will be perf or me d. 
4. 5. 2  W H O m ot or milest o nes  
T he W H O m ot or milest o nes are a set of si x milest o nes i n m ot or de vel o p me nt, all of w hic h 
w o ul d be e x pecte d t o be attai ne d b y a ge 1 8 m o nt hs i n healt h y c hil dre n. T he i n di vi d ual 
milest o nes are:  
• Sitti n g wit h o ut s u p p ort  
• Sta n di n g wit h assista nce 
• Ha n ds a n d k nees cra wli n g  
• Wal ki n g wit h assista nce  
• Sta n di n g al o ne  
• Wal ki n g al o ne  
T he m ot or milest o nes are assesse d at visits, after t he V 4 pr ot oc ol a p pr o val at sites, usi n g t he 
W H O m ot or milest o ne criteria [ W H O M ultice n tre Gr o wt h Refere nce St u d y Gr o u p 2 0 0 6]. As 
part of t he assess me nt, t he e xa mi ner rec or ds a n o verall rati n g of t he s u bj ect’s e m oti o nal state a n d 
t he n f or eac h milest o ne o ne of t he f oll o wi n g f o ur classificati o ns:  
• N o (i na bilit y) – C hil d trie d b ut faile d t o perf or m t he milest o ne  
• N o (ref usal) – C hil d ref use d t o perf or m des pite bei n g cal m a n d alert  
• Yes – C hil d was a ble t o perf or m t he milest o ne  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 2 of 5 4 
 
• U na ble t o test – C o ul d n ot be teste d beca use of irrita bilit y, dro wsi ness or sic k ness.  
I n a n eff ort tr y a n d attac h greater precisi o n t o t he dates of first ac hie ve me nt of 
milest o nes, t he care gi vers are rec or di n g t he first date t he y o bser ve t he c hil d ac hie vi n g 
eac h milest o ne a n d t his is a d diti o nall y ca pt ure d i n t he C R F 
Missi n g v al ues 
N o i m p utati o n will be perf or me d f or missi n g data. 
4. 6  
Cli nic al Gl o b al I m pressi o n of C h a n ge  (I n vesti g at or a n d C are gi ver assess me nts) 
T he Cli nical Gl o bal I m pressi o n of C ha n ge ( C GI C) is  assesse d at s pecific visit. At eac h visit t he 
i n vesti gat or a n d t he s u bject’s care gi ver eac h score h o w t he s u bject has c ha n ge d c o m pare d t o 
‘a d missi o n t o t he pr oject’. T he assess me nt is sc ore d o n a 7- p oi nt or di nal scale ( 1 = Ver y m uc h 
i m pr o ve d, 2 = “ M uc h i m pr o ve d”, 3 =” Mi ni mall y i mpr o ve d”, 4 = “ N o c ha n ge fr o m baseli ne”, 5 = 
“ Mi ni mall y w orse”, 6 = “ M uc h w orse”, 7 = “ Ver y m uc h w orse”).  
I n or der t o i n vesti gate res p o nse o n t hese scales, t hree defi niti o ns of res p o n der will be defi ne d: 
“ M uc h  i m pr o ve d”:  Res p o n der  ( < = 2)  vers us  N o n-res p o n der  ( > = 3),  “ A n y  i m pr o ve me nt”:  
Res p o n der ( < = 3) vers us N o n-re s p o n der ( > = 4), “ N o w orse ni n g”: Res p o n der ( < = 4) vers us N o n-
res p o n der ( > = 5). At t he start of Part 2 f or s u bjects t hat were pre vi o usl y o n s ha m, t he q uesti o n was 
c ha n ge d t o be h o w t he s u bject has c ha n ge d c o m pare d t o ‘a d missi o n t o Part 2, w hile f or s u bjects 
re mai ni n g  o n  N usi nerse n,  t he  q uesti o n  re mai ne d  h o w  t he  s u bject  has  c ha n ge d  c o m pare d  t o  
‘a d missi o n t o t he Part 1.’ 
T he  pr o p orti o n  of  s u bjects  w h o  were  res p o n ders  base d  o n  t he  “ M uc h  i m pr o ve d”,  ‘ A n y  
i m pr o ve me nt’ a n d ‘ N o w orse ni n g’ defi niti o n of res p o n der will be prese nte d b y wi n d o we d a nal ysis 
visit.  
T hese a nal yses will be perf or me d se paratel y f or i n vesti gat or s a n d care gi vers’ res p o nses. T he 
a nal yses will als o be stratifie d base d o n a ge of S M A o nset ( < = 6 m o nt hs, > 6 m o nt hs). I n Part 2 t he 
data will be c ollecte d referri n g t o t he a d missi o n t o Part 1 or 2 res pecti vel y de pe n di n g o n t he 
ori gi nal treat me nt i n Part 1: pre vi o us S ha m s u bj ects will be sc ore d i n c o m paris o n t o ‘a d missi o n t o 
Part 2’, pre vi o us N usi nerse n s u bjects will be sc ore d i n c o m paris o n t o ‘a d missi o n t o Part 1 
Missi n g v al ues 
N o i m p utati o n will be perf or me d f or missi n g data. 
 
 
 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 3 of 5 4 
 
4. 7  
A C E N D 
T he  A C E N D  i ncl u des  a  t otal  of  se ve n  d o ma i ns  assessi n g  p h ysical  i m pact  (i ncl u di n g  
fee di n g/ gr o o mi n g/ dressi n g, sitti n g/ pla y, tra nsfers, a n d m o bilit y) a n d ge neral care gi ver i m pact 
(i ncl u di n g ti me, e m oti o n, a n d fi na nce) a n d eac h d o mai n c o m prises se veral ite ms. All t he A C E N D 
sc ores will be liste d a n d n ot s u m marize d f or t his a nal ysis bei n g t he data c ollecte d o nl y after t he 
latest versi o n of t he pr ot oc ol. 
T he  A C E N D  i ncl u des  a  t otal  of  se ve n  d o ma i ns  assessi n g  p h ysical  i m pact  (i ncl u di n g  
fee di n g/ gr o o mi n g/ dressi n g, sitti n g/ pla y, tra nsfers, a n d m o bilit y) a n d ge neral care gi ver i m pact 
(i ncl u di n g ti me, e m oti o n, a n d fi na nce) a n d eac h d o mai n c o m prises se veral ite ms.  T he t otal sc ore 
f or a d o mai n wit h n ite ms, eac h ite m assesse d o n or di nal scale fr o m 1 t o z, is deri ve d as f oll o ws: 
1 0 0 m ulti plie d b y ( Mea n of t he n ite ms i n t he d o mai n  - 1) di vi de d b y (z- 1).  T his t otal sc ore will 
be o n a scale of 0 t o 1 0 0 wit h a hi g her sc ore i n dicati n g a greater i m p act o n t he care gi ver.  At least 
t w o ite ms f or t he ti me d o mai n a n d o ne ite m f or t he re mai ni n g d o mai ns nee d t o be n o n- missi n g f or 
a t otal t o be calc ulate d; else t he t otal sc ore will be set t o be missi n g. 
4. 8  
Bi o m ar kers 
C S F a n d plas ma sa m ples c ollecte d as o utli ne d i n t he sc he d ule of e ve nts will be teste d f or p Nf- H 
c o nce ntrati o n. 
 
Baseli ne p Nf- H is defi ne d as t he m ost rece nt n o n- missi n g meas ure me nt c ollecte d pri or t o t he first 
d ose or Da y 1. If a n y p Nf- H meas ure me nt is n o n- mi ssi n g pri or t o t he first d ose, t he val ue cl osest 
t o a n d pri or t o t he first d ose is use d as baseli ne val ue. If n o p Nf- H meas ure me nt is a vaila ble pri or 
t o t he first d ose b ut a n y n o n- missi n g p Nf- H measure me nt o n Da y 1 is c ollecte d, t he val ue cl osest 
t o t he first d ose o n Da y 1 is use d as baseli ne val ue. 
4. 8. 1  p Nf- H c o nce ntr ati o n a n d c h a n ge i n p Nf- H 
 
Baseli ne p Nf- H c o nce ntrati o ns will be s u m marize d o vera ll, b y a ge of o nset usi n g descri pti ve statistics.  
S pear ma n  c orrelati o n c oefficie nts bet wee n baseli ne p Nf- H a n d o ne of t he baseli ne meas ure me nts 
( Baseli ne  wei g ht,  A ge  at  first  d ose,  gestati o nal  a ge,  HI N E  m ot or  milest o nes  sc ore)  a n d  t he  
c orres p o n di n g p- val ues testi n g w het her s uc h c orrelati o n is e q ual t o zer o will be prese nte d 
 
S u m mar y ta bles will be prese nte d f or p Nf- H c o nce ntrati o n, c ha n ge a n d perce nta ge c ha n ge fr o m 
baseli ne p Nf- H b y visit. A pl ot of mea n o ver ti m e will be prese nte d f o r p Nf- H c o nce ntrati o n o n 
t he se mi-l o garit h mic scale. T he mea n c ha n ge fr o m baseli ne a n d perce nta ge c ha n ge fr o m baseli ne, 
res pecti vel y will be prese nte d o n t he ori gi nal scale.  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 4 of 5 4 
 
4. 8. 2  C h a n ge i n C S F S M N pr otei n c o nce ntr ati o n 
A n a p pr o priate assa y f or S M N pr otei n i n t he C S F has n ot bee n i de ntifie d.  O nce a vaila ble, 
a nal yses  will be perf or me d t o e x pl ore a n d c haracterize t his acr oss t he st u d y e n d p oi nts. 
 
4. 9  
Si bli n g S M A D at a C ollecti o n 
If a n y s u bject has or ha d a si bli n g(s) wit h S M A a n d if c o nse nt is gi ve n, data f or t he si bli n g(s) will 
be c ollecte d at Da y 1 a n d at t he E n d of St u d y E v al uati o n/ Earl y Ter mi nati o n Visit. Data t o be 
c ollecte d fr o m si bli n gs wit h S M A will be n o n- bi o l o gic a n d n o ni n vasi ve a n d will i ncl u de hist orical 
data f or S M N 2 ge ne c o p y n u m ber a n d si bli n g treat me nt hist or y. 
Part of pr ot oc ol a me n d me nt 4 i nc or p orate d retr os pecti ve a n d p ote ntial pr os pecti ve ca pt ure of data 
o n si bli n gs of s u bjects e nr olle d i nt o pr ot oc ol  2 3 2 S M 2 0 2 w h o were affecte d b y S M A. De pe n di n g 
o n t he a m o u nt a n d c o m plete ness of data c ollecte d it ma y be p ossi ble t o perf or m s o me a nal yses 
c o m pari n g s u bjects i n pr ot oc ol 2 3 2 S M 2 0 2 w h o were d ose d vers us si bli n gs. Differe nces i n a ge at 
s y m pt o m o nset, a ge at deat h a n d hi g hest m ot or fu ncti o n attai ne d bet wee n s uc h si bli n gs will be 
e x pl ore d. 
 
4. 1 0  I nteri m A n al yses 
N o f or mal i nteri m a nal yses will be c o n d ucte d. 
5  
S afet y D at a 
A nal yses of safet y data will i ncl u de a d verse e ve nts ( Secti o n 5. 1), la b orat or y data ( Secti o n 5. 2), 
E C Gs ( Secti o n 5. 3), vital si g ns ( Secti o n 5. 4), a n d ne ur ol o gical e xa mi na ti o ns ( Secti o n 5. 5).  
A nal yses of safet y data will be base d o n t he Safe t y Set. Baseli ne is defi ne d as t he last n o n- missi n g 
res ults pri or t o t he first d ose of N usi nerse n or s ha m pr oce d ure. 
5. 1  
Cli nic al a d verse e ve nts 
All a d verse e ve nts will be a nal yze d base d o n t he pri nci ple of treat me nt e mer ge nce. A n a d verse 
e ve nt will be re gar de d as treat me nt e mer ge nt if it was prese nt pri or t o recei vi n g t he first d ose of 
N usi nerse n or s ha m pr oce d ure a n d s u bse q ue ntl y w o rse ne d i n se verit y, or was n ot prese nt pri or t o 
recei vi n g t he first d ose of N usi nerse n or s ha m pr oce d ure b ut s u bse q ue ntl y a p peare d. F or s u bjects 
recei vi n g t he s ha m pr oce d ure i n Part 1, a n a d diti o nal treat me nt e mer ge nt defi niti o n will be use d 
t o defi ne if t he a d verse e ve nt is treat me nt e mer ge nt t o t he first d ose of N usi nerse n i n Part 2. 
 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 5 of 5 4 
 
I n t he sit uati o n w here c ha n ge i n se verit y ( b ut n o c ha n ge i n seri o us ness) occ urs f or a n a d verse 
e ve nt, st u d y sites are i nstr ucte d t o e nter a n e n d date a n d start a ne w rec or d f or t he a d verse e ve nt. 
I n t he ne w rec or d, t he c ha n ge d se verit y is t o be rec or de d a n d t he start date will be set t o be t he e n d 
date of t he pre vi o us rec or d. T hese rec or ds will be pr o gra m maticall y li n ke d b y preferre d ter m a n d 
start/e n d date. C o nsi der t hree sce nari os: 
 
 T he first A E rec or d occ urs pri o r t o t he first d ose, t he sec o n d A E rec or d occ urs o n or after 
t he first d ose, a n d t he se verit y i ncreases: o nl y t he sec o n d rec or d will be c o u nte d as 
treat me nt-e mer ge nt. 
 T he first A E rec or d occ urs pri o r t o t he first d ose, t he sec o n d A E rec or d occ urs o n or after 
t he first d ose, a n d t he se verit y decreases: neit her rec or d will be c o u nte d as treat me nt-
e mer ge nt. 
 B ot h rec or ds occ ur o n or after t he first d ose: if t he A E se verit y o n t he sec o n d rec or d is 
w orse t ha n t he se verit y o n t he first rec or d, t h e n b ot h rec or ds will be c o u nte d as treat me nt-
e mer ge nt. H o we ver, if t he se ve rit y decreases, t he n o nl y t he first rec or d will be c o u nte d as 
treat me nt-e mer ge nt. 
Of n ote, w he n c o u nti n g t he t otal n u m ber of tr eat me nt-e mer ge nt e ve nts, e ve nts li n ke d t hr o u g h 
c ha n ge i n se verit y will still be c o u nte d as se parate e ve nts. 
F or e ve nts wit h missi n g start or st o p dates, t he f oll o wi n g criteria will be use d f or t he 
p ur p ose of i de ntif yi n g treat me nt-e mer ge nt a d verse e ve nts:  
 if b ot h t he start a n d st o p dates f or a partic ular e ve nt are missi n g, t he n t he e ve nt is 
c o nsi dere d t o ha ve occ urre d o n or after t he first d ose of st u d y treat me nt; 
 if t he start date f or a partic ular e ve nt is missi n g a n d t he st o p date/ti me falls after t he first 
d ose date/ti me, t he n t he e ve nt is c o nsi dere d t o ha ve occ urre d o n or after t he first d ose of 
st u d y treat me nt; a n d 
 if t he start ti me is missi n g a n d t he start date is sa me as t he first d osi n g date, t he n t he e ve nt 
is c o nsi dere d t o ha ve occ urre d o n or after t he first d ose of st u d y treat me nt. 
 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 6 of 5 4 
 
If it ca n n ot be deter mi ne d w het her a n e ve nt has occ urre d o n or after d osi n g d ue t o a missi n g or 
partial date, t he n t he e ve nt will be ass u me d t o ha ve occ urre d o n or after t he first d ose f or t he 
p ur p ose of i de ntif yi n g treat me nt-e mer ge nt A Es. 
D ue t o t he l o n g half-life of N usi nerse n, a nal yses of treat me nt-e mer ge nt A Es will i ncl u de all e ve nts 
re p orte d d uri n g t he st u d y. 
A Es will be c o de d usi n g t he Me d D R A dicti o nar y. T his c o di n g s yste m pr o vi des m ore t ha n fi ve 
le vels t o classif y a d verse e ve nts. I n ge neral, a dverse e ve nts will be prese nte d b y s yste m or ga n class 
a n d preferre d ter ms b ut ot her classifi cati o ns ma y be use d if warra nte d.  
T he i nci de nce of treat me nt-e mer ge nt A Es will be s u m marize d. A s u bject ha vi n g t he sa me A E 
m ore t ha n o nce will be c o u nte d o nl y o nce i n t he i nci de nce f or t hat A E. T he s u m mar y t a bles will 
i ncl u de i nci de nce esti mates f or o verall s yste m or gan class as well as f or preferre d ter ms wit hi n 
eac h s yste m or ga n class. I nci de nce will be pres e nte d b y decreasi n g or der b y s yste m or ga n class 
a n d b y decreasi n g or der b y preferre d ter m wit hi n  eac h s yste m or ga n class. T he m ost c o m m o n 
A Es, i.e., t h ose t hat occ urre d i n at least 3 s u bj ects, will be prese nte d.  U p o n e xa mi nati o n of t he 
act ual data, differe nt c ut- offs ma y be us e d if it is dee me d m ore a p pr o priate.  
5. 1. 1  A d verse e ve nts b y se verit y 
T he i n vesti gat or is t o rec or d t he se verit y of eac h  a d verse e ve nt as mil d, m o derate, or se vere. If a 
s u bject e x perie nces t he sa me A E m ulti ple ti mes, t he e ve nt wit h t he w orst se verit y will be c o u nte d. 
T he i nci de nce wit hi n eac h cate g or y will be prese nte d. T he i nci de nce of se vere e ve nts will be 
s u m marize d.  
5. 1. 2  A d verse e ve nts b y rel ati o ns hi p t o st u d y tre at me nt 
T he i n vesti gat or is t o rec or d t he de gree t o w hic h eac h A E is relate d t o st u d y dr u g ( n ot relate d, 
u nli kel y or re m otel y relate d, p ossi bl y relate d, a n d relate d). If a s u bject e x perie nces t he sa me A E 
m ulti ple ti mes, t he e ve nt wit h t he str o n gest  relati o ns hi p t o st u d y dr u g will be  c o u nte d. T he 
i nci de nce wit hi n eac h cate g or y will be prese nte d. T he i nci de nce of dr u g-relate d e ve nts (t h ose 
cate g orize d as p ossi bl y relate d or  relate d) will be s u m marize d.  
5. 1. 3  Seri o us a d verse e ve nts 
T he i nci de nce of treat me nt-e mer ge nt S A Es w ill be s u m marize d b y ti me of o nset b y 3- m o nt h 
ti me i nter vals. All S A Es will be liste d i ncl u din g a n y t hat occ urre d pri or t o c o m me nce me nt of 
st u d y treat me nt.  
5. 1. 4  A d verse e ve nts t h at le d t o disc o nti n u ati o n fr o m tre at me nt a n d/ or 
wit h dr a w al fr o m st u d y 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 7 of 5 4 
 
T he i nci de nce of A Es t hat le d t o disc o nti n uati o n of st u d y treat me nt a n d t h ose t hat le d t o wit h dra wal 
fr o m t he st u d y will be prese nte d.  
5. 1. 5  De at hs 
T he i nci de nce of deat h will be s u m marize d. All deat hs will be liste d i ncl u di n g ca use of deat h. T he 
i nci de nce of e ve nts t hat le d t o deat h will be prese nte d. 
5. 1. 6  Prese nt ati o ns 
T he f oll o wi n g prese ntati o ns will be s h o w n f or t he i nte grate d a nal ysis:  
 
a n o verall s u m mar y s h o wi n g, t he n u m ber a n d perce nta ge of s u bjects wit h a n A E, a 
m o derate or se vere e ve nt, a se vere e ve nt, a p ossi bl y or relate d e ve nt, a relate d e ve nt, a 
seri o us e ve nt, a n e ve nt t hat le d t o disc o nti n uati o n of st u d y dr u g, a n d a n e ve nt t hat le d t o 
wit h dra wal fr o m t he st u d y, re peate d als o b y a ge at s y m pt o m o nset 
 
i nci de nce b y pri mar y s yste m or ga n class a n d preferre d ter m, re peate d als o b y a ge at 
s y m pt o m o nset 
 
Fre q ue nc y of a d verse e ve nts b y s yste m or ga n class a n d preferre d ter m, re peate d als o b y 
a ge at s y m pt o m o nset 
 
i nci de nce of mil d, m o derate a n d se vere e ve nts b y pri mar y s yste m or ga n class a n d 
preferre d ter m  
 
i nci de nce of se vere e ve nts b y pri mar y s yste m or ga n class a n d preferre d ter m 
 
i nci de nce of n ot relate d, u nli kel y t o be relate d, p ossi bl y relate d, a n d relate d e ve nts b y 
pri mar y s yste m or ga n class a n d preferre d ter m 
 
i nci de nce of dr u g-relate d e ve nts b y pri mar y s yste m or ga n class a n d preferre d ter m  
 
i nci de nce of S A Es b y pri mar y s yste m or ga n class a n d preferre d ter m a n d a listi n g of 
S A Es 
 
i nci de nce of deat h a n d a listi n g of eac h deat h 
 
i nci de nce of e ve nts t hat le d t o deat h 
 
i nci de nce of e ve nts lea di n g t o disc o nti n uati o n of st u d y dr u g b y pri mar y s yste m or ga n 
class a n d preferre d ter m a n d a listi n g of s uc h e ve nts  
 
i nci de nce of e ve nts lea di n g t o wit h dra wal fr o m t he st u d y b y pri mar y s yste m or ga n class 
a n d preferre d ter m a n d a listi n g of s uc h e ve nts 
 
i nci de nce of e ve nts of s pecial i nterest – A Es f oll o wi n g d osi n g pr oce d ure/ L P, A Es b y 
a nti b o d y stat us etc., b y pri mar y s yste m or ga n class a n d preferre d ter m a n d a listi n g of 
s uc h e ve nts. 
T o a v oi d t he p ote ntial f or mislea di n g i nter pretati o n of a nal ysis of A Es,  n o statistical testi n g 
will be perf or me d.  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 8 of 5 4 
 
 
O nl y t he f oll o wi n g prese ntati o ns wi ll be s h o w n f or Part 2 a nal ysis:  
 
a n o verall s u m mar y s h o wi n g, t he n u m ber a n d perce nta ge of s u bjects wit h a n A E, a 
m o derate or se vere e ve nt, a se vere e ve nt, a p ossi bl y or relate d e ve nt, a relate d e ve nt, a 
seri o us e ve nt, a n e ve nt t hat le d t o disc o nti n uati o n of st u d y dr u g, a n d a n e ve nt t hat le d t o 
wit h dra wal fr o m t he st u d y 
 
i nci de nce b y pri mar y s yste m or ga n class a n d preferre d ter m 
 
I nci de nce of seri o us a d verse e ve nts b y pri mary s yste m or ga n class a n d preferre d ter m a n d 
a listi n g of S A Es. 
 
Fre q ue nc y of a d verse e ve nts b y s yste m or ga n class a n d preferre d ter m 
5. 1. 7  S u b gr o u p a n al ysis 
F or t he i nte grate d a nal ysis, t he o verall s u m mar y of  A d verse e ve nts, t he i nci de nce of all A Es a n d 
S A Es b y pri mar y s yste m or ga n class a n d preferre d ter m ta bles will be re peate d b y a ge of o nset 
( < = 6 m o nt hs, > 6 m o nt hs).  
5. 2  
Cli nic al l a b or at or y d at a 
T he f oll o wi n g cli nical la b orat or y pa ra meters are t o be assesse d:  
 
Bl o o d c he mistr y:  t otal pr otei n, al b u mi n, cr eati ni ne, c ystati n C, creati ne p h os p h o ki nase, 
bl o o d urea nitr o ge n, t otal ser u m bilir u bi n ( direct a n d i n direct), al kali ne p h os p hatase, 
ala ni ne a mi n otra nsferase, as partate a mi n otra nsferase, gl uc ose, calci u m, p h os p h or us, 
c hl ori de, s o di u m, p otassi u m, bicar b o nate, creat i ne ki nase ( M B [is oe nz y me e x presse d i n 
t he m y ocar di u m], B B [is oe nz y me pre d o mi na ntl y e x presse d i n t he brai n], a n d M M 
[is oe nz y me e x presse d i n s keletal m uscle]), ga m ma- gl uta m yl tra nsferase 
 
 He mat ol o g y: re d bl o o d cells, he m o gl o bi n, he mat ocrit, platelets, w hite bl o o d cells, w hite 
bl o o d cell differe ntial 
 
 Uri nal ysis: s pecific gra vit y, p H, pr otei n, gl uc ose, ket o ne s, bilir u bi n, re d bl o o d cells, 
w hite bl o o d cells, e pit helial cell s, bacteria, casts, cr ystals 
 
T otal uri ne pr otei n 
 
C oa g ulati o n para meters (a P T T, P T T, a n d I N R) will be c ollecte d. 
 
As descri be d bel o w, la b orat or y data will be e xa mi ne d usi n g a n a nal ysis of “s hifts” a n d c ha n ge d 
fr o m baseli ne b y wi n d o we d visits. H o we ver, f urther a nal yses ma y be u n derta ke n t o m ore f ull y 
c haracterize  p ote ntial  la b orat or y  safet y  si g na ls,  s uc h  as  assess me nt  of  ti mi n g,  rec o ver y,  
re versi bilit y, ass ociati o n wit h A Es, etc.  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 4 9 of 5 4 
 
Eac h s u bject’s la b orat or y val ues will be classifie d acc or di n g t o w het her t he test res ult is “l o w” 
(i.e., bel o w t he l o wer li mit of n or mal [ L L N]), “ n or mal” ( wit hi n t he n or mal ra n ge), or “ hi g h” (i.e., 
a b o ve t he u p per li mit of n or mal [ U L N]). If a s u bject is missi n g a baseli ne val ue b ut ha d a p ost-
baseli ne val ue, t he n t he baseli ne assess me nt is la bele d as “ u n k n o w n”. Li ke wise, if a s u bject ha d a 
baseli ne val ue b ut ha d n o p ost- baseli ne val ues, t he n t he mi ni m u m a n d ma xi m u m are la bele d as 
“ u n k n o w n”. P ost- baseli ne la b orat or y res ults are de fi ne d as a n y assess me nt ta ke n after t he first 
d ose, i ncl u di n g data c ollecte d fr o m l ocal la b orat ories. T he s hifts (relati ve t o t he n or mal ra n ge) 
fr o m baseli ne t o t he mi ni m u m a n d ma xi m u m p ost- baseli ne val ues will be prese nte d. S h o ul d a 
treat me nt affect a la b orat or y para meter, t hat parameter c o ul d be affecte d at differe nt ti mes f or 
differe nt s u bjects. T heref ore, t hese a nal yses pres e nt t he m ost e xtre me val ues f or eac h s u bject. F or 
ma n y la b orat or y para meters, t he effect c o ul d be i n eit her directi o n, (i.e., a n i ncrease or a decrease), 
s o  b ot h  t he  ma xi m u m  a n d  mi ni m u m  val ues  ha ve bee n  a nal yze d.  Base d  o n  val ues  fr o m  t he  
la b orat or y para meters, t he s hifts (relati ve t o t he n or mal ra n ge) fr o m baseli n e t o l o w a n d hi g h will 
be calc ulate d. If a s u bject's val ue s hifts, it ca n c ha n ge fr o m n or mal t o eit her l o w or hi g h, fr o m l o w 
t o n or mal or hi g h, fr o m hi g h t o n or mal or l o w, or fr o m u n k n o w n t o l o w, n or mal, or hi g h. F or eac h 
para meter, t he i nci de nce of s hift t o l o w will be s u m marize d usi n g t he mi ni m u m p ost- baseli ne 
val ues. S hift t o l o w i ncl u des s u bjects wit h a n or mal, hi g h, or u n k n o w n base li ne val ue a n d at least 
o ne  p ost- baseli ne  val ue  of  t he  gi ve n  test.  Si milarl y,  t he  i nci de nce  of  s hift  t o  hi g h  will  be  
s u m marize d usi n g t he ma xi m u m p ost- baseli ne val ues. S hift t o hi g h i ncl u des s u bjects wit h a l o w, 
n or mal, or u n k n o w n baseli ne val ue a n d at least o ne p ost- baseli ne val ue. 
F or ma n y para meters pr ocesse d ce ntrall y, t he la b ora t or y has a d diti o nal ra n ges, e. g., a n otificati o n 
t o t he site b y telefacsi mile t hat t he s u bject’s res ult is far e n o u g h o utsi de t he n or mal ra n ge t o warra nt 
n otificati o n, a n d/ or a pa nic alert i n v ol vi n g a tele p h o ne call ma de t o t he i n vesti gati o nal site t o n otif y 
t he m t hat t he s u bject’s res ult is o utsi de of t he n or mal ra n ge wit h p ote ntiall y critical i m plicati o ns 
f or t he s u bject (see t he ta ble bel o w). Wit h t he e xcepti o n of li ver f u ncti o n te sts, s h o ul d s uc h ra n ges 
be a vaila ble f or a para meter, t hese a d diti o nal cat e g ories will be prese nte d i n listi n gs. F or s hift 
ta bles of la b orat or y para meters, t h ose a d diti o nal cate g ories will be c o m bi ne d wit h t he c o n ve nti o nal 
cate g ories. S pecificall y: 
 L T ( L o w – telefacsi mile) a n d L P ( L o w pa nic) will be classifie d as L ( L o wer li mit of 
n or mal) 
 
 H T ( Hi g h – telefacsi mile) a n d H P ( Hi g h pa nic) will be classifie d as H ( U p per li mit of 
n or mal)  
 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 5 0 of 5 4 
 
F or li ver f u ncti o n tests, t he a d diti o nal cate g ories will be defi ne d t o prese nt t he baseli ne a n d p ost-
baseli ne val ues as wit hi n t he u p per li mit of n or mal,  > 1 t o < 3 x U L N, > 3 t o 5 x U L N, > 5 t o 1 0 x 
U L N, > 1 0 t o 2 0 x U L N. F or s hift ta bles of la b or at or y para meters, a d diti o nal cate g ories will be 
c o m bi ne d wit h t he c o n ve nti o nal cate g ories. S pec ificall y, > 2 0 x U L N f or A L T/ A S T; > 1 t o 1. 5 x 
U L N, > 1. 5 t o 2 x U L N, a n d > 2 x U L N f or t otal bilir u bi n; a n d > 1 t o 1. 5 x U L N a n d > 1. 5 x U L N 
f or al kali ne p h os p hatase. I n a d diti o n, s hift fr o m baseli ne i n A L T a n d A S T will be s u m marize d b y 
ele vati o n i n bilir u bi n ( ma xi m u m p ost- base li ne bilir u bi n > 1. 5 x U L T a n d > 2 x U L N). 
 
T he mi ni m u m, me dia n a n d ma xi m u m vers us ti me pr ofiles ( wi n d o we d visits) f or s o me la b orat or y 
para meters of i nterest will be prese nte d gra p hicall y. 
5. 3  
E C G 
E C Gs are assesse d at a ce ntral rea di n g la b orat or y, a n d t he res ults pr o vi de d bac k t o sites t o be 
e ntere d i nt o t he e C R F. E C G q ualitati ve res ults i n cl u de a n o verall i nter pretati o n of ‘ n or mal’, 
‘a b n or mal b ut n ot cli nicall y si g nifica nt’ or ‘a b n or mal a n d cli nicall y si g nifica nt’. Q ua ntitati ve 
res ults will n ot be ca pt ure d i n t he cli nical data base. 
T he n u m ber a n d perce nta ge of s u bjects wit h s hifts  fr o m n or mal t o eac h of t he cate g orical val ues 
de n oti n g a n a b n or mal sca n (a b n or mal n ot A E, a b n or mal A E) will be s u m marize d b y treat me nt 
gr o u p. A listi n g of s u bjects wit h a b n or m al stat us i n E C G will be prese nte d. 
5. 4  
Vit al si g ns 
Vital si g ns are t o be meas ure d at Scree ni n g, pre- d osi n g a n d at vari o us ti me p oi nts p ost- d osi n g o n 
d osi n g da ys. At eac h of t hese ti mes, resti n g s yst olic a n d diast olic bl o o d press ure, p ulse rate, 
res pirat or y rate, te m perat ure, p ulse o xi metr y, an d pre- d osi n g tra nsc uta ne o us car b o n di o xi de will 
be meas ure d.  
T he n u m ber a n d perce nta ge of s u bjects meeti n g sel ecte d criteria p ost- baseli ne a n d o utliers will be 
s u m marize d o nl y f or t he i nte grate d a nal ysis. 
5. 5  
Ne ur ol o gic al e x a mi n ati o ns  
Ne ur ol o gical ite ms, c o m prisi n g me ntal stat us, le vel of c o nsci o us ness, se ns or y f u ncti o n, m ot or 
f u ncti o n, cra nial ner ve f u ncti o n, a n d refle xes, will be assesse d. T hese assess me nts will be d o ne at 
Scree ni n g, pre- d ose, a n d p ost- d ose.  
T he res ult c ollecte d f or t he maj orit y of t he tests is  ‘ n or mal’ or ‘a b n or mal’, h o we ver t he assess me nt 
of se nsati o ns is re p orte d as ‘ pre se nt’ or ‘a bse nt’ a n d t he assess me nt of refle xes is ca pt ure d o n a n 
or di nal scale. F or eac h test, c ha n ges sec o n dar y t o S M A will be rec or de d. F or eac h test a n d p ost-
d osi n g ti me p oi nt, t he n u m ber a n d pr o p orti o n of s u bjects w h o m o ve d fr o m ‘ N or mal’ t o ‘ A b n or mal’ 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 5 1 of 5 4 
 
will be prese nte d, a n d t he n u m ber a n d pr o p orti o n w h o m o ve fr o m ‘ Prese nt ’ t o ‘ A bse nt’ will be 
prese nte d f or se nsati o ns. F or t he assess me nt of refle xes, decreases (fr om pre- d osi n g 1 t o p ost-
d osi n g 0, 2 t o 1. etc.) will be prese nte d. O nl y  c ha n ges n ot dee me d sec o n dar y t o S M A will be 
prese nte d i n t he i nte grate d a nal ysis. T he perce nta ge  of t he differe nt res ults f or eac h test will be 
prese nte d gra p hicall y b y visit.  
 
5. 6  
I nteri m s afet y a n al yses 
N o f or mal i nteri m a nal yses are pla n ne d f or safe t y b ut data will be re vie we d o n a n o n g oi n g basis 
b y t he S p o ns or a n d t he Me dical M o nit or. 
6  
P h ar m ac o ki netic d at a 
C S F a n d plas ma sa m ples will be c ollecte d at pr ot oc ol desi g nate d ti mes f or N usi nerse n or s ha m 
pr oce d ure p har mac o ki netic assess me nts i n t he P har mac o ki netic P o p ulati o n. T he P har mac o ki netic 
P o p ulati o n i ncl u des all s u bjects w h o are d ose d a n d f or w hic h t here is at least o ne e val ua ble p ost-
d ose pr oce d ure p har mac o ki netic sa m ple.  
T he P K a nal ysis will be o n i nte grate d data a n d t he sa me wi n d o wi n g a p pr oac h use d f or t he efficac y 
a nal ysis will be use d. 
 
6. 1  
C S F c o nce ntr ati o n d at a 
C S F c o nce ntrati o ns of N usi nerse n or s ha m pr o ce d ure, al o n g wit h t he sc he d ule d ( n o mi nal) a n d 
act ual sa m pli n g ti mes (i.e., ti me fr o m I T d osi n g) wi ll be liste d ( w he n a p plica ble) f or eac h s u bject 
a n d da y. Differe nces bet wee n sc he d ule d a n d act ual sa m pli n g ti mes will als o be liste d f or all 
s u bjects. Perce nta ge differe nces bet wee n act ual a d mi nistere d d ose a n d n o mi nal d ose will als o be 
liste d.  
C S F c o nce ntrati o ns bel o w t he l o wer li mit of q ua n tificati o n ( L L O Q) will be i n dicate d b y “ B L Q”. 
F or t he p ur p ose of calc ulati n g t y pical descri pti ve statistics ( n, mea n, S D, % C V, ge o metric mea n, 
ge o metric % C V, me dia n, mi ni m u m, a n d ma xi m u m)  f or C S F c o nce ntrati o ns, all B L Q val ues will 
be set t o zer o. Mea n C S F c o nce ntrati o ns t hat ar e B L Q will be prese nte d as B L Q, a n d t he S D a n d 
% C V will be re p orte d as n ot a p plica ble. S u m mar y st atistics of C S F c o nce ntrati o ns of N usi nerse n 
or s ha m pr oce d ure C S F c o nce ntrati o ns will be ta b ulate d b y wi n d o we d visit f or t he i nte grate d 
a nal ysis o nl y. At t he discreti o n of t he p har mac o ki neticist a n d/ or bi ostatisticia n, sa m ples ma y be 
e xcl u de d fr o m descri pti ve statistics if t here ar e lar ge de viati o ns bet wee n sc he d ule d a n d act ual 
sa m pli n g da ys or ti mes, or lar ge de viati o ns bet wee n act ual d ose a n d n o mi nal d ose.  


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 5 2 of 5 4 
 
C S F c o nce ntrati o ns of N usi nerse n a n d s ha m pr oce d ure C S F c o nce ntrati o n vers us ti me (act ual) 
pr ofiles f or eac h s u bject, as well as t he mea n ( ± S E) C S F c o nce ntrati o n vers us ti me (sc he d ule d) 
pr ofiles will be prese nte d gra p hicall y o n li near  a n d se mil o garit h mic scales. Sa m ples ma y be 
e xcl u de d fr o m t he mea n pl ots if t here are lar ge de viati o ns bet wee n sc he d ule d a n d act ual sa m pli n g 
ti mes, or lar ge de viati o ns bet wee n act ual d ose a n d n o mi nal d ose. 
D ue t o t he li mite d C S F sa m ples c ollecte d n o C S F p har mac o ki netic para meters will be calc ulate d.  
 
6. 2  
Pl as m a c o nce ntr ati o n d at a 
Plas ma c o nce ntrati o ns of N usi nerse n, al o n g w it h t he sc he d ule d ( n o mi nal) a n d act ual sa m pli n g 
ti mes  (i.e., ti me  fr o m I T  d osi n g)  will  be  listed  ( w he n  a p plica ble)  f or  eac h s u bject  a n d da y.  
Perce nta ge differe nces bet wee n sc he d ule d a n d act ual sa m pli n g ti mes will als o be liste d f or all 
s u bjects. Perce nta ge differe nces bet wee n act ual a d mi nistere d d ose a n d n o mi nal d ose will als o be 
liste d.  
Plas ma  c o nce ntrati o ns  bel o w  t he  l o wer  li mit  of  q ua ntificati o n  ( L L O Q)  will  be  i n dicate d  b y  
“ B L Q”. F or t he p ur p ose of calc ulati n g t y pical desc ri pti ve statistics ( n, mea n, S D, % C V, ge o metric 
mea n, ge o metric % C V, me dia n, mi ni m u m, a n d ma xi m u m) f or plas ma c o nce ntrati o ns, all B L Q 
val ues will be set t o zer o. Mea n plas ma c o nce n trati o ns t hat are B L Q will be prese nte d as B L Q, 
a n d  t he  S D  a n d  % C V  will  be  re p orte d  as  n o t  a p plica ble.  S u m mar y  statistics  of  plas ma  
c o nce ntrati o n of N usi nerse n a n d s ha m pr oce d ure plas ma c o nce ntrati o ns will be ta b ulate d b y 
wi n d o we d visit f or t he i nte grate d a nal ysis o nl y. At  t he discreti o n of t he p har mac o ki neticist a n d/ or 
bi ostatisticia n, sa m ples ma y be e xcl u de d fr o m descri pti ve statistics if t here are lar ge de viati o ns 
bet wee n sc he d ule d a n d act ual sa m pli n g ti mes, or lar ge de viati o ns bet wee n act ual d ose a n d n o mi nal 
d ose.  
Plas ma c o nce ntrati o n of N usi nerse n a n d s ha m pr o ce d ure plas ma c o nce ntrati o n vers us ti me (act ual) 
pr ofiles f or eac h s u bject, as well as t he mea n ( ± S E ) plas ma c o nce ntrati o n vers us ti me (sc he d ule d) 
pr ofiles will be prese nte d gra p hicall y o n li near  a n d se mil o garit h mic scales. Sa m ples ma y be 
e xcl u de d fr o m t he mea n pl ots if t here are lar ge de viati o ns bet wee n sc he d ule d a n d act ual sa m pli n g 
ti mes, or lar ge de viati o ns bet wee n act ual d ose a n d n o mi nal d ose.  
7  
I m m u n o ge nicit y d at a 
I m m u n o ge nicit y  (I M)  testi n g  (a nti- N usi nerse n  a nti b o d y  p ositi vit y),  usi n g  desi g nate d  plas ma  
sa m ples  c ollecte d  fr o m  eac h  st u d y  s u bject,  is  pla n ne d  t o  be  c o n d ucte d  a n d  re p orte d.  
I m m u n o ge nicit y  plas ma  sa m ples  c ollecte d  at  ot her  ti me  p oi nts  f or  N usi nerse n  c o nce ntrati o n  
deter mi nati o ns ma y als o be e val ua te d f or I M testi n g if of f urt her i nterest a n d dee me d warra nte d 
b y t he p har mac o ki neticist. A n i n di vi d ual sa m ple res ult will be desi g nate d ‘a nti b o d y p ositi ve’ 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 5 3 of 5 4 
 
base d o n b ot h p ositi ve scree ni n g (fr o m Part 1) a n d c o nfir mati o n assa y res ults (i.e., c o nfir me d 
p ositi ve res ult), a n d ot her wise will be dee me d ‘a nti b o d y ne gati ve’. A st u d y s u bject will be gi ve n 
‘a nti b o d y p ositi ve’ stat us if t he y ha ve at least o ne c o nfir me d p ositi ve sa m ple res ult at a n y ti me 
d uri n g t he treat me nt or p ost-treat me nt e val uati o n peri o ds. A st u d y s u bject will be gi ve n ‘a nti b o d y 
ne gati ve’ stat us if all e val uate d I M sa m ple res ults are a nti b o d y ne gati ve a n d t h e y ha ve at least o ne 
e val ua ble I M res ult later d uri n g t he treat me nt a n d p ost-treat me nt e val uati o n peri o ds. Ot her wise, a 
st u d y s u bject will be gi ve n ‘a nti b o d y i nc o ncl usi ve’ stat us. 
 
T he I M i nci de nce a n d I M i nci de nce rate f or t he o verall treat me nt a n d p ost -treat me nt e val uati o n 
peri o d,  will  be  deter mi ne d  a n d  a p pr o priatel y  s u m marize d,  b y  gr o u p,  as  t he  n u m ber  of  a n d  
perce nta ge  of  e val uate d  s u bjects  wit h  a n ti b o d y  ne gati ve  a nti b o d y  p ositi ve,  a n d  a nti b o d y  
i nc o ncl usi ve stat us. I n a d diti o n, i n a nti b o d y p ositi ve st u d y s u bjects, a nti b o d y titers of a n y a nti b o d y 
p ositi ve sa m ples will be re p orte d (liste d) a n d a p pr o priatel y s u m marize d acr oss s u bjects a n d b y 
treat me nt (e. g., at eac h e val uate d ti me p oi nt, or b y o bser ve d pea k titer val ues, etc.) at t he discreti o n 
of t he desi g nate d st u d y p har mac o ki neticist a n d/ or statisticia n. 
 
A nti b o d y p ositi vit y i n a nti- N usi nerse n a nti b o d y- p ositi v e s u bjects will als o be desi g nate d ( w he n 
p ossi ble) as bei n g eit her ‘ persiste n t’ or ‘tra nsie nt’, b ut o nl y f or th ose s u bjects i n w h o m at least o ne 
c o nfir me d a nti b o d y p ositi ve sa m ple res ult is f oll o we d ( > 1 0 0 da ys later) b y at least o ne 
a d diti o nal I M sa m ple assess me nt ( w hic h ca n be e it her a c o nfir me d p ositi ve or ne gati ve res ult(s)). 
T h ose st u d y patie nts meeti n g t he a b o ve criteria a n d wit h at least 2 c o nfir me d p ositi ve I M res ults 
occ urri n g greater t ha n 1 0 0 da ys a part ( ~ 5 i m m u n o gl o b uli n half-li ves) or o ne or m ore p ositi ve 
sa m ples a n d n o ot her sa m ples m ore t ha n 1 0 0 da ys after t he first p ositi ve sa m ple will be c o nsi dere d 
t o ha ve a ‘ persiste nt’ a nti b o d y res p o nse. All ot her s u bjects m eeti n g t he a b o ve criteria will be 
c o nsi dere d t o ha ve a ‘tra nsie nt’ a nti b o d y res p o nse.  
8  
S a m ple size j ustific ati o n 
T here are n o f or mal sa m ple size calc ulati o ns f or t his st u d y. Sa m p le size is base d u p o n feasi bilit y. 
9  
Refere nces 
Mats u m ot o H, Cla yt o n- Krasi ns ki D A, Kli n ge S A, G o me x J A, B o o ker W A, H ma n J E, R o ye Jr. 
D P, Vitale M G. De vel o p me nt a n d i nitial vali dati o n of t he assess me nt of care gi ver e x perie nce wit h 
ne ur o m usc ular disease. J Pe diatr Ort h o p 2 0 1 1; 3 1: 2 8 4- 2 9 2 
W H O  M ultice nter  Gr o wt h  Refere nce  St u d y  Gr o u p.  W H O  C hil d  Gr o wt h  Sta n dar ds:  
Le n gt h/ hei g ht-f or-a ge, wei g ht-f or -a ge, wei g ht-f or-le n gt h, weig ht-f or- hei g ht a n d b o d y mass i n de x-
f or-a ge: Met h o ds a n d de vel o p me nt. Ge neva: W orl d Healt h Or ga nizati o n, 2 0 0 6. 


  
  
 
 
 
St u d y N u m b er:  2 3 2 S M 2 0 2  
St ati sti c al A n al y si s Pl a n
V er si o n N o.: FI N A L V 1. 0  
 
Release d o n: 1 6 J ul y 2 0 1 8 
Pa ge 5 4 of 5 4 
 
htt p:// w w w. w h o.i nt/c hil d gr o wt h/sta n dar ds/e n/ c hil dre n u p t o 5 years 
W H O A nt hr o: htt p:// w w w. w h o.i nt/c hil d gr o wt h/s oft ware/e n/  
A ge at Disease O nset Pre dicts  Li keli h o o d a n d Ra pi dit y of Gro wt h Fail ure A m o n g I nfa nts a n d 
Y o u n g C hil dre n Wit h S pi nal M usc ular Atr o p h y T y pe s 1 a n d 2, S pr o ule, J C hil d Ne ur ol 2 0 1 2 2 7: 
8 4 5 ori gi nall y p u blis he d o nli ne 3 0 Marc h 2 0 1 2