Clinical trial NCT02594124
Conditions: Spinal Muscular Atrophy
Keywords: SMA SMN SMNRx ISIS-SMNRx ISIS 396443 SHINE IONIS-SMNRx IONIS-SMN Rx Spinraza nusinersen
Sponsor: Biogen
Start date: 2015-11-04; Completion date: 2023-08-21
Enrollment: 292 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to evaluate long-term safety and tolerability of nusinersen (ISIS 396443) administered by intrathecal (IT) injection to participants with Spinal Muscular Atrophy (SMA) who previously participated in investigational studies of nusinersen. The secondary objective is to examine the long-term efficacy of nusinersen administered by IT injection to participants with SMA who previously participated in investigational studies of nusinersen.

Detailed description:
This study was initiated and the protocol was registered by Ionis Pharmaceuticals, Inc.

In August 2016, Biogen assumed responsibility for this study.

Arms: arm 1: Participants transitioned from ISIS 396443-CS3B (NCT02193074) arm 2: Participants transitioned from ISIS 396443-CS4 (NCT02292537) arm 3: Participants transitioned from ISIS 396443-CS12 (NCT02052791) arm 4: Participants transitioned from ISIS 396443-CS3A (NCT01839656) arm 5: Participants transitioned from 232SM202 (NCT02462759)
Interventions: intervention 1: nusinersen
Intervention descriptions: intervention 1: Administered by intrathecal (IT) injection

Protocol documents:
Prot_000.pdf: 
Official Title: 
An Open-Label Extension Study for Patients With Spinal Muscular 
Atrophy Who Previously Participated in Investigational Studies of ISIS 
396443 
NCT Number: 
NCT02594124 
Document Date: 
20 October 2021 


1 
 
 
Biogen MA Inc. 
 
ISIS 396443-CS11 
An Open-Label Extension Study for Patients With Spinal Muscular Atrophy 
Who Previously Participated in Investigational Studies of ISIS 396443 
 
Protocol Amendment Version 6.0 – 20 October 2021 
Supersedes original dated 12 May 2015, Version 1.0 dated 02 November 2015, 
Version 1.3 dated 28 September 2016, Version 2.0 dated 31 January 2017, Version 3.0 
dated 30 October 2017, Version 4.0 dated 19 November 2019, and Version 5.0 dated 
24 March 2020 
 
Clinical Phase:  3 
EudraCT No:  2015-001870-16 
Sponsor: 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA 02142 
United States 
Biogen Australia PTY Ltd. 
Suite 1, Level 3, 123 Epping Road 
North Ryde, NSW 2113 
Australia  
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire SL6 4AY 
United Kingdom 
 
Biogen Japan Ltd. 
Nihonbashi 1-chome Mitsui Building 14F 
4-1 Nihonbashi 1-chome 
Chuo-ku, Tokyo 103-0027 
Japan 
 
 
Confidentiality Statement 
The information contained herein may not be used, disclosed, or published without the written 
consent of Biogen MA Inc. 


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SIGNATURE OF BIOGEN THERAPEUTIC AREA HEAD 
Neurology 
 
Protocol ISIS 396443-CS11 was approved by: 
 
 
 
__________________________________________ 
 
______________ 
, MD, PhD 
 
 
 
 
 
Date 
  
Biogen


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................9 
PROTOCOL SYNOPSIS ..............................................................................................................10 
STUDY GLOSSARY ....................................................................................................................19 
1. 
OBJECTIVES .............................................................................................................21 
1.1. 
Primary Objective .......................................................................................................21 
1.2. 
Secondary Objective ...................................................................................................21 
 
21 
2. 
BACKGROUND AND RATIONALE .......................................................................21 
2.1. 
Spinal Muscular Atrophy ............................................................................................21 
2.2. 
Therapeutic Rationale .................................................................................................22 
2.3. 
Nusinersen ..................................................................................................................23 
2.3.1. 
Mechanism of Action .................................................................................................23 
2.3.2. 
Chemistry ....................................................................................................................24 
2.3.3. 
Nonclinical Experience ...............................................................................................24 
2.3.4. 
Clinical Experience .....................................................................................................26 
2.4. 
Rationale for Dose and Schedule of Administration ..................................................27 
3. 
EXPERIMENTAL PLAN ..........................................................................................29 
3.1. 
Study Design ...............................................................................................................29 
3.1.1. 
Important Study Design Update .................................................................................29 
3.2. 
Number of Study Centers ...........................................................................................29 
3.3. 
Number of Subjects ....................................................................................................29 
3.4. 
Overall Study Duration and Follow-Up .....................................................................29 
3.4.1. 
Screening ....................................................................................................................32 
3.4.2. 
Treatment ....................................................................................................................32 
3.4.3. 
Post-Treatment Follow-Up .........................................................................................35 
3.5. 
End of Study ...............................................................................................................35 
3.6. 
Safety Monitoring .......................................................................................................35 
4. 
SUBJECT ENROLLMENT .......................................................................................35 


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4.1. 
Screening ....................................................................................................................35 
4.2. 
Randomization ............................................................................................................35 
4.3. 
Replacement of Subjects .............................................................................................35 
4.4. 
Unblinding of Treatment Assignment ........................................................................35 
5. 
SUBJECT ELIGIBILITY ...........................................................................................36 
5.1. 
Inclusion Criteria ........................................................................................................36 
5.2. 
Exclusion Criteria .......................................................................................................37 
6. 
STUDY PROCEDURES ............................................................................................37 
6.1. 
Study Assessments for Injection Days Only ..............................................................37 
 
37 
6.2. 
Study Assessments for Screening Only ......................................................................38 
6.3. 
Study Assessments for Every Study Visit and the End-of-Study Evaluation 
Visit .............................................................................................................................38 
6.3.1. 
Ventilator Use Diary Recording .................................................................................38 
6.3.2. 
Dysphagia Assessment ...............................................................................................38 
6.3.3. 
Urine/Serum Pregnancy Tests ....................................................................................39 
6.3.4. 
Weight .........................................................................................................................39 
6.3.5. 
Growth Parameters .....................................................................................................39 
6.3.6. 
Physical Examinations ................................................................................................39 
6.3.7. 
Vital Signs ..................................................................................................................40 
6.3.8. 
Neurological Examinations ........................................................................................40 
6.4. 
Study Assessments for Screening and/or Modified Maintenance Dosing 
Regimen Day 1, Every 4 Months Thereafter (Every Modified Maintenance 
Dosing Regimen Visit), and the End-of-Study Evaluation/Early Termination 
Visit .............................................................................................................................40 
6.4.1. 
Clinical Safety Laboratory Evaluations ......................................................................40 
6.4.2. 
Coagulation Parameters ..............................................................................................41 
 
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6.5. 
Study Assessments for Screening and/or Modified Maintenance Dosing 
Regimen Day 1, Every 8 Months Until Modified Maintenance Dosing 
Regimen Day 720 and Every 12 Months Thereafter, and the End-of-Study 
Evaluation/Early Termination Visit ............................................................................42 


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6.5.1. 
Motor Milestones ........................................................................................................42 
6.5.2. 
Motor Function Assessments ......................................................................................42 
6.5.2.1. 
Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease ............43 
6.5.2.2. 
Hammersmith Functional Motor Scale – Expanded ...................................................43 
6.5.2.3. 
Revised Upper Limb Module .....................................................................................44 
6.5.2.4. 
Six-Minute Walk Test .................................................................................................44 
6.5.2.5. 
Contracture Assessment ..............................................................................................44 
6.6. 
Study Assessments to be Performed at Screening and/or Modified 
Maintenance Dosing Regimen Day 1, Annually, and at the End of Study 
Evaluation/Early Termination Visit ............................................................................45 
6.6.1. 
Electrocardiograms .....................................................................................................45 
6.6.2. 
X-Ray of Spine ...........................................................................................................45 
6.6.3. 
Quality of Life Questionnaires ...................................................................................45 
6.6.3.1. 
Pediatric Quality of Life Inventory (Generic Core Scales and Neuromuscular 
Module) .......................................................................................................................46 
6.6.3.2. 
Assessment of Caregiver Experience With Neuromuscular Disease .........................46 
6.7. 
Study Assessments to be Performed at Screening and/or Modified 
Maintenance Dosing Regimen Day 1, Every 16 Months Thereafter 
(Modified Maintenance Dosing Regimen Days 480, 960, and 1440), and the 
End-of-Study Evaluation/Early Termination Visit .....................................................46 
6.7.1. 
Compound Muscle Action Potential ...........................................................................46 
6.8. 
Study Assessments to be Performed at Modified Maintenance Dosing 
Regimen Days 1 and 840 and at the End-of-Study Evaluation/Early 
Termination Visit ........................................................................................................47 
 
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6.9. 
Study Assessments to be Performed Continuously Throughout the Study ................49 
6.9.1. 
Telephone Assessments ..............................................................................................49 
6.10. 
Study Assessments to be Repeated Due to Delayed Dosing ......................................50 


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7. 
STUDY DRUG ...........................................................................................................51 
7.1. 
Study Drug Description ..............................................................................................51 
7.2. 
Packaging and Labeling ..............................................................................................51 
7.3. 
Study Drug Accountability .........................................................................................51 
8. 
TREATMENT OF SUBJECTS ..................................................................................51 
8.1. 
Study Drug Administration.........................................................................................51 
8.2. 
Sham Procedure ..........................................................................................................52 
8.3. 
Other Protocol-Required Drugs ..................................................................................53 
8.4. 
Other Protocol-Required Procedures ..........................................................................53 
8.5. 
Treatment Precautions ................................................................................................53 
8.6. 
Safety Monitoring Rules .............................................................................................53 
8.7. 
Stopping Rules ............................................................................................................53 
8.8. 
Adjustment of Dose and/or Treatment Schedule ........................................................53 
8.9. 
Discontinuation of Study Treatment ...........................................................................53 
8.10. 
Withdrawal of Subjects From the Study .....................................................................54 
8.11. 
Concomitant Therapy and Procedures ........................................................................54 
8.11.1. 
Concomitant Therapy .................................................................................................54 
8.11.1.1. 
Allowed Concomitant Therapy ...................................................................................54 
8.11.1.2. 
Disallowed Concomitant Therapy ..............................................................................55 
8.11.2. 
Concomitant Procedures .............................................................................................55 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .....................55 
9.1. 
Sponsor Review of Safety Information ......................................................................55 
9.2. 
Regulatory Requirements ...........................................................................................56 
9.3. 
Definitions ..................................................................................................................56 
9.3.1. 
Adverse Event .............................................................................................................56 
9.3.2. 
Adverse Reaction and Suspected Adverse Reaction ..................................................56 
9.3.3. 
Serious Adverse Event ................................................................................................57 
9.4. 
Monitoring and Recording Adverse Events ...............................................................57 
9.4.1. 
Serious Adverse Events ..............................................................................................57 
9.4.2. 
Non-Serious Adverse Events ......................................................................................58 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) .........................................58 
9.4.3.1. 
Relationship to the Study Treatment ..........................................................................58 


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9.4.3.2. 
Severity .......................................................................................................................58 
9.4.3.3. 
Action Taken With Study Treatment ..........................................................................59 
9.4.3.4. 
Treatment Given for the Adverse Event .....................................................................59 
9.4.3.5. 
Outcome of the Adverse Event ...................................................................................59 
9.5. 
Procedures for Handling Special Situations ...............................................................59 
9.5.1. 
Abnormalities of Laboratory Tests .............................................................................59 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................60 
9.5.3. 
Dosing Errors ..............................................................................................................60 
9.5.4. 
Contraception and Pregnancy .....................................................................................60 
9.5.5. 
Medical Emergency ....................................................................................................61 
10. 
STATISTICAL CONSIDERATIONS .......................................................................62 
10.1. 
Study Endpoints, Subsets, and Covariates ..................................................................62 
10.1.1. 
Safety and Tolerability Endpoints ..............................................................................62 
10.1.2. 
Efficacy Endpoints ......................................................................................................62 
 
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63 
10.2. 
Sample Size Considerations .......................................................................................63 
10.3. 
Populations .................................................................................................................64 
10.4. 
Definition of Baseline .................................................................................................64 
10.5. 
Interim Analysis ..........................................................................................................64 
10.6. 
Planned Methods of Analysis .....................................................................................64 
10.6.1. 
Demographic and Baseline Characteristics ................................................................64 
10.6.2. 
Safety and Tolerability Analysis ................................................................................65 
 
65 
 
67 
10.6.5. 
Exploratory/Pharmacogenomic Assessments .............................................................67 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ...........................................67 
11.1. 
Informed Consent/Assent ...........................................................................................67 
11.2. 
Ethical Conduct of the Study ......................................................................................68 


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11.3. 
Institutional Review Board/Institutional Ethics Committee/Research Ethics 
Board ...........................................................................................................................68 
11.4. 
Subject Confidentiality ...............................................................................................68 
11.4.1. 
Subject Data Protection ..............................................................................................69 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................69 
12.1. 
Protocol Amendments ................................................................................................69 
12.2. 
Study Termination ......................................................................................................70 
12.3. 
Study Documentation and Storage .............................................................................70 
12.4. 
Study Monitoring ........................................................................................................70 
12.5. 
Language .....................................................................................................................71 
12.6. 
Compensation for Injury .............................................................................................71 
12.7. 
Conflict of Interest ......................................................................................................71 
12.8. 
Registration of Study and Disclosure of Study Results ..............................................71 
12.9. 
Study Funding .............................................................................................................71 
12.10. 
Publications .................................................................................................................72 
13. 
REFERENCES ...........................................................................................................73 
14. 
APPENDICES ............................................................................................................76 
APPENDIX A. SCHEDULE OF PROCEDURES:  GROUPS 1A/1B AND 2A/2B 
BLIND LOADING DOSE PERIOD AND ALL GROUPS MMDR 
SCHEDULE ...............................................................................................................77 
APPENDIX B. LABORATORY ANALYTES ..........................................................................82 
 
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15. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................84 
 
LIST OF TABLES 
 
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Table 2: 
Study Drug Characteristics .........................................................................................51 
Table 3: 
Hammersmith Infant Neurological Examination Section 2 - Motor 
Milestones ...................................................................................................................66 
 


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LIST OF FIGURES 
Figure 1: 
ASO Therapeutic Approach for Treatment of SMA ..................................................23 
Figure 2: 
Study Design and Treatment Schema:  Groups 1A and 1B ........................................30 
Figure 3: 
Study Design and Treatment Schema:  Groups 2A and 2B ........................................31 
Figure 4: 
Study Design and Treatment Schema:  Groups 3, 4, and 5 ........................................32 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Extension Study for Patients With Spinal Muscular 
Atrophy Who Previously Participated in Investigational Studies of 
ISIS 396443 
Study Phase 
Phase 3 
Indication 
Spinal Muscular Atrophy (SMA) 
Treatment Group 
12 mg 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. 
Objectives 
Primary Objective 
To evaluate the long-term safety and tolerability of nusinersen 
administered by intrathecal (IT) injection to subjects with SMA who 
previously participated in investigational studies of ISIS 396443 
Secondary Objective 
To examine the long-term efficacy of nusinersen administered by IT 
injection to subjects with SMA who previously participated in 
investigational studies of ISIS 396443 
 
 
 
 
Number of Subjects Up to 292 subjects who previously participated in investigational studies 
ISIS 396443-CS3A, ISIS 396443-CS3B, ISIS 396443-CS4, 
ISIS 396443-CS12, or 232SM202 may be eligible to enroll in this study. 
Important Study 
Design Update 
Change in Dosing Schedule Note:  From the Protocol Version 2.0, 
regardless of their original dosing visit schedule (i.e., 6-month dosing 
schedule), all subjects will begin receiving maintenance doses of 
nusinersen every 4 months upon entering the modified maintenance 
dosing period of the study; this updated maintenance dosing schedule 
will henceforth be referred to as the Modified Maintenance Dosing 
Regimen (MMDR) dosing period. 
Unblinding of Index Studies ISIS 396443-CS3B and ISIS 396443-
CS4:  Index studies ISIS 396443-CS3B and ISIS 396443-CS4 have 


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been unblinded, and treatment assignments for subjects in the applicable 
groups (Groups 1A, 2A, 1B, and 2B) were released.  Therefore, there 
was no longer any reason to continue the blinded loading dose period in 
a blinded fashion.  For subjects in Group 1A and Group 2A who were 
receiving active drug (i.e., nusinersen) within the blinding loading dose 
period, visits continued to occur as scheduled, with all predose and 
postdose assessments performed.  For subjects in Groups 1B and 2B 
who were still attending visits and receiving treatment (i.e., nusinersen 
and sham procedures) within the blinded loading dose period, all visits 
and predose assessments were continued per the protocol; however, the 
sham procedure and all postdose procedures were not performed for 
those applicable visits. 
Study Design  
This is an open-label extension study in subjects with SMA who 
previously participated in investigational studies of ISIS 396443.  The 
primary purpose of this study is to gather additional information on the 
long-term safety, tolerability, and efficacy of repeated doses of 
nusinersen (12 mg) administered as IT injections by lumbar puncture 
(LP) over a period of 5 years from MMDR Day 1 (End-of-Study [EOS] 
Evaluation Visit to occur at approximately MMDR Day 1800 
[±14 days]), or as determined by the Sponsor (via early termination or 
amendment to extend). 
For the purposes of this protocol, investigational studies of ISIS 396443, 
henceforth referred to as index studies, include 
studies ISIS 396443-CS3A, ISIS 396443-CS3B, ISIS 396443-CS4, 
ISIS 396443-CS12, and 232SM202. 
This study will consist of Screening, Treatment, and Post-Treatment 
Follow-Up Periods and an EOS Evaluation Visit.  After informed 
consent/assent is obtained, subjects will undergo a screening evaluation 
up to 21 days prior to the first dose administration, during which their 
eligibility for the study will be determined.  Subjects who meet the 
eligibility criteria will be enrolled in the study. 
Subjects who entered the study after completing the double-blind studies 
ISIS 396443-CS3B and ISIS 396443-CS4 (i.e., subjects in Groups 1A, 
1B, 2A, and 2B) completed a blinded loading dose period and then 
transitioned to an open-label MMDR period.  Subjects who were already 
enrolled in ISIS 396443-CS11 (SHINE) and had already participated in 
the blinded loading dose period continued their blinded loading 
dose/sham schedule through the last scheduled dose in that loading dose 
period and then transitioned to the open-label MMDR dosing schedule 
at their next study visit, which was scheduled as close as possible to 
120 days from the date of the last dosing visit (i.e., date of last dosing 
visit + 120 days = MMDR Day 1).  The schedule for other MMDR visits 
should be based on MMDR Day 1. 


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During the blinded loading dose period, subjects who previously 
received the sham procedure during the index study received blinded 
injections of nusinersen in order to achieve the full loading regimen of 
study treatment, and subjects who previously received nusinersen during 
the index study received a combination of nusinersen injections and 
sham procedures.  This design was necessary to protect the full blind of 
the treatment assignment in the ongoing index studies.  
Subjects who entered the study after completing open-label studies 
ISIS 396443-CS12 and ISIS 396443-CS3A (i.e., subjects in Groups 3 
and 4) will enter directly into the open-label MMDR period at MMDR 
Day 1. 
Subjects who were already enrolled in ISIS 396443-CS11 and were 
already receiving maintenance doses according to the original 
maintenance schedule transitioned to MMDR Day 1 at their next study 
visit (regardless of how many maintenance doses already received in the 
original schedule), which was scheduled as close as possible to 120 days 
from the date of the last dosing visit (i.e., date of last dosing 
visit + 120 days = MMDR Day 1).  Subjects entering the study after 
completing open-label study 232SM202 (i.e., subjects in Group 5) will 
enter directly into the open-label MMDR period at MMDR Day 1.  The 
schedule for other MMDR visits should be based on MMDR Day 1. 
MMDR Days will be calculated by adding 120 days (±14 days) to the 
date of the last dosing visit and will begin at MMDR Day 1 (for all 
subjects entering the MMDR dosing schedule).  The MMDR dosing 
schedule will consist of MMDR Days 1, 120, 240, 360, 480, 600, 720, 
840, 960, 1080, 1200, 1320, 1440, 1560, and 1680 (±14 days) until the 
EOS Evaluation/Early Termination (ET) Visit.  The EOS Evaluation 
Visit will occur 4 months after the last open-label maintenance dose of 
nusinersen on approximately MMDR Day 1800 (±14 days). 
Dosing for ISIS 396443-CS3B 
• Group 1A:  Subjects who entered the study after receiving sham 
procedures in the double-blind study ISIS 396443-CS3B received 
4 loading doses of nusinersen administered by IT injection on Days 
1, 15, 29, and 64 (±1 day) followed by maintenance doses of 
nusinersen approximately every 4 months according to the MMDR 
dosing schedule.  Subjects who participated in the loading dose 
treatment cycle in ISIS 396443-CS11 completed the cycle and then 
transitioned to MMDR Day 1. 
• Group 1B:  Subjects who entered the study after receiving 
nusinersen in the double-blind study ISIS 396443-CS3B received 
3 sham procedures on Days 1, 15, and 64 and 1 loading dose of 
nusinersen administered by IT injection on Day 29 (±1 day) 
followed by maintenance doses of nusinersen approximately every 


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4 months according to the MMDR dosing schedule.  Subjects who 
participated in the loading dose treatment cycle in ISIS 396443-
CS11 completed the cycle and then transitioned to MMDR Day 1. 
Dosing for ISIS 396443-CS4 
• Group 2A:  Subjects who entered the study after receiving sham 
procedures in the double-blind study ISIS 396443-CS4 received 
3 loading doses of nusinersen administered by IT injection on 
Days 1, 29, and 85 (±1 day) followed by maintenance doses of 
nusinersen approximately every 4 months according to the MMDR 
dosing schedule.  Subjects who participated in the loading dose 
treatment cycle in ISIS 396443-CS11 completed the cycle and then 
transitioned to MMDR Day 1. 
• Group 2B:  Subjects who entered the study after receiving 
nusinersen in the double-blind study ISIS 396443-CS4 received 
2 loading doses of nusinersen administered by IT injection on Days 
1 and 85 and 1 sham procedure on Day 29 (±1 day) followed by 
maintenance doses of nusinersen approximately every 4 months 
according to the MMDR dosing schedule.  Subjects who 
participated in the loading dose treatment cycle in ISIS 396443-
CS11 completed the cycle and then transitioned to MMDR Day 1. 
Dosing for ISIS 396443-CS12 
• Group 3:  Subjects who entered the study after receiving 
nusinersen in the open-label study ISIS 396443-CS12 received 
maintenance doses of nusinersen approximately every 4 months 
according to the MMDR dosing schedule.  Subjects who received 
open-label maintenance doses of nusinersen in ISIS 396443-CS11 
were transitioned to the MMDR dosing period at their next study 
visit, which was scheduled as close as possible to 120 days from 
the date of the last dosing visit (i.e., date of last dosing visit + 120 
days = MMDR Day 1). 
Dosing for ISIS 396443-CS3A 
• Group 4:  Subjects who entered the study after receiving 
nusinersen in the open-label study ISIS 396443-CS3A received 
maintenance doses of nusinersen approximately every 4 months 
according to the MMDR dosing schedule.  Subjects who received 
open-label maintenance doses of nusinersen in ISIS 396443-CS11 
were transitioned to the MMDR dosing period at their next study 
visit, which was scheduled as close as possible to 120 days from 
the date of the last dosing visit (i.e., date of last dosing visit + 
120 days = MMDR Day 1). 
Dosing for 232SM202 


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• Group 5:  Subjects entering the study after receiving nusinersen 
during the open-label phase of Study 232SM202 (i.e., Part 2) will 
receive maintenance doses of nusinersen approximately every 
4 months according to the MMDR dosing schedule. 
All subjects will undergo predose evaluations according to the schedule 
of procedures and will remain at the study center for at least 1 hour after 
the study drug dosing/sham procedure for safety monitoring; the 
subjects can be discharged at the discretion of the Site Investigator and 
in compliance with the institutional requirements once they adequately 
recover from the dosing procedure. 
 
 
   
Safety monitoring by telephone contact will occur to monitor the 
subjects’ condition 1 to 14 days postdose and every other month 
(±14 days) thereafter throughout the duration of the study, except for the 
months during which a study visit occurs. 
Subjects who discontinue treatment will complete an early termination 
visit 4 months (+14 days) after administration of the last dose of 
nusinersen, unless consent is withdrawn. Subjects who discontinue from 
the study early will not be replaced. 
Study Population 
and Main Criteria 
for 
Inclusion/Exclusion 
Inclusion Criteria: 
Subjects must meet all of the following criteria at Screening to be 
eligible: 
1. Signed informed consent of parent or guardian and signed 
informed assent of subject, if indicated per subject’s age and 
institutional guidelines. 
2. Completion of the index study in accordance with the study 
protocol or as a result of Sponsor decision (e.g., early 
termination of the index study) within the preceding 16 weeks. 
3. Ability to complete all study procedures, measurements, and 
visits, and parent/subject has adequately supportive psychosocial 
circumstances, in the opinion of the Investigator. 
4. Subjects who, in the opinion of the Investigator, have reached 
reproductive maturity, must satisfy one of the following: 
• Females must have a negative pregnancy test at Screening 
and must agree to employ adequate contraceptive measures 
for the duration of the study.  Acceptable contraception 
methods are restricted to abstinence*, barrier contraceptives, 


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intrauterine contraceptive devices, or licensed hormonal 
products. 
• Males must be abstinent* for the duration of the study or 
must be using an acceptable contraceptive method (i.e., use a 
condom together with spermicidal 
foam/gel/film/cream/suppository). 
*Abstinence is only acceptable as true abstinence (i.e., when this 
is representative of the preferred and usual lifestyle of the 
subject).  Periodic abstinence (e.g., abstinence for the duration of 
the study) and withdrawal are not acceptable methods of 
contraception. 
Exclusion Criteria: 
Subjects meeting any of the following criteria are not eligible for the 
study: 
1. Have any new condition or worsening of existing condition, 
which in the opinion of the Investigator would make the subject 
unsuitable for enrollment or could interfere with the subject 
participating in or completing the study. 
2. Clinically significant abnormalities in hematology or blood 
chemistry parameters or electrocardiogram (ECG), as assessed 
by the Site Investigator, at the Screening Visit that would render 
the subject unsuitable for participation in the study. 
3. 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 procedures. 
4. The subject’s parent or legal guardian is not willing or able to 
meet guidelines in the consensus statement for standard of care 
in SMA or provide nutritional and respiratory support 
throughout the study.  NOTE:  Routine vaccinations and 
respiratory syncytial virus (RSV) prophylaxis are recommended 
per consensus guidelines on standard of care but are not required 
for study enrollment.  Subjects who are not current on 
vaccinations or who are not receiving RSV prophylaxis, but 
otherwise meet study inclusion criteria, will be considered 
eligible for study enrollment. 
5. Treatment with another investigational agent, biological agent, 
or device within 1 month of Screening or 5 half-lives of study 
agent, whichever is longer. 
Study Treatment 
and Administration 
Nusinersen (2.4 mg/mL) will be administered as an IT LP injection. 
All subjects will receive the full 12-mg dose of the study drug (5 mL). 


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During the blinded loading dose period, the study treatment dosing or 
sham procedures were performed in a dedicated room and administered 
by dedicated study personnel who were unblinded to the treatment 
assignment; this was not any of the key study site personnel (i.e., the 
Investigator, Study Coordinator, or Outcomes Assessors), and the key 
study personnel or the parents were not present during the procedure to 
ensure blinding.  The sham procedure consisted of a small needle prick 
on the lower back at the location where the LP injection was normally 
made.  The needle broke the skin, but no LP injection or needle insertion 
occurred.  The site of the needle prick was covered in the same manner 
as that of the LP injection, thus simulating the appearance of an LP 
injection. 
If anesthesia or sedation was used for the LP procedure in 
nusinersen-treated subjects at an individual study center, in order to 
maintain the blind, minimal sedation (i.e., a low dose of an anxiolytic) 
was used for the sham procedure, following institutional procedures.  
Subjects who received the sham procedure were kept in the procedure 
room for the same amount of time as that for subjects who were 
administered study treatment, thus simulating the time period of a study 
treatment administration procedure. 
As index studies ISIS 396443-CS3B and ISIS 396443-CS4 have been 
unblinded, there was no longer any reason to continue the blinded 
loading dose period in a blinded fashion.  For subjects in Groups 1B and 
2B who were still attending visits and receiving treatment (i.e., 
nusinersen and sham procedures) within the blinded loading dose period 
since the time of unblinding, the sham procedure and all postdose 
procedures described above were not performed for those applicable 
visits.  During these visits, study drug was not administered, and these 
visits were considered safety visits. 
Criteria for 
Evaluation of Study 
Objectives For All 
Groups/Subjects 
Safety and Tolerability 
• Adverse events (AEs) and serious adverse events 
• Vital signs and weight 
• Neurological examinations 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis, 
and urine total protein) 
• Coagulation parameters (activated partial thromboplastin time and 
international normalized ratio) 
• ECGs 
• Use of concomitant medications 
Efficacy  


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• Achievement of motor milestones (World Health Organization 
motor milestones and/or Section 2 of Hammersmith Infant 
Neurological Examination) 
• Time to death or permanent ventilation (tracheostomy or 
≥16 hours ventilation/day continuously for >21 days in the absence 
of an acute reversible event) 
• Percentage of subjects not requiring permanent ventilation 
• Change from baseline in applicable motor function assessments:  
Children’s Hospital of Philadelphia Infant Test for Neuromuscular 
Disease, Hammersmith Functional Motor Scale – Expanded, 
Revised Upper Limb Module, 6-Minute Walk Test, and contracture 
assessment 
• Change from baseline in compound muscle action potential 
(CMAP) 
• Growth parameters 
• Proportion of CMAP responders 
• Number of motor milestones achieved per subject 
• Proportion of subjects who achieved standing alone 
• Proportion of subjects who achieved walking with assistance 
• Number of serious respiratory events 
• Number and length of hospitalizations 
• Change from baseline in Cobb-Angle on X-ray of the 
thoracolumbar spine 
• Changes in quality of life assessments: Pediatric Quality of Life 
Inventory, and/or Assessment of Caregiver Experience with 
Neuromuscular Disease 
• Disease-related hospitalizations and AEs 
• Survival rate 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Safety Monitoring  
Safety data will be reviewed on an ongoing basis by the Sponsor and the 
Medical Monitor, with data cuts at regular intervals. 
Statistical 
Considerations  
The sample size is based solely on the number of subjects enrolled in 
ISIS 396443-CS3A, ISIS 396443-CS3B, ISIS 396443-CS4, 
ISIS 396443-CS12, and 232SM202 studies who may be eligible for 
participation in this study. 
Sponsor 
Biogen 


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STUDY GLOSSARY 
Abbreviation /Acronym 
Definition 
6MWT 
6-Minute Walk Test 
ACEND 
Assessment of Caregiver Experience with Neuromuscular Disease 
AE 
adverse event 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
 
 
BiPAP 
bilevel positive airway pressure 
CHOP INTEND 
Children’s Hospital of Philadelphia Infant Test for Neuromuscular 
Disease 
CMAP 
compound muscle action potential 
CNS 
central nervous system 
CPAP 
continuous positive airway pressure 
CRF 
case report form 
CSF 
cerebrospinal fluid 
 
 
DHA 
Directions for Handling and Administration  
 
 
ECG 
electrocardiogram 
EOS 
End-of-Study 
ET 
Early Termination 
FL 
full-length  
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
HFMSE 
Hammersmith Functional Motor Scale – Expanded 
HINE 
Hammersmith Infant Neurological Examination 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
HRQOL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 


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INR 
international normalized ratio 
IRB 
Institutional Review Board 
IT 
intrathecal 
ITT 
Intent-to-Treat 
IxRS 
Interactive Voice/Web Response System 
LP 
lumbar puncture 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
MMDR 
Modified Maintenance Dosing Regimen 
 
  
 
id 
NCS 
not clinically significant 
PedsQL™ 
Pediatric Quality of Life Inventory 
 
 
 
 
 
 
RSV 
respiratory syncytial virus 
RULM 
Revised Upper Limb Module 
SAE 
serious adverse event 
SMA 
spinal muscular atrophy 
SMN 
survival motor neuron 
SMN1 
survival motor neuron 1 
SMN2 
survival motor neuron 2 
snRNA 
small nuclear ribonucleic acid 
SUSAR 
suspected unexpected serious adverse reaction 
US 
United States 
 
 
 
 
WHO 
World Health Organization 
 


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1. 
OBJECTIVES 
The objective of this open-label extension study is to gather additional information on the 
long-term safety, tolerability, and efficacy of repeated 12-mg doses of ISIS 396443 (also known 
as BIIB058 and nusinersen) administered as intrathecal (IT) injections by lumbar puncture (LP) 
in subjects with spinal muscular atrophy (SMA) who previously participated in investigational 
studies of 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. 
1.1. 
Primary Objective 
To evaluate the long-term safety and tolerability of nusinersen administered by IT injection to 
subjects with SMA who previously participated in investigational studies of ISIS 396443 
1.2. 
Secondary Objective 
To examine the long-term efficacy of nusinersen administered by IT injection to subjects with 
SMA who previously participated in investigational studies of ISIS 396443 
 
 
 
 
 
2. 
BACKGROUND AND RATIONALE 
2.1. 
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.  Despite being a rare disease, prior to the availability of 
therapeutic treatment options, SMA was one of the most common genetic causes of death in 
infants, with a reported birth prevalence ranging from 8.5 to 10.3 per 100,000 live births 
[Arkblad 2009; Jedrzejowska 2010; Prior 2010; Sugarman 2012; Tassie 2013].  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 1 SMA (equivalent to infantile-onset 
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 2 years of age.  Later-onset SMA can 
generally be divided into Type 2 and Type 3 SMA.  Patients with Type 2 SMA are able to sit but 
never walk unaided, with symptoms presenting between 6 and 18 months of age.  Patients with 
Type 3 SMA are able to sit and walk but may become severely and increasingly disabled.  
Patients with adult-onset SMA (Type 4) have an age of onset over 18 years and have normal life 
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In 95% of patients with SMA, a deletion in the survival motor neuron 1 (SMN1) gene on 
chromosome 5q11-q13 is found; with the remaining 5% attributable to small mutations in the 
same gene [Helmken 2003; Lefebvre 1995].  SMN1 lies in the telomeric portion of an inverted 
duplication of a region of chromosome 5.  The centromeric half of the duplication contains a 
homologous gene named survival motor neuron 2 (SMN2) that differs from SMN1 by 
5 nucleotides.  The open reading frames for both genes encode for proteins with identical amino 
acid sequences.  Survival motor neuron (SMN) gene transcripts, similar to most mammalian 
transcripts, undergo alternative splicing in which certain exons are either included or excluded 
from the mature protein coding transcripts [Keren 2010].  In particular, exon 7 of the SMN1 gene 
is alternatively spliced with 90% to 95% of the mature messenger ribonucleic acid (mRNA) 
transcripts derived from the SMN1 gene containing exon 7, and 5% to 10% of transcripts missing 
exon 7.  The transcripts missing exon 7 (often referred to as Δ7) produce a truncated protein that 
is defective and unstable [Cho and Dreyfuss 2010].  One of the 5 nucleotide differences between 
SMN1 and SMN2, a C to T substitution occurs in exon 7 of the SMN2 gene resulting in an 
alternative splicing pattern that favors skipping of exon 7.  The result is that as much as 90% of 
the transcripts produced from SMN2 are missing exon 7.  The remainder, SMN2 transcripts 
containing exon 7, produces a full-length (FL) protein product identical to the SMN1 protein 
because 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 
FL-SMN protein expressed in patients with SMA (10% to 40% of normal SMN protein levels) 
correlates with SMA disease severity, and thus, SMN2 is a key modifier of disease phenotype 
[Coovert 1997; Feldkötter 2002; Lefebvre 1997; Prior 2004]. 
2.2. 
Therapeutic Rationale 
Since the number of SMN2 gene copies and the resulting amount of SMN protein is correlated 
with disease onset and severity, a therapeutic approach predicted to benefit patients with SMA is 
to increase the levels of FL-SMN2 pre-mRNA by restoring the splicing pattern that gives rise to 
FL-SMN2 mRNA.  Increasing inclusion of exon 7 in the SMN2 transcript will increase FL-SMN 
protein levels and SMN protein activity.  A therapeutic strategy for promoting exon 7 inclusion 
is through the use of antisense oligonucleotides (ASOs) [see Figure 1]. 


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Figure 1: 
ASO Therapeutic Approach for Treatment of SMA 
 
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. 
The known potential risks associated with nusinersen are detailed in the Guidance to Investigator 
section of the Investigator’s Brochure. 
2.3. 
Nusinersen 
2.3.1. 
Mechanism of Action 
Nusinersen is a fully modified, 2′-O-2-methoxyethyl (MOE) chimeric ASO drug designed to 
bind to a specific sequence in the intron downstream of exon 7 of the SMN2 transcript.  The 
region of the pre-mRNA targeted by nusinersen is normally occupied by heterogeneous nuclear 
ribonucleoproteins (hnRNP) A1/2 proteins, masking the U1 small nuclear ribonucleic acid 
(snRNA) binding site at the 5′-exon-intron junction of exon 7, and is referred to as ISS-N1.  
U1 snRNA base pairs to the sequences that define the 5′-splice site, which is thought to be one of 
the first steps that initiate splicing of an intron.  Nusinersen displaces the hnRNP A1/2 proteins 
from the pre-mRNA binding site, allowing U1 snRNA to bind to the exon-intron junction and 
promote assembly of the spliceosomal complex, thus promoting inclusion of exon 7 into the 
mRNA, which results in production of FL-SMN protein. 


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2.3.2. 
Chemistry 
Chemically, nusinersen is a synthetic oligomer of 18 nucleotides (i.e., an 18-mer) that are 
connected sequentially by phosphorothioate linkages.  Each of the 17 internucleotide linkages is 
a 3′-O to 5′-O phosphorothioate diester.  The 18 sugar residues are uniformly modified with 
2′-O-(2-MOE).  These MOE-modified nucleotides confer (1) increased affinity to the target 
mRNA [McKay 1999], (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) [Geary 2003], and (3) amelioration of some of the high-dose 
toxicities associated with ASO containing only the phosphorothioate linkages [Henry 2000]. 
The sequence of nusinersen is written as follows: 
5′ -MeUMeCAMeCMeUMeUMeUMeCAMeUAAMeUGMeCMeUGG- 3ʹ 
where A and G are 2′-O-(2-methoxyethyl)nucleosides, MeC is 5-methyl-2′-O-(2-methoxyethyl) 
cytidine, and MeU designates 5-methyl-2′-O-(2-methoxyethyl)uridine. 
2.3.3. 
Nonclinical Experience 
Nusinersen was identified after an extensive screen of greater than 500 2′-MOE oligonucleotides 
in in vitro splicing assays, reporter gene assays, and fibroblast cells from patients with SMA 
[Hua 2007; Hua 2008].  Data have shown that nusinersen promotes a concentration-dependent 
increase in FL transcripts (including exon 7) in patients’ fibroblast cells, achieving greater than 
90% FL-SMN2 transcripts and forming nuclear structures, called gems, known to contain SMN 
protein.  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 2007] and in central 
nervous system (CNS) tissue, including spinal cord, when injected into the lateral ventricle.  
Nusinersen produced greater than 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 delivery of drug through the CNS produced a dose-dependent effect on SMN2 exon 7 
inclusion, SMN protein production, and survival.  These mice treated with nusinersen 
demonstrated improved weight gain; improved muscle morphology, muscle strength, and motor 
coordination; and improved morphology of the motor neuron junctions [Passini 2011].  Further, 
nusinersen was shown to distribute widely in the CNS following IT administration in monkey 
[Passini 2011]. 
The PK and toxicity of nusinersen were assessed 1) following single IT lumbar bolus injections 
(1 to 7 mg) in adult monkeys, 2) following 14 weeks (with a 4-week interim sacrifice) of 
repeated IT lumbar bolus injections (0.3 to 3 mg weekly or every other week) in juvenile 
monkeys, and 3) following 53 weeks of repeated IT lumbar bolus injections in juvenile monkeys.  
In addition, a dedicated PK study in adult monkeys was performed to assess the half-life of 
nusinersen in CSF, tissues, and plasma. 


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Main findings from these studies are as follows: 
• Dose-dependent concentrations of nusinersen were measured in spinal cord, brain, 
CSF, liver, and plasma of adult and juvenile monkeys and in kidney of juvenile 
monkeys. 
• Tissue concentrations of nusinersen were measurable in all spinal cord and brain 
sections examined indicating broad distribution associated with single and repeated 
IT slow bolus administration. 
• Highest tissue concentrations of nusinersen in monkey were generally observed in 
lumbar spinal cord, consistent with the IT route of administration. 
• Systemic tissue (liver and kidney) concentrations were measurable but low, relative to 
parenteral administration. 
• Neurological changes, assessed through evaluation of general sensory and motor 
functions, cerebral reflexes, and spinal reflexes, were limited to acute transient lower 
spinal reflex deficits in a few monkeys at the highest dose levels evaluated, 2 to 
8 hours following dose administration.  These effects were not observed in most 
monkeys within 48 hours postdose.  The clinical signs were directly associated with 
administration of large amounts of drug to the lumbar spinal cord at the higher doses 
examined in these studies and were not cumulative with continued dosing through 
14 or 53 weeks. 
• No adverse treatment-related histologic changes were observed in the CNS.  There 
was no evidence of neuronal cell death or degeneration in the brain or spinal cord 
through 4 weeks of treatment. 
• Histologic changes observed in the CNS after 14 weeks of treatment included slight 
to minimal vacuolation in a focal region of the inferior hippocampus 
(1 mg/dose × 10 doses and 3 mg/dose × 15 doses) and was associated with very rare 
neuronal or glial cell necrosis at the 3 mg/dose only. 
• Histologic changes observed in the CNS after 53 weeks of treatment included slight 
to mild vacuolation in a focal region of the inferior hippocampus (1 and 
4 mg/dose × 13 doses) and was associated with non-neuronal cell necrosis (graded 
slight, 1 of 5 males at the 1 mg/dose × 13 doses and 3 of 5 males at the 
4 mg/dose × 13 doses).  None of these changes were deemed to be adverse as there 
were no sustained decrements in neurological function or learning ability, and the 
necrotic changes observed were slight, limited to a single sex, and did not affect 
neurons. 
• Pro-inflammatory effects were limited in adult monkeys receiving single doses of 
nusinersen to very slight mononuclear cell infiltrates in the meninges of the brain and 
were similar in nature to those commonly observed in control animals from other IT 
studies.  Pro-inflammatory effects in juvenile monkeys receiving 4 weeks of 
treatment were limited to observations in a single animal and included scattered, 
slight microglial foci and slight perivascular infiltrates in the brain and spinal cord.  
Pro-inflammatory effects in juvenile monkeys receiving 14 weeks of treatment were 
limited to observations of perivascular macrophages in the central canal of the spinal 
cord in a single female in the high-dose group and an increase of infiltrates in the 


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cerebral meninges in the mid- and high-doses groups (1 mg/dose × 10 doses and 
3 mg/dose × 15 doses).  None of these findings were deemed to be adverse and were 
reversible following the cessation of treatment.  No local or systemic 
pro-inflammatory effects were observed following 53 weeks of treatment. 
• Nusinersen did not produce any changes in clinical pathology parameters, 
complement activation or indications of systemic toxicity. 
• No evidence of genotoxicity was observed in the Ames bacterial mutagenicity and 
in vitro chromosomal aberrations in Chinese hamster ovary cells. 
Detailed results from these nonclinical studies conducted with nusinersen can be found in the 
nusinersen Investigator’s Brochure. 
2.3.4. 
Clinical Experience 
Detailed information concerning the clinical studies conducted with nusinersen can be found in 
the current version of the Investigator’s Brochure.  A summary is included below. 
Nusinersen has been evaluated in a completed open-label, single-ascending-dose, Phase 1 study 
designed to assess the safety, tolerability, and PK of nusinersen in subjects with SMA 
(ISIS 396443-CS1).  A single dose of nusinersen was administered by IT injection to patients 
with SMA 2 to 14 years of age.  Four dose levels (1, 3, 6, and 9 mg) were evaluated sequentially.  
Each dose level was studied in a cohort of 6 or 10 subjects, where all subjects received 
nusinersen.  
Nusinersen was evaluated in 7 additional completed studies, ISIS 396443-CS2, 
ISIS 396443-CS10, ISIS 396443-CS12, ISIS 396443-CS3B, ISIS 396443-CS4, ISIS 396443-
CS3A, and 232SM202, and is being evaluated in 4 additional ongoing studies, 232SM201, 
232SM203, 232SM302, and 232SM404: 
• Study ISIS 396443-CS2 (completed) was an open-label, multiple-ascending-dose study 
designed to assess the safety, tolerability, and PK of nusinersen in patients with later-
onset SMA.  Multiple doses of nusinersen, ranging from 3 to 12 mg, were administered 
by IT injection to patients with SMA 2 to 15 years of age at screening. 
• Study ISIS 396443-CS10 (completed) was an open-label, single-dose, redosing study for 
patients with SMA who previously participated in Cohorts 2, 3, and 4 of Study 
ISIS 396443-CS1. 
• Study ISIS 396443-CS12 (completed) was an open-label, multiple-dose study to assess 
the safety and tolerability of a 12-mg dose level of nusinersen administered by IT 
injection in patients with SMA who previously participated in Study ISIS 396443-CS2 or 
Study ISIS 396443-CS10. 
• Study ISIS 396443-CS3B (completed) was a randomized, double-blind, sham-procedure 
controlled study designed to assess clinical efficacy, safety, and PK of nusinersen in 
patients with infantile-onset SMA.  A 12-mg dose equivalent scaled by CSF volume is 
being evaluated in infants with symptomatic SMA less than or equal to 7 months of age 
at screening.  


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• Study ISIS 396443-CS4 (completed) was a randomized, double-blind, sham-procedure 
controlled study designed to assess clinical efficacy, safety, and PK of nusinersen in 
patients with later-onset SMA 2 to 12 years of age at screening. 
• Study ISIS 396443-CS3A (completed) was an open-label, multiple-dose study designed 
to assess the safety, tolerability, and PK of nusinersen in patients with infantile-onset 
SMA.  Multiple doses of nusinersen were administered by IT injection to infants with 
symptomatic SMA who were less than or equal to 7 months of age at screening.  Two 
dose levels (6-mg and 12-mg dose equivalent scaled by CSF volume) were being 
evaluated sequentially. 
• Study 232SM201 (ongoing) is an open-label study to assess the efficacy, safety, 
tolerability, and PK of multiple doses of nusinersen delivered by IT injection to subjects 
with genetically diagnosed and presymptomatic SMA. 
• Study 232SM202 (completed) was a randomized, double-blind, sham-procedure 
controlled study to assess safety and tolerability and to explore efficacy of nusinersen 
administered by IT injection in subjects with SMA who were not eligible to participate in 
the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4. 
• Study 232SM203 (ongoing) is a 3-part dose-escalating and randomized control study to 
assess safety, efficacy, and PK of higher dose regimen of nusinersen in subjects with 
SMA. Part A is open-label with a 28-mg loading dose, Part B is double-blind with a 
50-mg loading dose, and Part C is open-label with a 50-mg loading dose. 
• Study 232SM302 (ongoing) is a long-term extension study; blinding only for subjects 
with SMA from Study 232SM203 Part B for the first dose in Study 232SM302 to assess 
the safety, efficacy, and PK of higher dose regimen of nusinersen. 
• Study 232SM404 (ongoing) is an open-label, single-arm study in patients who previously 
received onasemnogene abeparvovec to assess the efficacy, safety, and PK of nusinersen. 
The primary support for the safety and efficacy of nusinersen in the treatment of SMA derives 
from pre-planned interim analyses of Study ISIS 396443-CS3B, the sham-controlled study in 
subjects with infantile-onset SMA, and final analyses of Study ISIS 396443-CS4, the 
sham-controlled study in subjects with later-onset SMA.  Subjects receiving nusinersen in these 
2 studies achieved statistically significant improvements in motor function compared to subjects 
in the control arms.  
Nusinersen has a favorable safety profile.  Uncontrolled studies in presymptomatic infants 
(Study 232SM201), subjects with infantile-onset SMA (Study ISIS 396443-CS3A), and subjects 
with later-onset SMA (longitudinal analysis of studies ISIS 396443-CS2 and ISIS 396443-CS12) 
are highly supportive of the results of the pivotal efficacy studies (Studies ISIS 396443-CS3B 
and ISIS 396443-CS4) and provide evidence of the long-term benefit of treatment with 
nusinersen. 
2.4. 
Rationale for Dose and Schedule of Administration 
The proposed study will test the clinical efficacy, safety, tolerability, and PK of multiple doses of 
nusinersen administered by IT injection to subjects with SMA who previously participated in 
investigational studies of ISIS 396443.  A single dose level of 12 mg of nusinersen will continue 
to be evaluated in this long-term extension study. 


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The nusinersen dose level and dose interval were selected based on nonclinical toxicology and 
PK observations from studies in monkey utilizing single- and repeat-dosing IT administration, 
consideration of the target tissue concentration anticipated for drug pharmacology, severity of 
SMA phenotype, and safety data in the completed and ongoing clinical studies of ISIS 396443 to 
date.  Based on the pharmacology and PK results in SMA transgenic mice, it was estimated that 
the target tissue concentration to produce 50% to 90% SMN2 exon 7 inclusion is between 2 and 
10 μg/g spinal cord tissue.  Nonclinical studies in juvenile monkeys receiving IT 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 level selected for this 
multiple-dose clinical study (12 mg 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), 
following the first dose.   
The loading dose interval was selected as the dose interval based on the nonclinical PK and 
pharmacology data to achieve and maintain nusinersen spinal cord tissue levels that are predicted 
to be within the upper end of the pharmacologically active range by Day 64 in subjects with the 
more severe infantile-onset SMA phenotype (predicted to be approximately 30 µg/g lumbar and 
10 µg/g cervical spinal cord tissue concentrations) and by Day 85 in subjects with the less severe 
later-onset SMA phenotype (predicted to be approximately 24 μg/g lumbar and 8 μg/g cervical 
spinal cord tissue concentrations), while at the same time considering subject safety and 
convenience for repeated LP IT injections.   
The maintenance dose intervals were selected based on nonclinical PK and pharmacology data 
and clinical PK data from subjects in ongoing and completed clinical studies with the goal of 
maintaining the spinal cord tissue levels of nusinersen at a steady-state level within the estimated 
pharmacologically active range.  The elimination half-life of nusinersen from human CSF is 
approximately 135 to 177 days and was estimated based on a limited number of postdose 
levels.  Although CNS tissue half-life cannot be measured in humans, the median terminal 
elimination half-life was measured in the CNS tissue of adult monkeys and found to be 116 days, 
approximately 4 months.  Because the site of action of nusinersen is within the CNS tissues, 
these findings support maintenance doses administered every 4 months. 
The maintenance dosing regimen of 12 mg every 4 months was implemented in a 
sham-controlled study in infantile-onset SMA (Study ISIS 396443-CS3B [ENDEAR]), an 
open-label study in presymptomatic SMA (Study 232SM201 [NURTURE]), an open-label study 
in infantile-onset SMA (Study ISIS 396443-CS3A), and a sham-controlled study in both 
infantile-onset and later-onset SMA (Study 232SM202 [EMBRACE]).  For subjects in a 
sham-controlled study in later-onset SMA (Study ISIS 396443-CS4 [CHERISH]) and an 
open-label study in later-onset SMA (Study ISIS 396443-CS12) who are eligible to enroll in this 
open-label extension study (Study ISIS 396443-CS11), the maintenance dose schedule is 
shortened from every 6 months to every 4 months.  The change is further supported by available 
data on the exposure-response relationship as well as efficacy and safety data from the clinical 
studies.  Data from the population PK analyses suggest that higher CSF exposure leads to 
improvements in compound muscle action potential (CMAP), a measure of motor neuron health; 
Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease (CHOP INTEND), a 
measure of motor strength; and motor milestones in symptomatic infants with infantile-onset 
SMA treated with nusinersen.  While the clinical endpoints differ between populations, the 
relationship between increased CSF trough concentration or overall exposure and improved 


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functional outcomes is also anticipated in older subjects receiving more frequent maintenance 
doses.  Because the majority of adverse events (AEs) in the clinical studies have been more 
likely related to the natural history of the disease rather than to nusinersen, any additional safety 
concerns associated with the Modified Maintenance Dosing Regimen (MMDR) are expected to 
be mostly limited to procedure-related AEs, such as post-lumbar puncture syndrome and back 
pain. 
Additional details on dosing and expected CSF and tissue concentrations are summarized in the 
Investigator’s Brochure. 
3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This is an open-label extension study in subjects with SMA who previously participated in 
investigational studies of ISIS 396443.  For the purposes of this protocol, investigational studies 
of ISIS 396443, henceforth referred to as “index” studies, include studies ISIS 396443-CS3A, 
ISIS 396443-CS3B, ISIS 396443-CS4, ISIS 396443-CS12, and 232SM202.  
3.1.1. 
Important Study Design Update 
Change in Dosing Schedule Note:  From the Protocol Version 2.0, regardless of their original 
dosing visit schedule (i.e., 6-month dosing schedule), all subjects will begin receiving 
maintenance doses of nusinersen every 4 months upon entering the MMDR period of the study.  
This updated maintenance dosing schedule will henceforth be referred to as the MMDR dosing 
period. 
3.2. 
Number of Study Centers 
This study will be conducted at up to 50 sites in up to 15 countries worldwide. 
3.3. 
Number of Subjects 
Up to 292 subjects who previously participated in investigational studies ISIS 396443-CS3A, 
ISIS 396443-CS3B, ISIS 396443-CS4, ISIS 396443-CS12, or 232SM202 may be eligible to 
enroll in this study. 
3.4. 
Overall Study Duration and Follow-Up 
This study will consist of Screening, Treatment, and Post-Treatment Follow-Up Periods, and an 
End-of-Study (EOS) Evaluation Visit.  The total duration of participation in the study is 5 years 
from MMDR Day 1 (EOS Evaluation Visit to occur at approximately MMDR Day 1800 
[±14 days]).  A study schematic for Groups 1A and 1B, Groups 2A and 2B, and Groups 3, 4, and 
5 is provided in Figure 2, Figure 3, and Figure 4, respectively.  The Sponsor acknowledges that 
any references to Groups 3, 4, and 5 do not apply to participating clinical study sites that do not 
have subjects from these groups.  Please refer to the Schedule of Procedures in Appendix A. 


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Figure 2: 
Study Design and Treatment Schema:  Groups 1A and 1B 
 
MMDR = Modified Maintenance Dosing Regimen.
BLINDED LOADING DOSE 
PERIOD 
Group 1A  
Nusinersen on Days 1, 15, 29, and 64 (±1 day) 
Group 1B  
Sham procedure on Days 1, 15, and 64  
and nusinersen on Day 29 (±1 day) 
MMDR PERIOD  
Scheduled as close as possible to 120 days 
from the date of the last dosing visit  
(i.e., Day 64 visit + 120 days = MMDR Day 1). 
 
Open-label nusinersen on MMDR Days 1, 120, 
240, 360, 480, 600, 720, 840, 960, 1080, 1200, 
1320, 1440, 1560, and 1680 (±14 days)  
POST-TREATMENT 
EVALUATION 
Telephone follow-up calls 1 to 
14 days postdose and every other 
month (±14 days) thereafter (except 
dosing months) throughout the study 
END-OF-STUDY 
EVALUATION VISIT 
Scheduled 4 months after last 
open-label maintenance dose of 
nusinersen on approximately MMDR 
Day 1800 (±14 days) 
EARLY 
TREATMENT 
TERMINATION 
VISIT 
Scheduled 4 months 
after last dose of 
nusinersen 
(+14 days) 
SCREEN 
-21 to -1 days 
before Baseline 




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Figure 4: 
Study Design and Treatment Schema:  Groups 3, 4, and 5 
 
MMDR = Modified Maintenance Dosing Regimen. 
3.4.1. 
Screening 
After informed consent/assent is obtained, subjects will undergo a screening up to 21 days prior 
to first dose administration, during which their eligibility for the study will be determined.  
Subjects who meet the eligibility criteria will be enrolled into the study. 
3.4.2. 
Treatment 
Subjects who entered the study after completing the double-blind studies ISIS 396443-CS3B and 
ISIS 396443-CS4 (i.e., subjects in Groups 1A, 1B, 2A, and 2B) completed a blinded loading 
dose period and then transitioned to the open-label MMDR period.  Subjects who were already 
enrolled in ISIS 396443-CS11 (SHINE) and had already participated in the blinded loading dose 
period continued their blinded loading dose/sham schedule through the last scheduled dose in 
that loading dose period and then transitioned to the open-label MMDR dosing schedule at their 
next study visit, which was scheduled as close as possible to 120 days from the date of the last 
MMDR PERIOD  
Nusinersen on MMDR Days 1, 120, 240, 360, 480, 600, 
720, 840, 960, 1080, 1200, 1320, 1440, 1560, and 1680 
(±14 days) 
If already on original maintenance schedule, MMDR 
Day 1 should be scheduled as close as possible to 
120 days from the date of the last dosing visit (i.e., date 
of last dosing visit + 120 days = MMDR Day 1). 
POST-TREATMENT EVALUATION 
Telephone follow-up calls 1 to 14 days postdose and 
every other month (±14 days) thereafter (except dosing 
months) throughout the study 
END-OF-STUDY EVALUATION VISIT 
Scheduled 4 months after last open-label maintenance 
dose of nusinersen on approximately MMDR Day 1800 
(±14 days) 
EARLY 
TREATMENT 
TERMINATION 
VISIT 
Scheduled 4 months 
after last dose of 
nusinersen (+14 days) 
SCREEN 
-21 to -1 days before 
Baseline 


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dosing visit (i.e., date of last dosing visit + 120 days = MMDR Day 1).  The schedule for other 
MMDR dosing visits should be based on MMDR Day 1. 
During the blinded loading dose period, subjects who previously received the sham procedure 
during the index study received blinded injections of nusinersen in order to achieve the full 
loading regimen of study treatment, and subjects who previously received nusinersen during the 
index study received a combination of nusinersen injections and sham procedures.  This design 
was necessary to protect the full blind of the treatment assignment in the ongoing index studies. 
Subjects who entered the study after completing open-label studies ISIS 396443-CS12 and 
ISIS 396443-CS3A (i.e., subjects in Groups 3 and 4) will enter directly into the open-label 
MMDR period at MMDR Day 1.  Subjects who were already enrolled in ISIS 396443-CS11 and 
were already receiving maintenance doses according to the original maintenance schedule 
transitioned to MMDR Day 1 at their next study visit (regardless of how many maintenance 
doses already received in the original schedule), which was scheduled as close as possible to 
120 days from the date of the last dosing visit (i.e., date of last dosing visit + 120 days = MMDR 
Day 1).  Subjects entering the study after completing open-label Study 232SM202 (i.e., subjects 
in Group 5) will enter directly into the open-label MMDR period at MMDR Day 1.  The 
schedule for other MMDR dosing visits should be based on MMDR Day 1. 
The MMDR dosing schedule will consist of MMDR Days 1, 120, 240, 360, 480, 600, 720, 840, 
960, 1080, 1200, 1320, 1440, 1560, and 1680 (±14 days) until the EOS Evaluation/Early 
Termination (ET) Visit.  The EOS Evaluation Visit will occur 4 months after the last open-label 
maintenance dose of nusinersen on approximately MMDR Day 1800 (±14 days). 
Dosing for ISIS 396443-CS3B 
• Group 1A:  Subjects who entered the study after receiving sham procedures in the 
double-blind study ISIS 396443-CS3B received 4 loading doses of nusinersen 
administered by IT injection on Days 1, 15, 29, and 64 (±1 day) followed by 
maintenance doses of nusinersen approximately every 4 months according to the 
MMDR dosing schedule.  Subjects who participated in the loading dose treatment 
cycle in ISIS 396443-CS11 completed the cycle and then transitioned to MMDR 
Day 1. 
• Group 1B:  Subjects who entered the study after receiving nusinersen in the 
double-blind study ISIS 396443-CS3B received 3 sham procedures on Days 1, 15, 
and 64 and 1 loading dose of nusinersen administered by IT injection on Day 29 
(±1 day) followed by maintenance doses of nusinersen approximately every 4 months 
according to the MMDR dosing schedule.  Subjects who participated in the loading 
dose treatment cycle in ISIS 396443-CS11 completed the cycle and then transitioned 
to MMDR Day 1. 
Dosing for ISIS 396443-CS4 
• Group 2A:  Subjects who entered the study after receiving sham procedures in the 
double-blind study ISIS 396443-CS4 received 3 loading doses of nusinersen 
administered by IT injection on Days 1, 29, and 85 (±1 day) followed by maintenance 
doses of nusinersen approximately every 4 months according to the MMDR dosing 
schedule.  Subjects who participated in the loading dose treatment cycle in 
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• Group 2B:  Subjects who entered the study after receiving nusinersen in the 
double-blind study ISIS 396443-CS4 received 2 loading doses of nusinersen 
administered by IT injection on Days 1 and 85 and 1 sham procedure on Day 29 
(±1 day) followed by maintenance doses of nusinersen approximately every 4 months 
according to the MMDR dosing schedule.  Subjects who participated in the loading 
dose treatment cycle in ISIS 396443-CS11 completed the cycle and then transitioned 
to MMDR Day 1. 
Dosing for ISIS 396443-CS12 
• Group 3:  Subjects who entered the study after receiving nusinersen in the open-label 
study ISIS 396443-CS12 received maintenance doses of nusinersen approximately 
every 4 months according to the MMDR dosing schedule.  Subjects who received 
open-label maintenance doses of nusinersen in ISIS 396443-CS11 were transitioned 
to the MMDR dosing period at their next study visit, which was scheduled as close as 
possible to 120 days from the date of the last dosing visit (i.e., date of last dosing visit 
+ 120 days = MMDR Day 1). 
Dosing for ISIS 396443-CS3A 
• Group 4:  Subjects who entered the study after receiving nusinersen in the open-label 
study ISIS 396443-CS3A received maintenance doses of nusinersen approximately 
every 4 months according to the MMDR dosing schedule.  Subjects who received 
open-label maintenance doses of nusinersen in ISIS 396443-CS11 were transitioned 
to the MMDR dosing period at their next study visit, which was scheduled as close as 
possible to 120 days from the date of the last dosing visit (i.e., date of last dosing visit 
+ 120 days = MMDR Day 1). 
Dosing for 232SM202 
• Group 5:  Subjects who entered the study after receiving nusinersen during the 
open-label phase of Study 232SM202 (i.e., Part 2) received maintenance doses of 
nusinersen approximately every 4 months according to the MMDR dosing schedule. 
All subjects will undergo predose evaluations according to the schedule of procedures and will 
remain at the study center for at least 1 hour after the study drug dosing/sham procedure for 
safety monitoring; the subjects can be discharged at the discretion of the Site Investigator and in 
compliance with the institutional requirements once they adequately recover from the dosing 
procedure. 
 
  
Safety monitoring by telephone contact will occur to monitor the subjects’ condition 1 to 14 days 
postdose and every other month (±14 days) thereafter throughout the duration of the study, 
except for the months during which a study visit occurs. 
Subjects who discontinue treatment will complete an early termination visit 4 months (+14 days) 
after administration of the last dose of nusinersen, unless consent is withdrawn. 
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3.4.3. 
Post-Treatment Follow-Up 
After completion of the study treatment and open-label MMDR period, subjects will enter the 
Post-Treatment Follow-Up Period.  This period will consist of telephone contact with the subject 
(1 to 14 days postdose and every other month [±14 days]) thereafter throughout the duration of 
the study (except for the months during which a study visit occurs) and an EOS Evaluation Visit. 
3.5. 
End of Study 
The end of study is defined as the last study visit for the last study subject and will occur 
4 months after the last open-label maintenance dose of nusinersen on approximately MMDR 
Day 1800 (±14 days) or as determined by the Sponsor (via early termination). 
3.6. 
Safety Monitoring 
Safety data will be reviewed on an ongoing basis by the Sponsor and the Medical Monitor, with 
data cuts at regular intervals. 
4. 
SUBJECT ENROLLMENT 
4.1. 
Screening 
Before subjects may be screened for the study, the Sponsor will require a copy of the study 
center’s written Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
approval of the protocol, informed consent form (ICF), informed assent form (if applicable), and 
all other subject information and/or recruitment material. 
Before a subject’s participation in the study, the Investigator will be responsible for obtaining 
written informed consent from the parent(s) or legal guardian(s) and, in cases where institutional 
guidelines or the subject’s age dictate, informed assent from the subject.  Consent/assent must be 
signed before any study procedures, including screening procedures, are performed.  If all 
eligibility criteria are met and the subject is enrolled into the study, the extension study subject 
identification number will be maintained from, or linked to, the index study subject identification 
number.  This will be outlined in the ISIS 396443-CS11 data management documentation. 
4.2. 
Randomization 
No randomization of subjects will be utilized for this extension study. 
4.3. 
Replacement of Subjects 
Subjects will not be replaced. 
4.4. 
Unblinding of Treatment Assignment 
During the blinded loading dose period of this study, subjects received either blinded injections 
of nusinersen (Groups 1A and 2A) or a combination of nusinersen and sham procedures 
(Groups 1B and 2B) in order to allow subjects who previously participated in a sham procedure 
group of the index studies to obtain a loading regimen of nusinersen while maintaining the blind 
of the treatment assignment in the index study.  Following that, during the open-label 


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maintenance period of the study, all study subjects received nusinersen in an unblinded manner 
using a maintenance dosing regimen of once every 4 months. 
Index studies ISIS 396443-CS3B and ISIS 396443-CS4 have been unblinded, and treatment 
assignments for subjects in the applicable groups (Groups 1A, 2A, 1B, and 2B) were released.  
Therefore, there was no longer any reason to continue the blinded loading dose period in a 
blinded fashion.  Procedures for subjects still attending visits within the blinding loading dose 
period at the time of unblinding were revised as follows: 
• For subjects in Group 1A and Group 2A who were receiving active drug 
(i.e., nusinersen) within the blinding loading dose period, visits occurred as 
scheduled, with all predose and postdose assessments performed. 
• For subjects in Groups 1B and 2B who were still attending visits and receiving 
treatment (i.e., nusinersen and sham procedures) within the blinded loading dose 
period, all visits and predose assessments were continued per the protocol; however, 
the sham procedure and all postdose procedures were not performed for those 
applicable visits.  The required assessments for sham visits performed after the time 
of unblinding are described in Section 8.2. 
During the blinded loading dose period, all suspected unexpected serious adverse reactions 
(SUSARs) were unblinded by the Sponsor’s Drug Safety and Quality Assurance personnel for 
the purpose of regulatory reporting.  As index studies ISIS 396443-CS3B and ISIS 396443-CS4 
have been unblinded, SUSARs will be submitted to regulatory agencies and Investigators in an 
unblinded fashion (Section 9.2). 
5. 
SUBJECT ELIGIBILITY 
5.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria at Screening to be eligible: 
1. Signed informed consent of parent or guardian and signed informed assent of subject, if 
indicated per subject’s age and institutional guidelines.  
2. Completion of the index study in accordance with the study protocol or as a result of 
Sponsor decision (e.g., early termination of the index study) within the preceding 
16 weeks. 
3. Ability to complete all study procedures, measurements, and visits, and parent/subject has 
adequately supportive psychosocial circumstances, in the opinion of the Investigator. 
4. Subjects who, in the opinion of the Investigator, have reached reproductive maturity, 
must satisfy one of the following: 
• Females must have a negative pregnancy test at Screening and must agree to employ 
adequate contraceptive measures for the duration of the study.  Acceptable 
contraception methods are restricted to abstinence*, barrier contraceptives, 
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• Males must be abstinent* for the duration of the study or must be using an acceptable 
contraceptive method (i.e., use a condom together with spermicidal 
foam/gel/film/cream/suppository). 
*Abstinence is only acceptable as true abstinence (i.e., when this is representative of the 
preferred and usual lifestyle of the subject).  Periodic abstinence (e.g., abstinence for the 
duration of the study) and withdrawal are not acceptable methods of contraception. 
5.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for the study: 
1. Have any new condition or worsening of existing condition, which in the opinion of the 
Investigator would make the subject unsuitable for enrollment or could interfere with the 
subject participating in or completing the study.  
2. Clinically significant abnormalities in hematology or blood chemistry parameters or 
electrocardiogram (ECG), as assessed by the Site Investigator, at the Screening Visit that 
would render the subject unsuitable for participation in the study. 
3. 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 procedures. 
4. The subject’s parent or legal guardian is not willing or able to meet guidelines in the 
consensus statement for standard of care in SMA [Wang 2007] or provide nutritional and 
respiratory support throughout the study.  NOTE:  Routine vaccinations and respiratory 
syncytial virus (RSV) prophylaxis are recommended per consensus guidelines on 
standard of care [Wang 2007] but are not required for study enrollment.  Subjects who 
are not current on vaccinations or who are not receiving RSV prophylaxis, but otherwise 
meet study inclusion criteria, will be considered eligible for study enrollment. 
5. Treatment with another investigational agent, biological agent, or device within 1 month 
of Screening or 5 half-lives of study agent, whichever is longer. 
6. 
STUDY PROCEDURES 
Please note:  The following assessments are listed according to their assessment timing for each 
visit throughout the study as outlined in the Schedule of Procedures (Appendix A).  Please 
review each assessment for specific details and refer to the Schedule of Procedures in 
Appendix A for clarification. 
If any additional clarification is required, please contact the Study Medical Monitor. 
6.1. 
Study Assessments for Injection Days Only 
 
 
 
 
 


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6.2. 
Study Assessments for Screening Only 
Assessments to be performed at Screening only include informed consent/assent, 
inclusion/exclusion criteria, and medical history. 
6.3. 
Study Assessments for Every Study Visit and the End-of-Study 
Evaluation Visit 
6.3.1. 
Ventilator Use Diary Recording 
For all subjects, ventilator support/use will be assessed throughout the study, regardless of 
ventilation status.  This information will be obtained from the caregivers during onsite study 
visits and every-other-month telephone contacts.  This assessment will document whether 
respiratory support is being used (or not), what type of respiratory support is being used 
(noninvasive [i.e., bilevel positive airway pressure (BiPAP)/continuous positive airway pressure 
(CPAP)] or permanent ventilation), the number of hours per day, and the number of days the 
support is being used.   
Ventilator use should also be recorded within a ventilator use diary if the subject’s daily 
ventilator support increases to ≥16 hours/day.  The ventilator use diary should be dispensed 
during onsite study visits as needed.  Once ventilator use increases to ≥16 hours/day, ventilator 
use should continue to be recorded within the diary for a minimum of 30 days.  If ventilator use 
decreases to <16 hours/day and subsequently increases to ≥16 hours/day, the 30-day period for 
collecting the data should be restarted.  Investigators may instruct caregivers to continue 
recording in the ventilator use diary for an additional 30 or more days, based on clinical 
judgment.  The purpose of the ventilator use diary is to determine whether a subject has reached 
the permanent ventilation endpoint.  Thus, once a subject has met the permanent ventilation 
endpoint, the ventilator use diary should be discontinued, as it is no longer needed.  Once a 
subject has met the permanent ventilation endpoint, ventilation support/use should continue to be 
obtained at study visits and every-other-month telephone contacts, as described.   
Please note:  Predose ventilator use assessments should be repeated when the assessment falls 
outside the protocol-specified window due to a delay in dosing (Section 6.10). 
6.3.2. 
Dysphagia Assessment 
Dysphagia assessment may be performed at home up to 7 days prior to the dosing visit using the 
Parent Assessment of Swallowing Ability Weekly Version.  If an assessment is not performed at 
a visit, attempts should be made to perform the assessment at the subsequent dosing visit(s) until 
completed; however, an assessment should not be performed more than once at any visit. 
Assessment will be performed for all subjects including those on tube feeding; however, tube-fed 
subjects only need to be assessed with Questions 1 to 5 of the survey. 


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6.3.3. 
Urine/Serum Pregnancy Tests 
Urine pregnancy tests will be performed and evaluated predose (within 7 days of dosing) at 
every onsite visit for female subjects of childbearing potential (defined as any female who has 
experienced menarche).  If positive, the results will be confirmed locally by serum pregnancy 
test. 
Please note:  Predose pregnancy tests should be repeated when the assessment falls outside the 
protocol-specified window due to a delay in dosing (Section 6.10).  
6.3.4. 
Weight 
Weight will be collected predose (within 7 days of dosing) for all subjects at every onsite visit 
throughout the study. 
Please note:  Predose weight assessments should be repeated when the assessment falls outside 
the protocol-specified window due to a delay in dosing (Section 6.10).  
6.3.5. 
Growth Parameters 
Growth parameters of body length or height (for all subjects), head circumference (for subjects 
up to 36 months of age), chest circumference (for subjects up to 36 months of age), and arm 
circumference (for subjects up to 36 months of age) will be measured predose (within 7 days of 
dosing) by the Investigator (or designee) at every onsite visit throughout the study.  If an 
assessment is not performed at a visit, attempts should be made to perform the assessment at the 
subsequent dosing visit(s) until completed; however, an assessment should not be performed 
more than once at any visit. 
In subjects with scoliosis and contractures, the Investigator (or designee) may measure arm span 
or ulnar length in lieu of body length or height.  Arm span is defined as the distance from the 
fingertip in one hand to that in the opposite hand and should be measured with the arms 
outstretched laterally away from the body.  The investigator may measure ulnar length between 
the point of the elbow and the midpoint of the prominent bone of the wrist. 
Additional parameters of weight-for-age, weight-for-length, and head-to-chest circumference 
ratio will be calculated by the Sponsor during the analysis as described in the Statistical Analysis 
Plan (see Section 10.1.2). 
Please note:  Growth parameters should be repeated when the assessment falls outside the 
protocol-specified window due to a delay in dosing (Section 6.10).  
6.3.6. 
Physical Examinations 
Physical examinations will be performed predose (within 7 days of dosing) for all subjects at 
every onsite visit throughout the study.  Any abnormal findings observed during physical 
examinations will be captured as AEs and reported according to Section 9. 
If the consent for videotaping of the physical examination is provided, then videotaping should 
be performed. 
Please note:  Predose physical examinations should be repeated when the assessment falls 
outside the protocol-specified window due to a delay in dosing (Section 6.10).  


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6.3.7. 
Vital Signs 
Vital signs include resting blood pressure, pulse, pulse oximetry, respiratory rate, and 
temperature.  Vital signs will be taken predose and approximately 1 hour postdose at every 
onsite visit throughout the study. 
Please note:  Vital signs should be repeated when the assessment falls outside the 
protocol-specified window due to a delay in dosing (Section 6.10).  
6.3.8. 
Neurological Examinations 
Focused neurological examinations will be performed within 7 days of dosing and 
approximately 1 hour postdose at every onsite visit throughout the study.  Please 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. 
Sections 1 and 3 of the HINE will be conducted on all subjects ≤24 months of age.  This standard 
examination (developed by [Dubowitz and Dubowitz 1981]) is a quantitative scorable method 
for assessing the neurological development of infants between 2 and 24 months of age.  The 
examination includes assessment of cranial nerve functions, posture, movements, tone, and 
reflexes. 
For all subjects >24 months of age, focused neurological examinations, which include 
assessments of mental status, level of consciousness, sensory function, motor function, cranial 
nerve function, and reflexes, will be conducted. 
Please note:  Neurological examinations should be repeated when the assessment falls outside 
the protocol-specified window due to a delay in dosing (Section 6.10).  
6.4. 
Study Assessments for Screening and/or Modified Maintenance 
Dosing Regimen Day 1, Every 4 Months Thereafter (Every Modified 
Maintenance Dosing Regimen Visit), and the End-of-Study 
Evaluation/Early Termination Visit 
6.4.1. 
Clinical Safety Laboratory Evaluations 
Laboratory measurements of serum chemistry, hematology, urinalysis, and urine total protein 
will be collected at Screening and predose at MMDR Day 1 (not required to repeat on MMDR 
Day 1 if visit is within 7 days of Screening), predose (within 7 days of dosing) every 4 months 
thereafter (i.e., MMDR Days 1, 120, 240, 360, 480, 600, 720, 840, 960, 1080, 1200, 1320, 1440, 
1560, and 1680 [±14 days]), and at the EOS Evaluation/ET Visit.  The laboratory analytes to be 
measured are shown in Appendix B. 
Please note:  Predose clinical safety laboratory evaluations should be repeated when the 
assessment falls outside the protocol-specified window due to a delay in dosing (Section 6.10).  
For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. 
Quantitative urine total protein assessment should be prioritized if there is not enough urine 
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6.4.2. 
Coagulation Parameters 
Coagulation parameters (activated partial thromboplastin time [aPTT] and international 
normalized ratio [INR]) will be collected at MMDR Day 1, every 4 months thereafter 
(i.e., MMDR Days 1, 120, 240, 360, 480, 600, 720, 840, 960, 1080, 1200, 1320, 1440, 1560, and 
1680 [±14 days]), and at the EOS Evaluation/ET Visit.   
Coagulation testing will continue to be conducted at each visit or up to 7 days prior to dosing, 
and results should be reviewed prior to dosing.  In situations where predose verification of 
coagulation laboratory results is not feasible or optimal (e.g., prolonged sedation of the subject 
would be required to allow adequate time for laboratory processing), the Investigator may 
exercise discretionary clinical judgment and proceed with the LP procedure, based on the 
subject’s clinical and coagulation laboratory results history.  
Please note:  Predose coagulation parameters should be repeated when the assessment falls 
outside the protocol-specified window due to a delay in dosing (Section 6.10).  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.5. 
Study Assessments for Screening and/or Modified Maintenance 
Dosing Regimen Day 1, Every 8 Months Until Modified Maintenance 
Dosing Regimen Day 720 and Every 12 Months Thereafter, and the 
End-of-Study Evaluation/Early Termination Visit 
6.5.1. 
Motor Milestones 
For all subjects, motor milestones will be assessed using the World Health Organization (WHO) 
Motor Milestones criteria [WHO Multicentre Growth Reference Study Group 2006; Wijnhoven 
2004] at Screening and/or predose at MMDR Day 1, every 8 months until MMDR 
Day 720 (inclusive) [i.e., predose at MMDR Days 240, 480, and 720], and every 12 months 
thereafter (i.e., predose at MMDR Days 1080 and 1440), and at the EOS Evaluation (MMDR 
Day 1800 [±14 days])/ET Visit.  If the WHO motor milestones assessment has already been 
performed at MMDR Day 960 for a subject prior to approval of Protocol Version 5.0 at a site, 
the WHO motor milestones assessment will still need to be performed at MMDR Days 1080, 
1440, and 1800.  Assessment can be performed up to 7 days prior to the dosing visit.  If an 
assessment is not performed at a visit, attempts should be made to perform the assessment at the 
subsequent dosing visit(s) until completed; however, an assessment should not be performed 
more than once at any visit. 
For subjects <2 years of age who have not yet achieved independent walking, motor milestones 
will also be assessed using Section 2 of the HINE. 
Please note:  The WHO motor milestone assessment should be performed even if the subject is 
not ambulatory.  
If the consent for videotaping of the WHO and/or HINE motor milestone assessments is 
provided, then videotaping should be performed.  
6.5.2. 
Motor Function Assessments 
Motor function assessments include all assessments listed in Section 6.5.2.1, Section 6.5.2.2, 
Section 6.5.2.3, Section 6.5.2.4, and Section 6.5.2.5.  Motor function assessments will be 
performed at Screening and/or predose at MMDR Day 1, every 8 months until MMDR Day 
720 (inclusive) [i.e., predose at MMDR Days 240, 480, and 720], and every 12 months thereafter 
(i.e., predose at MMDR Days 1080 and 1440), and at the EOS Evaluation (MMDR Day 1800 
[±14 days])/ET Visit.  If motor function assessments have already been performed at Day 960 for 
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(i.e., CHOP INTEND, HFMSE, Revised Upper Limb Module [RULM], 6-Minute Walk Test 
[6MWT], and contracture assessment) will still need to be assessed at Days 1080, 1440, and 
1800.  Assessment can be performed up to 7 days prior to the dosing visit. 
The assessments that are performed at a given visit will depend on the subject’s age at that visit 
and current motor abilities.  For the purposes of this protocol, ambulatory will be defined as any 
subject who has achieved independent walking as defined by the WHO Motor Milestones criteria 
(Test Item #6 – Walking Alone). 
If the consent for videotaping of all motor function assessments is provided, then videotaping 
should be performed. 
6.5.2.1. 
Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease 
CHOP INTEND will be assessed in subjects with infantile-onset SMA until they have a 
maximum score of 64.  Once a score of 64 is achieved, CHOP INTEND will no longer be 
assessed.  If an assessment is not performed at a visit, attempts should be made to perform the 
assessment at the subsequent dosing visit(s) until completed; however, an assessment should not 
be performed more than once at any visit. 
The CHOP INTEND test was specifically designed to evaluate the motor skills of infants with 
significant motor weakness, including infants with SMA [Glanzman 2010].  The 
CHOP INTEND test captures neck, trunk, and proximal and distal limb strength in 14 elicited 
and 2 observational items.  The CHOP INTEND has been established as a safe and reliable 
infant motor measure in infantile-onset SMA and has been validated [Glanzman 2011]. 
6.5.2.2. 
Hammersmith Functional Motor Scale – Expanded 
All subjects ≥2 years of age will be evaluated using the HFMSE for the duration of the study.  
Subjects who are ≥2 years of age but have not yet achieved the maximum score of 64 with 
CHOP INTEND will be assessed with both until a CHOP INTEND maximum score of 64 is 
achieved.  The HFMSE should be performed after the CHOP INTEND with an approximately 
15-minute rest period in between to allow the subject to be fully engaged with both assessments.  
If an assessment is not performed at a visit, attempts should be made to perform the assessment 
at the subsequent dosing visit(s) until completed; however, an assessment should not be 
performed more than once at any visit. 
Note:  Any subjects currently being assessed with both the CHOP INTEND and HFMSE under a 
previous version of this protocol will continue to have both assessments performed under the 
current Version 6.0 of this protocol (even if they are <2 years of age) until they achieve a CHOP 
INTEND maximum score of 64. 
The HFMSE is a reliable and validated tool used to assess motor function in children with SMA.  
The scale was originally developed with 20 scored activities and was devised for use in children 
with Type 2 and Type 3 SMA with limited ambulation to give objective information on motor 
ability and clinical progression [Main 2003].  The expanded scale includes an additional module 
of 13 items developed to allow for evaluation of ambulatory patients with SMA [O'Hagen 2007].  
The HFMSE has been shown to be highly correlated with other clinical assessments and has 
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6.5.2.3. 
Revised Upper Limb Module  
All nonambulatory subjects ≥30 months of age will be evaluated using RULM [Mazzone 2016].  
The RULM will continue to be performed should subjects subsequently become ambulatory.  If 
an assessment is not performed at a visit, attempts should be made to perform the assessment at 
the subsequent dosing visit(s) until completed; however, an assessment should not be performed 
more than once at any visit. 
The RULM is an outcome measure developed to assess upper limb functional abilities in patients 
with SMA, including young children, and patients with severe contractures in the lower limbs in 
whom the possibility to detect functional changes, such as rolling or long sitting, is limited.  This 
test consists of upper limb performance items that are reflective of activities of daily living 
(i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a 
container).  The RULM is quickly administered and has been evaluated in patients with SMA 
2 to 52 years of age [Mazzone 2016]. 
The purpose of an upper limb scale for use in SMA is to assess change that occurs in motor 
performance of the upper limb over time.  Motor performance in SMA is defined as a 
demonstrated ability to perform a skill under certain test conditions.  This performance changes 
with disease progression and/or intervention (including surgery) and is based on the observed 
response on the day of the assessment.  Motor performance will be impacted by muscle strength, 
contractures, and maturational development (puberty), and the RULM aims to incorporate 
performance of the shoulder, elbow, wrist, and hand. 
6.5.2.4. 
Six-Minute Walk Test 
The 6MWT should be attempted once a subject achieves independent ambulation and will 
continue to be assessed in subjects who are ambulatory.  If an assessment is not performed at a 
visit, attempts should be made to perform the assessment at the subsequent dosing visit(s) until 
completed; however, an assessment should not be performed more than once at any visit. 
The 6MWT is an objective evaluation of functional exercise capability that measures the 
distance a person can walk quickly in 6 minutes.  The 6MWT can be performed safely in 
ambulatory patients with SMA and correlates with standard SMA outcome measures including 
timed walking tests [Montes 2010].  In SMA, the 6MWT may be more sensitive to clinically 
meaningful changes in patients with Type 3 SMA because it is a direct measure of their 
functional mobility.  The 6MWT has also been used as a primary outcome measure in several 
clinical studies in neuromuscular disease including Duchenne muscular dystrophy [McDonald 
2010] and late-onset Pompe disease [van der Ploeg 2010]. 
6.5.2.5. 
Contracture Assessment 
Motor performance in SMA is defined as a demonstrated ability to perform a skill under certain 
test conditions.  This performance changes with disease progression and/or intervention 
(including surgery) and is based on the observed response on the day of the assessment.  Motor 
performance will be affected by muscle strength, contractures, and maturational development 
(puberty).  All subjects will be evaluated for contractures.  If an assessment is not performed at a 
visit, attempts should be made to perform the assessment at the subsequent dosing visit(s) until 
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6.6. 
Study Assessments to be Performed at Screening and/or Modified 
Maintenance Dosing Regimen Day 1, Annually, and at the End of 
Study Evaluation/Early Termination Visit  
6.6.1. 
Electrocardiograms 
ECGs will be performed for all subjects at Screening and/or predose (within 7 days of dosing) at 
MMDR Day 1, approximately annually thereafter (i.e., MMDR Days 360, 720, 1080, and 1440), 
and at the EOS Evaluation/ET Visit.  If an assessment is not performed at a visit, attempts should 
be made to perform the assessment at the subsequent dosing visit(s) until completed; however, 
an assessment should not be performed more than once at any visit. 
Please note:  Predose ECGs should be repeated when the assessment falls outside the 
protocol-specified window due to a delay in dosing (Section 6.10).  
After the ECG is completed, an initial local read of the ECG should occur before the ECG is sent 
for a central read (all ECGs will be centrally read).  If the subject’s initial ECG results show a 
QTc interval of ≥500 milliseconds, then the ECG should be repeated prior to the subject leaving 
the visit.  If the second ECG QTc again reads ≥500 milliseconds, the Investigator should use best 
clinical judgment to address the condition.  
Additional ECGs may be performed per the judgment of the Investigator, as deemed clinically 
necessary. 
6.6.2. 
X-Ray of Spine 
Subjects currently ≥2 years of age or upon turning 2 years of age (with the exception of subjects 
treated at German sites) will have an X-ray of the thoracolumbar spine on Screening and/or 
predose (within 7 days of dosing) at MMDR Day 1, approximately annually thereafter 
(i.e., MMDR Days 360, 720, 1080, and 1440), and at the EOS Evaluation/ET Visit.  If an 
assessment is not performed at a visit, attempts should be made to perform the assessment at the 
subsequent dosing visit(s) until completed; however, an assessment should not be performed 
more than once at any visit.  X-ray assessments performed as standard of care may be used for 
protocol-required assessments, if the image acquisition guidelines are met and the X-ray was 
obtained within 4 months prior to the scheduled visit.  
The X-rays will be used to determine the severity of scoliosis by measuring the Cobb angle.  The 
spine X-ray was performed in the index studies, and the image acquisition guidelines will remain 
consistent between the index study and the current extension study.  The technical details for 
image acquisition will be outlined in a separate document provided to the sites. 
6.6.3. 
Quality of Life Questionnaires 
Quality of life questionnaires include all questionnaires listed below.  Generally, quality of life 
questionnaires will be collected at Screening and/or predose (within 7 days of dosing) at MMDR 
Day 1, approximately annually thereafter (i.e., MMDR Days 360, 720, 1080, and 1440), and at 
the EOS Evaluation/ET Visit.   
The questionnaires that are performed at a given visit will depend on the subject’s age at that 
visit.  If needed, the subject’s caregiver may complete the applicable quality of life 
questionnaires at home up to 7 days prior to dosing visit.  If a quality of life questionnaire is not 
performed at a visit, attempts should be made to perform the assessment at the subsequent dosing 


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visit(s) until completed; however, an assessment should not be performed more than once at any 
visit. 
6.6.3.1. 
Pediatric Quality of Life Inventory (Generic Core Scales and Neuromuscular 
Module) 
Subjects 2 to 25 years of age will be evaluated using the Pediatric Quality of Life Inventory 
(PedsQL™) Measurement 4.0 Generic Core Scales and 3.0 Neuromuscular Module [Varni 1999].  
This assessment has been validated by the American Spinal Muscular Atrophy Randomized 
Trials group [Iannaccone 2009]. The PedsQL Measurement Model is a modular approach to 
measuring health-related quality of life (HRQOL) in children and adolescents.  The PedsQL 
consists of brief, practical, generic core scales, as well as condition-specific modules for use in 
designated clinical populations.  Pediatric self-report is measured in children, adolescents, and 
young adults 5 to 25 years of age, and parent proxy-report of child HRQOL is measured for 
children, adolescents, and young adults 2 to 25 years of age.  The PedsQL 4.0 Generic Core 
Scales include assessment of physical functioning, emotional functioning, social functioning, and 
school functioning.  The PedsQL 3.0 Neuromuscular Module was designed to measure HRQOL 
dimensions specific to children, adolescents, and young adults 2 to 25 years of age with 
neuromuscular disorders, including SMA. 
6.6.3.2. 
Assessment of Caregiver Experience With Neuromuscular Disease 
Parents of subjects will complete the Assessment of Caregiver Experience with Neuromuscular 
Disease (ACEND) questionnaire.  This assessment instrument has been designed to quantify the 
caregiver impact experienced by parents of children affected with severe neuromuscular 
diseases, including children with SMA [Matsumoto 2011].  The ACEND includes domains 
assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and 
mobility) and general caregiver impact (including time, emotion, and finance). 
Please note:  Subjects should not complete quality of life questionnaires intended for completion 
by a caregiver. 
6.7. 
Study Assessments to be Performed at Screening and/or Modified 
Maintenance Dosing Regimen Day 1, Every 16 Months Thereafter 
(Modified Maintenance Dosing Regimen Days 480, 960, and 1440), 
and the End-of-Study Evaluation/Early Termination Visit 
6.7.1. 
Compound Muscle Action Potential  
For all subjects, measurements of ulnar and peroneal CMAP will be conducted at Screening 
and/or MMDR Day 1, approximately every 16 months thereafter (i.e., MMDR Days 480, 960, 
and 1440), and at the EOS Evaluation/ET Visit.  If an assessment is not performed at a visit, 
attempts should be made to perform the assessment at the subsequent dosing visit(s) until 
completed; however, an assessment should not be performed more than once at any visit.  If 
CMAP measurements are not approved as a mandatory outcome measure by local authorities, 
they will be considered optional in the respective country. 
CMAP is an electrophysiological technique that can be used to determine the approximate 
number of motor neurons in a muscle or group of muscles.  CMAP is a well-validated method 
for tracking disease progression in neuromuscular disorders such as SMA [Lewelt 2010; 


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Swoboda 2005] and amyotrophic lateral sclerosis [Shefner 2011] and has been proposed as a 
potential biomarker of a therapeutic effect in SMA. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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6.9. 
Study Assessments to be Performed Continuously Throughout the 
Study 
6.9.1. 
Telephone Assessments 
Follow-up safety monitoring telephone calls will occur 1 to 14 days postdose and every other 
month (±14 days) thereafter for the duration of the study, except for the months when in-clinic 
visits occur.  During these calls, changes in concomitant medications, AEs, ventilator use/status, 


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and contraceptive methods that have occurred since the last phone call or study visit will be 
recorded. 
6.10. 
Study Assessments to be Repeated Due to Delayed Dosing 
If a dosing visit is delayed, the following predose procedures should be repeated at the delayed 
dosing visit: 
• Vital signs (resting blood pressure, pulse, pulse oximetry, respiratory rate, and 
temperature)  
• Weight 
• Growth parameters 
• Ventilator use 
• Physical examination 
• Neurological examination 
o Focused neurological examination for subjects >24 months of age 
o HINE Section 1 and 3 for subjects ≤24 months of age 
• Safety laboratory evaluations: 
o Serum chemistry (central laboratory) 
o Hematology (central laboratory) 
o Urinalysis (central laboratory) 
o Urine total protein (local laboratory) 
• Coagulation parameters (local laboratory) 
 
 
• Urine/serum pregnancy test 
• ECG (predose at applicable visits: MMDR Days 1, 360, 720, 1080, and 1440) 
• Concomitant medications assessment 
• Ancillary procedure recording 
• AE collection 
All procedures should be performed predose (within 7 days of dosing).  Vital signs and 
neurological examination should also be performed at approximately 1 hour postdose.  The 
purpose of repeating these assessments is to ensure the safety of the subject prior to dosing and 
to collect important study information pertaining to each dose.  
At the discretion of the Investigator, additional visit-specific assessments may be repeated as 
needed, as long as they are performed predose within 7 days of the rescheduled dosing visit.  


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7. 
STUDY DRUG 
7.1. 
Study Drug Description 
The nusinersen (study drug) characteristics are listed in Table 2. 
The study drug is contained in a 6-mL clear glass vial.  The study drug and its storage and 
preparation instructions will be provided by the Sponsor or designee.  The study drug must be 
stored securely at 2°C to 8°C and protected from light. 
Table 2: 
Study Drug Characteristics 
Study Drug 
Nusinersen Drug Product 
Strength 
2.4 mg/mL 
Volume/vial 
5.0 mL solution per vial 
Route of administration 
IT injection 
IT = intrathecal. 
7.2. 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged study drug labeled in accordance with 
specific country regulatory requirements. 
7.3. 
Study Drug Accountability 
The study staff is required to document receipt, dispensing and return, and/or destruction of 
study drug supplies provided by the Sponsor. 
8. 
TREATMENT OF SUBJECTS 
8.1. 
Study Drug Administration 
Details regarding the LP dosing injection procedure are provided in the Dosing Administration 
Manual, also known as the Directions for Handling and Administration (DHA) guidelines.   
The DHA guidelines supersede all other references (e.g., protocol). 
Nusinersen will be administered as an IT LP injection.  All subjects will receive the full 12-mg 
dose of nusinersen (5 mL). 
During the blinded loading dose period, the study treatment dosing or sham procedures were 
performed in a dedicated room and administered by dedicated study personnel who were 
unblinded to the treatment assignment; this was not administered by any of the key study site 
personnel (i.e., the Investigator, Study Coordinator, or Outcomes Assessors), and the key study 
site personnel or the parents were not present during the procedure to ensure blinding. 
After the loading dose period has been completed (and/or after unblinding of index studies 
ISIS 396443-CS3B and ISIS 396443-CS4; see Section 4.4), subsequent doses of nusinersen will 
not involve a sham procedure and, with the agreement of the Sponsor, may be administered by 
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Nusinersen will be administered as an IT slow bolus (1 to 3 minutes) LP injection.  Nusinersen 
will be administered using a “spinal anesthesia” needle and syringe.  A 22G to 25G spinal 
anesthesia needle is recommended, but a 21G may be used if indicated by 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 or sedation may be used for the LP procedure, 
following institutional procedures.  Subjects will be encouraged to lie flat for 1 hour following 
dosing, if possible. 
8.2. 
Sham Procedure 
During the blinded loading dose period of this study, subjects received blinded injections of 
either nusinersen or sham procedures, to allow subjects who previously participated in a sham 
procedure group of the index studies to obtain a loading dose regimen of nusinersen and 
maintain the blind on the regimen that was administered in the index study.  Details of the sham 
procedure were provided in the Dosing Administration Manual (or DHA guidelines).  The sham 
procedure was performed in a dedicated room and administered by dedicated study personnel 
who were unblinded to the treatment group; this was not administered by any of the key study 
site personnel (i.e., the Investigator, Study Coordinator, or Outcomes Assessors), and the key 
study site personnel or the parents were not present during the sham procedure to ensure 
blinding.  
The sham procedure consisted of a small needle prick on the lower back at the location where the 
LP injection was normally made.  The needle broke the skin, but no LP injection or needle 
insertion occurred.  The site of the needle prick was covered in the same manner as that of the LP 
injection, thus simulating the appearance of an LP injection.  If anesthesia or sedation was used 
for the LP procedure in nusinersen-treated subjects at an individual study center, in order to 
maintain the blind, minimal sedation (i.e., a low dose of an anxiolytic) was used for the sham 
procedure, following institutional procedures.  Subjects who received the sham procedure were 
kept in the procedure room for the same amount of time as that for subjects who were 
administered study treatment, thus simulating the time period of a study treatment administration 
procedure. 
Study treatment and sham kits were packaged in a blinded fashion.  
 
 
 
As index studies ISIS 396443-CS3B and ISIS 396443-CS4 have been unblinded, there was no 
longer any reason to continue the blinded loading dose period in a blinded fashion 
(see Section 4.4).  For subjects in Groups 1B and 2B who were still attending visits and receiving 
treatment (i.e., nusinersen and sham procedures) within the blinded loading dose period since the 
time of unblinding, the sham procedure and all postdose procedures described above were not 
performed for those applicable visits.  The procedure at sham visits was recorded as “NOT 
DONE” in the eCRF, and the reason was specified as “subject is in Group 1B or Group 2B; visit 
occurred after treatment assignments were released by study Sponsor.”  During these visits, 
study drug was not administered, and these visits were considered safety visits.  The visit was 
still registered in the Interactive Voice/Web Response System (also known as the IxRS system) 
to allow for all future visits to be recorded without issue; however, the dispensed study drug was 


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set aside, marked as “Not Used,” recorded as such in the site and/or patient drug accountability 
log, and then returned for destruction.  Safety assessments of predose vital signs and neurological 
examination were performed, and AEs, concomitant medications, general health, and ventilator 
use/status were reviewed. 
8.3. 
Other Protocol-Required Drugs 
There are no other protocol required drugs. 
8.4. 
Other Protocol-Required Procedures 
There are no other protocol-required treatment procedures. 
8.5. 
Treatment Precautions 
There are no protocol-required treatment precautions. 
8.6. 
Safety Monitoring Rules 
Please refer to the Guidance to Investigator section of the Investigator’s Brochure. 
8.7. 
Stopping Rules 
There are no additional specific stopping rules for this study, but the Investigator should discuss 
significant concerns relating to individual subjects with the Medical Monitor and the Sponsor to 
ensure that it is appropriate for the subject to continue study treatment. 
8.8. 
Adjustment of Dose and/or Treatment Schedule 
No adjustment of dose is permitted.  If dosing does not occur as per the schedule of activities, a 
protocol deviation should be logged.  In the event of delayed or missed doses due to, for 
example, a concurrent illness or other circumstances (e.g., the coronavirus disease 2019 
pandemic), the Investigator should refer to the DHA, which includes recommended dosing 
administration in the event of delayed or missed doses. 
8.9. 
Discontinuation of Study Treatment 
A subject must permanently discontinue study treatment for any of the following reasons: 
• The subject or subject’s parent/guardian withdraws consent. 
• The subject experiences an AE that necessitates permanent discontinuation of study 
treatment. 
The reason for discontinuation of study treatment must be recorded in the case report form 
(CRF) and source documentation. 
Subjects who discontinue treatment will complete an early termination visit 4 months (+14 days) 
after administration of the last dose of nusinersen (Appendix A), unless consent is withdrawn 
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8.10. 
Withdrawal of Subjects From the Study 
Subjects must be withdrawn from the study for any of the following reasons: 
• The subject or the subject’s parent/guardian withdraws consent. 
• The subject or the subject’s parent/guardian is unwilling or unable to comply with the 
protocol. 
Other reasons for withdrawal of subjects from the study might include the following:   
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Initiation of commercial nusinersen treatment 
• Significant protocol deviation 
• Administrative decision by the Investigator or Sponsor 
All efforts should be made to complete and report the observations as thoroughly as possible up 
to the date of withdrawal from the study.  All information, including the reason for withdrawal 
from study, must be recorded in the CRF. 
Any subject for whom consent to participate in the study is withdrawn will be removed from 
further treatment and study observation immediately upon the date of request.  It should be 
encouraged that these subjects complete the early termination study procedures and observations 
at the time of withdrawal (Appendix A). 
For subjects withdrawn for reasons other than withdrawal of consent, every effort should be 
made to complete the early termination study procedures and observations at the time of 
withdrawal (Appendix A). 
8.11. 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the subject’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.11.1. 
Concomitant Therapy 
A concomitant therapy is any non-protocol-specified drug or substance (including 
over-the-counter medications, herbal medications, and vitamin supplements) administered 
between the beginning of Screening and the last telephone contact or study visit. 
Subject’s parents/guardians should consult with the Site Investigator or qualified designee prior 
to initiating any new medication, including non-prescription compounds or any other non-drug 
therapy.   
8.11.1.1. Allowed Concomitant Therapy 
Any concomitant medications, including SMA therapies, will be captured in the CRF.  
Approved concomitant therapies may be used at the discretion of the Investigator.  With 
implementation of Protocol Version 6.0, investigators with subjects newly seeking combination 
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This will be permitted for country-approved SMA therapies, if the total number of study subjects 
concurrently receiving nusinersen and other SMA therapies has not yet reached 20% of all 
enrolled subjects.  This is consistent with the primary and secondary objectives of this study.  
Any subjects already receiving combination therapy with other SMA therapies at the time of 
Protocol Version 6.0 implementation may continue this combination therapy regardless of the 
20% limit.  
Throughout the study, the Site Investigators or designated licensed physicians may prescribe 
concomitant medications or treatments deemed necessary for AEs or to provide adequate 
supportive care.  In addition, a mild sedative (e.g., midazolam) and a local anesthetic 
(e.g., lidocaine) may be used for the LP procedure (per institutional guidance).  
8.11.1.2. Disallowed Concomitant Therapy 
As noted above in Section 8.11.1.1, with implementation of the Protocol Version 6.0, new 
subjects seeking combination therapy of nusinersen with other SMA therapies should consult the 
Medical Monitor.  Any subjects already receiving investigational drug for any other condition 
should consult with the Medical Monitor. 
8.11.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, myringotomy, and 
placement of tympanostomy tubes) or diagnostic assessment (e.g., blood gas measurement, 
bacterial cultures) performed between the beginning of Screening and last telephone contact or 
study visit. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1. 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical study. 
The Investigator’s responsibilities include the following: 
• Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to the 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 that all AE and SAE reports are supported by documentation in the subjects’ 
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• 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. 
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. 
9.2. 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of SAEs 
including SUSARs per the International Council for Harmonisation (ICH) guidelines E2A and 
ICH E6.  Country-specific regulatory requirements will be followed in accordance with local 
country regulations and guidelines.  SUSARs are SAEs that are unexpected and judged by the 
Investigator or Biogen to be related to the study treatment administered. 
During the blinded loading dose period, SUSARs were unblinded by appropriate Sponsor 
personnel for the purpose of regulatory reporting.  The Sponsor submitted SUSARs (in blinded 
or unblinded fashion) to regulatory agencies according to local law and submitted SUSARs to 
Investigators in a blinded fashion. 
As index studies ISIS 396443-CS3B and ISIS 396443-CS4 have been unblinded, this unblinding 
is no longer needed.  SUSARs will be submitted to regulatory agencies and Investigators in an 
unblinded fashion. 
IRBs/IECs will be notified of any SAE according to applicable regulations.   
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the study or use of 
investigational drug product, whether or not the AE is considered related to the investigational 
drug product. 
9.3.2. 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any AE caused by the study treatment. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE.  A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction. 


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9.3.3. 
Serious Adverse Event 
An SAE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• Results in death. 
• Is life threatening (i.e., poses an immediate risk of death at the time of the event). 
− An AE or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the Investigator or Sponsor, its occurrence places the subject at 
immediate risk of death.  It does not include an AE or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
− Please note:  Hospitalization is defined as an admission of greater than 24 hours 
to a medical facility and does not always qualify as an AE. 
• Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
• Results in congenital anomaly or birth defect in the offspring of the subject (whether 
the subject is male or female). 
• Important medical events that may not result in death, are not life-threatening, or do 
not require hospitalization may also be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
9.4. 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of the 
study (i.e., before informed consent/assent) should be recorded as medical history and not 
recorded as AEs unless the pre-existing condition worsened.  The Investigator should always 
group signs and symptoms into a single term that constitutes a single unifying diagnosis, if 
possible. 
9.4.1. 
Serious Adverse Events 
In the interest of subject safety and to fulfill regulatory requirements, all SAEs (regardless of 
their relationship to study treatment) should be reported to the Sponsor within 24 hours of the 
study center’s first knowledge of the event.  The collection of SAEs will begin after the subject 
signs the ICF and will stop at the end of the subject’s follow-up period, which is defined as the 
subject’s last visit.  When the Investigator is reporting by telephone, it is important to speak to 
someone in person versus leaving a message.  An Initial SAE Form should be completed and a 
copy should be faxed to the Sponsor or designee; refer to the Study Reference Guide for 
complete contact information. 


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Detailed information should be actively sought and included on Follow-Up SAE Forms as soon 
as additional information becomes available.  All SAEs will be followed until resolution.  SAEs 
that remain ongoing past the subject’s last protocol-specified follow-up visit will be evaluated by 
the Investigator and Sponsor.  If the Investigator and Sponsor agree the subject’s condition is 
unlikely to resolve, the Investigator and Sponsor will determine the follow-up requirement. 
9.4.2. 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the ICF and will stop at the 
end of the subject’s follow-up period, which is defined as subject’s last visit.  The Investigator 
will monitor each subject closely and will record all observed or volunteered AEs on the AE 
CRF. 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the AE CRF. 
9.4.3.1. 
Relationship to the Study Treatment 
The event’s relationship to the study treatment is characterized by one of the following: 
• Related:  There is clear evidence that the event is related to the use of study treatment 
(e.g., confirmation by positive rechallenge test). 
• Possible:  The event cannot be explained by the subject’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and study treatment administration. 
• Unlikely/Remote:  An event for which an alternative explanation is more likely 
(e.g., concomitant medications or ongoing medical conditions) or the temporal 
relationship to study treatment administration and/or exposure suggests that a causal 
relationship is unlikely (for reporting purposes, unlikely/remote will be grouped 
together with not related). 
• Not Related:  The event can be readily explained by the subject’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator 
believes no relationship exists between the event and study treatment. 
9.4.3.2. 
Severity 
The event’s severity is characterized by one of the following: 
• Mild:  The event is easily tolerated by the subject and does not affect the subject’s 
usual daily activities. 
• Moderate:  The event causes the subject more discomfort and interrupts the subject’s 
usual daily activities. 
• Severe:  The event is incapacitating and causes considerable interference with the 
subject’s usual daily activities. 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 


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9.4.3.3. 
Action Taken With Study Treatment 
The action taken with study treatment due to the event is characterized by one of the following: 
• None:  No changes were made to study treatment administration and dose. 
• Permanently Discontinued:  Study treatment was discontinued and not restarted. 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily 
interrupted or delayed due to the AE and restarted at the same dose. 
9.4.3.4. 
Treatment Given for the Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the AE 
CRF (treatment should also be recorded on the concomitant treatment or ancillary procedures 
CRF as appropriate). 
9.4.3.5. 
Outcome of the Adverse Event 
If the event is a non-serious AE, then the event’s outcome is characterized by one of the 
following: 
• AE Persists:  Subject terminates from the study and the AE continues. 
• Recovered:  Subject recovered completely from the AE. 
• Became Serious:  The event became serious (the date when the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE). 
• Change in Severity (if applicable):  AE severity changed. 
If the event is a SAE, then the event’s outcome is characterized by one of the following: 
• Ongoing:  SAE continuing. 
• Persists (as non-serious AE):  Subject has not fully recovered but the event no 
longer meets serious criteria and should be captured as an AE on the non-serious AE 
CRF (the SAE resolution date should be entered as the date of onset of that AE). 
• Recovered:  Subject recovered completely from the SAE (the date of recovery should 
be entered as the SAE resolution date). 
• Fatal:  Subject died (the date of death should be entered as the SAE resolution date). 
9.5. 
Procedures for Handling Special Situations 
9.5.1. 
Abnormalities of Laboratory Tests 
Clinically significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment (e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia).  Whenever possible, 
the underlying diagnosis should be listed, in preference to abnormal laboratory values, as AEs.  
Clinically significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Medical 


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Monitor.  Laboratory abnormalities deemed not clinically significant (NCS) by the Investigator 
should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs by the 
Investigator should not be deemed NCS on the laboratory report. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2. 
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 center 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 the subject’s 
consent to participate in the study. 
• The condition that required 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 consent to participate in the study and the 
timing of the procedure or treatment. 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission. 
9.5.3. 
Dosing Errors 
All dosing errors (including but not limited to route of administration, wrong dose, etc.) must be 
reported as protocol deviations.  A brief description should be provided in the deviation, 
including information about whether the subject was symptomatic or not.  Dosing details should 
be captured on the Dosing CRF. 
A dosing error will be considered an overdose when any of the following conditions are met:   
• Any single dose given exceeds the dose level described in the protocol and DHA 
Guidelines. 
• Dosing frequency exceeds 4 doses in a 60-day period. 
• Study drug is administered less than 14 days from the previous dose. 
Overdoses are not considered AEs and should not be recorded as an AE on the CRF unless an 
AE or an SAE occurs.  All overdoses (regardless of whether or not they result in an AE) must be 
recorded on an overdose form and faxed to Biogen or designee within 24 hours of the site 
becoming aware of the overdose.  If an overdose results in an SAE, both the SAE and overdose 
forms must be completed and faxed to Biogen or designee.  Should an overdose occur, the 
Investigator or designee must contact the Medical Monitor within 24 hours; refer to the Study 
Reference Guide for complete contact information. 
9.5.4. 
Contraception and Pregnancy 
Female subjects of childbearing potential (defined as any female who has experienced menarche) 
must have a negative pregnancy test at every study visit as described in Section 6.3.3 and must 
either be abstinent or practice adequate contraception during the study. 


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Male subjects must remain abstinent during the study or must be using an acceptable 
contraceptive method. 
For the purposes of the study, acceptable contraception methods are abstinence, barrier 
contraceptives, intrauterine contraceptive devices, licensed hormonal products, and the use of a 
condom together with spermicidal foam/gel/film/cream/suppository.  Abstinence is only 
acceptable as true abstinence (i.e., when this is representative of the preferred and usual lifestyle 
of the subject).  Periodic abstinence (e.g., abstinence for the duration of the study) and 
withdrawal are not acceptable methods of contraception. 
If a subject becomes pregnant or a pregnancy is suspected, or if a male subject makes or believes 
that he has made someone pregnant during the study, then the study site staff must be informed 
immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or designee within 
24 hours of first learning of the occurrence of (possible) pregnancy.  Follow-up information 
including delivery or termination is reported on Follow-up Pregnancy Forms and is reported 
within 24 hours of the study site staff becoming aware. 
Payment for all aspects of obstetrical, child, or related care will be the subject’s responsibility. 
Female subjects:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The subject with a confirmed pregnancy will be immediately 
withdrawn from study drug treatment.  However, the subject will be encouraged to complete the 
post-treatment follow-up portion of the study to the extent that study procedures do not interfere 
with the pregnancy.  Regardless of continued study participation, the study physician will assist 
the subject in getting obstetrical care and the progress of the pregnancy will be followed until the 
outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the study center and Sponsor may 
require access to the mother and infant’s medical records for an additional 8 weeks after birth. 
Male subjects:  The progress of the pregnancy in a male subject’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, additional follow-up information may 
be requested for the mother and infant.  Follow-up will be performed to the extent permitted by 
relevant guidelines (e.g., Health Insurance Portability and Accountability Act [HIPAA]) and 
privacy considerations. 
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the conduct of the study (including follow-up). 
9.5.5. 
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 the study’s Medical Director.  Refer to the Study Reference Guide’s official study 
contact list for complete contact information. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Study Endpoints, Subsets, and Covariates 
10.1.1. 
Safety and Tolerability Endpoints 
• AEs and SAEs 
• Vital signs and weight 
• Neurological examinations 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis, and urine total 
protein) 
• Coagulation parameters (aPTT and INR) 
• ECGs 
• Use of concomitant medications 
10.1.2. 
Efficacy Endpoints  
For all groups/subjects: 
• Achievement of motor milestones (WHO motor milestones and/or Section 2 of 
HINE) 
• Time to death or permanent ventilation (tracheostomy or ≥16 hours ventilation/day 
continuously for >21 days in the absence of an acute reversible event).  The definition 
of an acute reversible event is provided in the SHINE Ventilation Endpoint Guidance.  
• Percentage of subjects not requiring permanent ventilation 
• Change from baseline in applicable motor function assessments:  CHOP INTEND, 
HFMSE, RULM, 6MWT, and contracture assessment 
• Change from baseline in CMAP 
• Growth parameters 
• Proportion of CMAP responders 
• Number of motor milestones achieved per subject 
• Proportion of subjects who achieved standing alone 
• Proportion of subjects who achieved walking with assistance 
• Number of serious respiratory events 
• Number and length of hospitalizations 
• Change from baseline in Cobb-Angle on X-ray of the thoracolumbar spine  
• Changes in quality of life assessments:  PedsQL, and/or ACEND 
• Disease-related hospitalizations and AEs  
• Survival rate 


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10.1.6. 
Future Scientific Research Assessments 
In subjects who provide additional optional consent, 
 may 
be stored for future, unspecified,
.  Subjects will sign a 
separate written ICF if they opt for samples (including samples collected during index studies) to 
be retained and used in this way. 
The samples collected may be utilized to identify or verify putative, prognostic, and predictive 
markers associated with the disease as well as markers of therapeutic response to treatment 
and/or develop diagnostic and analytical tests.  Background and dynamic clinical disease 
characteristics and associated 
 data may be utilized to predict subsequent disease 
worsening (severity), identify high-risk patient subgroups, and identify predictors of response to 
treatment. 
10.2. 
Sample Size Considerations 
The sample size is based solely on the number of subjects enrolled in the ISIS 396443-CS3A, 
ISIS 396443-CS3B, ISIS 396443-CS4, ISIS 396443-CS12, and 232SM202 studies who may be 
eligible for participation in this study. 


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10.3. 
Populations 
Intent-to-Treat (ITT) Set:  All subjects who are enrolled and received at least 1 dose of 
nusinersen. 
Safety Set:  All subjects who are enrolled and received at least 1 dose of nusinersen. 
 
 
10.4. 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
The analyses will focus on the ISIS 396443-CS11 data.  The baseline will be the last 
non-missing assessment prior to the first dose of study treatment in the ISIS 396443-CS11 study.  
If any integration of data with the index study is conducted, the following definitions of baseline 
will be used:   
• For safety, baseline for subjects on active treatment in the index study will be the 
index study baseline.  For subjects on sham in the index study, baseline for safety will 
be the last non-missing assessment prior to the first dose of study treatment in this 
study. 
• For efficacy, 2 baselines are defined for each subject:  index study baseline and the 
baseline in this study, which is defined as the end-of-treatment assessment in index 
studies or the last non-missing assessment before the first dose of study treatment in 
this study. 
10.5. 
Interim Analysis 
Interim analyses may be performed to provide content for regulatory submissions and to support 
nusinersen drug development planning and business activities. 
10.6. 
Planned Methods of Analysis 
Data collected on CRF, laboratory data transfers, as well as any outcomes derived from the data, 
will be provided in the subject data listings.  Subject data listings will be presented for all 
subjects enrolled into the study. 
Descriptive summary statistics including n, mean, median, standard deviation, standard error, 
interquartile range (25th percentile, 75th percentile), and range (minimum, maximum) for 
continuous variables and counts and percentages for categorical variables will be used to 
summarize most data. 
All efficacy endpoints will be assessed in the ITT Set.  All safety assessments will be performed 
on the Safety Set.  
 
10.6.1. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics, as well as subject disposition, will be summarized 
using descriptive statistics.  All subjects enrolled will be included in a summary of subject 
disposition. 


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10.6.2. 
Safety and Tolerability Analysis 
Safety analyses will be conducted in the Safety Set. Treatment duration and amount of study 
treatment received will be summarized. 
All treatment-emergent AEs and SAEs will be summarized 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 and SAEs, including early 
withdrawals from the study treatment and from the study due to AEs, will also be provided. 
When applicable for Groups 2A, 2B, and 3, the incidence of AEs will be evaluated by treatment 
phase (original dosing schedule phase versus MMDR). 
Laboratory tests, including chemistry panel and complete blood count with differential, will be 
summarized by study visit. These safety variables will also be presented over time after study 
treatment administration, as appropriate. Vital sign results will be presented similarly. 
Physical and neurological examination findings and results from ECG will be listed for review. 
As appropriate, results will also be summarized descriptively. Concomitant medication usage for 
each subject will be listed for review. 
The end date of study drug exposure will be set to be at 1 year following the last administration 
of study drug. This is based on considerations of the half-life of nusinersen in plasma and CSF. 
Treatment-emergent AEs will be presented to include events occurring within this time frame. 
Additional details of the analyses to be conducted will be provided in the Statistical Analysis 
Plan. 
10.6.3. 
Efficacy Analysis 
For subjects <2 years of age who have not yet achieved independent walking, motor milestones 
will be assessed using Section 2 of the HINE, which is composed of 8 motor milestone 
categories as follows: voluntary grasp, ability to kick in supine position, head control, rolling, 
sitting, crawling, standing, and walking. Within each motor milestone category, there are 3 to 5 
levels that can be achieved. All 8 motor milestones will be tested during each assessment. A 
subject whose results after testing all appear in the first column (no grasp, no kicking, unable to 
maintain head upright, and so on) has not achieved any motor milestone. Motor milestone 
achievement is depicted by movement from the left side of Table 3 to the right side of the table, 
as denoted by the Milestone Progression arrow in the table [Haataja 1999]. 


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Table 3: 
Hammersmith Infant Neurological Examination Section 2 - Motor 
Milestones 
Motor 
Milestone 
Category 
Milestone Level Progression 
(Age Expected in Heathy Infants)a 
 
Voluntary 
grasp 
No grasp 
Uses whole 
hand 
Finger and 
thumb; immature 
grasp 
Pincer grasp 
 
Ability to 
kick (in 
supine) 
No kicking 
Kicks 
horizontal; legs 
do not lift 
Upward 
(vertically) 
[3 months] 
Touches leg 
(4 to 
5 months) 
Touches toes 
(5 to 
6 months) 
Head control 
Unable to 
maintain 
upright 
(<3 months) 
Wobbles 
(4 months) 
All the time 
upright 
(5 months) 
 
 
Rolling 
No rolling 
Rolling to side 
(4 months) 
Prone to supine 
(6 months) 
Supine to 
prone 
(7 months) 
 
Sitting 
Cannot sit 
Sit with 
support at hips 
(4 months) 
Props 
(6 months) 
Stable sit 
(7 months) 
Pivots 
(rotates) 
[10 months] 
Crawling 
Does not lift 
head 
On elbow 
(3 months) 
On outstretched 
hand (4 to 
5 months) 
Crawling flat 
on abdomen 
(8 months) 
On hands 
and knees 
(10 months) 
Standing 
Does not 
support weight 
Supports 
weight (4 to 
5 months) 
Stands with 
support 
(8 months) 
Stands 
unaided 
(12 months) 
 
Walking 
No walking 
Bouncing 
(6 months) 
Cruising 
(holding on) 
[11 months] 
Walking 
independently 
(15 months) 
 
a Values for healthy infants in [Haataja 1999]. 
The proportion of motor milestone responders is defined based on the 7 motor milestones 
categories, with the exclusion of voluntary grasp using the assessment at the later study visits, as 
follows:  
1. Subject demonstrates at least a 2-point increase in the motor milestone category of ability 
to kick or achievement of the maximal score on that category (touching toes) or a 1-point 
increase in the motor milestones of head control, rolling, sitting, crawling, standing, or 
walking, AND  
2. Among the 7 motor milestone categories with the exclusion of voluntary grasp, subject 
demonstrates improvement (defined in [1]) in more categories than worsening.  
Note:  For the category of ability to kick, similar to the definition of improvement in (1) 
mentioned previously, worsening is defined as at least a 2-point decrease or decrease to 


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the lowest possible score of no kicking.  For the other 6 categories, worsening is defined 
as at least a 1-point decrease.  
Subjects who die or withdraw from the study will be counted as nonresponders and will be 
included in the denominator for the calculation of the proportion.  As a result, mortality will be 
accounted for in the motor milestone analysis.  For subjects on permanent ventilation, because 
motor milestone assessment continues, functional scores after permanent ventilation has been 
achieved will be used to assess improvement in motor milestones. 
The median time to death or permanent ventilation, survival rates over time, and the percentage 
of subjects requiring permanent ventilation will be estimated using the Kaplan-Meier method. 
Change from baseline in CHOP INTEND total score and HFMSE score for subjects as described 
in Section 6.5.2.1 and Section 6.5.2.2, respectively, proportion of subjects who achieved any new 
motor milestone, number of motor milestones achieved per subject, proportion of subjects who 
achieved standing alone milestone, proportion of subjects who achieved walking with assistance 
milestone, change from baseline in RULM, change from baseline in 6MWT distance, CMAP 
parameters, change from baseline in PedsQL, change from baseline in ACEND, and disease-
related hospitalizations and AEs, 
 
 
The proportion of CMAP responders is defined as the proportion of subjects with peroneal 
CMAP amplitude increasing to or maintained at ≥1 mV, comparing to the baseline, based on 
assessment at the later study visits. 
Additional details of the analyses to be conducted will be provided in the Statistical Analysis 
Plan. 
 
 
 
 
 
 
 
 
 
 
 
  
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1. 
Informed Consent/Assent 
The written informed consent and assent documents should be prepared in the language(s) of the 
potential subject population, based on an English version provided by the Sponsor and should be 
easy to understand. 
Before a subject’s participation in the study, the Investigator is responsible for obtaining written 
informed consent from the parent or legal guardian and, in cases where institutional guidelines 
and the subject’s age dictate, informed assent from the subject, after adequate explanation of the 


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aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any study treatment are administered.  Sufficient time 
must be given to consider whether to participate in the study. 
Subjects will be informed that their race and ethnicity may be collected and may be used during 
analysis of study results. 
The acquisition of informed consent/assent and the parent/legal guardian’s/subject’s agreement 
or refusal of his/her notification of the primary care physician should be documented in the 
subject’s medical records, and the informed consent/assent form(s) should be signed and 
personally dated by the parent/legal guardian/subject and by the study person who conducted the 
informed consent/assent discussion.  The original signed informed consent/assent form(s) should 
be retained in the Study Master File and in any other locations required by institutional policy, 
and a copy of the signed consent/assent form(s) should be provided to the parent or guardian. 
11.2. 
Ethical Conduct of the Study 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.  The applicable regulations and guidelines of current Good Clinical Practice (GCP), 
ICH, as well as the demands of national drug and data protection laws and other applicable 
regulatory requirements will be strictly followed. 
11.3. 
Institutional Review Board/Institutional Ethics Committee/Research 
Ethics Board 
A copy of the protocol, proposed ICF and optional genetics and future research ICFs, proposed 
informed assent form (if applicable), other written subject information, and any proposed 
advertising material must be submitted to the IRB/IEC for written approval by the Investigator.  
A copy of the IRB/IEC written approval must be received and approved by the Sponsor before 
recruitment of subjects into the study and shipment of study drug.  The Investigator’s Brochure 
must be submitted to the IRB/IEC for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IRB/IEC for all 
subsequent protocol amendments and changes to the informed consent/assent documents.  The 
Investigator should notify the IRB/IEC of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IRB/IEC of SAEs occurring at the 
study center and other AE reports received from the Sponsor, in accordance with local 
procedures. 
The Investigator will be responsible for obtaining annual IRB/IEC approval/renewal throughout 
the duration of the study.  A progress report must be submitted to the ethics committee at 
required intervals and not less than annually.  Copies of the Investigator’s reports, all IRB/IEC 
submissions, and the IRB/IEC continuance of approval must be sent to the Sponsor.  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). 
11.4. 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained.  On the CRFs or 
other documents submitted to the Sponsor, subjects should be identified by unique, anonymous 
initials and a subject study number only.  Documents that are not for submission to the Sponsor 


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(e.g., signed informed consent/assent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the subject’s parent or 
guardian to permit named representatives to have access to his/her study-related records without 
violating the confidentiality of the subject. 
11.4.1. 
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, the subjects’ race, ethnicity, and full date of birth will be collected (unless the 
collection is not permitted by applicable law or not approved by the governing ethics 
committee). These data will be used in the analysis of the efficacy, safety, and/or PK profile of 
the study treatment. 
SMA is caused by the loss of SMN protein due to a homozygous deletion or mutation or a 
compound heterozygous mutation in the SMN1 gene on chromosome 5q11-q13.  Thus, patients 
with SMA are completely dependent on the amount of SMN protein produced by the SMN2 
gene.  Genetic modifiers, such as the number of copies of the SMN2 gene, are known to impact 
the eventual phenotype of SMA.  The incidence and prevalence of SMA and its subtypes have 
been reported to vary based on country.  One hypothesis for these variances is a difference in the 
frequency of certain genetic mutations that may be associated with different racial and ethnic 
groups within each country.  Therefore, the race/ethnicity of subjects will be collected as part of 
the medical history, where local regulations allow.  The full date of birth is needed in order to 
precisely calculate the age at achievement of motor milestones and the weight-for-age 
percentiles. 
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.  Biogen, 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. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1. 
Protocol Amendments 
Agreement from the Investigator must be obtained for all protocol amendments and amendments 
to the informed consent/assent documents.  The regulatory authority and IRB/IEC must be 
informed of all amendments and give approval for any amendments likely to affect the safety of 
the subjects or the conduct of the study.  The Investigator must send a copy of the approval letter 
from the IRB/IEC to the Sponsor. 


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12.2. 
Study Termination 
The Sponsor reserves the right to terminate the study.  The Investigator reserves the right to 
terminate their participation in the study, according to the terms of the site contract.  The 
Investigator/Sponsor should notify the IRB/IEC in writing of the study’s completion or early 
termination and send a copy of the termination to the Sponsor. 
12.3. 
Study Documentation and Storage 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated study duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the subject’s CRF data 
are obtained.  These include, but are not limited to, hospital records, clinical and office charts, 
laboratory and pharmacy records, and correspondence.  In this study, CRFs may not be used as 
source documents. 
The Investigator and study center staff is responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include the following: 
• Subject files containing completed CRFs, informed consents/assents, and supporting 
copies of source documentation. 
• Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation and all correspondence to and from the IRB and 
the Sponsor. 
• If drug supplies are maintained at the study center, proof of receipt, study drug 
product accountability record, return of study drug for destruction, and all 
drug-related correspondence. 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor prior to doing so. 
12.4. 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (e.g., CRFs and other pertinent data) provided that subject 
confidentiality is respected. 
The Clinical Research Associate/Monitor (Sponsor or designee) is responsible for inspecting the 
CRFs at regular intervals throughout the study to verify adherence to the protocol; completeness, 
accuracy, and consistency of the data; and adherence to local regulations on the conduct of 
clinical research.  The Clinical Research Associate/Monitor should have access to subject 
medical records and other study-related records needed to verify the entries on the CRFs.  


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The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
study center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to in order evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data, a clinical data management review will be performed on 
subject data received by the Sponsor.  During this review, subject data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or study center notifications will be sent to the 
study center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the Principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the study center notifications, and agrees with the content. 
12.5. 
Language 
CRFs must be completed in English.  Whenever possible, the trade name rather than the generic 
name for concomitant medications should be recorded and, if possible, in English.  Generic 
names are acceptable if the trade name is unknown.  Combination medications should be 
recorded using their trade name in English, if possible. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6. 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws.  Subjects will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the ICF. 
12.7. 
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). 
12.8. 
Registration of Study and Disclosure of Study Results 
The Sponsor (or designee) will register the study and poststudy results regardless of outcome on 
a publicly accessible website in accordance with the applicable laws and regulations. 
12.9. 
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 Biogen. 


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12.10. 
Publications 
Details are included in the clinical trial agreement for this study. 
 


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13. 
REFERENCES 
Arkblad E, Tulinius M, Kroksmark AK, et al. A population-based study of genotypic and 
phenotypic variability in children with spinal muscular atrophy. Acta Paediatr. 
2009;98(5):865-72. 
Cho S, Dreyfuss G. A degron created by SMN2 exon 7 skipping is a principal contributor to 
spinal muscular atrophy severity. Genes Dev. 2010;24(5):438-42. 
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. 
Dubowitz L, Dubowitz V. The neurological assessment of the preterm and full-term newborn 
infant. London (UK): William Heinemann Medical books Ltd; 1981. 
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. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha 
phosphorothioate 2'-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across 
species. Drug Metab Dispos. 2003;31(11):1419-28. 
Glanzman AM, Mazzone E, Main M, et al. The Children's Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul 
Disord. 2010;20(3):155-61. 
Glanzman AM, McDermott MP, Montes J, et al. Validation of the Children's Hospital of 
Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther. 
2011;23(4):322-6. 
Haataja L, Mercuri E, Regev R, et al. Optimality score for the neurologic examination of the 
infant at 12 and 18 months of age. J Pediatr. 1999;135(2 Pt 1):153-61. 
Helmken C, Hofmann Y, Schoenen F, et al. Evidence for a modifying pathway in SMA 
discordant families: reduced SMN level decreases the amount of its interacting partners and 
Htra2-beta1. Hum Genet. 2003;114(1):11-21. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased 
immune stimulation in mice. J Pharmacol Exp Ther. 2000;292(2):468-79. 
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. 
Iannaccone ST, Hynan LS, Morton A, et al. The PedsQL in pediatric patients with Spinal 
Muscular Atrophy: feasibility, reliability, and validity of the Pediatric Quality of Life Inventory 
Generic Core Scales and Neuromuscular Module. Neuromuscul Disord. 2009;19(12):805-12. 


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Jedrzejowska M, Milewski M, Zimowski J, et al. Incidence of Spinal Muscular Atrophy in 
Poland--More Frequent Than Predicted? Neuroepidemiology. 2010;34(3):152-7. 
Keren H, Lev-Maor G, Ast G. Alternative splicing and evolution: diversification, exon definition 
and function. Nat Rev Genet. 2010;11(5):345-55. 
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, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular 
atrophy-determining gene. Cell. 1995;80(1):155-65. 
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. 
Lewelt A, Krosschell KJ, Scott C, et al. Compound muscle action potential and motor function in 
children with spinal muscular atrophy. Muscle Nerve. 2010;42(5):703-8. 
Main M, Kairon H, Mercuri E, et al. The Hammersmith functional motor scale for children with 
spinal muscular atrophy: a scale to test ability and monitor progress in children with limited 
ambulation. Eur J Paediatr Neurol. 2003;7(4):155-9. 
Matsumoto H, Clayton-Krasinski DA, Klinge SA, et al. Development and initial validation of the 
assessment of caregiver experience with neuromuscular disease. J Pediatr Orthop. 
2011;31(3):284-92. 
Mazzone ES, Mayhew A, Montes J, et al. Revised upper limb module for spinal muscular 
atrophy: Development of a new module. Muscle Nerve. 2016 Epub 2016/10/04. 
McDonald CM, Henricson EK, Han JJ, et al. The 6-minute walk test as a new outcome measure 
in Duchenne muscular dystrophy. Muscle Nerve. 2010;41(4):500-10. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of 
antisense oligonucleotide inhibitor of human protein kinase C-alpha expression. J Biol Chem. 
1999;274(3):1715-22. 
Montes J, McDermott MP, Martens WB, et al. Six-Minute Walk Test demonstrates motor fatigue 
in spinal muscular atrophy. Neurology. 2010;74(10):833-8. 
O'Hagen JM, Glanzman AM, McDermott MP, et al. An expanded version of the Hammersmith 
Functional Motor Scale for SMA II and III patients. Neuromuscul Disord. 2007;17(9-10):693-7. 
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. 


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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. 
Shefner JM, Watson ML, Simionescu L, et al. Multipoint incremental motor unit number 
estimation as an outcome measure in ALS. Neurology. 2011;77(3):235-41. 
Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for 
spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 
2012;20(1):27-32. 
Swoboda KJ, 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. 
Tassie B, Isaacs D, Kilham H, et al. Management of Children with Spinal Muscular Atrophy 
Type 1 in Australia. J Paediatr Child Health. 2013;49(10):815-9. 
van der Ploeg AT, Clemens PR, Corzo D, et al. A Randomized Study of Alglucosidase Alfa in 
Late-Onset Pompe's Disease. New England Journal of Medicine. 2010;362(15):1396-1406. 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
inventory. Med Care. 1999;37(2):126-39. 
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. 
WHO Multicentre Growth Reference Study Group. Assessment of sex differences and 
heterogeneity in motor milestone attainment among populations in the WHO Multicentre Growth 
Reference Study. Acta Paediatr Suppl. 2006;450:66-75. 
Wijnhoven TM, de Onis M, Onyango AW, et al. Assessment of gross motor development in the 
WHO Multicentre Growth Reference Study. Food Nutr Bull. 2004;25(1 Suppl):S37-45. 
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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14. 
APPENDICES 










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m Motor function assessment includes CHOP INTEND, HFMSE, RULM, 6MWT, and contracture assessment.  If motor function assessments have already been 
performed at Day 960 for a subject prior to approval of Protocol Version 5.0 at a site, motor function assessments (i.e., CHOP INTEND, HFMSE, RULM, 
6MWT, and contracture assessment) will still need to be assessed at Days 1080, 1440, and 1800.  Assessment can be performed up to 7 days prior to the dosing 
visit. 
n X-ray assessments performed as standard of care may be used for protocol-required assessments, if the image acquisition guidelines are met and the X-ray was 
obtained within 4 months prior to the scheduled visit. 
o If needed, the subject’s caregiver may complete the applicable quality of life questionnaires at home up to 7 days prior to the dosing visit.  If a quality of life 
questionnaire is not performed at a visit, attempts should be made to perform the assessment at the subsequent dosing visit(s) until completed; however, an 
assessment should not be performed more than once at any visit.  
p If CMAP measurements are not approved as a mandatory outcome measure by local authorities, they will be considered optional in the respective country. 
 
 
 
 
 
 
 
   


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APPENDIX B. LABORATORY ANALYTES 
Clinical Safety Assessments (minimum requirements) 
Other Assessments 
Blood Chemistry 
Sodium 
Potassium 
Chloride 
Total protein 
Albumin 
Calcium 
Phosphorus 
Bicarbonate 
Glucose 
BUN 
Creatinine 
Cystatin C 
Total serum bilirubin (direct 
and indirect) 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
CPK 
CK MB 
CK BB 
CK MM 
GGT 
Urinalysis 
Specific gravity 
pH 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Red blood cells 
White blood cells 
Epithelial cells 
Bacteria 
Casts 
Crystals 
 
Hematology 
Red blood cells 
Hemoglobin 
Hematocrit 
Platelets 
WBCs 
WBC differential (% and 
absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
Pregnancy 
Urine hCG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following are to be assessed 
by local laboratory only 
Urine total protein 
Coagulation (aPTT and INR) 
Ab = antibody; ALT = alanine aminotransferase; AST = aspartate aminotransferase; aPTT = activated partial 
thromboplastin time; BUN = blood urea nitrogen; CK BB = creatine kinase isoenzyme predominantly expressed in 
the brain; CK MB = creatine kinase isoenzyme expressed in the myocardium; CK MM = creatine kinase 
isoenzyme expressed in skeletal muscle; CPK = creatinine phosphokinase; CSF = cerebrospinal fluid; 
; GGT = gamma glutamyl transferase; hCG = human chorionic gonadotropin; 
INR = international normalized ratio; PK = pharmacokinetic(s); 
; SMA = spinal muscular 
atrophy; SMN = survival motor neuron; WBC = white blood cell; SGOT = serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic pyruvic transaminase. 
Note:  Quantitative urine total protein should be prioritized if there is not enough urine sample for all tests.


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15. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol ISIS 396443-CS11 V6.0, “An Open-Label Extension Study 
for Patients With Spinal Muscular Atrophy Who Previously Participated in Investigational 
Studies of ISIS 396443,” 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 Name (Print) 
 
 
 
Site Number 
 


CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
 
 
 
 
 
 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA  02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire 
SL6 4AY 
United Kingdom 
 
 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol ISIS 396443-CS11 
An Open-Label Extension Study for Patients With Spinal Muscular Atrophy Who Previously 
Participated in Investigational Studies of ISIS 396443 
Version 6.0 
Date: 20 October 2021 
EUDRA CT Number: 2015-001870-16 
Version 6.0 of the protocol has been prepared for this amendment, which supersedes Version 5.0 
dated 24 March 2020. 
 


Amendment Summary for Protocol ISIS 396443-CS11, Version 6.0 
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2 
PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol ISIS 396443-CS11 is to limit the number of 
subjects who are receiving nusinersen concomitantly with other SMA therapies to 20% (n = 58) 
of the total population. The text describing the number of subjects who will be able to be 
concurrently treated with nusinersen and other SMA therapies has been added 
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 8.11.1, Concomitant Therapy 
Now reads:  
8.11.1 Concomitant Therapy 
A concomitant therapy is any non-protocol-specified drug or substance (including 
over-the-counter medications, herbal medications, and vitamin supplements) administered 
between the beginning of Screening and the last telephone contact or study visit. 
Subject’s parents/guardians should consult with the Site Investigator or qualified designee prior 
to initiating any new medication, including non-prescription compounds or any other non-drug 
therapy. 
8.11.1.1 
Allowed Concomitant Therapy 
Any concomitant medications, including SMA therapies, will be captured in the CRF. 
Approved concomitant therapies may be used at the discretion of the Investigator.  With 
implementation of Protocol Version 6.0, investigators with subjects newly seeking 
combination therapy with other SMA therapies should consult and obtain approval from 
the Medical Monitor.  This will be permitted for country-approved SMA therapies, if the 
total number of study subjects concurrently receiving nusinersen and other SMA therapies 
has not yet reached 20% of all enrolled subjects.  This is consistent with the primary and 
secondary objectives of this study.  Any subjects already receiving combination therapy 
with other SMA therapies at the time of Protocol Version 6.0 implementation may continue 
this combination therapy regardless of the 20% limit. 
Throughout the study, the Site Investigators or designated licensed physicians may prescribe 
concomitant medications or treatments deemed necessary for AEs or to provide adequate 
supportive care.  Subjects will be allowed to take concomitant Food and Drug Administration
approved and/or country specific approved therapies and experimental therapies for SMA (at the 
Investigator’s discretion).  In addition, a mild sedative (e.g., midazolam) and a local anesthetic 
(e.g., lidocaine) may be used for the LP procedure (per institutional guidance).  


Amendment Summary for Protocol ISIS 396443-CS11, Version 6.0 
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3 
8.11.1.2 
Disallowed Concomitant Therapy 
None.As noted above in Section 8.11.1.1, with implementation of the Protocol Version 6.0, 
new subjects seeking combination therapy of nusinersen with other SMA therapies should 
consult the Medical Monitor.  Any subjects already receiving investigational drug for any 
other condition should consult with the Medical Monitor. 
Rationale:  The primary objective of this study is to evaluate the long-term safety and 
tolerability of nusinersen administered by intrathecal (IT) injection to subjects with SMA who 
previously participated in investigational studies of ISIS 396443.  The secondary objective is to 
examine the long-term efficacy of nusinersen administered by IT injection in these same 
subjects.  Including a limit on the total number of subjects concurrently treated with nusinersen 
and other SMA therapies is consistent with evaluating the primary and secondary objectives of 
the study in subjects receiving only nusinersen.  In addition, a limit on the total number of 
subjects concurrently treated with nusinersen and other SMA therapies will maintain the intent of 
the European Union post-authorization commitment to evaluate the long-term safety and efficacy 
of nusinersen. 


Amendment Summary for Protocol ISIS 396443-CS11, Version 6.0 
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Biogen MA Inc. 
4 
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Protocol Synopsis 
The Synopsis was revised to reflect changes made throughout the protocol. 
Sections 6.3.2, Dysphagia Assessment 
Change:  Text was added to clarify that if an assessment was not performed at a visit, then the 
assessment should be collected at subsequent visit(s) until the assessment is completed (but 
should not be done twice at any visit). 
Now reads: 
…If an assessment is not performed at a visit, attempts should be made to perform the 
assessment at the subsequent dosing visit(s) until completed; however, an assessment 
should not be performed more than once at any visit. 
Rationale:  To clarify that the investigator should continue to attempt to complete the missed 
assessment at subsequent visits until the assessment is completed. 
This change affects Sections 6.3.5 (Growth Parameters), 6.4.5 (
), 
6.5.1 (Motor Milestones), 6.5.2.1 (Children’s Hospital of Philadelphia Infant Test for 
Neuromuscular Disease), 6.5.2.2 (Hammersmith Functional Motor Scale – Expanded), 
6.5.2.3 (Revised Upper Limb Module), 6.5.2.4 (Six-Minute Walk Test), 6.5.2.5 (Contracture 
Assessment), 6.6.1 (Electrocardiograms), 6.6.2 (X-Ray of Spine), 6.6.3 (Quality of Life 
Questionnaires), 6.7.1 (Compound Muscle Action Potential), 6.8.1 (
), and 
Appendix A (Schedule of Procedures:  Groups 1A/1B and 2A/2B Blind Loading Dose Period 
and All Groups MMDR Schedule). 
Section 6.3.2, Dysphagia Assessment 
Change:  Text was added to allow the dysphagia assessment to be done at home 7 days prior to 
dosing. 
Now reads:  
Dysphagia will assessment may be assessed withinperformed at home up to 7 days prior to the 
dosing visit using the Parent Assessment of Swallowing Ability wWeekly surveyVersion. 
Rationale:  The change was made to allow for completion of the dysphagia assessment in 
alignment with other assessments that can be conducted at home. 


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This change also affects Appendix A (Schedule of Procedures:  Groups 1A/1B and 2A/2B Blind 
Loading Dose Period and All Groups MMDR Schedule). 
Section 6.3.5, Growth Parameters 
Change:  Text was revised to allow for ulnar length measurement (rather than only arm span) in 
lieu of body length or height. 
Now reads: 
… 
In subjects with scoliosis and contractures, the Investigator (or designee) may measure arm 
span or ulnar length in lieu of body length or height.  Arm span is defined as the distance from 
the fingertip in one hand to that in the opposite hand and should be measured with the arms 
outstretched laterally away from the body.  If arm span cannot be measured due to contractures, 
tThe investigator may measure ulnar length between the point of the elbow and the midpoint of 
the prominent bone of the wrist. 
Rationale:  This change will allow the sites more flexibility to measure growth parameters by 
using only ulnar length in instances where other growth parameters are challenging to measure. 
This change also affects Appendix A (Schedule of Procedures:  Groups 1A/1B and 2A/2B Blind 
Loading Dose Period and All Groups MMDR Schedule). 
Section 6.3.8, Neurological Examinations 
Change:  Text was revised to change the window of completion of the neurological examination 
to within 7 days of dosing. 
Now reads: 
Focused neurological examinations will be performed predosewithin 7 days of dosing and 
approximately 1 hour postdose at every onsite visit throughout the study.  Please 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. 
Rationale:  Clarification that the neurological examinations can be done along with other 
predose assessments. 
This change also affects Appendix A (Schedule of Procedures:  Groups 1A/1B and 2A/2B Blind 
Loading Dose Period and All Groups MMDR Schedule). 


Amendment Summary for Protocol ISIS 396443-CS11, Version 6.0 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
6 
Section 6.4.1, Clinical Safety Laboratory Evaluations 
Change:  Text was revised to provide details on prioritization of urinalysis tests in the event 
there is not enough sample for all tests. 
Now reads: 
… 
For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation.  
Quantitative urine total protein assessment should be prioritized if there is not enough 
urine sample for all tests. 
Rationale:  Clarification regarding prioritization of urinalysis tests in the event there is not 
enough sample for all tests. 
This change also affects Appendix A (Schedule of Procedures:  Groups 1A/1B and 2A/2B Blind 
Loading Dose Period and All Groups MMDR Schedule) and new Appendix B (Laboratory 
Analytes). 
Section 6.4.2, Coagulation Parameters 
Change:  Text was revised to provide additional clarity around the requirement that coagulation 
testing results must be reviewed prior to dosing. 
Now reads: 
… 
The coagulation testing must be performed and reviewed predose (within 7 days of 
dosing).Coagulation testing will continue to be conducted at each visit or up to 7 days prior 
to dosing, and results should be reviewed prior to dosing.  In situations where predose 
verification of coagulation laboratory results is not feasible or optimal (e.g., prolonged 
sedation of the subject would be required to allow adequate time for laboratory 
processing), the Investigator may exercise discretionary clinical judgment and proceed 
with the LP procedure, based on the subject’s clinical and coagulation laboratory results 
history. 
Rationale:  While coagulation results should be reviewed prior to dosing, there may be 
situations where this is not feasible, and the Investigator may proceed with the lumbar puncture 
(LP) based on clinical judgment. 
This change also affects Appendix A (Schedule of Procedures:  Groups 1A/1B and 2A/2B Blind 
Loading Dose Period and All Groups MMDR Schedule). 


Amendment Summary for Protocol ISIS 396443-CS11, Version 6.0 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
7 
Section 6.6.3, Quality of Life Questionnaires 
Change:  Text was added to clarify that if a quality-of-life questionnaire was not performed at a 
visit, then the assessment should be collected at subsequent visit(s) until the assessment is 
completed (but should not be done twice at any visit). 
Now reads: 
… 
The questionnaires that are performed at a given visit will depend on the subject’s age at that 
visit.  If needed, the subject’s caregiver may complete the applicable quality-of-life 
questionnaires at home up to 7 days prior to dosing visit.  If a quality-of-life questionnaire is not 
performed at a visit, itattempts should be collectedmade to perform the assessment at the next 
scheduledsubsequent dosing visit(s) until completed; however, an assessment should not be 
performed more than once at any visit. 
Rationale:  This text was revised to clarify that the investigator should continue to attempt to 
complete the missed assessment at subsequent visits. 
This change also affects Appendix A (Schedule of Procedures:  Groups 1A/1B and 2A/2B Blind 
Loading Dose Period and All Groups MMDR Schedule). 
Section 8.8, Adjustment of Dose and/or Treatment Schedule 
Change:  Text was revised to indicate that in the event of a delayed or missed dose, an 
adjustment in dosing schedule was allowed in the event of unique circumstances, including those 
related to the coronavirus disease 2019 pandemic, as indicated in the DHA. 
Now reads: 
No adjustment of dose will beis permitted. If dosing does not occur as per the schedule of 
activities, a protocol deviation should be logged.  In the event of delayed or missed doses due 
to, for example, a concurrent illness or ongoing AE that would prevent the dosing procedure 
from being performed safely, an adjustment in the dosing schedule may be permitted but must be 
approved by other circumstances (e.g., the coronavirus disease 2019 pandemic), the Medical 
Monitor.  In this case,Investigator should refer to the DHA, which includes recommended 
dosingwill be resumed as soon as possible.administration in the event of delayed or missed 
doses. 
Rationale:  Text was revised to broaden the circumstances in which delayed or missed doses 
may have occurred and to allow adjustment to the dose schedule as indicated in the DHA. 
Section 8.9, Discontinuation of Study Treatment 
Change:  Text was revised to indicate that all subjects who discontinue study treatment will 
complete an early termination visit approximately 4 months after their last dose of nusinersen.  


Amendment Summary for Protocol ISIS 396443-CS11, Version 6.0 
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Now reads: 
A subject must permanently discontinue study treatment for any of the following reasons: 
• The subject or subject’s parent/guardian withdraws consent. 
• The subject experiences an AE that necessitates permanent discontinuation of study 
treatment. 
The reason for discontinuation of study treatment must be recorded in the case report form 
(CRF) and source documentation. 
Subjects who discontinue treatment and do not agree to continue in the study should havewill 
complete an ET Visit performed (Appendix A).   
Subjects who discontinue treatment but agree to continue in the study should have an ETearly 
termination visit performed (Appendix A).  Subsequently, the first follow-up assessment will be 
planned approximately 4 months (±(+14 days) after administration of the last open-label 
maintenance dose of nusinersen.  Afterward, annual (±30 days) follow-up assessments will be 
performed (Appendix B).  Telephone contact will occur every 4 months (±14 days), except for 
months when in-clinic visits occur. During these calls, changes in concomitant medications, 
ancillary procedures, AEs, and ventilator use/status will be recorded. 
The following assessments will be conducted at these follow up visits: 
• Assessment of ventilator support/use 
• Weight 
• Growth parameters 
• Physical examination 
• Vital signs 
• Focused neurological examination 
• Motor milestones 
• Motor function assessments, as appropriate per Investigator’s discretion, including 
CHOP INTEND, HFMSE, RULM, and/or 6MWT (optional) 
The following assessments will be collected on a continuous basis: 
• AEs and serious adverse events (SAEs) (see  (Appendix A), unless consent is 
withdrawn (Section 8.1010.6.2 for analysis of AEs).  


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• Use of concomitant medications  
• Ancillary procedure recording 
For subjects who discontinue from study treatment but agree to continue the study, the end date 
of study exposure will be set to be at 1 year following the last administration of study drug. 
Rationale:  These changes are consistent with the rationale of this study to assess long-term 
safety, efficacy, and tolerability of nusinersen. Additional follow-up beyond 4 months for 
collection of safety assessments in subjects who discontinued nusinersen is no longer required. 
This change also affects Figure 2 (Study Design and Treatment Schema: Groups 1A and 1B), 
Figure 3 (Study Design and Treatment Schema: Groups 2A and 2B), Figure 4 (Study Design and 
Treatment Schema: Groups 3, 4, and 5), Section 3.4.2 (Treatment), Section 10.6.2 (Safety and 
Tolerability Analysis), and Appendix A (Schedule of Procedures:  Groups 1A/1B and 2A/2B 
Blind Loading Dose Period and All Groups MMDR Schedule). Appendix B (Schedule of 
Procedures for Subjects Who Discontinued Nusinersen but Agree to Remain in the Study) was 
deleted due to this change. 
Section 11.4.1, Subject Data Protection 
Change: Text was added to include language regarding the collection of a subject’s race, 
ethnicity, and full date of birth. 
Now reads: 
Prior to any testing under this protocol, including screening tests and assessments, the subject’s 
legally authorized representative(s) must also provide all authorizations required by local law 
(e.g., Protected Health Information authorization in North America). 
During the study, the subjects’ race, ethnicity, and full date of birth maywill be collected 
for(unless the collection is not permitted by applicable law or not approved by the purposes 
ofgoverning ethics committee). These data will be used in the analysis. of the efficacy, safety, 
and/or PK profile of the study treatment. 
SMA is caused by the loss of SMN protein due to a homozygous deletion or mutation or a 
compound heterozygous mutation in the SMN1 gene on chromosome 5q11-q13.  Thus, 
patients with SMA are completely dependent on the amount of SMN protein produced by 
the SMN2 gene.  Genetic modifiers, such as the number of copies of the SMN2 gene, are 
known to impact the eventual phenotype of SMA.  The incidence and prevalence of SMA 
and its subtypes have been reported to vary based on country.  One hypothesis for these 
variances is a difference in the frequency of certain genetic mutations that may be 
associated with different racial and ethnic groups within each country.  Therefore, the 
race/ethnicity of subjects will be collected as part of the medical history, where local 
regulations allow.  The full date of birth is needed in order to be able toprecisely calculate the 
age at achievement of motor milestones and the weight -for -age percentiles. 


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Rationale: Race and ethnicity data can be collected, provided it is noted in the protocol; 
therefore, this text has been added to indicate that these parameters will be collected to be used in 
the analysis of the efficacy, safety and/or PK profile of nusinersen.  
Appendix A, Schedule of Procedures:  Groups 1A/1B and 2A/2B Blind Loading Dose Period 
and All Groups MMDR Schedule 
Change:  Text was added to clarify that if a quality-of-life questionnaire was not performed at a 
visit, then the assessment should be collected at subsequent visit(s) until the assessment is 
completed (but should not be done twice at any visit).  Text was also added to provide additional 
clarity on prioritization of assessments on visit days when a substantial number of assessments 
are planned.  
Now reads: 
Notes:  For growth parameters, dysphagia assessment, motor milestones, motor function 
assessments, 
, 
, ECGs, X-ray of the spine, 
and quality of life questionnaires, if an assessment is not performed at a visit, attempts 
should be made to perform the assessment at the subsequent dosing visit(s) until 
completed; however, an assessment should not be performed more than once at any visit.  
For study visits with a large number of planned assessments, assessments can be completed 
over 1 to 2 days and assessments for primary and secondary outcomes (e.g., motor 
milestones/functional assessments) should be prioritized.  Among the laboratory 
measurements, quantitative urine total protein should be prioritized if there is not enough 
urine sample for all tests. 
Rationale:  To clarify that the investigator should continue to attempt to complete the missed 
assessment at subsequent visits. Clarification regarding prioritization of urinalysis tests in the 
event there is not enough sample for all tests. In the event that all assessments cannot be done at 
1 visit (e.g., due to limited time, patient fatigue), allowance is provided to complete all 
assessments over 2 days instead of 1 day and prioritization of assessments is provided. 
The change regarding urine total protein assessment also affects new Appendix B (Laboratory 
Analytes). 


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
• The version number and date were revised throughout the protocol. 
• Background information on SMA and the clinical experience with nusinersen were 
updated and sources were added to references. 
• Numbering of the Appendices was updated due to deletion of previous Appendix B 
(Schedule of Procedures for Subjects Who Discontinued Nusinersen but Agree to 
Remain in the Study). 
• Minor editorial changes were made throughout the document. 
• Typographical errors and formatting were corrected. 


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12 
LIST OF ABBREVIATIONS 
AE 
adverse event 
CRF 
case report form 
DHA 
Directions for Handling and Administration 
ECG 
electrocardiogram 
IT 
intrathecal 
LP 
lumbar puncture 
MMDR 
Modified Maintenance Dosing Regimen 
PK 
pharmacokinetic(s) 
SMA 
spinal muscular atrophy 
SMN 
survival motor neuron 
SMN1 
survival motor neuron 1 
SMN2 
survival motor neuron 2 
 


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1 
 
 
 
 
 
 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA  02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire 
SL6 4AY 
United Kingdom 
 
 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol ISIS 396443-CS11 
An Open-Label Extension Study for Patients With Spinal Muscular Atrophy Who Previously 
Participated in Investigational Studies of ISIS 396443 
Version 5.0 
Date: 24 March 2020 
EUDRA CT Number: 2015-001870-16 
Version 5.0 of the protocol has been prepared for this amendment, which supersedes Version 4.0. 
 


Protocol ISIS 396443-CS11, Version 5.0 
 
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2 
PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol ISIS 396443-CS11 is to change the standard 
neurological examination to a focused neurological examination. 
Section 6.3.8, Neurological Examinations 
Now reads: 
Focused Nneurological examinations will be performed predose and approximately 1 hour 
postdose at every onsite visit throughout the study.  Please 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. 
… 
For all subjects >24 months of age, standardfocused neurological examinations, which include 
assessments of mental status, level of consciousness, sensory function, motor function, cranial 
nerve function, and reflexes, will be conducted. 
… 
Rationale:    
The focused neurological examination will allow the collection of sufficient data on neurological 
status with a significant reduction in burden for participants in this long-term extension study.    
This change also affects Section 6.10, Study Assessments to be Repeated Due to Delayed 
Dosing: Section 8.9, Discontinuation of Study Treatment; Appendix A, Schedule of Procedures:  
Groups 1A/1B and 2A/2B Blind Loading Dose Period and All Groups MMDR Schedule; and 
Appendix B, Schedule of Procedures for Subjects Who Discontinued Nusinersen but Agree to 
Remain in the Study. 
 


Protocol ISIS 396443-CS11, Version 5.0 
 
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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Protocol Synopsis 
The Synopsis was revised to reflect changes made throughout the protocol. 
Section 6.3.5, Growth Parameters 
Change:  Ulnar length was added as a growth parameter measurement for a subset of 
participants whose height, body length, and arm span cannot be measured. 
Now reads:  
… 
In subjects with scoliosis, the Investigator (or designee) may measure arm span in lieu of body 
length or height.  Arm span is defined as the distance from the fingertip in one hand to that in the 
opposite hand and should be measured with the arms outstretched laterally away from the body.  
If arm span cannot be measured due to contractures, the investigator may measure ulnar 
length between the point of the elbow and the midpoint of the prominent bone of the wrist. 
… 
Rationale:  Height, body length, and arm span measurements in participants with scoliosis may 
not be possible in those who have severe contractures. The inclusion of ulnar length allows 
investigators a viable option to include a growth parameter measurement for these participants. 
This change also affects Appendix A, Schedule of Procedures:  Groups 1A/1B and 2A/2B Blind 
Loading Dose Period and All Groups MMDR Schedule; and Appendix B, Schedule of 
Procedures for Subjects Who Discontinued Nusinersen but Agree to Remain in the Study. 
 
 
 


Protocol ISIS 396443-CS11, Version 5.0 
 
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4 
 
 
 
  
 
 
 
 
 
    
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 


Protocol ISIS 396443-CS11, Version 5.0 
 
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Protocol ISIS 396443-CS11, Version 5.0 
 
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SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
• The version number and date were revised throughout the protocol. 
• On the Sponsor Signature Page, the signatory’s role and name and were updated.  The 
Sponsor name was updated to align with the current protocol template. 
• The date was removed from the headings. 
• The List of Abbreviations and abbreviations in text were updated. 
• Minor editorial changes were made throughout the document. 
• Typographical errors and formatting were corrected. 
 
 
 
 
• In Section 11.4.1, Subject Data Protection, the collection of the full date of birth and 
the rationale to include these data were added to the protocol. 
 
 
 
 
  


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1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol ISIS 396443-CS11
An Open-Label Extension Study for Patients With Spinal Muscular Atrophy Who Previously 
Participated in Investigational Studies of ISIS 396443
Version 4.0
Date: 19 November 2019
EUDRA CT Number: 2015-001870-16
Version 4 of the protocol has been prepared for this amendment, which supersedes Version 3.0
dated 30 October 2017.


Protocol ISIS 396443-CS11, Version 4
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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol ISIS 396443-CS11 is to change the interval 
of clinical assessment visits after the Modified Maintenance Dosing Regimen (MMDR) Day 720 
Visit from every 8 months to every 12 months.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 6.5, Study Assessments for Screening and/or Modified Maintenance Dosing Regimen 
Day 1, Every 8 Months Until MMDR Day 720 and Every 12 Months Thereafter, and the End-of-
Study Evaluation/Early Termination Visit
Now reads: 
6.5.
Study Assessments for Screening and/or Modified Maintenance Dosing Regimen Day 1, 
Every 8 Months Until MMDR Day 720 and Every 12 Months Thereafter (Every Other 
Modified Maintenance Dosing Regimen Visit), and the End-of-Study Evaluation/Early 
Termination Visit
Section 6.5.1, Motor Milestones
For all subjects, motor milestones will be assessed using the World Health Organization (WHO) 
Motor Milestones criteria [WHO Multicentre Growth Reference Study Group 2006; Wijnhoven 
2004] at Screening and/or predose at MMDR Day 1, every 8 months until MMDR Day 720 
(inclusive) [i.e., predose at MMDR Days 240, 480, and 720] and every 12 months thereafter 
(i.e., predose at MMDR Days 1080 and 1440240, 480, 720, and so on), and at the EOS 
Evaluation (MMDR Day 1800 [±14 days])/ET Visit.  If the WHO motor milestones 
assessment has already been performed at Day 960 for a participant prior to approval of 
this protocol version at a site, the WHO motor milestones assessment will still need to be 
performed at Days 1080, 1440, and 1800.  Assessment can be performed up to 7 days prior 
to the dosing visit.
…
Section 6.5.2, Motor Function Assessments
Motor function assessments include all assessments listed in Section 6.5.2.1, Section 6.5.2.2, 
Section 6.5.2.3, and Section 6.5.2.4, and Section 6.5.2.5.  Motor function assessments will be 
performed at Screening and/or predose at MMDR Day 1, every 8 months until MMDR Day 
720 (inclusive) [i.e., predose at MMDR Days 240, 480, and 720] and every 12 months
thereafter (i.e., predose at MMDR Days 1080 and 1440240, 480, 720, and so on), and at the 
EOS Evaluation (MMDR Day 1800 [±14 days])/ET Visit.  If motor function assessments have 
already been performed at Day 960 for a participant prior to approval of this protocol 
version at a site, motor function assessments (i.e., CHOP INTEND, HFMSE, Revised 
Upper Limb Module [RULM], 6-Minute Walk Test [6MWT], and contracture assessment) 


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will still need to be assessed at Days 1080, 1440, and 1800.  Assessment can be performed 
up to 7 days prior to the dosing visit.
Rationale: Frequency of motor milestones and motor function assessments were reduced from 
every 8 months to every 12 months to minimize burden for subjects and their families (thus 
potentially helping with trial retention), while maintaining meaningful intervals between 
assessments. This change in frequency of assessments is to begin after Day 720, as most subjects 
have already had assessments until Day 720. To account for the variable availability of this 
protocol version at sites, language was added to emphasize that if a subject has had assessments 
on MMDR Day 960, he/she will also need to be assessed on MMDR Days 1080, 1440, and 1800 
to ensure consistent collection of data for all subjects at these less frequent time points in Year 3 
and beyond of participation in this study.
This change also affected Appendix A, Schedule of Procedures: Groups 1A/1B and 2A/2B Blind 
Loading Dose Period and All Groups MMDR Schedule.


Protocol ISIS 396443-CS11, Version 4
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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Protocol Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 3.4.2, Treatment
Change: The window for each MMDR dosing visit was extended from ±7 days to ±14 days. In 
addition, a sentence for the schedule of other MMDR dosing visits was added.
Now reads:
Subjects who entered the study after completing the double-blind studies ISIS 396443-CS3B and 
ISIS 396443-CS4 (i.e., subjects in Groups 1A, 1B, 2A, and 2B) completed a blinded loading 
dose period and then transitioned to the open-label MMDR period.  Subjects who were already 
enrolled in ISIS 396443 CS11 (SHINE) and had already participated in the blinded loading dose 
period continued their blinded loading dose/sham schedule through the last scheduled dose in 
that loading dose period and then transitioned to the open-label MMDR dosing schedule at their 
next study visit, which was scheduled as close as possible to 120 days from the date of the last 
dosing visit (i.e., date of last dosing visit + 120 days = MMDR Day 1).  The schedule for other 
MMDR dosing visits should be based on MMDR Day 1.
…
Subjects who entered the study after completing open-label studies ISIS 396443-CS12 and 
ISIS 396443-CS3A (i.e., subjects in Groups 3 and 4) will enter directly into the open-label 
MMDR period at MMDR Day 1.  Subjects who were already enrolled in ISIS 396443-CS11 and 
were already receiving maintenance doses according to the original maintenance schedule 
transitioned to MMDR Day 1 at their next study visit (regardless of how many maintenance 
doses already received in the original schedule), which was scheduled as close as possible to 
120 days from the date of the last dosing visit (i.e., date of last dosing visit + 120 days = MMDR 
Day 1).  Subjects entering the study after completing open-label Study 232SM202 (i.e., subjects 
in Group 5) will enter directly into the open-label MMDR period at MMDR Day 1.  The 
schedule for other MMDR dosing visits should be based on MMDR Day 1.
The MMDR dosing schedule will consist of MMDR Days 1, 120, 240, 360, 480, 600, 720, 840, 
960, 1080, 1200, 1320, 1440, 1560, and 1680 and so on every 4 months (±714 days) until the 
EOS Evaluation/Early Termination (ET) Visit.  The EOS Evaluation Visit will occur 4 months 
after the last open-label maintenance dose of nusinersen on approximately MMDR Day 1800 
(±714 days).




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Section 6.6.3.3, Clinical Global Impression – Improvement
Change: Section 6.6.3.3 was deleted.
Now reads:
Section 6.6.3.3, Clinical Global Impression Improvement
The Clinical Global Impression of Change Rating Scale (CGI) was developed as a brief, 
stand alone assessment of the clinician’s view of the patient’s global functioning after initiating a 
study medication[Guy 1976].  The CGI provides an overall clinician determined summary 
measure that takes into account all available information, including knowledge of the patient’s 
history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the 
patient’s ability to function.  CGI is administered by an experienced clinician who is familiar 
with the disease under study and the likely progression of treatment.  The clinician makes a 
judgment about the total picture of the patient at each visit:  the severity of illness, the patient’s 
level of distress and other aspects of impairment, and the impact of the illness on functioning.  
The CGI is rated without regard to the clinician’s belief that any clinical changes are or are not 
due to medication and without consideration of the etiology of the symptoms.
The Clinical Global Impression Improvement (CGI I) scale is a 7 point scale that requires the 
clinician to assess how much the patient’s illness has improved or worsened relative to a baseline 
state at the beginning of the intervention and is rated as follows:  1, very much improved; 
2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 
7, very much worse.  For assessment of CGI I, the baseline state is defined as follows:

Groups 1, 3, and 4:  Baseline is defined as the CGI I score at Screening for the present 
extension study.

Group 2:  Baseline is defined as the CGI-I score at Screening in the index 
study ISIS396443-CS4.

Group 5:  Baseline is defined as the CGI I score at Screening in the index 
study 232SM202.
CGI I is to be administered consistently by the same rater for each study subject.  Separate CGI I 
assessment will be administered to the Investigator (Principal Investigator or Subinvestigator) 
and caregiver.
Rationale: The Clinical Global Impression – Improvement (CGI-I) scale was removed from 
participants’ schedule of assessments because the data collected from this assessment would 
likely be difficult to reliably interpret. The CGI-I assessment requires comparison of a subject’s 
current state to a baseline state. The duration of time since initiation of treatment (upward of 
3 years for most participants in this study) compromises the quality of the data collected and the 
interpretation of the results. Furthermore, there have been inconsistencies across participants in 
the definition of “baseline.” Given these concerns in addition to the goal of reducing participant 
burden in the trial, the decision was made to stop assessing CGI-I. 


Protocol ISIS 396443-CS11, Version 4
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This change also affected Section 10.1.2, Efficacy Endpoints; Section 10.6.3, Efficacy Analysis; 
and Appendix A, Schedule of Procedures: Groups 1A/1B and 2A/2B Blind Loading Dose Period 
and All Groups MMDR Schedule.
Section 6.10, Study Assessments to be Repeated Due to Delayed Dosing
Change: A new section for repeated procedures due to a delay in dosing was added.
Now reads:
If a dosing visit is delayed, the following predose procedures should be repeated at the 
delayed dosing visit:

Vital signs (resting blood pressure, pulse, pulse oximetry, respiratory rate, and 
temperature) 

Weight

Growth parameters

Ventilator use

Physical examination

Neurological examination
o
General neurological examination for subjects >24 months of age
o
HINE Section 1 and 3 for subjects ≤24 months of age

Safety laboratory evaluations:
o
Chemistry (central laboratory)
o
Hematology (central laboratory)
o
Urinalysis (central laboratory)
o
Urine total protein (local laboratory)

Coagulation parameters (local laboratory)

Urine/serum pregnancy test


Protocol ISIS 396443-CS11, Version 4
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
ECG (predose at applicable visits: MMDR Days 1, 360, 720, 1080, and 1440)

Concomitant medications assessment

Ancillary procedure recording

AE collection
All procedures should be performed predose (within 7 days of dosing).  Vital signs and 
neurological examination should also be performed at approximately 1-hour postdose.  The 
purpose of repeating these assessments is to ensure the safety of the subject prior to dosing 
and to collect important study information pertaining to each dose. 
At the discretion of the Investigator, additional visit-specific assessments may be repeated 
as needed, as long as they are performed predose within 7 days of the rescheduled dosing 
visit. 
Rationale: The text was added to ensure the safety of the subject prior to dosing and to collect 
important study information pertaining to each dose.
This change also affected Section 6.3.1, Ventilator Use Diary Recording; Section 6.3.3, Urine 
Pregnancy Tests; Section 6.3.4, Weight; Section 6.3.5, Growth Parameters; Section 6.3.6, 
Physical Examinations; Section 6.3.7, Vital Signs; Section 6.3.8, Neurological Examinations, 
Section 6.4.1, Clinical Safety Laboratory Evaluations; Section 6.4.2, Coagulation Parameters; 
 
and Section 6.6.1, Electrocardiograms.
Section 8.9, Discontinuation of Study Treatment
Change: Text was added for study assessments that need to be performed when a subject stops 
treatment but agrees to continue in the study.
Now reads:
A subject must permanently discontinue study treatment for any of the following reasons:

The subject or subject’s parent/guardian withdraws consent.

The subject experiences an AE that necessitates permanent discontinuation of study 
treatment.
The reason for discontinuation of study treatment must be recorded in the case report form 
(CRF) and source documentation.
Subjects who discontinue treatment will continue follow up through scheduled study visits, 
unless consent is withdrawn and do not agree to continue in the study should have an ET 
Visit performed (Appendix A).


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Subjects who discontinue treatment but agree to continue in the study should have an ET 
visit performed (Appendix A). Subsequently, the first follow-up assessment will be planned 
approximately 4 months (±14 days) after the last open label maintenance dose of 
nusinersen.  Afterward, annual (±30 days) follow-up assessments will be performed 
(Appendix B). Telephone contact will occur every 4 months (±14 days), except for months 
when in-clinic visits occur.  During these calls, changes in concomitant medications, 
ancillary procedures, AEs, and ventilator use/status will be recorded.
The following assessments will be conducted at these follow-up visits:

Assessment of ventilator support/use

Weight

Growth parameters

Physical examination

Vital signs

Neurological examination

Motor milestones

Motor function assessments, as appropriate per Investigator’s discretion, 
including CHOP INTEND, HFMSE, RULM, and/or 6MWT (optional)
The following assessments will be collected on a continuous basis:

AEs and serious adverse events (SAEs) (see Section 10.6.2 for analysis of AEs)

Use of concomitant medications 

Ancillary procedure recording
Rationale: Subjects are given the option to continue participation in the study even after 
discontinuation of nusinersen treatment, which allows for the collection of valuable follow-up 
information after nusinersen treatment. Subjects who choose to remain in the study despite 
discontinuing nusinersen treatment should continue to have a predefined set of safety and 
efficacy assessments to ensure consistent collection of data.
This change also affected Section 3.4.2, Treatment; Section 10.6.2, Safety and Tolerability 
Analysis; and Appendix B, Schedule of Procedures for Subjects Who Discontinued Nusinersen 
but Agree to Remain in the Study.






Protocol ISIS 396443-CS11, Version 4
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12
SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were revised throughout the protocol.

On the Sponsor Signature Page, the signatory’s role and name were updated.

The List of Abbreviations and abbreviations in text were updated.

In Section 2.3.4, Clinical Experience, the list of completed and ongoing studies was 
updated

In Section 3.2, Number of Study Centers, the number of study centers was updated to 
50 sites.

In Section 3.4, Overall Study Duration and Follow-Up, MMDR visits after Day 840 
to Day 1680 were listed in Figure 2: Study Design and Treatment Schema:  Groups 
1A and 1B; in Figure 3: Study Design and Treatment Schema:  Groups 2A and 2B; 
and in Figure 4: Study Design and Treatment Schema:  Groups 3, 4, and 5.

In Section 6.3.1, Ventilator Use Diary Recording, text was updated to clarify the 
conditions and period for which ventilator use should be recorded.

In Section 6.3.2, Dysphagia Assessment, text was revised to indicate the survey used 
for assessment and the time period for assessment of dysphagia and to specify the 
questions to be assessed in tube-fed subjects. This change also affected Appendix A, 
Schedule of Procedures: Groups 1A/1B and 2A/2B Blind Loading Dose Period and 
All Groups MMDR Schedule.

In Section 6.3.5, Growth Parameters, text was updated to indicate that body length or 
height will be measured.

In Section 6.3.6, Physical Examinations; Section 6.5.1, Motor Milestones; and 
Section 6.5.2, Motor Function Assessments, text was updated to clarify that 
videotaping of physical examinations, WHO and/or HINE motor milestone 
assessments, and all motor function assessments will occur only if the consent is 
provided. 

In Section 6.4.2, Coagulation Parameters, assessment of prothrombin time was 
deleted. This change also affected Section 10.1.1, Safety and Tolerability Endpoints 
and Appendix C: Laboratory Analytes.




Protocol ISIS 396443-CS11, Version 4
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14
Procedures: Groups 1A/1B and 2A/2B Blind Loading Dose Period and All Groups 
MMDR Schedule.

In Section 8.11.2, Concomitant Procedures, additional examples of therapeutic 
intervention of non-drug related treatment were provided.

In Section 9.5.5, Medical Emergency, the Investigator’s ability to unblind the study 
treatment assignment in a medical emergency was deleted. 

In Section 10.1.2, Efficacy Endpoints, text was updated to include contracture 
assessment as a motor function assessment. Compound muscle action potential was 
presented in a separate bullet point. In addition, a sentence was added to clarify that 
the definition for acute reversible events is provided in the SHINE Ventilation 
Endpoint Guidance.

In Section 10.3, Populations, the Per-Protocol Set was removed. This change also 
affected Section 10.6, Planned Methods of Analysis.

In Appendix A, Schedule of Procedures: Groups 1A/1B and 2A/2B Blind Loading 
Dose Period and All Groups MMDR Schedule, a footnote was provided to indicate 
that motor function assessment includes Children’s Hospital of Philadelphia Infant 
Test for Neuromuscular Disease, Hammersmith Functional Motor Scale - Expanded, 
Revised Upper Limb Module, 6-Minute Walk Test, and contracture assessment. 

Minor editorial changes were made throughout the document.

Typographical errors and formatting were corrected.


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1 
 
 
 
 
 
 
 
 
 
 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA  02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
 
Biogen Australia PTY Ltd. 
Suite 1, Level 3, 123 Epping Road 
North Ryde, NSW 2113 
Australia  
 
Biogen Japan Ltd. 
Nihonbashi 1-chome Mitsui Building 14F 
4-1 Nihonbashi 1-chome 
Chuo-ku, Tokyo 103-0027 
Japan 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol ISIS 396443-CS11 
An Open-Label Extension Study for Patients With Spinal Muscular Atrophy Who Previously 
Participated in Investigational Studies of ISIS 396443 
Version 3.0 
Date:  30 October 2017 
EUDRA CT Number:  2015-001870-16 
Version 3.0 of the protocol has been prepared for this amendment, which supersedes 
Versions 1.0, 1.1, 1.3, and 2.0.  
 


Protocol ISIS 396443-CS11, Version 3.0 
 
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2 
PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol ISIS 396443-CS11 is to allow enrollment of 
subjects from the newly added index study 232SM202 into this extension study.  As a result of 
this change, the approximate number of subjects has increased from 239 to 292 subjects, the 
approximate number of study sites from 37 up to 45 sites, and the approximate number of 
countries from 14 up to 15 worldwide. 
Subjects entering the extension study from the index study 232SM202 will be enrolled into a 
new cohort, Group 5.  Subjects will enter directly into the open-label period at Modified 
Maintenance Dosing Regimen (MMDR) Day 1. 
 
New text is shown in bold type; deleted text is shown with a strikethrough. 
 
Section 3.1, Study Design 
Now reads: 
This is an open-label extension study in subjects with SMA who previously participated in 
investigational studies of ISIS 396443.  For the purposes of this protocol, investigational studies 
of ISIS 396443, henceforth referred to as “index” studies, include Studies ISIS 396443-CS3A, 
ISIS 396443-CS3B, ISIS 396443-CS4, and ISIS 396443-CS12, and 232SM202.  Subjects from 
other studies of ISIS 396443 may be included into the current long term extension study with 
future amendments of the protocol. 
 
Rationale: 
Subjects from Study 232SM202 are being enrolled to enable collection of long-term safety and 
efficacy data from these subjects.  At the present time, no other studies are planned to be added 
as index studies into the extension study.  The study design summary was revised accordingly.  
This change also affects Section 3.2.  Number of Study Centers; Section 3.3, Number of 
Subjects; Section 3.4, Overall Study Duration and Follow-Up; Section 3.4.2, Treatment; and 
Figure 4.  In addition, text listing the applicable index studies and subject groups for this 
extension study was updated throughout the protocol to include Study 232SM202 and Group 5. 




Protocol ISIS 396443-CS11, Version 3.0 
 
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Now reads: 
3.6 
Safety Monitoring and Data and Safety Monitoring Board 
Safety data will be reviewed on an ongoing basis by the Sponsor and the Medical Monitor, with 
data cuts at regular intervals.  Safety may also be reviewed by an independent Data and Safety 
Monitoring Board (DSMB).  It is anticipated that meetings may occur approximately 4 times per 
year (i.e., approximately every 3 months).  The DSMB will review safety, tolerability, and 
efficacy data collected on nusinersen during this study.  The details of the DSMB operation and 
the data reviewed will be outlined in the DSMB Charter.  Based on its ongoing assessment of the 
data, the DSMB will provide recommendations to the Sponsor for modifying, stopping, or 
continuing the study.  The DSMB may be discontinued at the Sponsor’s discretion. 
 
Rationale: 
A DSMB will no longer be used in this study; therefore, text describing its formation and 
function is no longer applicable.  Safety data in the study will continue to be reviewed by the 
Sponsor and the Medical Monitor on an ongoing basis.   
This change also affects Section 9.2, Regulatory Requirements. 
 
Section 4.1, Screening 
Change: 
Text summarizing assignment of subject identification numbers was revised. 
 
Now reads: 
Before a subject’s participation in the study, the Investigator will be responsible for obtaining 
written informed consent from the parent(s) or legal guardian(s) and, in cases where institutional 
guidelines or the subject’s age dictate, informed assent from the subject.  Consent/assent must be 
signed before any study procedures, including screening procedures, are performed.  If all 
eligibility criteria are met and the subject is enrolled into the study, subjects will maintain the 
sameextension study subject identification numbers that were assigned in the number will be 
maintained from, or linked to, the index study throughout this extension studysubject 
identification number.  This will be outlined in the ISIS 396443-CS11 data management 
documentation. 
 
Rationale: 
The procedure for maintenance of subject identification numbers from the index study upon 
enrollment into the extension study was clarified. 
 


Protocol ISIS 396443-CS11, Version 3.0 
 
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5 
Section 4.4, Unblinding of Treatment Assignment 
Change: 
Text describing procedures for unblinding of index studies ISIS 396443-CS3B and 
ISIS 396443-CS4 was added. 
 
Now reads: 
During the blinded loading dose period of this study, subjects will receivereceived either blinded 
injections of nusinersen (Groups 1A and 2A) or a combination of nusinersen and sham 
procedures (Groups 1B and 2B) in order to allow subjects who previously participated in a sham 
procedure group of the index studies to obtain a loading regimen of nusinersen while maintaining 
the blind of the treatment assignment in the index study.  Following that, during the open-label 
maintenance period of the study, all study subjects will receivereceived nusinersen in an 
unblinded manner using a maintenance dosing regimen of once every 4 months. 
Since the key study site personnel will be blinded to the subjects’ treatment assignments during 
the loading dose period of the study, in case of a medical emergency where knowing the 
subject’s treatment assignment may influence the subject’s clinical care, the Investigator has the 
ability to unblind the treatment assignment (as defined in Section 9.5.5) using the 
Interactive Voice/Web Response System (also known as the IxRS system).  The Sponsor or 
designee will be informed of the unblinding of a subject within 24 hours.  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 the personnel involved with the analysis and 
conduct of the study.Index studies ISIS 396443-CS3B and ISIS 396443-CS4 have been 
unblinded, and treatment assignments for subjects in the applicable groups (Groups 1A, 
2A, 1B, and 2B) were released.  Therefore, there was no longer any reason to continue the 
blinded loading dose period in a blinded fashion.  Procedures for subjects still attending 
visits within the blinding loading dose period at the time of unblinding were revised as 
follows: 
• For subjects in Group 1A and Group 2A who were receiving active drug (i.e., 
nusinersen) within the blinding loading dose period, visits occurred as 
scheduled, with all predose and postdose assessments performed. 
• For subjects in Groups 1B and 2B who were still attending visits and receiving 
treatment (i.e., nusinersen and sham procedures) within the blinded loading dose 
period, all visits and predose assessments were continued per the protocol; 
however, the sham procedure and all postdose procedures were not performed 
for those applicable visits.  The required assessments for sham visits performed 
after the time of unblinding are described in Section 8.2. 
In additionDuring the blinded loading dose period, all suspected unexpected serious adverse 
reactions (SUSARs) will bewere unblinded by the Sponsor’s Drug Safety and Quality Assurance 
personnel for the purpose of regulatory reporting (Section 9.2).  As index studies 


Protocol ISIS 396443-CS11, Version 3.0 
 
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6 
ISIS 396443-CS3B and ISIS 396443-CS4 have been unblinded, SUSARs will be submitted 
to regulatory agencies and Investigators in an unblinded fashion (Section 9.2). 
 
Rationale: 
A clarification letter was previously distributed to Investigators describing unblinding of index 
studies ISIS 396443-CS3B and ISIS 396443-CS4.  As a result of the unblinding, there was no 
longer any reason to continue procedures in a blinded fashion for subjects who were in the 
blinded loading dose period at the time of unblinding.  Study assessments, including those for 
sham visits, and safety reporting procedures were revised accordingly.  
This change also affects Section 8.1, Study Drug Administration; Section 8.2, Sham Procedure; 
and Section 9.2, Regulatory Requirements. 
 
Section 5.2, Exclusion Criteria 
Change: 
New text defining the applicable standard of care guidelines in spinal muscular atrophy (SMA) 
was added to exclusion criterion #4. 
 
Now reads: 
4. The subject’s parent or legal guardian is not willing or able to meet standard of care 
guidelines (including vaccinations and respiratory syncytial virus prophylaxis, if 
available) guidelines in the consensus statement for standard of care in SMA [Wang 
2007] or provide nutritional and respiratory support throughout the study.  NOTE:  
Routine vaccinations and respiratory syncytial virus (RSV) prophylaxis are 
recommended per consensus guidelines on standard of care [Wang 2007] but are not 
required for study enrollment.  Subjects who are not current on vaccinations or who 
are not receiving RSV prophylaxis, but otherwise meet study inclusion criteria, will 
be considered eligible for study enrollment. 
 
Rationale: 
A clarification letter was previously distributed to Investigators clarifying the applicable SMA 
standard of care guidelines being referred to in this exclusion criterion, as well as guidance for 
enrollment of subjects not current on routine vaccinations or respiratory syncytial virus 
prophylaxis.  These clarifications were incorporated into exclusion criterion #4. 
 




Protocol ISIS 396443-CS11, Version 3.0 
 
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8 
subsequently decreases to <16 hours/day during the 30-day period.  Investigators may 
instruct caregivers to continue recording in the ventilator use diary for an additional 30 or 
more days based on clinical judgment.  The ventilator use diary should be dispensed during 
onsite study visits as needed. 
Once the caregiver is instructed by the Investigator to stop recording ventilator use, the 
caregiver may discontinue collecting the subject’s daily ventilator use.  If the subject’s 
ventilator use increases to ≥16 hours/day again at another time, the subject’s daily 
ventilator support use should be recorded as described above. 
 
Rationale: 
The requirements for ventilator use diary recording and dispensation, including when diary use is 
initiated and the duration of recording, were clarified within the protocol based on current 
guidelines stated within the ventilator diary instructions. 
This change also affects Appendix A, Schedule of Procedures. 
 
Section 6.3.2, Dysphagia Assessment 
Change: 
New text was added describing dysphagia assessment in subjects. 
 
Now Reads: 
6.3.2 Dysphagia Assessment 
Caregivers will be asked a series of questions regarding mealtime behavior of the subject. 
 
Rationale: 
Beginning with this protocol amendment, changes in mealtime behavior during the 7 days prior 
to each study visit will be assessed in study subjects in order to detect potential dysphagia that 
may occur during study treatment. 
This change also affects Appendix A, Schedule of Procedures. 
 
Section 6.3.5, Growth Parameters 
Change: 
New text specifying the timing of growth parameter measurement, alternative procedures for 
subjects with scoliosis, and the analysis plan for growth parameter data was added.  
 


Protocol ISIS 396443-CS11, Version 3.0 
 
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9 
Now reads: 
Growth parameters of body length and/or height (for all subjects), head circumference (for 
subjects up to 36 months of age), chest circumference (for subjects up to 36 months of age), and 
arm circumference (for subjects up to 36 months of age) will be measured predose (within 
7 days) by the Investigator (or designee) at every onsite visit throughout the study.  
In subjects with scoliosis, the Investigator (or designee) may measure arm span in lieu of 
body length and/or height.  Arm span is defined as the distance from the fingertip in one 
hand to that in the opposite hand and should be measured with the arms outstretched 
laterally away from the body. 
Additional parameters of weight-for-age, weight-for-length, and head-to-chest circumference 
ratio will be calculated by the Sponsor during the analysis as described in the Statistical 
Analysis Plan (see Section 10.1.2). 
 
Rationale: 
Scoliosis or lower limb contractures can interfere with body length and/or height measurement.  
Arm span is an alternative measurement for height; therefore, it is considered an appropriate 
alternative in subjects with scoliosis or other conditions that prevent body length or height 
measurement.  The timing for growth parameter data collection and the summary of the planned 
analysis was also clarified. 
 
Section 6.5.2.3, Revised Upper Limb Module 
Change: 
New text describing performance of the Revised Upper Limb Module (RULM) in subjects was 
added, and the age range that the RULM has been evaluated in was revised. 
 
Now reads: 
All nonambulatory subjects ≥30 months of age will be evaluated using the Revised Upper Limb 
Module (RULM) [Mazzone 2016].  The RULM will continue to be performed should 
subjects subsequently become ambulatory. 
The RULM is an outcome measure developed to assess upper limb functional abilities in patients 
with SMA, including young children, and patients with severe contractures in the lower limbs in 
whom the possibility to detect functional changes, such as rolling or long sitting, is limited.  This 
test consists of upper limb performance items that are reflective of activities of daily living 
(i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a 
container).  The RULM is quickly administered and has been evaluated in patients with SMA 30 
months 2 to 27 52 years of age [Mazzone 2016]. 
 


Protocol ISIS 396443-CS11, Version 3.0 
 
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10 
Rationale: 
The procedure for performing the RULM in subjects who subsequently become ambulatory was 
clarified.  In addition, the age range that the RULM has been evaluated in was updated to reflect 
currently available information. 
 
Section 6.5.2.5, Contracture Assessment 
Change: 
New text for contracture assessment was added. 
 
Now reads: 
6.5.2.5. 
Contracture Assessment 
Motor performance in SMA is defined as a demonstrated ability to perform a skill under 
certain test conditions.  This performance changes with disease progression and/or 
intervention (including surgery) and is based on the observed response on the day of the 
assessment.  Motor performance will be affected by muscle strength, contractures, and 
maturational development (puberty).  All subjects will be evaluated for contractures. 
 
Rationale: 
Motor performance during motor function assessments can be affected by a variety of factors, 
including contractures, among others; a summary of these potential relevant factors was added 
for clarity.  Assessment for contractures was added to monitor for its occurrence. 
 
Section 6.6.3.1, Pediatric Quality of Life Inventory (Generic Core Scales and Neuromuscular 
Module) 
Change: 
The upper age limit for the Pediatric Quality of Life Inventory (PedsQL) was revised. 
 
Now reads: 
Subjects 2 to 1825 years of age will be evaluated using the Pediatric Quality of Life Inventory 
(PedsQL™) Measurement 4.0 Generic Core Scales and 3.0 Neuromuscular [Varni 1999].  This 
assessment has been validated by the American Spinal Muscular Atrophy Randomized Trials 
group [Iannaccone 2009]. 
The PedsQL Measurement Model is a modular approach to measuring health-related quality of 
life (HRQOL) in children and adolescents.  The PedsQL consists of brief, practical, generic core 
scales, as well as condition-specific modules for use in designated clinical populations.  Pediatric 
self-report is measured in children, and adolescents, and young adults 5 to 1825 years of age, 


Protocol ISIS 396443-CS11, Version 3.0 
 
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11 
and parent proxy-report of child HRQOL is measured for children and, adolescents, and young 
adults 2 to 1825 years of age.  The PedsQL 4.0 Generic Core Scales include assessment of 
physical functioning, emotional functioning, social functioning, and school functioning.  The 
PedsQL 3.0 Neuromuscular Module was designed to measure HRQOL dimensions specific to 
children, adolescents, and young adults 2 to 1825 years of age with neuromuscular disorders, 
including SMA. 
 
Rationale: 
The upper age limit for collection of the PedsQL was broadened to allow collection of quality of 
life data in subjects who turn age 19 years or older during the study duration.  Quality of life 
measures will continue to be surveyed in young adult subjects and their caregivers. 
 
Section 6.6.3.3, Clinical Global Impression – Improvement 
Change: 
Text defining baseline for the Clinical Global Impression – Improvement (CGI-I) scale 
assessment during study visits was added. 
 
Now reads: 
The Clinical Global Impression – Improvement (CGI-I) scale is a 7-point scale that requires the 
clinician to assess how much the patient’s illness has improved or worsened relative to a baseline 
state at the beginning of the intervention and is rated as follows:  1, very much improved; 
2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 
7, very much worse.  For assessment of CGI-I, the baseline state is defined as follows: 
• Groups 1, 3, and 4:  Baseline is defined as the CGI-I score at Screening for the 
present extension study. 
• Group 2:  Baseline is defined as the CGI-I score at Screening in the index 
study ISIS396443-CS4. 
• Group 5:  Baseline is defined as the CGI-I score at Screening in the index 
study 232SM202. 
 
Rationale: 
The baseline for CGI-I assessment during study visits varies according to study group within the 
present extension study and was therefore clarified. 
 
















Protocol ISIS 396443-CS11, Version 3.0 
 
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19 
period at the time of unblinding.  The sham procedure was no longer performed in affected 
subjects, and sham visits were considered safety visits.  Study procedures for the sham visit were 
revised accordingly.  
 
Section 8.10, Withdrawal of Subjects From the Study 
Change: 
New text listing initiation of commercial treatment was added as a withdrawal criterion. 
 
Now reads: 
Other reasons for withdrawal of subjects from the study might include the following: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Initiation of commercial nusinersen treatment 
• Significant protocol deviation 
• Administrative decision by the Investigator or Sponsor 
 
Rationale: 
Initiation of commercial nusinersen treatment is currently included within the case report form as 
a potential reason for study withdrawal and was added to the protocol accordingly. 
 
Section 8.11.1, Concomitant Therapy 
Change: 
Oral albuterol/salbutamol and carnitine were removed as disallowed concomitant therapies. 
 
Now reads: 
Disallowed Concomitant Therapy 
Study subjects are prohibited from receiving other experimental agents during the study.  This 
includes marketed agents being used off-label and/or at experimental doses that are being tested 
for the treatment of SMA (e.g., oral albuterol/salbutamol, riluzole, carnitine, creatine, sodium 
phenylbutyrate, valproate, or hydroxyurea). 
 


Protocol ISIS 396443-CS11, Version 3.0 
 
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20 
Rationale: 
Based on investigator feedback, oral albuterol/salbutamol and carnitine are now permitted as 
concomitant therapy during the study. 
 
Section 9.2, Regulatory Requirements 
Change: 
The procedure for reporting of serious adverse reactions (suspected unexpected serious adverse 
reactions [SUSARs]) was revised based on the unblinding of index studies ISIS 396443-CS3B 
and ISIS 396443-CS4. 
 
Now reads: 
During the blinded loading dose period, Appropriate personnel at Biogen will unblind 
SUSARs were unblinded by appropriate Sponsor personnel for the purpose of regulatory 
reporting.  Biogen willThe Sponsor submitted SUSARs (in blinded or unblinded fashion) to 
regulatory agencies according to local law and.  Biogen will submitted SUSARs to Investigators 
in a blinded fashion. 
As index studies ISIS 396443-CS3B and ISIS 396443-CS4 have been unblinded, this 
unblinding is no longer needed.  SUSARs will be submitted to regulatory agencies and 
Investigators in an unblinded fashion. 
IRBs/IECs will be notified of any SAE according to applicable regulations.  The DSMB will be 
notified of any SAE as specified in the DSMB charter. 
 
Rationale: 
Index studies ISIS 396443-CS3B and ISIS 396443-CS4 were unblinded, and treatment 
assignments were released as of 24 April 2017.  As a result, there was no longer any reason to 
continue procedures in a blinded fashion for subjects who were in the blinded loading period at 
the time of unblinding.  Study procedures for SUSAR reporting were revised accordingly.  
Additionally, a DSMB will no longer be used in this study; therefore, text describing its 
formation and function is no longer applicable and was removed. 
 
 
 
 
 




Protocol ISIS 396443-CS11, Version 3.0 
 
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22 
SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
• The version number and date were updated throughout the protocol. 
• The Study Glossary was updated. 
• Typographical and formatting errors were corrected. 
• The term “date of the last visit” was revised to “date of the last dosing visit” 
throughout the protocol. 
• The term “blinded loading period” was revised to “blinded loading dose period” 
throughout the protocol. 
• When discussing the blinded loading dose period, the verb tense was changed from 
the present to past tense throughout the protocol, as this study stage has completed. 
• An abbreviations list was added to the footnotes for each table and figure throughout 
the protocol to align with Biogen style guidelines.  
• Throughout the protocol, the term “clinical chemistry” was revised to “blood 
chemistry” to align with Biogen style guidelines. 
• On the title and sponsor pages, the sponsor address was corrected due to a change in 
the corporate address. 
• In Section 2.3.3, “preclinical” was replaced with “nonclinical” to align with Biogen 
style guidelines.  
• In Section 2.3.4, Clinical Experience, the summary of nusinersen clinical studies was 
revised to reflect changes in study status.  The clinical study summary was 
reorganized to group completed studies together in order to improve readability. 
• In Section 2.4, Rationale for Dose and Schedule of Administration, study names for 
index studies ISIS 396443-CS3B (ENDEAR) and ISIS 396443-CS4 (CHERISH) 
were added. 
• In Section 3.4, Overall Study Duration and Follow-Up, Figures 2, 3, and 4, the 
“Baseline Day 1” box was removed for clarification.  Upon completion of screening, 
subjects immediately proceed into the blinded loading dose period or MMDR period, 
as appropriate, with no additional Day 1 visit.  
• Throughout Section 6 and the entire protocol where applicable, the visit windows 
were clarified for specific study procedures as follows:  
 
; Section 6.3.1, Ventilator Use Diary 
Recording; Section 6.3.3, Urine Pregnancy Tests; Section 6.3.4, Weight; 
Section 6.3.5, Growth Parameters; Section 6.3.6, Physical Examinations; 
Section 6.3.7, Vital Signs; Section 6.3.8, Neurological Examinations; Section 6.4.1, 
Clinical Safety Laboratory Evaluations; Section 6.4.2, Coagulation Parameters; 
; Section 6.6.1, 
Electrocardiograms; Section 6.6.2, X-Ray of Spine; Section 6.6.3, Quality of Life 




CONFIDENTIAL
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Biogen MA Inc.
1
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
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol ISIS 396443-CS11
An Open-Label Extension Study for Patients With Spinal Muscular Atrophy Who Previously 
Participated in Investigational Studies of ISIS 396443
Version 2.0
Date:  31 January 2017
EUDRA CT Number:  2015-001870-16
Version 2.0 of the protocol has been prepared for this amendment, which supersedes 
Versions 1.0 and 1.3.


Protocol ISIS 396443-CS11, Version 2.0
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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol ISIS 396443-CS11 is to transition the dosing 
regimen for the open-label maintenance dosing period for all index studies (ISIS 396443-CS3B 
[Groups 1A and 1B], ISIS 396443-CS4 [Groups 2A and 2B], ISIS 396443-CS12 [Group 3], and 
ISIS 396443-CS3A [Group 4]) to the Modified Maintenance Dosing Regimen (MMDR) 
schedule, during which maintenance doses of nusinersen are administered every 4 months.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 3.4.2, Treatment
Now reads:
Subjects who are meet the eligibility criteria will be admitted to the study center on study Day 1 
to begin their Treatment Period.  For subjects entering the study after completing the double-
blind studies ISIS 396443-CS3B and ISIS 396443-CS4 (i.e., subjects those in Groups 1A, 1B, 
2A, and 2B) will complete a below), the Treatment Period in the current study will consist of the 
blinded loading dose period phase and then be transitioned to the an open-label MMDR 
period.  Subjects already enrolled in Study ISIS 396443-CS11 (SHINE) maintenance phase 
(Figure 2 and already participating in the blinded loading dose period will continue their 
blinded loading dose/sham schedule through the last scheduled dose in that loading period 
and then be transitioned to the Figure 3).  For subjects entering the study after completing the
open-label MMDR dosing schedule at their next study visit, which should be scheduled as 
close as possible to 120 days from the date of the last visit study ISIS 396443 CS12 (i.e., date
those in Group 3 below), the Treatment Period in the current study will consist of last visit + 120 
days = MMDR Day 1).an open label maintenance phase only.  
During the blinded loading period phase of the study, subjects who previously received the 
participated in a sham procedure during group of the index study will receive blinded injections 
of nusinersenISIS 396443 in order to achieve the full loading regimen of study treatment drug, 
and subjects who previously received nusinersen ISIS 396443 during the index study will 
receive a combination of nusinersen ISIS 396443 injections and sham procedures.  This design 
is necessary to protect the full blind of the treatment assignment in the ongoing index studies.  
Following the loading phase, during the maintenance period of the study, all study subjects will 
receive drug in an unblinded manner using a maintenance dose regimen received by the 
treatment arm during the corresponding index study, as detailed below.
Subjects entering the study after completing open-label studies ISIS 396443-CS12 and 
ISIS 396443-CS3A (i.e., subjects in Groups 3 and 4) will enter directly into the open-label 
MMDR period at MMDR Day 1.  Subjects already enrolled in ISIS 396443-CS11 and 
already receiving maintenance doses according to the original maintenance schedule will 
transition to MMDR Day 1 at their next study visit (regardless of how many maintenance 


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doses already received in original schedule), which should be scheduled as close as possible
to 120 days from the date of the last visit (i.e., date of last visit + 120 days = MMDR Day 1).
The MMDR dosing schedule will consist of MMDR Days 1, 120, 240, 360, 480, 600, 720, 
840, and so on every 4 months (±7 days) until the EOS Evaluation/Early Termination (ET) 
Visit.  The EOS Evaluation Visit will occur 4 months after the last open-label maintenance 
dose of nusinersen on approximately MMDR Day 1800 (±7 days).
Rationale:  The frequency of nusinersen dosing for Groups 2A and 2B consists of 3 and 
2 blinded loading doses of 12 mg nusinersen, respectively, on Days 1, 29, and 85 (Group 2A) or 
Days 1 and 85 (Group 2B) followed by maintenance doses of 12 mg every 4 months in the 
MMDR.  The frequency of nusinersen dosing for Group 3 will transition from every 6 months to 
every 4 months in the MMDR. The recommended dosing regimen is strongly supported by the
following considerations:

The robust efficacy and safety data from Study ISIS 396443-CS3B, in which subjects 
received maintenance doses every 4 months.

Although central nervous system (CNS) tissue half-life cannot be measured in 
humans, the median terminal elimination half-life was measured in the CNS tissue of 
adult monkeys and found to be 116 days, approximately 4 months.  Because the site 
of action of nusinersen is within the CNS, these findings support the revised regimen 
with maintenance doses administered every 4 months.

Population pharmacokinetics (PK) analyses suggest that higher cerebrospinal fluid 
(CSF) exposure leads to improvements in motor milestones; in compound muscle 
action potential (CMAP), a measure of motor neuron health; and Children’s Hospital 
of Philadelphia Infant Test for Neuromuscular Disease (CHOP INTEND), a measure 
of motor strength in symptomatic infants with infantile-onset SMA treated with 
nusinersen.  While the clinical endpoints differ between populations, the relationship 
between increased CSF trough concentration or overall exposure and improved 
functional outcomes is also anticipated in older subjects. 

No additional safety concerns are anticipated with administration of the proposed 
dosing regimen in the later-onset population in light of the fact that the majority of 
adverse events (AEs) in the clinical studies have been considered to be related to the 
natural history of the disease or intrathecal administration procedure rather than to 
nusinersen, and the maximum observed concentration and partial area under the 
concentration-time curve values of nusinersen in CSF are predicted to be lower in 
older children than in infants receiving the same regimen.
In light of these data and the severity of the disease, irrespective of phenotype, the ongoing 
extension study in patients with infantile-onset and later-onset SMA (Study ISIS 396443-CS11) 
will be amended so that all subjects, including those with later-onset SMA, will receive the same 
maintenance dosing regimen.
This change also affects Section 2.4, Rationale for Dose and Schedule of Administration;
Section 3.4, Overall Study Duration and Follow-Up; Section 3.5, End of Study; Section 6, Study 


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Procedures; Section 8.1, Study Drug Administration; Section 10.6.2, Safety and Tolerability 
Analysis; and Appendix A, Schedule of Procedures and resulted in the creation of Section 3.1.1, 
Important Study Design Update.




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Rationale:  Biogen assumed sponsorship of Study ISIS 396443-CS11 in September 2016.  In 
addition to listing Biogen as the Sponsor, this amendment adds safety and administrative 
language, making this protocol consistent with Biogen’s protocol template.  
This change also affects Pages 1 and 2 and the following sections:  Section 9.1, Sponsor Review 
of Safety Information; Section 9.2, Regulatory Requirements; Section 9.4.1, Serious Adverse 
Events; Section 9.5.3, Dosing Errors; Section 9.5.4, Contraception and Pregnancy; Section 9.5.5, 
Medical Emergency; Section 11.1, Informed Consent/Assent; Section 11.2, Ethical Conduct of 
the Study; Section 11.3, Institutional Review Board/Institutional Ethics Committee/Research 
Ethics Board; Section 11.4.1, Subject Data Protection; Section 12.7, Conflict of Interest; Section 
12.8, Registration of Study and Disclosure of Study Results; Section 12.9, Study Funding; 
Section 12.10, Publications; and Section 15, Signed Agreement of the Study Protocol.
Protocol Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 1, Objectives
Change:  Text was added to the objectives section to provide further details regarding the 
open-label extension study and to clarify the use of “nusinersen,” “study drug,” and “study 
treatment” in the protocol.
Now reads:
The objectives of this open-label extension study isare to gather additional information on the 
long-term safety, tolerability, and efficacy of repeated 12-mg doses of ISIS 396443 (also known 
as BIIB058 and nusinersen12 mg) administered as intrathecal (IT) injections by lumbar 
puncture (LP) in subjects with spinal muscular atrophy (SMA) who previously participated in 
investigational studies of 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.
Rationale:  This language was added to provide clarity regarding the use of “nusinersen,” “study 
drug,” and “study treatment” in the protocol.
Section 2.4, Rationale for Dose and Schedule of Administration
Change:  Text in this section was updated to reflect the change in maintenance dose from every 
6 months to every 4 months and to provide justification for the change in frequency.


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Now reads:  
The proposed study will test the clinical efficacy, safety, tolerability, and PK of multiple doses of 
nusinersen ISIS 396443 administered as by IT injections to subjects with SMA who previously 
participated in investigational studies of ISIS 396443.  A single dose level of 12 mg equivalent 
of nusinersen ISIS 396443 will continue to be evaluated in this long-term extension study.
The nusinersen ISIS 396443 dose level and dose interval were selected based on prenonclinical 
toxicology and PK pharmacokinetic observations from monkey studies in monkey utilizing 
single- and repeat -dosing IT administration, consideration of the target tissue concentration 
anticipated for drug pharmacology, severity of SMA phenotype, and safety data in the completed 
and ongoing clinical studies of ISIS 396443 to date. Based on the upon pharmacology and PK
pharmacokinetic results in SMA transgenic mice, it was we estimated that the target tissue 
concentration to produce 50% to 90% SMN2 Exon exon 7 inclusion is between 21 and 10 μg/g
spinal cord tissue. Nonclinical studies in juvenile monkeys receiving IT doses of nusinersen
ISIS 396443 showed a resulting gradient of distribution of nusinersen 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 level 
selected for this multiple-dose clinical study (12 mg nusinersenISIS 396443) is predicted to 
achieve levels at the high end of this range (approximately 10 μg/g lumbar and 3 µgug/g cervical 
spinal cord tissue concentrations), following the first dose.
The loading dose interval was selected as the dose interval based on the nonclinical
PKpharmacokinetic and pharmacology data as the dose interval to achieve and maintain 
nusinersen ISIS 396443 spinal cord tissue levels that are predicted to be within the upper end of 
the pharmacologically active range by Day 64 in subjects patients with the more severe 
infantile-onset SMA phenotype (predicted to be approximately 30 µg/g lumbar and 10 µg/g 
cervical spinal cord tissue concentrations) and by Day 85 in subjects patients with the less 
severe later-onset SMA phenotype (predicted to be approximately 24 μg/g lumbar and 8 μg/g 
cervical spinal cord tissue concentrations), while at the same time considering subject safety and 
convenience for repeated LP ITintrathecal injections.  Similarly, the maintenance dose interval, 
once every 4 months for patients with the more severe infantile onset SMA phenotype and once 
every 6 months for patients with the less severe later onset SMA phenotype, was selected based 
on the estimated spinal tissue and CSF drug half life (4 6 months) with the goal of maintaining 
the spinal cord tissue levels of ISIS 396443 at a steady state level within the estimated 
pharmacologically active range.
The maintenance dose intervals were selected based on nonclinical PK and pharmacology 
data and clinical PK data from subjects in ongoing and completed clinical studies with the 
goal of maintaining the spinal cord tissue levels of nusinersen at a steady-state level within 
the estimated pharmacologically active range. The elimination half-life of nusinersen from
human CSF is approximately 135 to 177 days and was estimated based on a limited 
number of postdose levels. Although CNS tissue half-life cannot be measured in humans, 
the median terminal elimination half-life was measured in the CNS tissue of adult monkeys 
and found to be 116 days, approximately 4 months. Because the site of action of nusinersen 
is within the CNS tissues, these findings support maintenance doses administered every 
4 months.


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The maintenance dosing regimen of 12 mg every 4 months was implemented in a 
sham-controlled study in infantile-onset SMA (Study ISIS 396443-CS3B), an open-label 
study in presymptomatic SMA (Study 232SM201 [NURTURE]), an open-label study in 
infantile-onset SMA (Study ISIS 39644-CS3A), and a sham-controlled study in both 
infantile-onset and later-onset SMA (Study 232SM202 [EMBRACE]). For subjects in a 
sham-controlled study in later-onset SMA (Study ISIS 396443-CS4) and an open-label 
study in later-onset SMA (Study ISIS 396443-CS12) who are eligible to enroll in this 
open-label extension study (Study ISIS 396443-CS11), the maintenance dose schedule is
shortened from every 6 months to every 4 months. The change is further supported by 
available data on the exposure-response relationship as well as efficacy and safety data 
from the clinical studies. Data from the population PK analyses suggest that higher CSF 
exposure leads to improvements in compound muscle action potential (CMAP), a measure 
of motor neuron health; Children’s Hospital of Philadelphia Infant Test for 
Neuromuscular Disease (CHOP INTEND), a measure of motor strength; and motor 
milestones in symptomatic infants with infantile-onset SMA treated with nusinersen. 
While the clinical endpoints differ between populations, the relationship between increased 
CSF trough concentration or overall exposure and improved functional outcomes is also 
anticipated in older subjects receiving more frequent maintenance doses. Because the 
majority of adverse events (AEs) in the clinical studies have been more likely related to the 
natural history of the disease rather than to nusinersen, any additional safety concerns 
associated with the Modified Maintenance Dosing Regimen (MMDR) are expected to be 
mostly limited to procedure-related AEs, such as post lumbar puncture syndrome and back 
pain.
Additional details on dose scalingdosing and expected CSF and tissue concentrations are 
summarized in the Investigator’s Brochure.
Rationale: This update was necessary to clarify the change in dosing frequency and to provide 
relevant data to support the change.
Section 3.1, Study Design
Change:  Protocol ISIS 396443-CS11 now allows inclusion of subjects who completed an 
additional index study, ISIS 396443-CS3A.  
Now reads:  
This is an open-label extension study (OLE) for patients in subjects with Spinal Muscular 
AtrophySMA who previously participated in investigational studies of ISIS 396443.  For the 
purposes of the current this protocol, investigational studies of ISIS 396443, henceforth referred 
to as “index” studies, include sStudies ISIS 396443-CS3A, ISIS 396443-CS3B, ISIS 396443-
CS4, and ISIS 396443-CS12.  Subjects from other studies of ISIS 396443 may be included into 
the current long-term extension study with future amendments of the protocol.


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Rationale:  The addition of the index Study ISIS 396443-CS3A will provide subjects from this 
study with the opportunity to continue to receive open-label nusinersen through the current 
study, Study ISIS 396443-CS11, which assesses the clinical efficacy, safety, tolerability, and PK 
of multiple doses of nusinersen.  
This change also affects Study Design and Treatment Schema and the following sections:  
Section 2.3.4, Clinical Experience; Section 2.4, Rationale for Dose and Schedule of 
Administration; Section 3, Experimental Plan; Section 6.5.1, Motor Milestones; Section 10.2, 
Sample Size Considerations; Section 10.3, Populations; Section 10.6.3, Efficacy Analysis; and 
Appendix A, Schedule of Procedures.
Section 3.4, Overall Study Duration and Follow-Up
Change:  The language describing the duration of study was updated.
Now reads:  
Theis Sstudy will consist of sScreening, tTreatment, and pPost-tTreatment fFollow-uUp 
pPeriods, and an End-of-Study (EOS) Evaluation Visit.  The total duration of participation in 
the study is approximately31 (Groups 1A, 1B and 3) to 34 (Groups 2A and 2B) months5 years
from MMDR Day 1 (EOS Evaluation Visit to occur at approximately MMDR Day 1800) or 
as determined by the Sponsor (via early termination or amendment to extend).  A study 
schematic for Groups 1A and 1B, Groups 2A and 2B, and Groups 3 and 4 are provided in 
Figure 2, Figure 3, and Figure 4, respectively.  Please refer to the Schedule of Procedures in 
Appendix A.
Rationale:  The duration of study was updated to reflect changes to the overall study period that 
resulted from the implementation of MMDR schedule and to provide clarification regarding 
decisions made by the Sponsor.
This change also affects the Study Design and Treatment Schema for Groups 1A and 1B, Groups
2A and 2B, and Groups 3 and 4 (Figures 2, 3, and 4, respectively).
Section 5.1, Inclusion Criteria
Change:  Criterion #2 was updated to allow subjects to enroll in the study up to 16 weeks after 
completion of the index study.
Now reads:  


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2. Completion of the index study in accordance with the study protocol or as a result of 
Sponsor decision (e.g., early termination of the index study) within the preceding 
1612 weeks.
Rationale:  The window of time between the completion of the index study and enrollment in 
Study ISIS 396443-CS11 was extended up to 16 weeks to accommodate subjects who are rolling 
over from studies that will have been completed by the time this amendment is in place.
Section 6.3.4, Growth Parameters
Change:  A section describing growth parameter assessments for subjects in Group 4 was added 
to clarify the timing and extent of the assessments.
Now reads:  
6.3.4
Growth Parameters
Growth parameters of body length and/or height (for all subjects), head circumference (for 
subjects up to 36 months of age), chest circumference (for subjects up to 36 months of age), 
and arm circumference (for subjects up to 36 months of age) will be measured at every 
onsite visit throughout the study. 
Additional parameters of weight-for-age, weight-for-length, and head-to-chest 
circumference ratio will be calculated.
Rationale:  These assessments were added because they are standard assessments for young 
children and are collected in other studies of nusinersen.
This change also affects Appendix A, Schedule of Procedures.
Section 6.3.7, Neurological Examinations
Change:  Text specifying the Hammersmith Infant Neurological Examination (HINE)
assessments to be performed for subjects ≤24 months was added.
Now reads:
Sections 1 and 3 of the Hammersmith Infant Neurological Examination (HINE) will be 
conducted inon all subjects ≤24 months of age.
Rationale: This language was clarified to specify that all subjects <24 months of age will be 
assessed using Sections 1 and 3 of the HINE.


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Section 6.4.2, Coagulation Parameters
Change:  Coagulation parameters were added to the list of assessments that are performed at 
MMDR Day 1, every 4 months thereafter, and at the EOS Evaluation/ET Visit.
Now reads:  
6.4.2
Coagulation Parameters
Coagulation parameters (activated partial thromboplastin time [aPTT], partial 
thromboplastin time [PTT], and international normalized ratio [INR]) will be collected at 
MMDR Day 1, every 4 months thereafter (i.e., MMDR Days 1, 120, 240, 360, 480, 600, 720, 
840, and so on), and at the EOS Evaluation/ET Visit.  
The coagulation testing must be performed and reviewed prior to dosing. 
Rationale:  These assessments were added to thoroughly evaluate coagulation parameters in 
study subjects receiving nusinersen.
This change also affects Appendix A, Schedule of Procedures, and Appendix B, Laboratory 
Analytes.
Section 6.5.1, Motor Milestones
Change:  Text was added specifying the HINE assessments to be performed for subjects 
<2 years who have not achieved independent walking.
Now reads:
6.5.1 6.2.6 Motor Milestones
Subjects will be evaluated for motor milestones at the times shown in the Schedule of Procedures
(Appendix A).  In Groups 2 and 3, motor milestones will be assessed with the WHO Motor 
Milestone Criteria.  In Groups 1 and 4, motor milestones will be assessed using Section 2 of the 
Hammersmith Infant Neurological Exam (HINE) for all subjects.  In those subjects of Groups 1 
and 4 who achieve the motor milestone of independent sitting, WHO Motor Milestone criteria 
will be assessed, too (Wijnhoven et al. 2004; WHO Multicentre Growth Reference Study 
Group 2006).
For all subjects, motor milestones will be assessed using the World Health Organization 
(WHO) Motor Milestones criteria [WHO Multicentre Growth Reference Study Group 
2006; Wijnhoven 2004] at Screening and/or MMDR Day 1, every 8 months thereafter (i.e., 
MMDR Days 240, 480, 720, and so on), and at the EOS Evaluation/ET Visit.
For subjects <2 years of age who have not yet achieved independent walking, motor 
milestones will also be assessed using Section 2 of the HINE.


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Rationale:  This language was clarified to state that all subjects <2 years of age who have not 
achieved independent walking will be assessed using Section 2 of the HINE.
Section 6.5.2.1, Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease
Change:  Text clarifying the criterion for performing CHOP INTEND assessment was added.
Now reads: 
6.5.2.1 6.2.4 Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease
CHOP INTEND will be assessed in subjects with infantile-onset SMA until they have a 
maximum score of 64.  Once a score of 64 is achieved, CHOP INTEND will no longer be 
assessed.
The Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease (CHOP 
INTEND) test was specifically designed to evaluate the motor skills of infants with significant 
motor weakness, including infants with SMA [Glanzman 2010].  The CHOP INTEND test 
captures neck, trunk, and proximal and distal limb strength in 14 elicited and 2 observational 
items.  The CHOP INTEND has been established as a safe and reliable infant motor measure in 
infantile-onset SMA, but its validity has not been established and has been validated 
[Glanzmann 2011].  CHOP INTEND will be assessed in subjects in Groups 1A, 1B, and 4 at the 
times shown in the Schedule of Procedures (Appendix A).
Rationale:  The criterion for performing CHOP INTEND until a maximum score of 64 is 
achieved was validated, and the criterion in effect for this protocol was revised accordingly.  
This change also affects Section 6.5.2.2, Hammersmith Functional Motor Scale - Expanded.
Section 6.5.2.2, Hammersmith Functional Motor Scale - Expanded
Change:  Text clarifying the criteria for performing Hammersmith Functional Motor Scale –
Expanded (HFMSE) and CHOP INTEND assessment was added.
Now reads:
6.5.2.2 6.2.5 Hammersmith Functional Motor Scale - Expanded
All subjects in Groups 2A, 2B and 3, and any subject in Group 1A, 1B, or 4 who has maintained 
a CHOP INTEND total score of ≥ 50 for 2 consecutive study visits (including post baseline visits 
of the index study), will be evaluated using the Hammersmith Functional Motor Scale 
Expanded (HFMSE) at the times shown in the Schedule of Procedures (Appendix A).  All 
subjects ≥2 years of age will be evaluated using the HFMSE for the duration of the study.  
Subjects who are ≥2 years of age but have not yet achieved the maximum score of 64 with 
CHOP INTEND will be assessed with both until a CHOP INTEND maximum score of 64 is 


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achieved.  The HFMSE should be performed after the CHOP INTEND with an 
approximately 15-minute rest period in between to allow the subject to be fully engaged 
with both assessments.
Note:  Any subjects currently being assessed with both the CHOP INTEND and HFMSE 
under a previous version of this protocol will continue to have both assessments performed 
under the current Version 2.0 of this protocol (even if they are <2 years of age) until they 
achieve a CHOP INTEND maximum score of 64.
Rationale:  The criterion for performing CHOP INTEND until a maximum score of 64 is 
achieved was validated, and the criterion in effect for this protocol was revised accordingly.  The 
procedure for subjects currently undergoing CHOP INTEND assessment based on criteria in 
effect in a previous protocol version (e.g., subjects <2 years of age undergoing CHOP INTEND 
assessment) was also clarified to align with the criterion in effect for the current Version 2.0 
protocol.
Section 6.5.2.3, Revised Upper Limb Module
Change:  The Revised Upper Limb Module (RULM) was added as a motor function assessment, 
and the Upper Limb Module was removed.
Now reads:
6.5.2.3 6.2.8
Upper Limb Module Revised Upper Limb Module Test
Subjects will be evaluated using the Upper Limb Module Test (Mazzone et al. 2011) at the times 
shown in the Schedule of Procedures (Appendix A).  The Upper Limb Module Test is an 
outcome measure specifically developed to assess upper limb functional abilities in SMA 
patients, including young children and patients with severe contractures in the lower limbs in 
whom the possibility to detect functional changes, such as rolling or long sitting, is limited.  This 
test consists of upper limb performance items that are reflective of activities of daily living (i.e., 
raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a 
container).  The Upper Limb Module Test is quickly administered and has been evaluated in 
SMA patients age 30 months to 27 years (Mazzone et al. 2011).All nonambulatory subjects ≥30 
months of age will be evaluated using the Revised Upper Limb Module (RULM) [Mazzone 
2011].
All nonambulatory subjects ≥30 months of age will be evaluated using the Revised Upper 
Limb Module (RULM) [Mazzone 2011].
The RULM is an outcome measure developed to assess upper limb functional abilities in 
patients with SMA, including young children, and patients with severe contractures in the 
lower limbs in whom the possibility to detect functional changes, such as rolling or long 
sitting, is limited.  This test consists of upper limb performance items that are reflective of 
activities of daily living (i.e., raise a can to mouth as if drinking, take a coin and place it in a 


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box, remove the lid of a container).  The RULM Test is quickly administered and has been 
evaluated in patients with SMA 30 months to 27 years of age [Mazzone 2011].
The purpose of an upper limb scale for use in SMA is to assess change that occurs in motor 
performance of the upper limb over time.  Motor performance in SMA is defined as a 
demonstrated ability to perform a skill under certain test conditions.  This performance 
changes with disease progression and/or intervention (including surgery) and is based on 
the observed response on the day of the assessment.  Motor performance will be impacted 
by muscle strength, contractures, and maturational development (puberty) and the RULM 
aims to incorporate performance of the shoulder, elbow, wrist, and hand. 
Rationale:  The RULM Test was used to assess limb mobility in subjects entering from
Study ISIS 396443-CS4 and was added to enable long-term evaluation of limb mobility in these 
subjects.
This change also affects Section 10.1.2, Efficacy Endpoints, and Appendix A, Schedule of 
Procedures.
Section 6.6.1, Electrocardiograms
Change:  Language describing second ECG reads for subjects who have QTc values 
≥500 milliseconds was added.
Now reads:  
6.6.1
Electrocardiograms
ECGs will be performed for all subjects at Screening and/or MMDR Day 1, approximately 
annually thereafter (i.e., MMDR Days 360, 720, and so on), and at the EOS Evaluation/ET 
Visit.  
After the ECG is completed, an initial local read of the ECG should occur before the ECG 
is sent for a central read (all ECGs will be centrally read).  If the subject’s initial ECG 
results show a QTc interval of ≥500 milliseconds, then the ECG should be repeated prior to 
the subject leaving the visit.  If the second ECG QTc again reads ≥500 milliseconds, the 
Investigator should use best clinical judgment to address the condition.
Additional ECGs may be performed per the judgment of the Investigator, as deemed clinically 
necessary.
Rationale:  This language was added to thoroughly monitor ECG readings for study subjects
receiving nusinersen.










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ventilator use/status, and contraceptive methods that have occurred since the last phone call or 
study visit will be recorded. In addition, the extent of ventilatory support used since the last 
phone call or study visit will be collected.
Rationale:  The frequency of follow-up safety monitoring telephone calls was updated to 1 to 
7 days postdose and every other month for the duration of the study to reduce the overall burden 
of study participation on study subjects and their families.
This change also affects Section 3.4.2, Treatment; Section 3.4.3, Post-Treatment Follow-Up;
Section 6.3.1, Ventilator Use Diary Recording; and Appendix A, Schedule of Procedures.
Section 8.1, Study Drug Administration
Change:  The regimen for study drug administration was revised to state that all subjects, 
regardless of age, will receive the full 12 mg dose of nusinersen.
Now reads:
NusinersenISIS 396443 will be administered as an ITintrathecal LP injection.  All Ssubjects 
who are older than 24 months (>730 days) on the day of dosing will receive the full 12-mg dose 
of nusinersenISIS 396443 (5 mL).  For subjects who are 24 months of age or younger, the 
volume of the injection will be adjusted based on the subject’s age on the day of dosing per 
Table 2, such that each subject will receive a 12 mg equivalent dose based on CSF volume 
scaling.
Table 2
ISIS 396443 Dose Volume to be Administered
Age
Estimated CSF 
Volume*
Injection Volume
(mL)
Dose
(mg)
0-3 months
(0-90 Days)
120 mL
4 mL
9.6
3-6 months
(91-180 Days)
130 mL
4.3 mL
10.3
6-12 months
(181-365 Days)
135 mL
4.5 mL
10.8
12-24 months
(366-730 Days)
140 mL
4.7 mL
11.3
> 24 months
(> 730 days)
150 mL
5 mL
12
*Matsuzawa et al. 2001


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Rationale:  The current regimen for study drug administration is that all subjects will receive the 
full 12-mg dose of nusinersen at a dosing regimen of 4 loading doses followed by maintenance 
dosing every 4 months thereafter.  Over the course of the clinical development program, data 
from early studies have informed the dose regimens used in later studies.
The population PK model supports the conclusion that fixed dosing is appropriate.  This model 
suggests that there is a similar area under the concentration-time curve (AUC) across all age 
groups, but a higher maximum concentration (Cmax) in the youngest age group (i.e., subjects 
<3 months of age) with the fixed dose (relative to the age-adjusted dose).  There was high 
variation in the prediction of Cmax as a result of only trough CSF data being available for 
population PK model analysis and distribution of parameters across age groups that largely 
overlap, regardless of whether fixed dosing or age-adjusted dosing was used. Given that the 
AUC is similar regardless of whether fixed dosing or age-adjusted dosing is used and the 
substantial overlap in the range of estimates for each age group, neither method is likely to 
produce clinically relevant differences in exposure across different age groups. As a result, a 
fixed-dosing regimen is deemed appropriate to reduce the likelihood of dosing errors. 
Population PK analysis predicts higher trough concentration and partial AUC values in CSF in 
subjects who receive the 4 loading dose/every 4-month maintenance dose regimen compared 
with subjects receiving less frequent doses. The Sponsor considers the more frequent dose 
regimen appropriate for all subjects, regardless of age and SMA type. This judgment is based on 
safety and efficacy data observed in Studies ISIS 396443-CS3B and 232SM201, as well as 
results from the PK analysis that showed greater improvement in motor function in subjects with 
a higher concentration of nusinersen. Although available safety and efficacy data from 
Study ISIS 396443-CS4 support a positive risk:benefit profile for subjects with a less frequent 
dosing regimen, the favorable safety and efficacy data from Studies ISIS 396443-CS3B and 
232SM201, along with the PK analysis results, suggest potentially even greater benefit without 
any significantly increased risk with the proposed dosing dose regimen for all subjects.
Therefore, a dose regimen of 4 loading doses of 12 mg nusinersen delivered on Days 0, 15, 29, 
and 64 followed by maintenance dosing of 12 mg nusinersen every 4 months thereafter is 
considered appropriate for all subjects, regardless of age or SMA type.


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Section 9.1, Sponsor Review of Safety Information
Change:  Language clearly defining the responsibilities of the Investigator and the Sponsor was 
added to this section.
Now reads:  
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial study.
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, regardless of the severity or 
relationship to the 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 that 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.
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.
Rationale:  This text was added to adequately collect safety information across the study 
population.


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Section 9.2, Regulatory Requirements
Change:  Language defining a suspected unexpected serious adverse reaction (SUSAR) was 
added to this section, and the definition for International Council for Harmonisation (ICH) was 
updated.
Now reads:  
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of SAEs 
including suspected unexpected serious adverse reactions (SUSARs) per the International 
Conference on Harmonization Council for Harmonisation (ICH) guidelines E2A and ICH E6.  
Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines.  SUSARs are SAEs that are unexpected and judged by the 
Investigator or Biogen to be related to the study treatment administered.
Appropriate personnel at Biogen will unblind SUSARs for the purpose of regulatory 
reporting.  Biogen will submit SUSARs (in blinded or unblinded fashion) to regulatory 
agencies according to local law.  Biogen will submit SUSARs to Investigators in a blinded 
fashion.
Rationale:  The ICH definition was updated for accuracy, and the language pertaining to 
SUSARs was added to describe the collection of safety information that is consistent with 
internationally recognized standards.
Section 9.5.3, Dosing Errors
Change:  This section was updated to include instructions for mediating the event of a study 
treatment overdose.
Now reads:  
Study drug All dosing errors (including but not limited to route of defined as errors in
administration, wrong or the administered dose, etc.) must should be reported documented as 
protocol deviations Protocol Deviations.  A brief description should be provided in the 
deviation, including information about whether the subject was symptomatic or not. (list 
symptoms) or asymptomatic.  Dosing details should be captured on the Dosing CRF.
A dosing error will be considered an overdose when any of the following conditions are 
met:

Any single dose given exceeds the dose level described in the protocol and Drug 
Handling and Administration (DHA) Guidelines.

Dosing frequency exceeds 4 doses in a 60-day period.

Study drug is administered less than 14 days from the previous dose.


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Overdoses are not considered AEs and should not be recorded as an AE on the CRF unless 
an AE or an SAE occurs.  All overdoses (regardless of whether or not they result in an AE) 
must be recorded on an overdose form and faxed to Biogen or designee within 24 hours of 
the site becoming aware of the overdose.  If an overdose results in an SAE, both the SAE 
and overdose forms must be completed and faxed to Biogen or designee.  Should an 
overdose occur, the Investigator or designee must contact the Medical Monitor within 24 hours;
refer to the Study Reference Guide for complete contact information.
Rationale:  There was no text in the previous version of the protocol that addressed a study 
treatment overdose.  This text was added to address this potential event and to collect 
information on overdoses.
Section 9.5.4, Contraception and Pregnancy
Change:  Language was added to define childbearing potential and to describe acceptable 
contraception methods.  A sentence was added to clarify how congenital abnormalities and birth 
defects in the offspring of study subjects should be reported.
Now reads:  
Female subjects of childbearingchild bearing potential (defined as any female who has 
experienced menarche) must have a negative pregnancy test at every study visit as described 
in Section 6.3.2 Screening and must either be abstinent or practice adequate contraception 
during the study, as described in Section 6.3.
Male subjects must remain abstinent during the study or must be using an acceptable 
contraceptive method.
For the purposes of the study, acceptable contraception methods are abstinence, barrier 
contraceptives, intrauterine contraceptive devices, licensed hormonal products, and the use 
of (i.e, use a condom together with spermicidal foam/gel/film/cream/suppository.  Abstinence is 
only acceptable as true abstinence (i.e., when this is representative of the preferred and 
usual lifestyle of the subject).).  Periodic abstinence (e.g., abstinence for the duration of the 
study) and withdrawal are not acceptable methods of contraception.
If a subject becomes pregnant or a pregnancy is suspected, or if a male subject makes or believes 
that he has made someone pregnant during the study, then the study site staff must be informed 
immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or designee within 
24 hours of first learning of the occurrence of (possible) pregnancy.  Follow-up information 
including delivery or termination is reported on Follow-up Pregnancy Forms and is reported 
within 24 hours of the study site staff becoming aware.
Payment for all aspects of obstetrical care, child, or related care will be the subject’s 
responsibility.


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Female subjects patients:  If a suspected pregnancy occurs while on the study (including follow-
up), a pregnancy test will be performed.  The subject patient with a confirmed pregnancy will be 
immediately withdrawn from study drug treatment with study drug.  However, the subject
patient will be encouraged to complete the post-treatment follow-up portion of the study to the 
extent that study procedures do not interfere with the pregnancy.  Regardless of continued study 
participation, the study physician will assist the subject patient in getting obstetrical care and the 
progress of the pregnancy will be followed until the outcome of the pregnancy is known (i.e., 
delivery, elective termination, or spontaneous abortion).  If the pregnancy results in the birth of a 
child, the study center Study Center and Sponsor may require access to the mother and infant’s 
medical records for an additional 8 weeks after birth.
Male subjects patients:  The progress of the pregnancy in a male subject’s patient’s partner 
should be followed until the outcome of the pregnancy is known (i.e., delivery, elective 
termination, or spontaneous abortion).  If the pregnancy results in the birth of a child, additional 
follow-up information may be requested for the mother and infant.  Follow-up will be performed 
to the extent permitted by relevant guidelines (e.g., Health Insurance Portability and 
Accountability Act [HIPAA]) and privacy considerations.
Congenital abnormalities and birth defects in the offspring of male or female subjects 
should be reported as an SAE if conception occurred during the conduct of the study
(including follow-up).
Rationale:  This text was added to provide clarity regarding the appropriate way to report 
congenital abnormalities and birth defects for subjects who conceive a child during the study 
treatment period.
Section 9.5.5, Medical Emergency
Change:  Text providing guidance to address a medical emergency was added.
Now reads:  
9.5.5
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply 
appropriate medical intervention, according to current standards of care.  In case of a 
medical emergency where knowing the subject’s treatment assignment may influence the 
subject’s clinical care, the Investigator has the ability to unblind the treatment assignment.  
The Investigator (or designee) should contact the study’s Medical Director.  Refer to the 
Study Reference Guide’s official study contact list for complete contact information.
Rationale:  This text was added to provide guidance in the event of a medical emergency.


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Section 10.1.1, Safety and Tolerability Endpoints
Change:  Physical examinations were removed as an endpoint and urine total protein was added 
as a clinical laboratory assessment.
Now reads:  
Safety and/ Tolerability Endpoints

AEs adverse events and SAEs

Vital signs and weight

Neurological examinations

Physical examinations

Clinical laboratory tests (serum chemistry, hematology, urinalysis, and urine total 
protein)

Coagulation parameters (aPTT, PTT, and INR)

Electrocardiograms (ECGs)

Use of concomitant medications
Rationale:  Physical examinations were removed as an endpoint because no data related to the 
examinations are collected (any findings are reported as AEs).  Urine total protein collection is a 
standard laboratory assessment and was added to ensure adequate collection of subject’s samples 
to monitor the safety of nusinersen.  Coagulation parameters were added to thoroughly evaluate
coagulation parameters in study subjects receiving nusinersen.
This change also affects Section 6.3.5, Physical Examinations; Section 6.4.1, Clinical Safety
Laboratory Evaluations; Appendix A, Schedule of Procedures, and Appendix B, Laboratory 
Analytes.
Section 10.1.2, Efficacy Endpoints
Change:  The efficacy endpoints for each study group were revised and resulted in the 
generation of a subsection titled 
.


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Now reads:  
Groups 1A and 1B For all groups/subjects:

Achievement of motor milestones (WHO motor milestones and/or Section 2 of 
HINE)

Time to death or permanent ventilation (tracheostomy or ≥16 hours ventilation/day 
continuously for >21 days in the absence of an acute reversible event)

Survival rate

Proportion Percentage of subjects not requiring permanent ventilation

Change from baseline in applicable motor function assessments: CHOP INTEND, 
HFMSE, RULM, 6MWT, and CMAP

Growth parameters

Proportion of CMAP responders patients achieving a CHOP INTEND score of at 
least 50

Hammersmith Functional Motor Scale Expanded (HFMSE) total score and change 
from first to last assessment

Proportion of subjects that achieve any new motor milestone

Proportion of patients achieving all maximum motor milestones in HINE 
(Hammersmith Infant neurological Examination)

Proportion of subjects that achieve standing alone

Proportion of subjects that achieve walking with assistance

CMAP total and change from baseline 

Change from baseline in CSF SMN protein concentration

Clinical Global Impression Improvement

Disease-related hospitalizations and adverse events

Change from baseline in HFMSE (Hammersmith Functional Motor Scale 
Expanded)

Proportion of subjects that achieve any new motor milestone

Number of motor milestones achieved per subject

Proportion of subjects that achieve who achieved standing alone

Proportion of subjects who achieved that achieve walking with assistance

CMAP total and change from baseline 

Change from baseline in cerebrospinal fluid (CSF) SMN protein concentration

Number of serious respiratory events








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Section 10.3, Populations
Change:  The definition for the Intent-to-Treat Set was updated and the definition for the 
Per-Protocol Set for Group 4 was added.
Now reads:  
Intent-to-Treat (ITT) Set:  All subjects who are enrolled and received at least 1 dose of 
nusinersen.
Per-Protocol Set (PPS): For Groups Group 1A and 2A, PPS will include the subset of the ITT 
who complete the loading period in this study and who have no significant protocol deviations 
that would be expected to affect efficacy assessments. For Groups Group 1B and 2B, PPS will 
include the subset of the ITT who complete the loading period in index studies and who have no 
significant protocol deviations that would be expected to affect efficacy assessments.  For 
Groups Group 3 and 4, PPS will include the subset of the ITT who have no significant protocol 
deviations that would be expected to affect efficacy assessments.
Rationale:  The definition for PPS was updated for all groups to align with the updated 
statistical plan for this study.
Section 10.4, Definition of Baseline
Change:  The definition for baseline was revised.
Now reads:  
Definitions of baseline are given below for the purposes of the final analysis.
The analyses will focus on the ISIS 396443-CS11 data.  The baseline will be the last 
non-missing assessment prior to the first dose of study treatment in the ISIS 396443-CS11 
study.  If any integration of data with the index study is conducted, the following 
definitions of baseline will be used:  
For safety, baseline for subjects on active treatment in the index study will be the index study 
baseline.  For subjects on sham in the index study, baseline for safety will be the last 
non-missing assessment prior to the first dose of study treatment Study Drug in this study.
For efficacy, 2 two baselines are defined for each subject:  index study baseline and the baseline 
in this study, which is defined as the end-of-treatment assessment in index studies or the last 
non-missing assessment before the first dose of study treatment Study Drug in this study.
Rationale:  The definition for baseline was revised to provide clarity regarding baseline for the 
ISIS 396443-CS11 study and baseline if the data will be integrated with data from the index 
studies.


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Section 10.5, Interim Analysis
Change:  The text was updated to reflect that interim analyses may be performed.
Now reads:
Interim analyses may be performed to provide content for regulatory submissions and to 
support nusinersen drug development planning and business activities. No formal interim 
analysis is planned for this study.
Rationale:  The purpose of interim analyses would be to provide study Sponsors and regulators 
with information on the status of this ongoing study.
Section 10.6.2, Safety and Tolerability Analysis
Change:  Text was added to describe the evaluation of AEs for subjects in Groups 2A, 2B, 
and 3.
Now reads:  
All treatment-emergent AEs adverse events and SAEs serious adverse events will be 
summarized using the Medical Dictionary for Regulatory Activities (MedDRA™) coding 
system, by system organ class, preferred term, relationship to study treatment Study Drug, and 
severity. Narratives of deaths and, SAEs serious adverse events, including early withdrawals 
from the study treatment Study Drug and from the study due to AEs adverse events, will also 
be provided. 
When applicable, for Groups 2A, 2B, and 3, the incidence of AEs will be evaluated by 
treatment phase (original dosing schedule phase versus MMDR).
Rationale:  The description of evaluation of AEs for Groups 2A, 2B, and 3 was updated to align 
with the statistical plan for this study.
Section 10.6.3, Efficacy Analysis
Change:  This section was updated to align with the most recent statistical analyses and the 
current efficacy endpoints for this study.
Now reads:  
For subjects <2 years of age who have not yet achieved independent walking, motor 
milestones will be assessed using Section 2 of the HINE, which is composed of 8 motor 
milestone categories as follows:  voluntary grasp, ability to kick in supine position, head 


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control, rolling, sitting, crawling, standing, and walking.  Within each motor milestone 
category, there are 3 to 5 levels that can be achieved.  All 8 motor milestones will be tested 
during each assessment.  A subject whose results after testing all appear in the first column 
(no grasp, No kicking, Unable to maintain head upright, and so on) has not achieved any 
motor milestone.  Motor milestone achievement is depicted by movement from the left side 
of Table 3 to the right side of the table, as denoted by the Milestone Progression arrow in 
the table [Haataja 1999]. 
Table 3
Hammersmith Infant Neurological Examination Section 2 - Motor 
Milestones
Motor 
Milestone 
Category
Milestone Level Progression
(Age Expected in Heathy Infantsa)
Voluntary 
grasp
No grasp
Uses whole 
hand
Finger and 
thumb; 
immature grasp
Pincer grasp
Ability to 
kick (in 
supine)
No kicking
Kicks 
horizontal; 
legs do not lift
Upward 
(vertically) 
[3 months]
Touches leg 
(4 to 
5 months)
Touches toes 
(5 to 
6 months)
Head control
Unable to 
maintain 
upright
(<3 months)
Wobbles 
(4 months)
All the time 
upright 
(5 months)
Rolling
No rolling
Rolling to side 
(4 months)
Prone to supine 
(6 months)
Supine to 
prone 
(7 months)
Sitting
Cannot sit
Sit with 
support at 
hips 
(4 months)
Props
(6 months)
Stable sit 
(7 months)
Pivots 
(rotates) 
[10 months]
Crawling
Does not lift 
head
On elbow 
(3 months)
On outstretched 
hand (4 to 
5 months)
Crawling flat 
on abdomen 
(8 months)
On hands 
and knees 
(10 months)
Standing
Does not 
support weight
Supports 
weight (4 to 
5 months)
Stands with 
support
(8 months)
Stands 
unaided 
(12 months)
Walking
No walking
Bouncing 
(6 months)
Cruising 
(holding on) 
[11 months]
Walking 
independentl
y (15 months)
*Values for healthy infants in [Haataja 1999].


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The proportion of motor milestone responders is defined based on the 7 motor milestones 
categories, with the exclusion of voluntary grasp using the assessment at the later study 
visits, as follows: 

Subject demonstrates at least a 2-point increase in the motor milestone category 
of ability to kick or achievement of the maximal score on that category (touching 
toes) or a 1-point increase in the motor milestones of head control, rolling, 
sitting, crawling, standing, or walking, AND 

Among the 7 motor milestone categories with the exclusion of voluntary grasp, 
subject demonstrates improvement (defined in [i]) in more categories than 
worsening.  Note:  For the category of ability to kick, similar to the definition of 
improvement in (i) above, worsening is defined as at least a 2-point decrease or 
decrease to the lowest possible score of no kicking.  For the other 6 categories, 
worsening is defined as at least a 1-point decrease. 
Subjects who die or withdraw from the study will be counted as nonresponders and will be 
included in the denominator for the calculation of the proportion.  As a result, mortality 
will be accounted for in the motor milestone analysis.  For subjects on permanent 
ventilation, because motor milestone assessment continues, functional scores after 
permanent ventilation has been achieved will be used to assess improvement in motor 
milestones.
The median time to death or permanent ventilation, survival rates over time, and the percentage 
proportion of subjects requiring permanent ventilation in Group 1A and 1B at end of treatment 
will be estimated using Kaplan-Meier method. 
Change from baseline in CHOP INTEND total score and HFMSE score for subjects as 
described in Section 6.5.2.1 and Section 6.5.2.2, respectively, proportion of subjects who 
achieved that achieve any new motor milestone, number of motor milestones achieved per 
subject, proportion of subjects who achieved that achieve standing alone milestone, proportion 
of subjects who achieved that achieve walking with assistance milestone, change from baseline 
in RULMUpper Limb Module Test, change from baseline in 6MWT 6 MWT distance, CMAP, 
MUNE, and myometry parameters, change from baseline in CSF SMN protein concentration, 
change from baseline in PedsQL, change from baseline in ACEND, CGI-I clinical global 
impression improvement, and disease-related hospitalizations and AEs adverse events will be 
summarized.  
The proportion of CMAP responders is defined as the proportion of subjects with peroneal 
CMAP amplitude increasing to or maintained at ≥1 mV, comparing to the baseline, based 
on assessment at the later study visits.
Rationale:  The text pertaining to efficacy analyses was updated to align with the revised 
endpoints.  Myometry and motor unit number estimation assessments were removed to reduce 
the burden of study participation on subjects and their families.
This change also affects Section 10.1.2, Efficacy Endpoints.




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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).
Rationale:  This information was added to clarify when progress reports will be submitted 
during the study and the responsibilities of the investigational site after the completion or the 
termination of the study.
Section 11.4.1, Subject Data Protection
Change:  A section describing subject data protection was added to the protocol.
Now reads:  
11.4.1 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, the subjects’ race and ethnicity may 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.  Biogen, 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.
Rationale:  This text was added to align with the most current version of the Biogen protocol 
template.
This change also affects Section 11.1, Informed Consent/Assent.


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

The Ionis logo was replaced with the Biogen logo on the title page.

The Sponsor Information was updated.

The Sponsor Signatory information was updated, and a signature page was added.

The Study Glossary was updated.

Typographical errors and formatting were corrected.

“Subject” replaced most instances of “Patient” to align with Biogen style (1 exception 
is the protocol title). 

“Study” replaced most instances of “Trial” throughout the protocol, except on 
pages 2, 43, and 68.

When referring to “study drug,” nusinersen is used in place of ISIS 396443.  When 
referring to the Protocol Title or previous (“index”) studies, ISIS 396443 is used.  The 
term “study treatment” refers to administration of nusinersen or the sham procedure 
during the blinded portion of the study.

Information in the Confidentiality Statement was updated to align with the most 
recent version of the Biogen protocol template.

Section 2.1, Spinal Muscular Atrophy, was updated to include “5 nucleotides” instead 
of “11 nucleotides.”

Section 2.3.4, Clinical Experience, was updated to align with the most recent version 
of the Investigator’s Brochure.

Section 3.2, Number of Study Centers, was revised to include approximately 37 sites 
in 14 countries.

Section 3.3, Number of Subjects, was revised to include up to 289 subjects who 
previously participated in investigational studies with ISIS 496443.

Section 3.5, End of Study, was updated with language to reflect the MMDR schedule 
and early termination.

Section 3.6, Safety Monitoring and Data and Safety Monitoring Board (DSMB), was 
updated to include text stating that the DSMB may be discontinued at the Sponsor’s 
discretion.

Section 6, Study Procedures, was reorganized to present study assessments according 
to their timing within the study (on injection day only; screening only; every study 
visit and the EOS Evaluation Visit; MMDR Day 1, every 4 months thereafter [every 
MMDR visit], and the EOS Evaluation/ET Visit; screening and/or MMDR Day 1,
every 8 months thereafter [every other MMDR visit], and the EOS Evaluation/ET 




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
Section 12.3, Study Documentation and Storage, was updated for clarity.

Sections 12.7, Conflict of Interest; 12.8, Registration of Study and Disclosure of 
Study Results; 12.9, Study Funding; and 12.10, Publications were added.

Appendix A, Schedule of Procedures, was updated to combine the schedules for all 
groups under the MMDR schedule, and footnotes describing vital signs, ECGs, 
, and X-ray of spine were removed from the 
Schedules of Procedures and added to Section 6, Study Procedures.

Appendix B, Laboratory Analytes, was updated to include gamma glutamyl 
transferase as a clinical chemistry assessment, and urine total protein and coagulation 
assessments were added as assessments that will be assessed by local laboratory only.

SAP_001.pdf: 
Offi ci al  Titl e:   
A n   O p e n  -L a b el   E xt e n si o n   St u d y f or   P ati e nt s    Wit h   S pi n al   M u s c ul ar  
Atr o p h y    W h o   Pr e vi o u sl y   P arti ci p at e d i n I n v e sti g ati o n al   St u di e s  of I  SI  S 
3 9 6 4 4 3  
N  C T   N u  m b er:      N  C T 0 2 5 9 4 1 2 4   
D o c u  m e nt   D at e  : 
0 6 - Se pt e m b er - 20 2 3 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 
St atistic al A n al ysis Pl a n  
 
 
Versi o n N o.: 5. 0  
A n O pe n- La b el E xte nsi o n St u d y f or Patie nts Wit h S pi nal M us c ular Atr o p h y W h o 
Pre vi o usl y Partici p ate d i n I n vesti gati o n al St u dies of I SI S 3 9 6 4 4 3 
A nal ysis of C S 1 1, i nte grati n g C S 1 1 wit h C S 1, C S 2, C S 1 0, C S 1 2, C S 3 A, C S 3 B, C S 4 
a n d 2 3 2 S M 2 0 2 ( C S 7) 
 
Na m e of St u d y Treat m e nt: I SI S 3 9 6 4 4 3 
Pr ot oc ol N o.:  Versi o n 6, 2 0 Oct o b er 2 0 2 1
St u d y P hase: P h as e 3  
 
 
 
 
 
 
C o nfi de nti al I nf or m ati o n 
T he i nf or m ati o n c o nt ai n e d i n t his St atistic al A n alysis Pl a n ( S A P) is c o nfi de nti al a n d m a y 
n ot b e re pr o d uc e d or ot her wise disse mi n ate d wit h o ut t h e a p pr ov al of Bi o ge n, I nc. 
 








     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
T A B L E O F C O N T E N T S
 
 
C o nt e nts 
 
1. 0  
I N T R O D U C TI O N.................................................................................................................. 1 0 
1. 1  
A Brief Des cri pti o n of t h e I n d e x St u dies F oll o ws: ...................................................... 1 0  
1. 1. 1  O ver vie w of I nfa ntile O ns et S M A St u dies ........................................................................... 1 0  
1. 1. 2  O ver vie w of Later- o nset S M A St u dies ................................................................................. 1 2  
1. 1. 3
O v er vie w of I nfa ntile a n d Later- o nset S M A St u d y ( 2 3 2 S M 2 0 2)....................................... 1 4
1. 1. 4
O v er vie w of C S 1 1 ( S HI N E).................................................................................................. 1 5
2. 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 .................................................... 1 6  
2. 1  
Safet y a n d T olera bilit y E n d p oi nts ................................................................................. 1 7  
2. 2  
Effica c y E n d p oi nts .......................................................................................................... 1 7  
 
 1 8 
 
 1 8 
 
 1 8 
 
 1 8 
3. 0  
I N T E RI M A N A L Y S E S ......................................................................................................... 1 8 
4. 0  
G E N E R A L C O N SI D E R A TI O N S......................................................................................... 1 9  
 
Safet y Dis pla ys ............................................................................................................... 2 0  
4. 1. 1  I nte grate d Dis pla ys................................................................................................................. 2 0 
4. 1. 2  C S 1 1 O nl y Dis pla ys ............................................................................................................... 2 1  
4. 2  
Effica c y Dis pla ys ............................................................................................................ 2 1  
4. 2. 1  A ge at First N usi n erse n D os e ................................................................................................ 2 1  
4. 2. 2  Ot h er Dis pla ys ........................................................................................................................ 2 2  
5. 0  
S T U D Y S U BJ E C T S .............................................................................................................. 2 3  
5. 1  
S u bje ct Acc o u nta bilit y ................................................................................................... 2 3  
5. 2  
De m o gra p hic a n d Bas eli n e Dise ase C hara cteristics ..................................................... 2 3  
5. 3  
E xte nt of E x p os ure.......................................................................................................... 2 3  
5. 4  
C o nc o mita nt T h era p y ..................................................................................................... 2 4  
5. 5  
Pr ot oc ol De viati o n .......................................................................................................... 2 5  
5. 6  
Ga p b et we e n I n de x St u dies a n d C S 1 1 ........................................................................... 2 5  
6. 0  
E F FI C A C Y D A T A ................................................................................................................ 2 5  


     
   
 
 
   
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6. 1  
I m p utati o n of Missi n g Data............................................................................................ 2 5 
6. 1. 1  I m p utati o n f or I nte grate d Dis pla ys ....................................................................................... 2 5 
6. 1. 2  I m p utati o n f or Dis pla ys fr o m M M D R Da y 1 ....................................................................... 2 7  
6. 2  
Wi n d o wi n g ...................................................................................................................... 2 8  
6. 3  
Res p o n der A n al ysis........................................................................................................ 2 8  
6. 4  
A nal ysis Met h o ds f or t h e Effic ac y E n d p oi nts .............................................................. 3 0  
6. 4. 1  M ot or Milest o nes ................................................................................................................... 3 0  
6. 4. 2  Ti m e t o E ve nt E n d p oi nts ....................................................................................................... 3 4  
6. 4. 3  C H O P I N T E N D...................................................................................................................... 3 6  
6. 4. 4  C M A P ..................................................................................................................................... 3 7  
6. 4. 5  H F M S E ................................................................................................................................... 3 7  
6. 4. 6  U p p er Li m b M o d ule ( U L M) a n d Re vise d U p per Li m b M o d ule ( R U L M) Tests ............... 3 9  
6. 4. 7  6 Mi n ute- Wal k Test ............................................................................................................... 4 0  
6. 4. 8  Perf or m a n ce Li miti n g C o ntract ure Ass ess m e nt ................................................................... 4 1  
6. 4. 9  C h a n ge i n Gr o wt h Para m eters ............................................................................................... 4 1  
6. 4. 1 0  Pe ds Q L .................................................................................................................................... 4 2  
6. 4. 1 1  A C E N D ................................................................................................................................... 4 2  
6. 4. 1 2  Cli nical Gl o bal I m pressi o n of C ha n g e (I n v esti g at or a n d Care gi v er ass ess m e nts) ............ 4 3  
6. 4. 1 3  X- Ra y of S pi ne ....................................................................................................................... 4 3  
6. 4. 1 4  N u m b er a n d Le n gt h of H os pitaliz ati o ns ............................................................................... 4 4  
6. 4. 1 5
N u m ber of H os pitaliz ati o ns D ue t o Seri o us Res pirat or y A d v erse E ve nt........................... 4 5
6. 4. 1 6  Dis ease-relate d ( S M A) H os pitaliz ati o ns a n d A Es ............................................................... 4 5  
6. 4. 1 7  Si g ns a n d S y m pt o ms of D ys p h a gia ....................................................................................... 4 5  
6. 4. 1 8  C o g niti v e Ass ess m e nts.......................................................................................................... 4 6  
 5 0 
 5 0 
 5 1 
 5 3 
7. 0  
S A F E T Y D A T A..................................................................................................................... 5 3  
7. 1  
A d v erse E ve nts ............................................................................................................... 5 3  
7. 1. 1  A d v erse E ve nts F oll o wi n g D osi n g ........................................................................................ 5 5  
7. 1. 2  A d v erse E ve nts P ote ntiall y Relate d t o L u m b ar P u nct ure .................................................... 5 5  


     
   
 
 
   
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 5 5 
7. 1 . 4 A d v erse E ve nts b y Se verit y ................................................................................................... 5 5  
7. 1. 5  A d v erse E ve nts b y Relati o ns hi p t o St u d y Tre at m e nt .......................................................... 5 5  
7. 1. 6  Seri o us A d v erse E ve nts ......................................................................................................... 5 5  
7. 1. 7  A d v erse E ve nts t h at Le d t o Dis c o nti n u ati o n fr o m Treat m e nt ............................................. 5 5  
7. 1. 8  Deat hs...................................................................................................................................... 5 6  
7. 1. 9  Pres e ntati o ns ........................................................................................................................... 5 6  
7. 2  
Cli nical La b orat or y Data ................................................................................................ 5 7  
7. 3  
E C Gs ................................................................................................................................ 5 8  
7. 3. 1  Q ualitati v e A nal ysis ............................................................................................................... 5 9  
7. 3. 2  E C G O utliers .......................................................................................................................... 5 9  
7. 4  
Vital Si g ns ....................................................................................................................... 5 9  
7. 5  
Ne ur ol o gical E x a mi n ati o ns ............................................................................................ 6 0  
7. 5. 1  HI N E Se cti o ns 1 a n d 3........................................................................................................... 6 0  
7. 5. 2  Ne ur ol o gical a n d F o c use d Ne ur ol o gic al E xa mi n ati o ns ....................................................... 6 0  
 
 6 2 
 
 6 2 
 
 6 3 
 
 6 3 
 
 6 3 
1 0. 0 
A D DI TI O N A L A N A L Y S E S ................................................................................................ 6 5
1 0. 1  
Ass ess m e nt of C O VI D- 1 9 I m pa ct ................................................................................. 6 5  
1 0. 2  
Ris di pla m A nal yses........................................................................................................ 6 5  
1 0. 3  
A nal ysis b y E xter nal Part y ............................................................................................. 6 6  
1 1. 0  
S A M P L E SI Z E C O N SI D E R A TI O N S .................................................................................. 6 6  
1 2. 0  
C H A N G E T O P R E VI O U S V E R SI O N S O F T H E S A P ...................................................... 6 6  
 
 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
A B B R E VI A TI O N S 
A C E N D                     Ass ess m e nt of Care gi v er E x perie n c e wit h Ne ur o m usc ular Dis eas e 
A L T/ S G P T     
ala ni n e a mi n otra nsferase/s er u m gl uta mic p yr u vic tra nsa mi nase   
A S T/ S G O T     
as partate a mi n otra nsferas e/ser u m gl uta mic- o x al oa c etic tra ns a mi n ase     
A T C 
A n at o mical T h era p e utic Class 
A U C 
area u n der t h e c ur ve 
 
 
B L Q 
bel o w t he l o wer li mit of q ua ntific ati o n 
B U N 
bl o o d urea nitr o g e n 
C H O P I N T E N D    
C hil dre n's H os pital of P hila d el p hia I nfa nt Test of Ne ur o m us c ular 
Dis or ders 
C M A P
C o m p o u n d
M us cle Acti o n P ote ntial         
C m a x 
m a xi m u m o bser ve d dr u g c o n c e ntrati o n    
 
 
C R F 
c as e re p ort f or m 
 
 
  
 
C V 
c oefficie nt of v ariati o n 
CI 
c o nfi d e nce i nter val 
                          
 
D S M B 
Data Safet y M o nit ori n g B o ar d      
E A C   
E v e nt A dj u dicati o n C o m mittee  
E C G                            Ele ctr o car di o gra m  
E D C 
Ele ctr o nic data c olle cti o n  
E O D B P 
E n d of D o u ble Bli n d Peri o d 
H F M S E                       Ha m m ers mit h F u ncti o nal M ot or Sc ale - E x p a n de d
HI N E 
Ha m m ers mit h I nfa nt Ne ur ol o gic al E xa mi n ati o n 
I M 
i m m u n o ge nicit y 
I T 
i ntrat h ec al 
I T T 
i nte nt-t o-tre at 
L L N 
l o wer li mit of n or m al 
L L O Q 
l o wer li mit of q u a ntific ati o n 
L P 
l u m bar- p u n ct ure 
Me d D R A     
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M M D R 
M o difie d Mai nte n a n ce D osi n g Re gi m e n 
P C R 
p ol y m erase c h ai n rea cti o n 
  Pe ds Q L                      p e diatric Q u alit y of Life I n v e nt or y 
 
      
      
                        
 
P T 
Preferre d ter m          


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
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R B C 
re d bl o o d cell 
R U L M                        Re vise d u p p er li m b m o d ule 
S D 
sta n d ar d d e viati o n 
6 M W T                        6- Mi n ute Wal k Test 
S E 
sta n d ar d err or 
S M A 
S pi n al M usc ular Atr o p h y 
S O C 
S yste m Or ga n Class 
T ma x
ti m e at w hic h C m a x oc c urs 
U L M                           u p per li m b m o d ul e 
U L N 
u p per li mit of n or m al  
      
     
  
 
                     
 
W B C 
w hite bl o o d c ell 
W H O Dr u g     
W orl d He alt h Or g a niz ati o n dr u g            
dicti o n ar y  
 
 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
1. 0  
I N T R O D U C TI O N
 
T he first pla n n e d i nteri m a nal ysis f or t h e C S 1 1 st u d y was c o n d u cte d wit h a c ut off date of 3 0J u n e 2 0 1 7 
a n d was detaile d i n t w o s e parate i nteri m statistical a n al ysis pla ns:  
 C S 1 1 o nl y [ 1 8 J ul 2 0 1 7] 
 I nte grati o n of C S 1 1 a n d i n de x st u dies.  
T his statistical a nal ysis pla n ( S A P) c o m bi n es b ot h i nte grate d a n d C S 1 1 o nl y re p orti n g. 
 
C S 1 1 is a n o p e n-la b el e xte nsi o n st u d y i n s u bje cts wit h S M A w h o pre vi o usl y partici p ate d i n 
i n v esti g ati o nal st u dies of n usi n erse n. T he pri m ar y p ur p ose of t his st u d y is t o g at her a d diti o n al 
i nf or m ati o n o n t he l o n g-ter m s afet y, t olera bilit y, a n d effic ac y of re pe ate d d os es of n usi n erse n ( 1 2 
m g) a d mi nistere d as I T i njecti o ns b y l u m b ar p u nct ure ( L P). 
S u bje cts will e nter C S 1 1 fr o m fi v e differe nt st u dies, t w o of t hese were ra n d o mize d, d o u ble- bli n d, 
s h a m- pr oce d ure c o ntr olle d st u dies ( C S 3 B a n d C S 4) a n d t hre e were o p e n-la bel st u dies ( C S 3 A, C S 1 2 
a n d 2 3 2 S M 2 0 2 Part 2). T h e p o p ulati o ns p artici p ati n g i n t h es e st u dies are i nfa ntile ( C S 3 A a n d C S 3 B), 
later o ns et S M A ( C S 1 2 a n d C S 4) a n d i nfa ntile a n d later o ns et ( 2 3 2 S M 2 0 2).  
1. 1  A Brief Des cri pti o n of t he I n de x St u dies F oll o ws: 
1. 1. 1     
O v er vie w of I nf a ntile O nset S M A St u dies 
C S 3 A was a P h as e 2, m ultice nter, o p e n-la bel, m ulti ple- d os e, d ose-esc alati o n st u d y t o e v al uate t h e 
safet y, t olera bilit y, a n d p har m ac o ki netics of n usi n erse n a d mi nistere d i ntrat he c all y t o s u bjects wit h 
d os e le vels, 6 or 1 2 m g (sc ale d e q ui vale nt) were e val u ate d s e q u e ntiall y.  T he i nitial d ose le vel of 6 
m g was st u die d i n a c o h ort of 4 s u bjects, a n d t he 1 2 m g d ose le vel i n 1 6 s u bje cts.  L oa di n g d oses 
were a d mi nistere d o n Da ys 1, 1 5, a n d 8 5.  T hereafter, all s u bje cts rec ei ve d m ai nte n a n ce d oses of 1 2 
m g e q ui v ale nt n usi nerse n o n Da ys 2 5 3, 3 7 9, 5 0 5, 6 3 1, 7 5 7, 8 8 3, 1 0 0 9, 1 1 3 5 a n d 1 2 6 1.  S u bjects 
were f oll o we d u ntil Da y 1 3 5 2 ( 4 5 m o nt hs). T h e st u d y was ter mi n ate d e arl y. 
C S 3 B was a P h as e 3, m ultic e nter, ra n d o miz e d, d o u ble- bli n d, parallel- gr o u p, s ha m- pr oce d ure-
c o ntr olle d st u d y t o e v al uate t he effic ac y, safet y, t olera bilit y, a n d p har m ac o ki netics of n usi n erse n 
a d mi nistere d t o s u bjects wit h 2 S M N 2 c o pies w h o ha d o nset of cli nical si g ns a n d s y m pt o ms of S M A 
 m o nt hs of a ge.  1 2 1 s u bje cts were ra n d o miz e d 2: 1 t o recei ve a s cale d e q ui vale nt 1 2 m g d ose 
of n usi n erse n or u n der we nt a s h a m pr oce d ure as c o ntr ol, res pe cti vel y.  N usi nerse n was a d mi nistere d 
usi n g a l oa di n g re gi m e n ( d osi n g o n St u d y Da ys 1, 1 5, 2 9, a n d 6 4) f oll o we d b y mai nte n a nc e d osi n g 
o nc e e ver y 4 m o nt hs ( d osi n g o n Da ys 1 8 3 a n d 3 0 2).  S u bje cts ra n d o miz e d t o t h e s h a m- pr oc e d ure 
c o ntr ol gr o u p u n d er we nt a s ha m- pr o ce d ure o n St u d y Da ys 1, 1 5, 2 9, 6 4, 1 8 3, a n d 3 0 2.  T he t otal 
d urati o n f or treat m e nt a n d f oll o w- u p was t o be 1 3 m o nt hs.  As t his st u d y s h o we d si g nific a nt effic ac y 
of n usi ners e n c o m p are d t o s ha m at t he pre-s p ecifie d i nteri m a nal ysis, t h e st u d y was ter mi n ate d e arl y.  
 
St u d y 
n o. 
/ 
st u d y t y pe 
 
Desi g n     
S a m ple size     
D oses a n d d ur ati o n 


     
   
 
 
   
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St atistical A nal ysis Pl a n  
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C S 3 A/  
P h ase 
2, safet y 
a n d effi cac y 
M ultice nter, 
o pe n-l a bel, 
m ulti pl e- d ose, 
d ose-escal ati o n 
2 0 t ot al: 
 
   C o h ort 1: 4 
 
 
 
 
 
 
   C o h ort 2: 1 6 
 
 
 
6 m g (scale d e q ui v ale nt) o n Da ys 1, 1 5, a n d 8 5 
f oll o we d b y 1 2 m g (scal e d e q ui vale nt) o n Da ys 
2 5 3, 3 7 9, 5 0 5, 6 3 1, 7 5 7, 8 8 3, 1 0 0 9, 1 1 3 5, a n d 
1 2 6 1
 
 
1 2 m g (scale d e q ui v ale nt) o n Da ys 1, 1 5, 8 5, 2 5 3, 
3 7 9, 5 0 5, 6 3 1, 7 5 7, 8 8 3, 1 0 0 9, 1 1 3 5, a n d 1 2 6 1. 
 
T ot al d urati o n: 1 3 5 2 d a ys 
( 4 5 m o nt hs) 
 
C S 3 B/ 
P h ase 3, effi cac y 
a n d safet y 
M ultice nter, 
ra n d o mize d, 
d o u ble- bli n d, 
p arallel- gr o u p, 
s h a m-
pr oce d ure-
c o ntr olle d 
 
1 2 1 t otal:
 
   8 0 I SI S 3 9 6 4 4 3 * 
 
   4 1 S h a m 
 
 
1 2 m g (scale d e q ui vale nt) o n Da ys 1, 1 5, 2 9, 6 4, 
1 8 3, a n d 3 0 2. 
 
T ot al d urati o n: 4 4 2 da ys 
( 1 4 ½ m o nt hs) 
 
 
* O n e s u bject i n C S 3 B ra n d o miz e d t o re cei ve n usi ners e n di d n ot rec ei ve a n y m e dic ati o n 
wit hi n C S 3 B b ut is d ose d wit hi n C S 1 1 
 
 


     
   
 
 
   
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1. 1. 2     
 O v er vie w of L ater- o nset S M A St u dies  
 
A brief d es cri pti o n of C S 1 2 a n d t he ot h er 3 st u dies t h at prec e de d it ( C S 1, C S 2 a n d C S 1 0) is gi ve n 
b el o w:   
  
C S 1 was a P h as e 1, m ultic e nter, o pe n-la bel, si n gle- d os e, d ose-escalati o n st u d y t o e val u ate t h e s afet y, 
t olera bilit y, a n d p h ar m ac o ki n etics of n usi n erse n i n s u bjects wit h S M A.  A si n gle d ose of n usi nerse n 
was a d mi nistere d t o s u bjects wit h S M A w h o were 2 t o 1 4 years of a ge.  F o ur d oses, 1, 3, 6, a n d 9 
m g, were e v al u ate d se q u e ntiall y.  Ea c h d ose was st u die d i n a c o h ort of 6 or 1 0 s u bje cts, w h ere all 
s u bje cts recei v e d st u d y treat m e nt.  S u bje cts i n C o h orts 1 a n d 2 were f oll o we d u ntil Da y 2 9 ( 1 m o nt h), 
a n d s u bje cts i n C o h orts 3 a n d 4, u ntil Da y 8 5 ( 3 m o nt hs).
C S 2 was a P hase 1/ 2, o p e n-la bel, m ulti ple- d os e, d ose-es calati o n st u d y d esi g ne d t o ass ess t h e s afet y, 
t olera bilit y, a n d p h ar m ac o ki netics of n usi n erse n i n 2- t o 1 5- ye ar- ol d s u bjects wit h S M A.  F o ur d os e 
le vels ( 3, 6, 9, a n d 1 2 m g) were e v al uate d se q u e ntiall y.  D oses w ere a d mi nist ere d o n Da ys 1, 2 9, a n d 
8 5 at t he 3, 6, a n d 1 2 m g d ose gr o u ps a n d o n Da ys 1 a n d 8 5 f or t h e 9 m g d ose gr o u p.  S u bjects i n 
C o h ort 1 of C S 1, w h o ha d rec ei v e d a si n gle d ose of 1 m g, were eli gi ble t o partici p ate as were 
u ntreate d s u bjects w h o s atisfie d t h e i ncl usi o n/e x cl usi o n criteria.  S u bjects were f oll o we d u ntil Da y 
2 5 3 ( 8 m o nt hs). 
 
C S 1 0 
was a P h as e 1, o p e n-la b el, si n gle- d os e st u d y t o assess t h e s afet y, t olera bilit y, a n d 
p har m ac o ki n etics of n usi nerse n i n s u bje cts wit h S M A w h o ha d pre vi o usl y partici p ate d i n C o h orts 2, 
3, a n d 4 ( 3, 6, a n d 9 m g, res p e cti v el y) of C S 1.  Si n gle d oses of 6 or 9 m g of n usi n erse n were e v al uate d 
se q ue ntiall y.  S u bje cts were f oll o we d u ntil Da y 1 6 9 ( 5 ½ m o nt hs). 
 
C S 1 2 was a P hase 1, o pe n-la bel, m ulti ple- d os e st u d y t o assess t he safet y a n d t olera bilit y of a 1 2 m g 
n usi n erse n d ose i n s u bje cts wit h S M A w h o pre vi o usl y p artici p ate d i n eit her C S 2 or C S 1 0.  D os es 
were a d mi nistere d o n Da ys 1, 1 6 9, 3 5 1, a n d 5 3 3. T h e st u d y was ter mi n ate d e arl y. 
Data fr o m t hese st u dies will b e c o m bi n e d l o n git u di nall y.
 
C S 4 was a P hase 3, m ultice nter, d o u ble- bli n d, ra n d o mize d, s ha m- pr oce d ure-c o ntr olle d st u d y of 
n usi n erse n a d mi nistere d i ntrat hec all y o v er 1 5 m o nt hs t o patie nts, fr o m a g e bet we e n 2 t o 1 2 ye ars at 
scre e ni n g, wit h later- o nset S M A. 1 2 6 s u bje cts were ra n d o miz e d 2: 1 t o rec ei v e a 1 2 m g d os e of 
n usi n erse n or u n der g o a s ha m pr oce d ure as c o ntr ol, res pe cti v el y. Ra n d o miz ati o n was stratifie d b as e d 
l o a di n g re gi m e n ( d osi n g o n St u d y Da ys 1, 2 9, a n d 8 5) f oll o we d b y a m ai nte na n ce d osi n g 6 m o nt hs 
t h ereafter ( Da y 2 7 4). S u bjects ra n d o mize d t o t he s ha m- pr oc e d ure c o ntr ol gr o u p u n der we nt a s ha m-
pr oc e d ure o n St u d y Da ys 1, 2 9, 8 5, a n d 2 7 4. T he st u d y c o nsiste d of scree ni n g, treat m e nt, a n d p ost-
treat m e nt f oll o w- u p- peri o ds. T he t otal d urati o n of p artici p ati o n i n t h e st u d y was a p pr o xi m atel y 1 6 
m o nt hs. As t his st u d y de m o nstrate d si g nific a nt effic ac y of n usi nerse n c o m pare d t o s h a m, at t h e pre-
s p e cifie d i nteri m a nal ysis, t h e st u d y was ter mi n ate d e arl y. 
 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
St u d y n o. 
/ st u d y 
t y pe 
 
Desi g n 
S a m ple si ze     
D oses a n d d ur ati o n 
C o m plete d 
st u dies 
 
 
 
C S 1/  
P hase 1, 
safet y 
M ultice nter, o pe n-
la bel, si n gle- d os e, 
d os e-es calati o n 
3 4 t otal: 
 
   C o h ort 1:   6 
   C o h ort 2:   6 
C o h ort 3:   6
   C o h ort 4: 1 0 
 
 
 
 
C o h ort 1: 1 m g
C o h ort 2: 3 m g
C o h ort 3: 6 m g
C o h ort 4: 9 m g
 
Si n gle d ose o n Da y 1 
 
T otal d urati o n: 2 9 da ys ( 1 m o nt h) f or C o h orts 
1 a n d 2, 8 5 da ys ( 3 m o nt hs) f or C o h orts 3 a n d 
4  
C S 1 0/  
P hase 1, 
safet y 
M ultice nter, o pe n-
la bel, si n gle- d os e, 
e xte nsi o n t o C S 1.
 
1 8 t otal: 
 
   C o h ort 1:   4 
   C o h ort 2: 1 4 
 
 
 
C o h ort 1: 6 m g
C o h ort 2: 9 m g
 
Si n gle d ose o n Da y 1 
 
T otal d urati o n: 1 6 9 d a ys  
( 5 ½ m o nt hs)
C S 2/  
P hase 1/ 2, 
safet y a n d 
effica c y 
M ultice nter, o pe n-
la bel, m ulti ple-
d os e, d ose-
esc alati o n
3 4 t otal: 
 
C o h ort 1: 8 
   C o h ort 2: 8  
   C o h ort 3: 9  
   C o h ort 4: 9  
 
 
 
 
C o h ort 1: 3 m g o n Da ys 1, 2 9, 8 5
C o h ort 2: 6 m g o n Da ys 1, 2 9, 8 5 
C o h ort 3: 9 m g o n Da ys 1, 2 9, 8 5 
C o h ort 4: 1 2 m g o n Da ys 1, 2 9, 8 5 
 
T otal d urati o n: 2 5 3 d a ys  
( 8 m o nt hs)  
C S 1 2/  
P hase 1, 
safet y 
 
M ultice nter, o pe n-
la bel, m ulti ple- d ose 
e xte nsi o n t o C S 1, 
C S 1 0, C S 2 
4 2 t otal 
1 2 m g o n Da ys 1, 1 6 9, 3 5 1, 5 3 3 
 
T otal d urati o n: 5 4 2 d a ys 
( 1 8 m o nt hs) 
C S 4/  
P hase 3, 
effica c y 
a n d s afet y 
M ultice nter, 
ra n d o mi ze d, 
d o u ble- bli n d, 
p arallel- gr o u p, 
s h a m- pr oce d ure-
c o ntr olle d
1 2 6 t otal: 
 
   8 4 I SI S 3 9 6 4 4 3 
   4 2 S h a m 
 
1 2 m g o n Da ys 1, 2 9, 8 5, a n d 2 7 4. 
 
T otal d urati o n: 4 8 2 d a ys  
( 1 6 m o nt hs) 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 
1. 1. 3     
O v er vie w of I nf a ntile a n d L ate r- o nset S M A St u d y ( 2 3 2 S M 2 0 2) 
 
2 3 2 S M 2 0 2 was a P hase 2 m ultice nter st u d y c o n d u cte d i n 2 parts.  Part 1 was ori gi n all y d esi g n e d as 
a ra n d o miz e d, d o u ble- bli n d, s h a m- pr oc e d ure c o ntr olle d st u d y t o ass ess t h e s afet y a n d t olera bilit y a n d 
e x pl ore t h e effic ac y of i ntrat he c all y a d mi nistere d n usi n erse n o ver a p eri o d of a p pr o xi m atel y 1 4 
m o nt hs (fr o m t h e first d ose u ntil t h e E n d of Part 1 E v al u ati o n). 2 1 s u bje cts were ra n d o miz e d i n a 
rati o of 2: 1 t o rec ei ve n usi n erse n b y i ntrat h e cal l u m b ar p u n ct ure ( L P) i njecti o n or a s h a m- pr oce d ure 
c o ntr ol. Ra n d o miz ati o n was stratifie d base d o n a ge at o ns et of cli nical si g ns a n d s y m pt o ms c o nsiste nt 
wit h S M A: > 6 m o nt hs v ers us < = 6 m o nt hs. Part 1 of t h e st u d y was st o p p e d e arl y d u e t o t h e effica c y 
res ults s ee n i n t he C S 3 B st u d y.
 
Part 2 st u d y pr o ce d ures was d eter mi n e d b as e d o n t he treat m e nt assi g n m e nt i n Part 1. F or s u bjects 
w h o were ra n d o miz e d t o rec ei ve n usi n erse n i n Part 1, Part 2 Da y 1 oc c urre d 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 nt hs f oll o wi n g t h e last i njecti o n of n usi n erse n i n Part 1. O n 
Part 2 Da y 1 s u bje cts recei v e d t heir first d ose of n usi n erse n f or Part 2 a n d ret ur n e d t o t h e 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 m ai nte na nce 
d os e i njecti o ns. F or s u bje cts w h o were rec ei vi n g s ha m pr o ce d ure i n Part 1, Part 2 Da y 1 o cc urre d 
f oll o wi n g t h e 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 v al u ati o n. 
At Da y 1, s u bjects re cei v e d t heir first d os e of n usi n ers e n (first l o a di n g d os e). S u bje cts ret ur ne d t o t h e 
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 v al u ati o ns a n d 
s u bse q ue nt i njecti o ns. T he st u d y was ter mi n ate d earl y. 
 
 
St u d y n o. / st u d y 
t y pe 
 
Desi g n    
S a m ple si ze 
D os es a n d d ur ati o n 
2 3 2 S M 2 0 2 Part 1/  
P hase 2, safet y 
M ultice nter, 
ra n d o mi ze d, 
d o u ble- bli n d, 
p arallel-
gr o u p, s ha m-
pr oc e d ure-
c o ntr olle d 
2 1 t otal: 
 
1 4 I SI S 3 9 6 4 4 3 
 
   7 S h a m 
 
 
 
1 2 m g (sc ale d e q ui v ale nt) o n Da ys 1, 
1 5, 2 9, 6 4, 1 8 3, a n d 3 0 2. 
 
T otal d urati o n: 3 8 5 d a ys 
( 1 3 m o nt hs) 
2 3 2 S M 2 0 2 Part 2 
M ultic e nter, 
o pe n-la bel, 
m ulti ple d ose 
2 0 t otal: 
 
   1 4  
pre vi o us 
I SI S 
3 9 6 4 4 3 
 
   6 pre vi o us S ha m 
 
 
 
1 2 m g (sc ale d e q ui vale nt) 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 
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 
 
T otal d urati o n: 6 5 9 d a ys 
( 2 2 m o nt hs) 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
1. 1. 4     
O v er vie w of C S 1 1 ( S HI N E) 
 
Si n ce t h e start of C S 1 1 st u d y, t h ere h a ve b ee n pr ot oc ol a m e n d m e nts t h at ha ve all o we d f or s u bjects 
fr o m ot her st u dies t o e nter t his l o n g e xte nsi o n st u d y (f or e xa m ple, C S 3 A a n d 2 3 2 S M 2 0 2). T h e ai m 
of e ac h of t h e pr ot oc ol a m e n d m e nts was als o t o m o dif y a n d u nif y t h e visit str u ct ures, assess m e nts 
a n d re gi m e ns. T h e m ai n c ha n g es were: 
 
 T he d ose re gi m e n was c h a n g e d t o be e ver y 1 2 0 da ys f or t he s u bje cts fr o m lat er o ns et st u dies. 
Visit na m es were c h a n ge d t o b e m o difie d m ai nte na nce d osi n g re gi m e n (i.e. M M D R Da y 1, 
M M D R Da y 1 2 0 etc.) 
 
Ne w assess m e nts (i.e. H F M S E, R U L M a n d ot h ers f or i nfa ntile o nset st u dies) were i ntr o d u ce d 
a n d h ar m o nize d, s uc h t h at all st u dies ha d t he s a m e ass ess m e nts
 T he M M D R d osi n g sc he d ule c o nsists of M M D R Da ys 1, 1 2 0, 2 4 0, 3 6 0, 4 8 0, 6 0 0, 7 2 0, 8 4 0, 
9 6 0, 1 0 8 0 1 2 0 0, 1 3 2 0, 1 4 4 0, 1 5 6 0, a n d 1 6 8 0 ( ± 1 4 d a ys) u ntil t h e E O S E val uati o n/ Earl y 
Ter mi n ati o n ( E T) Visit. T h e st u d y will last 5 y ears fr o m M M D R Da y 1 
 F or Pr ot oc ol Versi o n 4, t h e Cli nic al Gl o b al I m pressi o n of C ha n ge ( C GI C) was re m o v e d, 
alt h o u g h d ata was a nal yze d f or C GI C s c ores c olle cte d w hile t he pre vi o us pr ot o c ol v ersi o ns 
a p plie d. F or Pr ot oc ol Versi o n 5, t he Pe diatric V oic e Ha n dica p i n de x ( p V HI) was a d de d 
 I n Pr ot oc ol Versi o n 6, a li mit was set f or t h e n u m ber of s u bje cts w h o are rec ei vi n g n usi nerse n 
c o n c o mit a ntl y wit h ot her S M A t h era pies t o 2 0 % ( n = 5 8) of t he t otal p o p ulati o n. T he f oll o w-
u p visits f or s u bje cts w h o dis c o nti n ue d st u d y treat m e nt were re m o v e d. F or v ari o us effic ac y 
a n d s afet y assess m e nts, if a n assess m e nt is n ot perf or me d at a visit, atte m pts were m a d e t o 
p erf or m t he assess me nts at t he s u bse q u e nt d osi n g visit(s) u ntil c o m plete d.  
 
E nr oll m e nt:  2 9 2 p atie nts (fr o m C S 3 B, C S 4. C S 1 2, C S 3 A st u dies a n d 2 3 2 S M 2 0 2). 
 
St u d y 
n o. 
/ 
st u d y t y pe 
 
Desi g n     
S a m ple size 
D oses  
C S 1 1 
P hase 3 s afet y 
a n d effic ac y 
M ultice nter, 
o pe n-la bel, 
m ulti ple- d ose 
e xte nsi o n 
2 9 2 t otals: 
 
 
 
 
Gr o u p 1 A (s h a m pr oc e d ure i n 
C S 3 B t o n usi ners e n i n C S 1 1): 
2 4  
 
 
Gr o u p 
1 B ( n usi ners e n i n 
C S 3 B t o n usi ners e n i n C S 1 1): 
6 5  
 
 
1 2 
m g o n 
Da ys 1, 1 5, 2 9, 6 4, 
f oll o we d b y m ai nte na nc e d oses of 
n usi n erse n a p pr o xi m atel y e ver y 4 
m o nt hs a cc or di n g t o t he 
M M D R 
d osi n g s c he d ule 
 
1 2 m g of n usi n erse n o n Da ys 2 9 a n d 
3 s ha m pr oce d ures o n Da ys 1, 1 5, 
a n d 6 4 f oll o we d b y m ai nte n a nc e 
d os es of n usi n erse n a p pr o xi m atel y 
e ver y 4 m o nt hs ac c or di n g t o t h e 
M M D R d osi n g sc he d ule.  


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 
 
Gr o u p 2 A (s h a m pr oc e d ure i n 
C S 4 t o n usi n ers e n i n C S 1 1): 
4 2 
 
 
 
Gr o u p 2 B ( n usi ners e n i n C S 4 
t o n usi nerse n i n C S 1 1): 8 3 
 
1 2 m g o n Da ys 1, 2 9, 8 5, f oll o we d 
b y m ai nte na nc e d oses of n usi nerse n 
a p pr o xi m atel y 
e v er y 
4 
m o nt hs 
a cc or di n g t o t he 
M M D R d osi n g 
sc h e d ule 
 
1 2 m g of n usi nerse n o n Da ys 1 a n d 
8 5 a n d 1 s ha m pr oc e d ure o n Da y 2 9 
f oll o we d b y m ai nte na nc e d oses of 
n usi n erse n a p pr o xi m at el y e ver y 4 
m o nt hs a cc or di n g t o t he 
M M D R 
d osi n g s c he d ule  
Gr o u p 3 ( n usi n erse n i n C S 1 2 
t o n usi nerse n i n C S 1 1): 4 5  
1 2 m g o n M M D R Da ys 1, f oll o we d 
b y m ai nte na nc e d oses of n usi nerse n 
a p pr o xi m atel y 
e v er y 
4 
m o nt hs 
a cc or di n g t o t he 
M M D R d osi n g 
sc h e d ule 
 
 
Gr o u p 4 ( n usi n ers e n i n C S 3 A 
t o n usi nerse n i n C S 1 1): 1 3  
1 2 m g o n M M D R Da ys 1, f oll o we d 
b y m ai nte na nc e d oses of n usi nerse n 
a p pr o xi m atel y 
e v er y 
4 
m o nt hs 
a cc or di n g t o t he 
M M D R d osi n g 
sc h e d ule  
 
 
Gr o u p 
5 
( n usi n erse n 
i n 
2 3 2 S M 2 0 2 t o n usi n erse n i n 
C S 1 1): 2 0  
1 2 m g o n M M D R Da ys 1, f oll o we d 
b y m ai nte na nc e d oses of n usi nerse n 
a p pr o xi m atel y 
e v er y 
4 
m o nt hs 
a cc or di n g t o t he 
M M D R d osi n g 
sc h e d ule  
 
 
2. 0  
D E S C RI P TI O N O F O B J E C TI V E S A N D E N D P OI N T S 
T he o bjecti v e of t h e C S 1 1 pr ot oc ol is t o g at her a d diti o n al i nf or m ati o n o n t he l o n g ter m s afet y, 
t olera bilit y, a n d effic ac y of re p eate d 1 2- m g d oses of n usi n erse n (als o k n o w n as BII B 0 5 8 a n d I SI S 
3 9 6 4 4 3) a d mi nistere d as i ntrat hecal (I T) i njecti o ns b y l u m b ar p u n ct ure ( L P) i n s u bje cts wit h s pi n al 
m usc ular atr o p h y ( S M A). 
 
Pri m ary o bjectiv e 
 
T o e v al u ate t h e l o n g-ter m safet y a n d t olera bilit y of n usi nerse n a d mi nistere d b y I T i nje cti o n t o 
s u bje cts wit h S M A w h o pre vi o usl y partici pate d i n i n vesti g ati o nal st u dies of I SI S 3 9 6 4 4 3 
 
S ec o n d ar y o bjective 
 
T o e x a mi ne t h e l o n g-ter m effic ac y of n usi n erse n a d mi nistere d b y I T i njecti o n t o s u bjects wit h 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
S M A w h o pre vi o usl y p artici pate d i n i n vesti g ati o nal st u dies of I SI S 3 9 6 4 4 3 
 
 
 
 
 
 
 
T his statistic al a nal ysis pla n descri b es t he a nal yses t o be p erf or me d, w hic h will p o ol t he d ata fr o m 
t h e i n de x st u dies wit h t h e C S 1 1 d ata.  
T he e n d p oi nts w hic h will be i nte grate d a n d a nal y ze d are liste d b el o w.
 
2. 1  S afet y a n d T ole r a bilit y E n d p oi nts 
 A Es a n d S A Es 
 Vital si g ns a n d wei g ht.
 Ne ur ol o gical e x a mi n ati o ns 
 Cli nical la b orat or y tests (ser u m c h e mistr y, he m at ol o g y, uri n al ysis, a n d uri n e t otal 
pr otei n) 
 C o a g ulati o n para meters (a P T T, a n d I N R) 
 E C Gs 
 Use of c o n c o mita nt m e dicati o ns 
2. 2  Effic a c y E n d p oi nts 
 Ac hie ve me nt of m ot or milest o nes ( W H O m ot or milest o nes a n d/ or Secti o n 2 of 
HI N E) 
 Ti m e t o de at h or p er m a n e nt ve ntilati o n (trac h e ost o m y o r 
 
c o nti n u o usl y f or > 2 1 da ys i n t he a bse nc e of a n ac ute re v ersi ble e ve nt). T h e d efi niti o n of a n 
a c ute re v ersi ble e ve nt is pr o vi de d i n t h e S HI N E Ve ntilati o n E n d p oi nt G ui d a n ce. 
 Perce nta g e of s u bje cts n ot re q uiri n g per m a ne nt ve ntilati o n 
 C h a n ge fr o m baseli ne i n a p plic a ble m ot or f u ncti o n ass ess m e nts: C H O P I N T E N D, 
H F M S E, R U L M, 6 M W T, a n d c o ntract ure assess me nt 
 C h a n ge fr o m baseli ne i n C M A P 
 Gr o wt h p ara m eters
 Pr o p orti o n of C M A P res p o n ders 
 N u m b er of m ot or milest o nes ( W H O or HI N E- 2) a c hie ve d per s u bje ct 
 Pr o p orti o n of s u bjects w h o a c hie v e d sta n di n g al o n e 
 Pr o p orti o n of s u bje cts w h o ac hie v e d wal ki n g wit h assista n c e
 N u m b er of s eri o us res pirat or y e ve nts 
 N u m b er a n d le n gt h of h os pitaliz ati o ns
 C h a n ge fr o m baseli ne i n C o b b- A n gle o n X-ra y of t he t h orac ol u m b ar s pi n e 
 C h a n ges i n q ualit y of life assess m e nts: Pe ds Q L, a n d/ or A C E N D 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 Dis ease-relate d h os pitaliz ati o ns a n d A Es
 S ur vi val rate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
3. 0  
I N T E RI M A N A L Y S E S 
T he first i nteri m a n al ysis was c o n d ucte d usi n g a c ut- off d ate of 3 0 J u n e 2 0 1 7.  F urt her i nteri m 
a nal yses h a ve b ee n/ m a y b e c o n d ucte d wit h alter n ati v e c ut off d ates deter mi n e d b y e xa mi ni n g t he 
pr o gress of s u bjects i n or d er t o s u p p ort re g ulat or y s u b missi o ns, n usi nerse n dr u g de vel o p m e nt 
pla n ni n g, a n d b usi ness a cti vities. It m a y be t hat o nl y certai n s u bje cts a n d o nl y a pre- defi n e d list of 
assess me nts is cle a n e d a n d l oc k e d f or a partic ular i nteri m a n al ysis. 
 
F or t h e i nteri m a n al ys es f or effic ac y e n d p oi nts, effic a c y s ets at ea c h visit will b e defi n e d as t he 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
s u bset of s u bje cts i n t h e Safet y set w h o ha ve t h e o p p ort u nit y t o b e assess e d at t hat visit. 
 
4. 0  
G E N E R A L C O N SI D E R A TI O N S 
 
t of s u bjects 
w h o were ra n d o miz e d t o u n der g o t h e s ha m pr oc e d ure d uri n g t he i n d e x st u d y C S 3 B ( gr o u p 1 A) a n d 
C S 4 ( gr o u p 2 A) a n d 2 3 2 S M 2 0 2 ( gr o u p 5). 
 
I n or der t o disti n g uis h n o mi nal visit n a m es fr o m d urati o n defi n e d i n ter ms of da ys, visit n a mes will 
ti m e i nter v als.  
Safet y s et: safet y pres e ntati o ns will utilize t he s afet y p o p ulati o ns as d efi n e d i n t h e i n de x st u dies 
w hic h was b ase d o n s u bje cts w h o re cei v e d at least o n e d ose of n usi n erse n or s h a m pr o ce d ure. A 
se c o n d Safet y set will b e defi n e d as all s u bje cts w h o are e nr olle d a n d re c ei ve d at least 1 d ose of 
n usi n erse n or u n der we nt s ha m pr oc e d ure d uri n g C S 1 1.  B ot h Safet y s ets will be us e d f or s afet y a n d 
effica c y a nal ys es.   
 
T he M M D R Safet y set will be d efi n e d as t he s u bset of s u bje cts t hat ha d rec ei v e d a n M M D R da y 1 
d os e. 
 
O ne C S 3 B s u bject was ra n d o miz e d t o n usi nerse n b ut wit h dre w fr o m t h e st u d y pri or t o rec ei vi n g a n y 
d os e d u e t o a n a d v erse e v e nt. T his s u bje ct we nt o n t o b e d ose d wit h n usi n erse n i n t h e C S 1 1 st u d y. 
F or i nte grate d safet y a n al ysis, b aseli n e f or t his s u bject will be b as e d o n t h e first n usi nerse n d os e i n 
C S 1 1. F or t he m ai n effic ac y a n al ysis c o nsi d eri n g all p atie nts fr o m t h e start of C S 3 B, si n ce t his s u bje ct 
was n t d ose d i n C S 3 B, t h e date of ra n d o mizati o n will b e c o nsi d ere d as b aseli n e a n d C S 1 1 effic ac y 
visits will be wi n d o we d t o t h e pla n ne d a n al ysis visits a cc or di n gl y.  I n effica c y a nal yses w here t h e 
p atie nts are gr o u p e d bas e d o n a ge at first d ose, t h e b aseli n e will b e t h e first d ose i n C S 1 1 a n d t his 
s u bje ct will be i n cl u d e d i n t h e > = 1 0 m o nt h t o < 2 3 m o nt h gr o u p.   
 
  
 
Ne w e n d p oi nts were i ntr o d u ce d as p art of C S 1 1 a n d d uri n g C S 1 1 as p art of pr ot oc ol a m e n d me nts 
c o m p are d t o t h ose use d i n t h e i n de x st u dies.  I n or der t o all o w pres e ntati o n of res ults l o n git u di nall y, 
a nal yses will be pres e nte d fr o m t he f oll o wi n g b aseli n es, b ase d o n t h e ti m e p oi nts t h at e n d p oi nts were 
i ntr o d uc e d: 
- 
First d os e of n usi n erse n i n i n de x st u dies 
- 
First d os e of n usi n erse n i n C S 1 1 
- 
D os e of M M D R Da y 1 i n C S 1 1 
 
Pres e ntati o ns of i m m u n o g e nicit y data will b e base d o n all d ose d s u bjects.
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
S u m m ar y statistics will be pres e 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, t he s u m m ar y statistics 
will g e n erall y i n cl u d e n u m ber of s u bje cts wit h data, m ea n, sta n dar d de viati o n, me dia n, mi ni m u m a n d 
m a xi m u m. F or cate g oric al e n d p oi nts, t h e s u m mar y statistics will g e nerall y i ncl u de: n u m b er of 
s u bje cts d os e d, n u m ber of s u bje cts wit h data, a n d t he p erce nta g e of t h ose wit h d ata i n ea c h c ate g or y. 
Fre q ue nc y distri b uti o ns will b e prese nte d as a p pr o priate. 
 
T he statistic al s oft ware, S A S ® versi o n 9. 3 or a b o v e, will b e us e d f or all s u m m aries a n d statistic al 
a nal yses. 
 
 S afet y Dis pl a ys 
4. 1. 1     
I nte g r ate d Dis pl a ys 
F or i nte grate d a nal yses, t h e  f oll o wi n g gr o u pi n gs will b e us e d.  I nfa ntile o ns et is defi n e d as a g e at 
s y m pt o m o nset < = 6 m o nt hs a n d later o ns et is d efi ne d as a ge at s y m pt o m o ns et > 6 m o nt hs. Scree ni n g 
a ge i n t hes e dis pla ys is t he a ge at scree ni n g i n t he first st u d y at w hic h t he y are d ose d wit h I SI S 
3 9 6 4 4 3. 
1)  I nf a ntile- o ns et: 
 C o ntr olle d st u d y ( C S 3 B): t his will i ncl u d e o nl y t he i n d e x st u d y d ata  
 C o ntr ol  
 I SI S 3 9 6 4 4 3
 C o ntr olle d a n d u nc o ntr olle d st u dies i n cl u di n g e xte nsi o ns ( w hic h i n cl u d e all t h e i nfa ntile o nset 
s u bje cts treate d wit h I SI S 3 9 6 4 4 3 i n C S 3 B, C S 3 A a n d 2 3 2 S M 2 0 2) b y a g e at s cree ni n g (t h e 
a ge at s cree ni n g here refers t o t h e s cree ni n g visit pri or t o starti n g I SI S 3 9 6 4 4 3; f or e x a m ple, 
f or a s u bject w h o was i n t h e C S 3 B pre vi o us c o ntr ol gr o u p, it will be t h e scree ni n g visit f or 
C S 1 1) 
 Scree ne d < = 7 m o nt hs of a ge ( pre vi o us I SI S 3 9 6 4 4 3 data fr o m C S 3 B a n d C S 3 A t o 
C S 1 1 i n cl usi v e)
 Scree ne d > 7 m o nt hs of a ge ( pre vi o us c o ntr ol data fr o m C S 3 B t o C S 1 1 i ncl usi ve o nl y 
a n d 2 3 2 S M 2 0 2 i nfa ntile o ns et, w hic h i n cl u d es pre vi o us I SI S 3 9 6 4 4 3 data fr o m Part 
1/ Part 2 a n d pre vi o us c o ntr ol s u bjects fr o m Part 1 d ata t o C S 1 1 i n cl usi v e) 
 T otal (s u m of t h e Scree ne d < = 7 a n d > 7 m o nt hs c ol u m ns) 
 
2)  L ater- o nset: 
 C o ntr olle d st u d y ( C S 4) t his will i ncl u de o nl y t h e i n d e x st u d y d ata  
 C o ntr ol  
 I SI S 3 9 6 4 4 3
 C o ntr olle d a n d u nc o ntr olle d st u dies i n cl u di n g e xte nsi o ns (t his will i ncl u d e all t he later o ns et 
S M A s u bjects treate d wit h I SI S 3 9 6 4 4 3)  


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 S u bje cts first d os e d wit h I SI S 3 9 6 4 4 3 i n eit h er C S 4 or 2 3 2 S M 2 0 2 Part 1, pl us a n y 
f oll o w- u p i n C S 1 1 or 2 3 2 S M 2 0 2 Part 2.   
 S u bje cts first d ose d i n C S 1 or C S 2 a n d f oll o w- u p i n C S 1 0, C S 1 2, C S 1 1  
 S u bje cts w h o rec ei ve d s h a m i n C S 4 or 2 3 2 S M 2 0 2 Part 1 fr o m t h e first d ose of I SI S 
3 9 6 4 4 3 i n C S 1 1 or 2 3 2 S M 2 0 2 Part 2, pl us a n y f oll o w- u p i n C S 1 1  
3)  All S M A s u bjects tr e ate d wit h I SI S 3 9 6 6 4 3 
 I nfa ntile o nset  
 Scree ne d < = 7 m o nt hs of a ge ( pre vi o us I SI S 3 9 6 4 4 3 d ata fr o m C S 3 B a n d C S 3 A t o 
C S 1 1 i n cl usi v e)
 Scree ne d > 7 m o nt hs of a ge ( pre vi o us c o ntr ol data fr o m C S 3 B o nl y a n d 2 3 2 S M 2 0 2 
i nfa ntile o nset, w hic h i n cl u des pre vi o us I SI S 3 9 6 4 4 3 data fr o m Part 1/ P art 2 a n d 
pre vi o us c o ntr ol s u bje cts fr o m Part 1 data t o C S 1 1 i n cl usi v e) 
 Later o ns et  
 All treate d s u bje cts
 
4. 1. 2     
C S 1 1 O nl y Dis pl a ys
F or a n al yses of C S 1 1 o nl y data t h e f oll o wi n g gr o u pi n gs will b e use d.  It s h o ul d be n ote d t h at s cree ne d 
< = 7 a n d > 7 m o nt hs of a ge will be as descri b e d i n t h e i nte grate d a n al ysis (i.e. usi n g t he s cree ni n g 
d ate of t he st u d y i n w hic h t he s u bje ct first rec ei ve d I SI S 3 9 6 4 4 3 treat m e nt). 
 I nfa ntile o nset  
 Scree ne d < = 7 m o nt hs of a g e ( pre vi o us I SI S 3 9 6 4 4 3 i n C S 3 B a n d C S 3 A) 
 Scree ne d > 7 m o nt hs of a ge ( pre vi o us c o ntr ol i n C S 3 B a n d 2 3 2 S M 2 0 2)  
 Later o ns et C S 1 1 d ata fr o m s u bjects ori gi n ati n g fr o m C S 4, C S 1, C S 2, 2 3 2 S M 2 0 2 
 T otal (i nfa ntile a n d later o ns et) 
4. 2  Effic a c y Dis pl a ys 
4. 2. 1     
 A g e at First N usi ne rs e n D ose  
Si n ce a g e is a n i m p orta nt c o variate i n S M A, f or t h e C S 4 a n d C S 3 B st u dies a n al yses will b e perf or m e d 
c ate g orize d b y a ge at first n usi nerse n d ose gr o u p f or b ot h s afet y a n d effic ac y a n al yses. T h e f oll o wi n g 
d e picts t he a g e gr o u ps:   
 F or C S 3 B s u bje cts ( pre vi o us I SI S 3 9 6 4 4 3 data fr o m C S 3 B t o C S 1 1 i ncl usi v e) 
 A ge < 6 m o nt hs 
 A ge > = 6 t o < 1 0 m o nt hs 
 F or C S 3 B s u bje cts ( pre vi o us c o ntr ol) d ose d i n C S 1 1: A g e > = 1 0 t o < 2 3 m o nt hs 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 F or C S 4 s u bje cts ( pre vi o us I SI S 3 9 6 4 4 3 data fr o m C S 3 B t o C S 1 1 i n cl usi v e) 
 A ge > = 2 t o < 3. 5 y e ars 
 A ge > = 3. 5 t o < 5 y e ars 
 F or C S 4 s u bje cts ( pre vi o us c o ntr ol) d os e d i n C S 1 1: A g e > = 5 t o < 9. 5 ye ars  
 
4. 2. 2     
Ot her Dis pl a ys  
I n a d diti o n, dis pla ys will be prese nte d w here t h e a p pr oac h is t o pres er v e t he i n d e x st u d y gr o u pi n gs 
s o f or i nfa ntile o ns et st u dies:
 C S 3 A fr o m t h eir first n usi n erse n d ose i n C S 3 A 
 C S 3 B pre vi o us c o ntr ol fr o m t h eir first s ha m pr oc e d ure i n C S 3 B i n cl u di n g all efficac y i n 
C S 3 B o nl y 
 C S 3 B pre vi o us c o ntr ol fr o m t heir first n usi n ers e n d os e i n C S 1 1
 C S 3 B pre vi o us c o ntr ol fr o m t heir first s h a m pr oc e d ure i n C S 3 B a n d i ncl u di n g all effic ac y i n 
b ot h C S 3 B a n d C S 1 1
 C S 3 B pre vi o us I SI S 3 9 6 4 4 3 fr o m t h eir first n usi n erse n d ose i n C S 3 B 
A n d t he later o ns et st u dies: 
 T y p e 2 s u bje cts w h o recei ve d t h eir first e ver n usi nerse n d ose i n C S 2/ C S 1 2 
 T y p e 3 s u bje cts w h o rec ei ve d t h eir first e ver n usi n erse n d ose i n C S 2/ C S 1 2 
 C S 4 pre vi o us c o ntr ol fr o m t h eir first s ha m pr oc e d ure i n C S 4 i n cl u di n g all effic ac y i n C S 4 
o nl y 
 C S 4 pre vi o us c o ntr ol fr o m t heir first n usi ners e n d os e i n C S 1 1 
C S 4 pre vi o us c o ntr ol fr o m t heir first s ha m pr o ce d ure i n C S 4 a n d i ncl u di n g all effic ac y i n 
b ot h C S 4 a n d C S 1 1 
 C S 4 pre vi o us I SI S 3 9 6 4 4 3 fr o m t h eir first n usi n erse n d ose i n C S 4 
Effica c y a nal ysis fr o m M M D R Da y 1: 
Fr o m M M D R Da y 1, t he sites will atte m pt t o p erf or m t h e sa m e set of effi c a c y assess m e nts o n all 
s u bje cts. I n l o n git u di nal s u m m aries f or t hese m e as ures, s u bje cts will b e p o ole d usi n g t h e sa m e 
gr o u pi n gs as pla n n e d f or safet y pres e ntati o ns b y i nfa ntile or later o nset S M A.  I n a d diti o n, s u m m aries 
fr o m M M D R Da y 1 will be pr o d uc e d usi n g t he ori gi n al st u
t y p e. 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
F or o utc o m es starte d at M M D R d a y 1 i n patie nts i n C S 3 B or C S 4 we will pl ot t h e a g e at visit d ate 
t h e h oriz o ntal a xis vs c ha n g e o n t he vertic al a xis. Ea c h p atie nt will be re pres e nte d b y a li n e (s p a g hetti 
pl ot). A m ea n li ne will b e fitte d t o t h e o utc o m es wit h its c orres p o n di n g c o nfi de n ce i nter vals.  
5. 0  
S T U D Y S U B J E C T S 
5. 1  S u bje ct Ac c o u nt a bilit y 
T he n u m b er of s u bje cts w h o were d ose d, c o m plete d t he i n de x st u d y a n d di d n ot e nter C S 1 1, a n d 
c o m plete d C S 1 1, al o n g wit h reas o ns f or disc o nti n ui n g treat m e nt a n d wit h dra wi n g fr o m t he i n d e x or 
C S 1 1 st u dies will be s u m m ariz e d. Listi n gs of t h os e s u bjects w h o disc o nti n u e d treat m e nt a n d/ or 
wit h dre w fr o m t he i n d e x or C S 1 1 st u dies a n d t h e re as o ns f or disc o nti n uati o n/ wit h dra wal will be 
pres e nte d. S u bjects w h o die d d uri n g t h e i n de x or C S 1 1 st u dies will als o be liste d s e p aratel y. 
5. 2  De m o gr a p hic a n d B aseli ne Dis e ase C h ar acteristics 
F or all t he s u bjects w h o rec ei v e d n usi n erse n i n t h e i n de x st u dies, b as eli n e will b e t h e i n de x st u d y 
b as eli n e. F or s u bje cts o n s ha m pr oc e d ure i n t h e i n de x st u dies or i n Part 1 f or 2 3 2 S M 2 0 2, a se c o n d 
b as eli n e will be d efi ne d pri or t o t h eir first d ose of I SI S 3 9 6 4 4 3 i n C S 1 1 or 2 3 2 S M 2 0 2 Part 2, 
res p ecti v el y.  I n t h e s u m maries base d o n M M D R Da y 1, t h e M M D R Da y 1 d osi n g d ate will b e 
c o nsi dere d t he starti n g p oi nt a n d d e m o gra p hics a n d dise ase c haracteristics will b e s u m m ariz e d at t his 
ti m e p oi nt.  
 
Baseli n e data f or d e m o gra p h y, m e dic al hist or y, S M A hist or y, a n d b as eli n e dise as e c h aracteristics 
m a y b e ta ke n fr o m t h e i n d e x st u dies d ata. 
 
De m o gra p h y i n cl u d es a ge, s e x, et h nicit y, a n d rac e. Me dic al hist or y will be c o d e d i n Me d D R A a n d 
t h e n u m ber a n d p erce nta g e of s u bje cts wit h ea c h m e dical hist or y pres e nte d b y preferre d ter m. S M A 
hist or y, de pe n di n g o n t he d ata c olle cte d o n t h e i n d e x st u dies (e x a m ple g estati o nal a g e, birt h wei g ht, 
a ge at s y m pt o m o nset, a g e at S M A dia g n osis, a n d t he n u m b er of c o pies of t h e S M N 2 ge n e.). 
Ra ce a n d et h nicit y are n ot a vaila ble f or all s u bjects i n C S 1 1 si n c e certai n c o u ntries d o n ot p er mit 
c olle cti o n.  If rac e was n ot p er mitte d t o b e c olle cte d i n C S 1 1 t h e n f or t hese s u bje cts it will b e 
et h nicit y is a vaila ble fr o m a n i n de x st u d y.  
 
De m o gra p hic a n d b aseli n e dis ease c hara cteristics will be pres e nte d f or t h e Safet y set a n d Effic ac y 
set as a p pr o priate.  
5. 3  E xte nt of E x p os ur e 
T he n u m b er of d os es rec ei ve d a n d t h e n u m ber of s ha m pr oc e d ures perf or me d will b e dis pla y e d usi n g 
fre q u e nc y distri b uti o ns. T h e a m o u nt of n usi n erse n recei ve d will be pres e nte d usi n g s u m m ar y 
statistics. N u m b er of d os es a n d o verall ti m e o n t hera p y will b e pres e nte d f or a ge at first d os e dis pla y. 
 
O verall ti m e o n st u d y will be d efi n e d as t he t otal n u m b er of da ys a s u bje ct is k n o w n t o b e f oll o we d 
o n st u d y c alc ulate d as f oll o ws:


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 
O verall ti m e o n st u d y = ( Last d ate o n st u d y) 
 ( Date of first d os e or first s ha m pr oc e d ure) + 1. 
 
T he last date o n st u d y is d efi n e d as t h e date of t he latest visit or e v al u ati o n or tele p h o n e c o nta ct, or 
ti m e of de at h fr o m all a v aila ble d ata f or a gi v e n s u bje ct. T he date of first d ose or first s h a m pr oc e d ure 
is t h e first date i n t he i n d e x st u d y. 
 
Ti m e o n st u d y will be c ate g oriz e d i nt o i nter vals a n d s u m m ariz e d b y tre at m e nt gr o u p a n d o verall. 
Gi v e n t he l o n g half-life of n usi ners e n, s u bje cts 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 h e ti m e t h e first d os e was a d mi nistere d t o t h e last d a y of f oll o w- u p. Esse ntiall y, e x p os ure is 
e q ui v ale nt t o ti m e o n st u d y.
 
T he n u m b er of d oses of dr u g rec ei ve d a n d ti m e o n st u d y u p t o M M D R Da y 1 a n d fr o m M M D R Da y 
1 t o t h e last d a y o n st u d y will be pres e nte d. 
5. 4  C o nc o mit a nt T he r a p y 
T hr o u g h o ut t h e st u d y, c o nc o mita nt m e dicati o ns or treat m e nts d e e me d ne cess ar y f or m a na ge me nt of 
a d v erse e ve nts or t o pr o vi d e a de q u ate s u p p orti ve care m a y be pres cri be d. A c o nc o mita nt m e dic ati o n 
is a n y n o n- pr ot oc ol s pecifie d dr u g or s u bsta n c e i n cl u di n g o v er-t h e-c o u nter m e dicati o ns, h er bal 
m e dic ati o ns a n d vita mi n s u p ple m e nts. As per Pr ot o c ol Versi o n 5, st u d y s u bje cts are all o we d t o ta ke 
c o n c o mit a nt F o o d a n d Dr u g A d mi nistrati o n-a p pr o ve d a n d/ or c o u ntr y-s p ecific a p pr o v e d t hera pies 
pr ot oc ol). I n a d diti o n, a mil d s e d ati v e (e. g., mi da z ola m) a n d a l ocal a n est h etic (e. g., li d o c ai ne) m a y 
b e us e d f or t h e L P pr o ce d ures ( per i nstit uti o nal g ui d a n ce).  
 
All c o n c o mita nt m e dic ati o ns will be c o d e d usi n g t h e 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 n c o mita nt pr oc e d ure is a n y t h era pe utic i nter ve nti o n (e. g., s ur ger y/ bi o ps y, m yri n g ot o m y, a n d 
plac e me nt of t y m p a n ost o m y t u b es) or dia g n ostic ass ess m e nt (e. g., bl o o d g as m eas ure me nt, ba cterial 
c ult ures) p erf or m e d b et wee n s cree ni n g a n d last visit. All a n cillar y pr oc e d ures will be c o d e d usi n g 
Me d D R A. 
 
F or t h e p ur p os es of a n al ysis, a c o n c o mita nt t hera p y (i n cl u di n g m e dicati o n or a ncillar y pr o ce d ure) is 
d efi ne d as a n y t h era p y t h at was ta ke n o n or after t he first i nje cti o n of n usi n erse n or first s ha m 
pr oc e d ure. T his i n cl u des t h era pies w hic h were starte d pri or t o t h e i nitiati o n of i nje cti o n of n usi n ersi n 
or s h a m pr oc e d ure if t h eir use c o nti n u e d o n. I n or der t o d efi n e c o nc o mita nt t h era pies wit h missi n g 
start or st o p d ates, t h e f oll o wi n g a d diti o n al criteria will b e use d: 
 if b ot h t h e start a n d st o p d ates of a p artic ular t h era p y were missi n g, t h at t h era p y is 
c o nsi dere d c o n c o mita nt; 
 if t h e start d ate of a t h era p y was missi n g a n d t he st o p date of t h at t hera p y fell o n or after 
t h e date of d osi n g, t h at t h era p y is c o nsi d ere d c o n c o mita nt; 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 if t h e start d ate of a t hera p y was pri or t o t h e date of d osi n g a n d t he st o p d ate of t h at t h era p y 
was 
missi n g a n d t he t h era p y was liste d as c o nti n ui n g, t h at t hera p y is c o nsi dere d 
c o n c o mita nt; 
 if t h e start d ate of a t h era p y was pri or t o t he d ate of d osi n g a n d t h e st o p date of t h at 
t h era p y was missi n g a n d t h e t h era p y was liste d as n ot c o nti n ui n g, t h at t h era p y is 
c o nsi dere d c o n c o mita nt, or 
 if t h e start/st o p date of a t hera p y is p artial t h e n w h ere 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 it will b e c o nsi d ere d c o n c o mita nt
 
De n ote t he e n d d ate of m e dic ati o n as C M E N D T a n d t h e st u d y tre at m e nt/s ha m pr oc e d ure start date 
as T R T S T D T. T he m e dic ati o n is classifie d c o nc o mita nt pr o vi d e d a n y of t he f oll o wi n g is N O T tr ue: 
 
C M E N D T is c o m plete a n d C M E N D T is less t h a n T R T S T D T. 
 
Da y of C M E N D T missi n g a n d y ear/ m o nt h of C M E N D T is strictl y b ef ore ye ar- m o nt h of 
T R T S T D T. 
 
M o nt h of C M E N D T is missi n g a n d y e ar of C M E N D T is strictl y b ef ore ye ar of T R T S T D T.  
 
T he n u m b er a n d p erce nta g e of s u bje cts ta ki n g ea c h t y pe of c o n c o mita nt m e dicati o n at Baseli n e 
a n d d uri n g t h e st u d y will be pres e nte d b y preferre d n a m e.  T h e n u m b er a n d perce nta g e of s u bjects 
w h o u n der we nt e ac h t y pe of a ncillar y pr o ce d ure d uri n g t h e st u d y will be pres e nte d.  
5. 5  Pr ot oc ol De vi ati o n 
Maj or pr ot oc ol d e viati o ns will b e s u m m arize d, a n d all pr ot oc ol d e viati o ns will b e pr o vi d e d as a 
listi n g.  
5. 6  G a p bet wee n I n de x St u dies a n d C S 1 1 
A s u m m ar y will b e prese nte d f or t h e g a p ( da ys) b et wee n i n de x st u dies ( C S 3 A, C S 3 B, C S 1 2, C S 4 
a n d 2 3 2 S M 2 0 2) a n d first d os e i n C S 1 1. 
6. 0  
E F FI C A C Y D A T A
6. 1  I m p ut ati o n of Missi n g D at a  
6. 1. 1     
I m p ut ati o n f or I nte gr ate d Dis pl a ys 
 
I m p uti n g a n d wi n d o wi n g se q ue nce of e v e nts:  
 
 First ste p is t o c o nsi d er all t h e visits (sc he d ule d a n d u nsc he d ule d), w here at le ast o ne ite m has 
b ee n assess e d, missi n g ite ms will be i m p ute d usi n g t h e r ules bel o w. 
 Sec o n d ste p is t o wi n d o w as descri b e d i n Se cti o n 6. 2. 
 
F or s u bje cts ra n d o mize d t o n usi nerse n i n t h e i n de x st u dies ( or 2 3 2 S M 2 0 2 Part 1), t h e i n de x st u dies 
(e xa m ple C S 3 B or 2 3 2 S M 2 0 2 Part 1 a n d 2) a n d C S 1 1 will be c o nsi dere d as o n e peri o d ( n usi n erse n 
p eri o d) a n d all d ata a v aila ble will b e us e d f or i m p utati o n. F or s u bje cts w h o were ra n d o mize d t o 


     
   
 
 
   
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re cei v e S ha m i n t h e i n de x st u dies or 2 3 2 S M 2 0 2 Part 1, t h e t w o peri o ds 
i.e. t h e s ha m p eri o d (i n de x 
st u d y/ 2 3 2 S M 2 0 2 Part 1) a n d n usi nerse n peri o d ( C S 1 1 / 2 3 2 S M 2 0 2 Part 2 + C S 1 1) 
 will be 
c o nsi dere d c o m pletel y s e parate d a n d n o i m p utati o n will b e all o we d (i.e., n o i nter p olati o n) b et wee n 
t h e 2 peri o ds. T h e e xce pti o n is f or t he c o m bi n e d a nal ysis w here s h a m a n d n usi nerse n are prese nte d 
as o n e tre at m e nt ar m.  
 
T he i m p utati o n f or H F M S E a n d u p per li m b will b e base d o n t he t otal sc ore, w hile t h e i m p utati o n f or 
W H O, C H O P I N T E N D a n d HI N E will b e b as e d o n ite m le vel/ m ot or milest o ne le v el. T he i m p utati o n 
of missi n g d ata will f oll o w t h es e r ules: 
 
1)
A n y missi n g baseli n e will b e i m p ute d usi n g m e dia n wit hi n strat u m ( defi n e d at t he e n d of t his 
Secti o n) c o nsi d eri n g n o n- missi n g baseli n e rec or ds. 
F or W H O a n d HI N E m ot or milest o nes, if t h e calc ulate d m e dia n is n ot a n i nt e g er n u m b er, 
t h e n it will be r o u n d e d t o be a n i nte ger (i.e. a m e dia n of 0. 5 will b e r o u n de d t o 1.) 
2)  F or p ost baseli n e visits, fla n k e d b y n o n- missi n g visits, missi n g val ues will b e i m p ute d usi n g 
li ne ar i nter p olati o n. F or t he li near i nter p olati o n if baseli n e is missi n g t h e n t he i m p ute d baseli n e 
will b e use d (se e ste p 1). O nl y a ct ual visits wit h a n o n
missi n g d ate will b e i m p ute d f or e ac h 
s u bje ct.  
 F or H F M S E, if 6 or m ore ite m s c ores are missi n g, t he n i m p ute t h e t otal sc ore as if all t h e 
3 3 ite ms were missi n g.  
 F or R U L M, if 3 or m ore ite ms are missi n g, t h e n i m p ute t he t otal s c ore as if all t h e 1 9 
ite ms were missi n g. 
 F or U L M, if m ore t h a n 2 ite ms are missi n g, t he n i m p ute t he t otal sc ore as if all t he 9 ite ms 
were missi n g.
 
o bs er ve d at a visit, t he n t h e res ult will be first s et t o missi n g. 
 
3)  If it was t he last ass ess m e nt a n d d ate was prese nt a n d at least o n e ite m was n o n- missi n g t he 
f oll o wi n g a p pr oac h es will be f oll o we d:
F or t h e H F M S E a n d R U L M/ U L M, t h e val u e will be i m p ute d usi n g t h e l ast o bser ve d t otal 
sc ore.  
 F or t h e ot h er assess m e nts, t h e l o west o bser ve d val ue f or ite m assi g n e d t o t h e a nal ysis visit 
wit hi n t h e strat u m will b e use d f or t h e i m p utati o n. F or e x a m ple, f or missi n g C H O P I N T E N D 
at t he last visit, C H O P I N T E N D at t h e last visit was i m p ute d usi n g t he mi ni m u m of t h e 
strat u m. F or e x a m ple, if t he last t hree visits h a v e t h e s a m e ite m missi n g, t he n t h e mi ni m u m 
of t h e strat u m will be use d f or all t h ese visits. 
 
T he strat u m f or t h e i m p utati o n of b as eli n e a n d last assess m e nt, m e nti o n e d i n p oi nt 1 a n d 3 are as 
f oll o ws: 
 T y p e 2 (first n usi n erse n d ose o n C S 1/ C S 2). 
 T y p e 3 (first n usi n erse n d ose o n C S 1/ C S 2). 
 Pre vi o us c o ntr ol (first s ha m pr oc e d ure o n C S 3 B/ C S 4/ 2 3 2 S M 2 0 2 Part 1). 
 Pre vi o us c o ntr ol i n C S 1 1/ Part 2 (first n usi n erse n d ose o n C S 1 1/ 2 3 2 S M 2 0 2 Part 2). 
 Pre vi o us I SI S 3 9 6 4 4 3 (first n usi nerse n d ose i n C S 3 B, C S 4, C S 3 A a n d 2 3 2 S M 2 0 2 Part 2)   
 


     
   
 
 
   
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T he m e dia n val u e calc ulate d f or i m p uti n g missi n g b aseli n e will b e wit hi n a strat u m defi n e d b y: 
1.  F or 2 3 2 S M 2 0 2 a g e of S M A o nset ( < = 6 m o nt hs, > 6 m o nt hs)  
2.  F or 
 
 
Dis ease d urati o n at first d ose = a ge at first d os e or s ha m pr oc e d ure - a g e of S M A o nset 
 
6. 1. 2     
I m p ut ati o n f or Dis pl a ys fr o m M M D R D a y 1 
 
I m p uti n g a n d wi n d o wi n g se q ue nce of e v e nts:  
T he effic ac y assess m e nt at M M D R Da y 1 (c orres p o n di n g t o b as eli ne) will be t he ass ess me nt at 
M M D R Da y 1 ( or a n y ot her visit wit hi n 6 0 d a ys pri or t o M M D R Da y 1 d osi n g date).  If t his 
assess m e nt is missi n g at M M D R Da y 1, t h e n it will b e i m p ute d p er t h e f oll o wi n g r ules: 
 
 F or H F M S E, R U L M a n d 
W H O, t h e s a m e m et h o d ol o g y f or i m p utati o n will b e us e d as 
d es cri be d i n secti o n 6. 1. 1 a n d t his will b e wit hi n t h e i n de x st u d y ar m i.e. C S 3 B pre vi o us 
c o ntr ol 
 F or C H O P I N T E N D, use li ne ar i nter p olati o n bet wee n visits t h at o cc urre d pri or t o M M D R 
Da y 1 a n d p ost M M D R Da y 1 (e. g. if ite m 1 of C H O P is missi n g b ut is pres e nt at visit Da y 
1 8 3 a n d M M D R Da y 2 4 0, t h e n li n ear i nter p olati o n will be use d t o i m p ute C H O P ite m 1). 
 
F or effic ac y visits p ost M M D R Da y 1: 
 
 Fr o m M M D R Da y 1, a n y u nsc h e d ule d or e n d of st u d y visits will be m a p p e d t o t h e sc h e d ule d 
M M D R visit usi n g a wi n d o w of +/- 6 0 d a ys ea c h si d e of t h e tar get d a y.  If > = 2 assess m e nts 
are assi g ne d t o t h e s a m e wi n d o w t he n t h e cl osest ass ess m e nt t o t h e tar g et da y will be s ele cte d. 
I n a sit uati o n w here t w o assess me nts are e q ui dista n ce t o t h e tar get da y, t h e n t he latest o ne 
will b e sele cte d. N o ot her wi n d o wi n g will be a p plie d f or t h ese a n al ys es. 
 F or s u bje cts wit h a n a vaila ble bas eli n e (eit her i m p ute d or o bser ve d), missi n g data o n st u d y 
will b e i m p ute d usi n g a c o nsiste nt a p pr oac h t o t h at defi ne d i n t he i nte grate d a n al ysis se cti o n. 
If li n ear i nt er p olati o n is use d, t h e n all t h e o bser ve d data will be us e d i n cl u di n g u nsc he d ule d 
visits. 
 
N ote t h at after t h e a b o ve i m p utati o ns, e xtra ste ps will b e ta ke n f or s u bjects w h o t o o k ris di pla m t o 
disti n g uis h visits u p t o ris di pla m ta k e n (ie pre-ris di pla m visits or S pi nraz a o nl y visits) a n d visits p ost 
ris di pla m. T his will all o w a nal yses t o b e perf or m e d w h ere t he res ult fr o m a n a nal ysis visit after 
i nitati o n of ris di pla m ca n b e e x cl u de d. All t h e rec or ds wit hi n a n a nal ysis visit will be e val u ate d 
a gai nst ris di pla m start d ate t o fla g t he ass ess m e nts ac c or di n gl y. F or t h ose res ults bei n g i m p ute d as 
a vera g e or li n ear i nter p olati o n, if all t h e rec or ds fr o m w hic h t h e i m p ute d res ults are c alc ulate d all 
o cc urre d pri or t o ris di pla m, a vera g e d or li near i nter p olate d res ults will be cle arl y n ote d as s uc h. 
Ot h er wise, o nl y res ults w hic h occ urre d pri or t o ris di pla m will b e us e d f or a n al yses w here ris di pla m 
use is e xcl u de d.  
   
 


     
   
 
 
   
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6. 2  Wi n d o wi n g 
Ass ess m e nts were wi n d o we d t o a nal ysis visits t o ac c o u nt f or t h e f oll o wi n g reas o ns: 
 
 e arl y cl os ure of i n d e x st u dies 
 g a p b et wee n i n d e x st u dies a n d C S 1 1 
 differe nt visit s c h e d ule wit hi n i n d e x st u dies a n d C S 1 1 a n d t h e i ntr o d u cti o n of a n e w sc h e d ule 
wit hi n C S 1 1 
 
T he pr o p ose d wi n d o ws are detaile d i n A p pe n di x A. F or i nte grate d dis pla y, if > = 2 assess m e nts are 
assi g ne d t o t he s a m e wi n d o w, a vera ge is ta ke n f or H F M S E, R U L M a n d C H O P I N T E N D. F or 
W H O/ HI N E M M, t h e cl osest ass ess m e nt t o t he t ar get d a y will be sele cte d. I n a sit uati o n w here t w o 
assess me nts are e q ual dista nc e t o t h e tar get d a y, t h e n t h e latest o ne will be s ele cte d.
6. 3  Res p o n de r A n al ysis  
Res p o n der a n al ysis b y visit will be p erf or me d b as e d o n C H O P I N T E N D ass ess m e nt a n d W H O 
milest o nes f or C S 3 B a n d C S 4 p o p ulati o ns, res pe cti vel y. 
 
At i nteri m a nal yses, i n or der t o ac c o u nt f or t h e d e n o mi nat or a cr oss t h e a n al ysis visits, a n Effic ac y 
set f or ea c h wi n d o we d a nal ysis visit ( Da y X) will be d efi n e d as: a s u bset of s u bjects i n t h e Safet y set 
w h o h a v e t h e o p p ort u nit y t o b e assess e d at t he Da y X visit, w here t he l o wer b o u n d f or t h e wi n d o we d 
a nal ysis visit are d e n ote d: L = l o wer. S p ecific all y, it will i n cl u de all s u bjects wit h a ti m e differe nc e 
of at le ast L da ys b et wee n t he d ate of first d ose a n d t he e n d of st u d y ( or s p e cific d ata c uts d ate). A 
s u bje ct w h o h as die d or wit h dra w n will be i n cl u d e d pr o vi d e d t h at t h ere is a differe n c e of at least L 
d a ys bet wee n t h e d ate of first d os e a n d t he e n d of st u d y ( or s p e cific d ata c uts d ate). If a s u bject was 
k n o w n t o ha v e wit h dra w n fr o m t he st u d y at a date, wit hi n t h e wi n d o w, d u e t o r olli n g o ver t o 
c o m m ercial n usi n ers e n dr u g, t h e n t h e y will be e xcl u de d fr o m t he c orres p o n di n g Effic ac y set a n d 
 
A n e v al ua ble s et will b e defi ne d f or e ac h a n al ysis visit as t h e s u bset of s u bjects i n t he Effic ac y set at 
t h e a n al ysis visit w h o me et t he f oll o wi n g criteria:  
 
 Val u e assi g ne d fr o m t h e wi n d o wi n g  
 S u bje ct w h o die d or dis c o nti n ue d fr o m t he st u d y 
 n o i m p utati o n of effic ac y data will be 
p erf or m e d f or s u c h s u bje cts a n d t he y will b e c o nsi dere d n o n-res p o n ders. 
 N o v al ue assi g n e 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 u e nt ass ess m e nt 
assi g ne d t o a later a nal ysis visit.  I n t his sit u ati o n, a val u e will be i m p ute d as t he last o bser ve d 
e arlier ass ess m e nt w h ere all ass ess m e nts m a d e wit hi n t he wi n d o w at t h e pre vi o us a nal ysis 
visit are c o nsi d ere d a n d t h e last assess me nt is pic ke d, rat h er t h a n o nl y c o nsi d eri n g a nal ysis 
visits. 
 
At t he fi nal a nal ysis, d ue t o t he v ar yi n g d urati o n of i n de x st u dies a n d t h e i ntr o d ucti o n of differe nt 
visit sc h e d ules t hr o u g h pr ot oc ol a me n d m e nts it m ea ns t h at s u bje cts ha ve var yi n g le n gt hs of f oll o w-
u p.  T his is attri b uta ble t o t he e arl y ter mi n ati o n of i n de x st u dies at i nteri m a nal yses f or effic ac y a n d 
w he n t he C S 1 1 a m e n d m e nt wit h M M D R visits was i ntr o d uc e d at sit es. T his mea ns t h at f or s u bjects 


     
   
 
 
   
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w h o disc o nti n u e d or die d it is n ot p ossi ble t o d eter mi n e h o w l o n g t h e y w o ul d ha v e b e e n f oll o we d if 
t h e y ha d c o m plete d C S 1 1.  I n or d er t o all o w res p o n der a nal yses t o be pres e nte d t he f oll o wi n g 
a p pr oac h will b e i m ple m e nte d f or t h e gr o u ps of s u bje cts bel o w.  
 
C H O P I N T E N D: 
 C S 3 B pre vi o us c o ntr ol fr o m t heir first n usi n ers e n d os e i n C S 1 1
 C S 3 B pre vi o us c o ntr ol fr o m t heir first s h a m pr oc e d ure i n C S 3 B a n d i ncl u di n g all effic ac y i n 
b ot h C S 3 B a n d C S 1 1
 C S 3 B pre vi o us I SI S 3 9 6 4 4 3 fr o m t h eir first n usi ners e n d os e i n C S 3 B 
 
W H O m ot or milest o nes:
 C S 4 pre vi o us c o ntr ol fr o m t heir first n usi ners e n d os e i n C S 1 1 
 C S 4 pre vi o us c o ntr ol fr o m t heir first s ha m pr oc e d ure i n C S 4 a n d i ncl u di n g all effic ac y i n 
b ot h C S 4 a n d C S 1 1 
 C S 4 pre vi o us I SI S 3 9 6 4 4 3 fr o m t h eir first n usi n erse n d ose i n C S 4 
Bel o w is a n e x a m ple of t h e a p pr oa c h f or C S 3 B pre vi o us I SI S s u bjects a n d t h e sa m e a p pr oa c h 
a p plies t o t h e ot her gr o u ps of s u bje cts. 
F or a gr o u p of p atie nts, ie C S 3 B pre vi o us I SI S, t h e patie nts w h o c o m plete d S HI N E will be 
c o nsi dere d a n d t he s h ortest f oll o w- u p ti m e will b e i de ntifie d as M. T h e wi n d o wi n g s c h e m e a p plie d 
t o t his gr o u p will b e cr oss c h ec ke d wit h M a n d t h e i nter v al w hic h is pri or t o t he o ne c o ntai ni n g M 
will b e i d e ntifie d as t h e m a xi m u m visit at w hic h a res p o n der a nal ysis will b e pres e nte d. 
F or e x a m ple wit h M = 1 4 2 0 a n d t h e f oll o wi n g i nter val a n d tar get da ys: 
 
St u d y da ys > 1 1 7 8 t o < = 1 4 1 8 will b e la bele d Da y 1 2 9 8 
St u d y da ys > 1 4 1 8 t o < = 1 6 5 8 will b e la bele d Da y 1 5 3 8
Si n ce M falls i n t h e Da y 1 5 3 8 i nter val it m e a ns t h at Da y 1 2 9 8 will b e t h e m a xi m u m visit u p t o 
w hic h a res p o n d er a n al ysis is pres e nte d. 
A d diti o nal c o nsi d erati o ns are descri b e d as b el o w: 
 T he d e n o mi nat ors f or res p o n d er a nal ysis acr oss visits will be fi x e d as f or t h e safet y set, 
h o we ver, s u bje cts w h o wit h dra w t o ta ke c o m mercial t h era p y or c o m plete t h e i n d e x st u d y a n d 
wit h dra w a n d ot h er wis e will b e re m o ve d fr o m t he d e n o mi nat or at s u bs e q ue nt visits. If t h e 
assess me nt is a vaila ble at t h e wit h dra wal, t h e res ult will b e e v al u ate d a g ai nst res p o n der 
criteria a n d c o u nte d as a res p o n der if criteria is m et.  
 F or s u bje cts w h o die d or disc o nti n ue d fr o m t he st u d y wit hi n t he i nter val ( wit h t he e xc e pti o n 
of s u bje cts descri b e d i n pre vi o us b ullet p oi nt)  n o i m p utati o n of effic ac y d ata will be 


     
   
 
 
   
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p erf or m e d a n d t he y will be c o nsi dere d as n o n-res p o n ders at visits fr o m w he n t h e y die d or 
wit h dra w. 
 
p oi nts, t he n t he res p o n d er stat us will be ass ess e d b ase d o n t h e res ult. 
 F or s u bje cts wit h n o val ue assi g n e d fr o m wi n d o wi n g, b ut k n o w n t o b e still i n st u d y at a 
s u bse q ue nt a nal ysis visit.  I n t his sit u ati o n, a val u e will be i m p ute d as t h e last o bser v e d e arlier 
assess me nt w here all assess me nts m a d e wit hi n t h e wi n d o w at t he pre vi o us a n al ysis visit are 
c o nsi dere d a n d t he last assess m e nt is pic k e d, rat her t h a n o nl y c o nsi deri n g a nal ysis visits.  
 I n a sit u ati o n f or C H O P I N T E N D w h ere n o s u bs e q ue nt assess me nts are a vaila ble a n d at t he 
last visit a sc ore of 6 4 was a c hie ve d t h e n t he last o bser ve d val u e will be use d as s u bse q ue nt 
assess me nts u ntil s u bje cts die d or disc o nti n ue d. 
Res p o n der a n al ysis will als o be pres e nte d f or C M A P at last visit f or t he f oll o wi n g gr o u ps of
s u bje cts a n d t he d e n o mi nat ors will b e as f or safet y p o p ulati o n:  
 C S 3 B s u bjects: fr o m b aseli n e of C S 3 B st u d y  
 C S 3 A s u bje cts: fr o m b aseli n e of C S 3 A st u d y 
 C S 2/ C S 1 2 s u bjects: fr o m baseli n e of C S 1 2 st u d y 
 I nfa ntile S M A o nset s u bje cts i n C S 1 1 fr o m M M D R Da y 1 
 Later S M A o nset s u bje cts i n C S 1 1 fr o m M M D R Da y 1 
6. 4  A n al ysis Met h o ds f or t he Effic a c y E n d p oi nts 
M ot or f u ncti o n assess m e nts will b e perf or me d at Scree ni n g a n d/ or pre d os e at M M D R Da y 1, e ver y 
8 m o nt hs u ntil M M D R Da y 7 2 0 a n d e v er y 1 2 m o nt hs t h ereafter. If m ot or f u ncti o n assess m e nts 
h a v e alrea d y b e e n perf or me d at Da y 9 6 0 f or a partici p a nt pri or t o a p pr o v al of Pr ot oc ol A m e n d m e nt 
Versi o n 4. 0 at a site, m ot or f u n cti o n ass ess me nts (i.e., C H O P I N T E N D, H F M S E, R U L M, 6 M W T, 
a n d c o ntract ure ass ess me nt) will still ne e d t o be assess e d at Da ys 1 0 8 0, 1 4 4 0, a n d 1 8 0 0.  
6. 4. 1     
M ot or Milest o nes 
Fr o m Pr ot oc ol A m e n d m e nt Versi o n 4, m ot or milest o n es will b e assess e d usi n g t h e W orl d Healt h 
Or g a niz ati o n ( W H O) M ot or Milest o nes criteria [ W H O M ultic e ntre Gr o wt h Refere n ce St u d y Gr o u p 
2 0 0 6; Wij n h o ve n 2 0 0 4]. F or s u bje cts < 2 ye ars of a ge w h o ha ve n ot y et a c hie ve d i n de pe n de nt 
wal ki n g, m ot or milest o n es will als o be assess e d usi n g Se cti o n 2 of t he HI N E. 
 
6. 4. 1. 1  W H O M ot o r 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 v el o p m e nt, all of w hic h w o ul d be 
e x p ecte d t o be attai n e d b y 2 4 m o nt hs of a g e i n h ealt h y c hil dre n. T h e i n di vi d ual milest o n es are: sitti n g 
wit h o ut s u p p ort, sta n di n g wit h assista n c e, h a n ds a n d k n ees cra wli n g, wal ki n g wit h assista nc e, 
sta n di n g al o n e a n d wal ki n g al o n e. T he W H O re p orte d [ W H O M ot or De vel o p m e nt St u d y] t hat i n 
a b o ut 9 0 % of c as es t he or d er of attai n me nt f oll o we d a fi xe d s e q ue nc e f or fi v e of t h e milest o nes 
( n a m el y, sitti n g wit h o ut s u p p ort, sta n di n g wit h assista n ce, wal ki n g wit h assista n c e, sta n di n g al o n e 
a n d wal ki n g al o ne) wit h o nl y h a n ds a n d k nees cra wli n g s hifti n g b et we e n t he e arlier milest o nes.  


     
   
 
 
   
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St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 
T he f oll o wi n g fi g ure s h o ws t he a ge i n m o nt hs at w hic h m ot or milest o n es are attai n e d a n d t h e b o u n ds 
of t h e 1 st a n d 9 9 t h p erce ntiles re p orte d b y t h e W H O. 
 
 
Wi n d o ws of milest o ne a c hieve me nt: W H O m ot or d ev el o p me nt st u d y  
 
As part of 
e m oti o nal state a n d t h e n f or e ac h milest o ne o ne of t h e f oll o wi n g f o ur classificati o ns:  
 
 N o (i n a bilit y) 
 C hil d trie d b ut faile d t o perf or m t he milest o n e  
 N o (ref us al) 
 C hil d ref use d t o p erf or m d es pite b ei n g cal m a n d alert  
 Yes 
 C hil d was a ble t o p erf or m t h e milest o ne  
 U na ble t o test 
 C o ul d n ot be teste d b e ca use of irrita bilit y, dr o wsi ness or sic k n ess  
 
A n al ys es  
  
 S u m m ar y of m ot or milest o n es at b as eli n e 
 
 A n y ne w m ot or milest o n es b y visit f or t h e i n de x st u d y C S 4 p o p ulati o n o nl y.  A s u bject will 
b e c o nsi dere d a res p o n der if at t h e visit u n d er c o nsi derati o n t h e y ca n still de m o nstrate t h e 
sa m e milest o n es t he y c o ul d ac hie v e at b aseli n e, b ut i n a d diti o n t h e y n ee d t o ha ve ac hie ve d at 
le ast o n e ne w milest o ne.
 
F or t h e f oll o wi n g gr o u ps a n d b as eli n es i) i n de x st u d y f or C S 4, ii) C S 1 1 baseli ne f or later- o ns et 
p atie nts a n d iii) fr o m M M D R Da y 1 f or all p atie nts, t w o t y p es of dis pla y will be pr o d uc e d as f oll o ws: 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 N u m b er of ne w m ot or milest o nes ac hi e v e d p er s u bje ct b y visit, de p e n di n g o n t h e gr o u p 
pres e nte d t his will be fr o m w he n W H O was c olle cte d. 
 Pr o p orti o n of s u bje cts ac hie vi n g milest o n es will be prese nte d wit h s hift ta bles s h o wi n g 
b as eli n e stat us a n d t h e n stat us at last visit (se e a d diti o n al d etail b el o w). U ni m p ute d res ults 
will b e use d f or s hift ta bles. 
 
S u m m ary of s hifts i n m ot or milest o n es 
 
F or e ac h milest o n e, t he pr o p orti o n of s u bje cts w h o ha ve t h e f oll o wi n g stat us will be pres e nte d b y 
b as eli n e stat us as f oll o ws: 
Ac hie ve d at b as eli n e
o
Mai ntai ne d ac hie ve m e nt  
if t he s u bje ct a c hie v e d t he milest o ne at baseli ne a n d all 
s u bse q ue nt assess m e nts 
o  Ac hie ve d at last visit ( n ot mai ntai n e d fr o m baseli n e ) 
o  I n a bilit y at last visit 
o  Die d 
o  Wit h dra w n f or reas o ns ot her t h a n d eat h 
 
 I n a bilit y at bas eli n e 
o  Ac hie ve d o n treat m e nt 
- 
i n a bilit y at last visit  
- 
Ac hie ve at last visit a n d d e m o nstrate d at all s u bse q u e nt visits f oll o wi n g first 
a c hie ve me nt 
- 
Ac hie ve d at last visit 
o  I n a bilit y at last visit 
o  Die d 
o  Wit h dra w n f or reas o ns ot her t h a n d eat h 
 
S u bje cts wit h u n k n o w n stat us at baseli ne will b e s u m m ariz e d usi n g t he sa m e cate g ories as f or 
i n a bilit y at bas eli n e.  S u bjects w h o disc o nti n u e d ue t o m o vi n g t o c o m mercial treat m e nt will be 
c o u nte d b as e d o n t h e last o bser ve d W H O res ult.
 
6. 4. 1. 2  HI N E M ot or Milest o nes 
 
M ot or milest o nes will be ass ess e d usi n g Secti o n 2 of t h e HI N E i n s u bje cts < 2 y ears of a g e w h o ha v e 
n ot y et ac hie ve d i n de pe n d e nt wal ki n g. HI N E m ot or milest o nes assess m e nt is c o m p ose d of 8 m ot or 
milest o ne cate g ories as f oll o ws: v ol u ntar y gras p, a bilit y t o ki c k i n s u pi n e p ositi o n, he a d c o ntr ol, 
r olli n g, sitti n g, cra wli n g, sta n di n g, a n d wal ki n g. Wit hi n e ac h m ot or milest o ne c ate g or y, t h ere are 3 
t o 5 le vels t h at c a n be ac hie v e d. All 8 m ot or milest o nes will be teste d d uri n g e a c h ass ess m e nt. A 
s u bje ct w h o res ults after testi n g all a p p e ar i n t he first c ol u m n ( n o gras p, n o kic ki n g, u n a ble t o 
m ai ntai n hea d u pri g ht, a n d s o o n) has n ot a c hie v e d a n y m ot or milest o n e. 
M ot or milest o n e 
a c hie ve me nt is de picte d b y m o v e m e nt fr o m t he left si d e of t h e ta ble t o t he ri g ht si d e of t h e ta ble, as 
d e n ote d b y t h e Milest o n e Pr o gressi o n arr o w i n t h e ta ble ( Ha ataja 1 9 9 9). 
 


     
   
 
 
   
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St atistical A nal ysis Pl a n  
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M ot or 
mil e st o n e 
Mil e st o n e Pr o gr e s si o n 
------------------------------------------------------------------------------------------------------------ 
 
 
V ol u nt ar y gr a s p   
N o gr a s p
U s e s w h ol e h a n d 
 
 
 
Fi n g er 
a n d t h u m b; 
i m m at ur e gr a s p 
Pi n c er gr a s p     
 
 
 
 
 
 
A bilit y t o 
ki c k 
(i n s u pi n e) 
N o ki c ki n g 
Ki c k s h ori z o nt al; l e g s 
d o n ot lift 
U p w ar d ( v erti c all y)     
T o u c h e s l e g 
T o u c h e s t o e s 
 
 
 
( 3 m o nt h s) 
( 4- 5 m o nt h s)     
( 5- 6 m o nt h s) 
H e a d c o ntr ol 
U n a bl e t o m ai nt ai n 
u pri g ht
W o b bl e s 
 
All t h e ti m e u pri g ht 
 
 
( n or m al < 3 m o)     
( 4 m o nt h s) 
( 5 m o nt h s) 
 
 
 
 
 
 
R olli n g 
N o r olli n g 
R olli n g t o si d e     
Pr o n e t o s u pi n e     
S u pi n e t o pr o n e     
 
 
 
( 4 m o nt h s) 
( 6 m o nt h s) 
 
 
 
 
 
 
Sitti n g 
C a n n ot sit 
Sit 
wit h 
s u p p ort at 
hi p s 
Pr o p s 
St a bl e sit 
Pi v ot s 
(r ot at e s) 
 
 
( 4 m o nt h s) 
( 6 m o nt h s) 
( 7 m o nt h s 
( 1 0 m o nt h s) 
 
 
 
 
 
Cr a wli n g 
D o e s n ot lift h e a d     
O n el b o w 
O n o ut str et c h e d 
h a n d 
Cr a wli n g fl at o n 
a b d o m e n 
O n h a n d s a n d 
k n e e s 
 
 
( 3 m o nt h s) 
( 4- 5 m o nt h s)     
( 8 m o nt h s) 
( 1 0 m o nt h s) 
 
 
 
 
 
St a n di n g    
D o e s 
n ot s u p p ort 
w ei g ht 
S u p p orts w ei g ht     
St a n d s wit h s u p p ort     
St a n d s u n ai d e d     
 
 
 
( 4- 5 m o nt h s)     
( 8 m o nt h s) 
( 1 2 m o nt h s) 
 
 
 
 
 
 
W al ki n g 
N o w al ki n g
B o u n ci n g 
Cr ui si n g ( w al k s 
h ol di n g o n) 
W al ki n g 
i n d e p e n d e ntl y 
 
 
 
( 6 m o nt h s) 
( 1 1 m o nt h s) 
( 1 5 m o nt h s) 
 
 
 
 
 
 
 
T he a g e restricti o n ( < 2 ye ars of a ge) d es cri b e d a b o ve was i ntr o d uce d as p art of Pr ot oc ol A m e n d m e nt 
Versi o n 2. T h e m aj orit y of s u bjects will st o p t he HI N E m ot or milest o ne ass ess m e nt b y M M D R Da y 
1 ( b ec a use t h e y will be > 2 ye ars of a ge b ef ore or ar o u n d t his visit). 
 
A n alyses 
 
HI N E M M a nal ysis will be d o ne f or C S 3 B s u bjects.  
 
 S u m m ar y of t otal m ot or milest o nes at baseli n e.  


     
   
 
 
   
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St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 T he c ha n g e i n t otal m ot or milest o nes fr o m b aseli ne o v er ti m e. 
 S u m m ar y of hi g h est m ot or milest o nes ite m a c hie ve d at last a n al ysis visit.        
                                                                                                                                                                           
T he s u bje cts t hat e nter t h e st u d y fr o m 2 3 2 S M 2 0 2 will be u n der Pr ot oc ol A m e n d m e nt Versi o n 3. 
Si n ce t h e y are e x p ecte d t o b e greater t ha n t w o y ears of a g e, we d o n ot e x pe ct a n y m ore HI N E- 2 
assess me nts p erf or m e d i n C S 1 1.
 
T he HI N E- 2 m ot or milest o n e res p o n der a nal ysis d efi n e d i n t he pr ot o c ol will n ot be pres e nte d si n ce 
t h ere are differe nt d urati o ns of f oll o w- u p f or s u bje cts d e p e n di n g w h e n t he a m e n d me nt was 
i m ple m e nte d. HI N E- 2 data will be c o m bi ne d wit h W H O d ata as d escri b e d i n t he f oll o wi n g Secti o n. 
6. 4. 1. 3  HI N E a n d W H O M ot o r Milest o nes 
F or C S 3 A a n d C S 3 B t he HI N E- 2 a n d W H O milest o n e res ults will b e c o m bin e d t o all o w ass ess m e nt 
of ac hie v e m e nt d uri n g t he e ntire treat m e nt peri o d fr o m first d os e i n t h e i n de x st u d y.  T he f oll o wi n g 
d efi niti o ns will b e utilize d:
 
Milest o nes  
HI N E -2  
W H O
Sitti n g  
Sta ble sit or Pi v ots r otates   
Sitti n g wit h o ut s u p p ort  
Cra wli n g  
O n ha n ds a n d k n ees     
Ha n ds a n d K nees Cra wli n g  
Sta n di n g wit h assista n c e    
Sta n ds wit h s u p p ort or sta n ds 
u nai d e d 
Sta n di n g wit h assista n e. 
Sta n di n g al o n e  
Sta n ds u n ai d e d  
Sta n di n g al o n e  
Wal ki n g wit h assista nc e    
Cr usi n g ( wal ks h ol di n g o n) 
or Wal ki n g i n d e p e n d e ntl y  
Wal ki n g wit h assista nc e 
Wal ki n g al o n e  
Wal ki n g i n de pe n d e ntl y     
Wal ki n g Al o ne  
T he first i nsta nc e t h at p atie nt a c hie ves a milest o ne b ase d o n t hes e defi niti o ns will be d eter mi n e d.  
D ue t o t he pres e n ce of de at h t h e Fi n e a n d Gra y m o d el ( Fi ne et al 1 9 9 9) will be i m ple m e nte d t o 
i n cl u de deat h as a c o m peti n g ris k. Pl ots of t h e c u m ulati ve i nci d e nc e f or e ac h milest o ne b y st u d y da y 
will b e prese nte d a n d t h e c u m ulati v e i n ci de nce at 1, 1. 5, 2, 3, 4 a n d 5 years wit h c orres p o n din g 
c o nfi d e nce i nter vals pres e nte d. 
 
6. 4. 2     
Ti m e t o E ve nt E n d p oi nts 
Ev e nt of p er m a ne nt ve ntil ati o n or d e at h  
 
I n C S 3 B a n d 2 3 2 S M 2 0 2, p er ma n e nt ve ntilati o n was defi n e d as tra c he ost o m y or > = 1 6 h o urs of 
v e ntilat or s u p p ort p er d a y c o nti n u o usl y f or > 2 1 da ys i n t he a bse n ce of a n ac ute re v ersi ble e ve nt.  A 
g ui da nce d o c u m e nt c o ntai ni n g details o n h o w a n ac ute re v ersi ble e v e nt was d efi n e d i n cl u di n g t h e 
c o n ce pt of a grac e peri o d, was pr o vi de d t o sites. T he grace peri o d of a n ac ute re v ersi ble e ve nt was 
d efi ne d as 1 4 d a ys after t he e ve nt, t h e starti n g p oi nt t h e t hres h ol d of p er m a ne nt v e   
 1 6 
h o urs per d a y) f or > 2 1 c o nsec uti v e da ys starts t o c o u nt. T h e rati o nale is t h at i n t h e c o nte xt of a n 


     
   
 
 
   
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St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
re c o ver fr o m s ur ger y/a nest h esia.  O n ce t h e grac e peri o d has e x pire d, if t h e s u bject re q uires t hres h ol d 
le vel ve ntilati o n f or > 2 1 c o ns ec uti ve d a ys, t his res pirat or y de p e n de nc e is li kel y t o be d ue t o S M A 
dise as e pr o gressi o n a n d t he e n d p oi nt is m et. 
 
T he ori gi n al defi niti o n of per m a n e nt v e ntilati o n i n C S 3 A was > = 1 6 h o urs of v e ntilati o n p er da y 
c o nti n u o usl y f or at least 1 4 da ys i n t h e a bse n c e of a n a c ute re v ersi ble ill n ess.  I n t he C S 1 1 Pr ot o c ol 
A m e n d me nt Versi o n 2, C S 3 A e n d p oi nt was u p date d t o m atc h t he C S 3 B defi niti o n ( > = 1 6 h o urs of 
v e ntilati o n per d a y c o nti n u o usl y f or at least 2 1 da ys i n t he a bse nc e of a n a c ute re v ersi ble ill n ess).  
E xa mi n ati o n of t he ve ntilati o n d ata c olle cte d i n C S 3 A b ef ore e ntr y t o C S 1 1 re v eale d t h at it w o ul d 
b e i m p ossi ble t o reass ess C S 3 A s u bjects u n d er t h e C S 3 B defi niti o n. C S 3 A s u bje cts t hat ha ve n ot yet 
re ac he d t he e n d p oi nt i n t h e i n de x st u d y, will b e ass esse d i n C S 1 1 usi n g t he C S 3 B d efi niti o n f or 
e n d p oi nt. 
 
Ve ntilati o n use d uri n g t he st u d y will be c olle cte d via t h e ve ntilati o n diar y f or all t he s u bje cts. T he 
m et h o d ol o g y of rec or di n g t he v e ntilati o n data wit hi n t h e e C R F h as c ha n g e d o v er t he c o urse of t he 
st u d y.  Ori gi n all y e v er y d a y was e ntere d w hic h f oll o we d t h e a p pr oa c h i n t h e C S 3 B st u d y, b ut t his 
a n d t h e n e ntere d f or a 
mi ni m u m of 3 0 da ys. I n a d diti o n, t h e i n vesti g at or was as k e d t o assess t h e v e ntilati o n e n d p oi nt a n d 
re c or d t he d ate of t h e 2 2 n d da y of c o ns ec uti v e v e ntilat or use at of > = 1 6 h o urs a n d n ote t h e prese nc e 
of a n ac ute re versi ble e v e nt. T h e C R F p a ge of v e ntilati o n e n d p oi nt will be c o nfir m e d b y t h e sites 
re gar dless w h et her a s u bject h as m et p er m a n e nt ve ntilati o n criteria or n ot. 
 
All t h e a b o v e i nf or m ati o n, al o n gsi d e a d v erse e ve nts, a n cillar y pr oc e d ures a n d h os pitaliz ati o n data 
fr o m t h e e C R F will b e ta k e n i n ac c o u nt i n v erif yi n g if a n y s u bjects ha ve m et t he e n d p oi nt as c olle cte d 
fr o m v e ntilati o n e n d p oi nt C R F p a g e.  T his v erific ati o n will b e perf or m e d b y t h e Bi o ge n m e dic al 
dire ct or a n d statisticia n. 
 
If n e cessar y, missi n g dail y v e ntilat or use, i n t h e ori gi n al p art of t h e st u d y w here v e ntilati o n was 
c olle cte d dail y a n d i m p utati o n will b e p erf or me d usi n g t h e greater of t h e da ys t h at fla n k t h e missi n g 
d a y(s).  S h o ul d t h e dail y ve ntil ati o n us e be re p orte d as a ra n ge, e. g., 6 t o 1 2 h o urs, t h e m a xi m u m will 
b e us e d. F oll o wi n g Pr ot o c ol A m e n d m e nt Versi o n 2, ve ntilati o n data was n ot c olle cte d d ail y b y t h e 
sites, a n d i m p utati o ns will n ot b e perf or m e d.  
 
A n alyses 
 
T h e Ka pla n- Meier m et h o d will b e us e d f or esti m ati n g t h e ti m e fr o m first d ose i n C S 3 A, C S 3 B a n d 
2 3 2 S M 2 0 2 f or t h e f oll o wi n g e n d p oi nts: 
 
 t o d eat h 
 t o p er m a ne nt ve ntilati o n 
 t o d eat h or p er m a n e nt v e ntilati o n or trac h e ost o m y 
 Pl ots of K M c ur ves will be pres e nte d 
 
F or C S 3 B s u bje cts i n C S 1 1, t h e esti m ate d ti me t o de at h fr o m t h e first d ose / s h a m pr o ce d ure i n C S 1 1 
will als o be pres e nte d usi n g Ka pla n- Meier m et h o d.  


     
   
 
 
   
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St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 
S u bje cts w h o d o n ot m eet t h e e n d p oi nt d efi niti o n will b e ce ns ore d f or:
 
 ti m e t o de at h at t he last o cc asi o n t h e s u bject was se e n a n d c o nfir m e d ali ve (eit her i n- p ers o n 
visit or b y tele p h o n e c o ntact) 
 ti m e t o per ma n e nt ve ntilati o n at t h e last date a s u bject h a d a diar y e ntr y f or ve ntilati o n w here 
s u bje ct wit h dre w pri or t o m o vi n g o nt o Pr ot o c ol A m e n d m e nt Versi o n 2.  F or s u bje cts w h o 
m o ve d o v er t o h a ve diar y c olle cti o n less fre q u e ntl y t he last occ asi o n t h e s u bje ct was se e n a n d 
c o nfir me d ali v e will b e us e d. S u bje cts w h o die d pri or t o t he e ve nt will be ce ns ore d. 
 
T he refere nce d ate f or c alc ulati o n of ti m e t o e v e nt will b e d ate of t h e first d os e.
 
I n a d diti o n, t h e pr o p orti o ns of s u bje cts w h o die d or met per m a n e nt ve ntilati o n will be s u m m arize d 
f or s u bje cts i n C S 1 1.  
 
6. 4. 3     
C H O P I N T E N D
of 6 4 is ac hie ve d a n d after t h e y will st o p t his assess m e nt. 
 
T he C H O P I N T E N D i nfa nt m ot or f u ncti o n sc ale is c o m pris e d of 1 6 test ite ms, ni n e of w hic h are 
sc ore d 0, 1, 2, 3, or 4 wit h gre ater sc ores i n dic ati n g greater m us cle stre n gt h, fi v e are sc ore d as 0, 2, 
or 4, o ne is sc ore d as 0, 1, 2, or 4, a n d o ne as 0, 2, 3, or 4. T his ca n res ult i n a w orst p ossi ble t otal 
sc ore of 0 t o a b est p ossi ble t otal sc ore of 6 4. C H O P I N T E N D is us e d t o assess s p o nta ne o us 
m o ve m e nt i n t h e u p per e xtre mities, s p o nta ne o us m o ve m e nt i n t h e l o wer e xtr e mities, h a n d gri p, h ea d 
i n mi dli n e wit h vis u al sti m ulati o n, hi p a d d uct ors, r olli n g elicite d fr o m t h e le gs, r olli n g elicite d fr o m 
t h e ar ms, s h o ul der a n d el b o w fle xi o n a n d h oriz o ntal a b d u cti o n, s h o ul d er fle xi o n a n d el b o w fle xi o n, 
k ne e e xte nsi o n, hi p fle xi o n a n d f o ot d orsifle xi o n, he a d c o ntr ol, el b o w fle xi o n, n e c k fle xi o n, 
h ea d/ nec k e xte nsi o n, a n d s pi nal i n c ur vati o n.  C H O P I N T E N D is t o b e e val u ate d d uri n g t h e st u d y. 
F or ea c h ite m, a s c ore will b e c olle cte d o n t h e left a n d ri g ht si d e.
Defi niti o n of Res p o n d er
 
A s u bject is d efi n e d as a C H O P I N T E N D res p o n der if t h e c h a n g e fr o m baseli n e i n C H O P I N T E N D 
t otal s c ore is greater or e q ual t o 4 p oi nts. A d diti o nal detail re g ar di n g h a n dli n g of t his are d escri b e d 
i n Secti o n 6. 3.  
 
I n or der t o e x a mi n e if t h e res p o nse is c o nsiste nt wit h a ra n ge of t hres h ol ds, t he pr o p orti o n of s u bjects 
a c hie vi n g: w orse ni n g of > = 6, > = 5, > = 4, > = 3, > = 2, > = 1 p oi nts, n o c h a n ge ( = 0 p oi nts), a n d 
i m pr o ve me nt of > = 1, > = 2, > = 3, > = 4 (e n d p oi nt f or m ai n a n al ysis), > = 5, > = 6 p oi nts will be pres e nte d. 
 
A n alyses 
 S u m m ar y at baseli n e.  
 T he c ha n g e fr o m baseli n e o ver ti m e 
 T hres h ol ds of c h a n ge fr o m b aseli n e b y visit.  


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 Pl ots of b ot h t otal s c ore a n d c h a n g e fr o m baseli ne. 
 Perce nta g es of p atie nts w h o a c hie v e p artic ular t hres h ol ds (e. g. 
4 0,  5 0). 
 F or C S 3 B s u bje cts (i n d e x st u d y + C S 1 1 i nte grate d) a n d a g e at first d ose dis pla y, s p a g hetti 
pl ots of t otal s c ore vs. a g e at visit will be prese nte d wit h fitte d li n es dis pla y e d. 
 
6. 4. 4     
C M A P 
C M A P ( C o m p o u n d M us cle Acti o n P ote ntial) is a n ele ctr o p h ysi ol o gical m eas ure us e d t o d eter mi n e 
t h e a p pr o xi m ate n u m b er of m ot or ne ur o ns i n a m uscle or gr o u p of m uscles. C M A P a m plit u d e a n d 
C M A P area will b e e val u ate d at t w o sites, ri g ht si de ul n ar n er v e a n d ri g ht si d e p er o neal n er ve.  C M A P 
was c olle cte d fr o m Scree ni n g i n C S 1 1 f or all s u bje cts e x ce pt t h os e pre vi o usl y d os e d i n C S 4.  
F oll o wi n g t he i m ple m e ntati o n of versi o n 2. 0 of t he pr ot o c ol, fr o m t h e M M D R Da y 1 visit, all s u bje cts 
will h a v e C M A P a d mi nistere d.
 
T he a nal yses of C M A P will b e base d o n o bser ve d val ues. T he c h a n ge a n d p erce nta ge c ha n ge fr o m 
b as eli n e C M A P a m plit u de a n d C M A P area at e ac h sit e will b e pres e nte d b y wi n d o we d a nal ysis visit. 
A pl ot of t he m e a n c ha n g e fr o m baseli ne o ver ti m e a n d t h e act u al s c ore o v er ti me will be prese nte d 
a n d si milarl y a pl ot of t h e p erce nta g e c h a n g e will b e pr o vi d e d.  
 
T he pr o p orti o n of s u bjects wit h: i) a w orse ni n g fr o m baseli ne i n C M A P a m plit u de of > = 0. 3 m V, 
> = 0. 5 m V, > = 1 m V, > = 2 m V a n d > = 3 m V a n d ii) a n i m pr o v e m e nt fr o m baseli n e i n C M A P a m plit u d e 
of > = 0. 3 m V, > = 0. 5 m V, > = 1 m V, > = 2 m V a n d > = 3 m V a n d iii) n o c h a n ge as a c ha n ge of b et wee n -
0. 3 a n d 0. 3 m V (- 0. 3 < C M A P a m plit u d e < 0. 3) will b e prese nte d f or ea c h site b y visit.  
 
T he a nal yses will be perf or m e d f or t h e i nfa ntile o ns et ( C S 3 A, C S 3 B) a n d later o ns et ( C S 2/ C S 1 2) 
st u dies w h ere C M A P was ca pt ure d i n t he i n de x st u d y or c olle cte d fr o m t h e i nitiati o n of C S 1 1.  
A d diti o nall y, C M A P will b e s u m m ariz e d f or all s u bjects fr o m M M D R Da y 1. 
 
Res p o n der a n alysis   
 
A s u bject is d efi n e d as a res p o n d er if (s) he ha d a p er o n eal a m plit u d e > = 1 m V at last visit (i n cl u di n g 
t h e a m plit u de > = 1 m V at b as eli n e a n d als o de m o nstrate d as s u c h at last visit). T h e pr o p orti o n of 
res p o n ders will b e s u m m ariz e d. T h e res p o n der a n al yses will b e pres e nte d f or t h e f oll o wi n g gr o u ps 
of s u bje cts:  
 C S 3 B s u bjects: b as eli n e fr o m C S 3 B st u d y t hr o u g h C S 1 1 
 C S 3 A s u bje cts: b as eli n e fr o m C S 3 A st u d y t hr o u g h C S 1 1 
 C S 2/ C S 1 2 s u bjects: b aseli n e fr o m C S 1 2 st u d y t hr o u g h C S 1 1
 I nfa ntile S M A o nset s u bje cts i n C S 1 1 fr o m M M D R Da y 1 
 Later S M A o ns et s u bje cts i n C S 1 1 fr o m M M D R Da y 1 
 
6. 4. 5     
H F M S E 
T he Ha m m ers mit h F u n cti o n al M ot or Sc ale 
 E x pa n de d ( H F M S E) is a t o ol use d t o ass ess m ot or 
f u ncti o n i n c hil dre n wit h S M A.  T he sc ale was ori gi n all y d e vel o pe d wit h 2 0 sc ore d a cti vities a n d 
was d e vise d f or use i n c hil dre n wit h T y p e 2 a n d T y p e 3 S M A wit h li mite d a m b ulati o n t o gi ve 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
o bjecti v e i nf or m ati o n o n m ot or a bilit y a n d cli nic al pr o gressi o n.  T h e e x p a n de d s cale i ncl u d es a n 
a d diti o nal m o d ule of 1 3 ite ms de vel o pe d t o all o w e v al u ati o n of a m b ulat or y S M A p atie nts.   
 
Eac h ite m is s c ore d 0, 1 or 2 a n d t h e t otal s c ore is c alc ulate d b y s u m mi n g t he 3 3 ite ms a n d ra n ges 
fr o m 0 t o 6 6 wit h hi g her s c ores i n dicati n g greater m ot or f u ncti o n. If 6 or fe wer ite ms are missi n g, 
t h e n t h ese ite ms will be i m p ute d t o b e 0 w he n s u m mi n g all 3 3 ite ms.   P ost baseli n e, if greater t h a n 
6 ite ms are missi n g, t h e n t he t otal sc ore will be i m p ute d b y i nter p olati n g sc ores b et wee n t he pre vi o us 
a n d s u bse q u e nt visit or, if t here is n o s u bse q ue nt visit, b y usi n g t h e s c ore fr o m t h e pre vi o us visit. 
 
T he pr o p orti o n of s u bjects a c hie vi n g a res p o nse o ver ti m e will b e prese nte d as f oll o ws: 
T he pr o p orti o n of s u bje cts ac hie vi n g: w orse ni n g of > = 1 0, > = 5, > = 3, > = 2, > = 1 p oi nts, a n y 
w orse ni n g, n o c ha n g e ( = 0 p oi nts), a n y i m pr o v e me nt, > = 1, > = 2, > = 3, > = 5, > = 1 0 p oi nts i m pr o v e me nt 
will b e prese nte d. 
 
A n alyses  
 
 H F M S E at bas eli n e
 C h a n ge fr o m baseli ne 
 T hres h ol ds of c h a n ge fr o m b aseli n e  b y visit 
 T hres h ol ds of c h a n ge fr o m b aseli n e t o last a vaila ble assess m e nt
 T otal sc ore b y visit ( Wi n d o we d visits u p t o Da y 3 5 0, Last assess me nt pri or t o M M D R Da y 1 
a n d b y M M D R visit)
 Pl ots of b ot h t otal s c ore a n d c h a n g e fr o m baseli n e a n d i n di vi d u al s c ores o ver ti me.  
F or C S 4 s u bje cts (i n de x st u d y + C S 1 1 i nte grate d) a n d a ge at first d os e dis pla y, a mi xe d m o d el 
of re pe ate d me as ure m e nts ( M M R M) will b e use d t o a n al yz e c h a n ge fr o m baseli n e b y visits 
wit h a g e gr o u p, visit a n d t h eir i nter a cti o n as m ai n fa ct ors, a n d b as eli n e H F M S E a n d a g e at 
first- d ose as c o variates. Baseli ne H F M S E b y visit i nteracti o ns will als o be i ncl u d e d i n m o del. 
U nstr uct ure d c o varia nc e matri x will b e use d. Least s q uare ( L S) m ea ns a n d 9 5 % c o nfi d e n ce 
i nter vals ( CI) will b e esti m ate d. M o del c o n v er ge nc e will be c h e c k e d a n d if n o n-c o n ver g e nce 
e xists, it will b e i n vesti g ate d b y statisticia n a n d a p pr o priate a dj ust m e nts ma y b e i m ple m e nte d.  
T he s a me M M R M m o d el will be use d b ut e x cl u di n g d ata f oll o wi n g i nitiati o n of ris di pla m 
treat m e nt. 
 F or C S 3 B or C S 4 s u bjects (i n de x st u d y + C S 1 1 i nte grate d) a n d a g e at first d os e dis pla y, 
s p a g h etti pl ots of t otal sc ore vs. a g e at visit will be pres e nte d wit h fitte d li n es dis pla y e d. 
 
As all s u bje cts are eli gi ble t o ha v e H F M S E assess e d fr o m Pr ot oc ol Versi o n 2 a n d t he M M D R Da y 1 
visit t he f oll o wi n g will be prese nte d: 
 
 S u m m ar y of t otal s c ore fr o m M M D R Da y 1 b y visit 
 
S u m m ar y statistics will be dis pla y e d f or b ot h t h e sc ore a n d c h a n ge fr o m baseli ne o ver wi n d o we d 
a nal ysis ti me.  T h e m ea n sc ore a n d m e a n c ha n g e fr o m baseli ne o v er ti m e will b e pres e nte d 
gra p hicall y wit h err or bars t o d e n ote t h e sta n d ar d err or of m e as ure me nt.  I n t his dis pla y t h e n u m ber 
of s u bje cts at e ac h wi n d o we d a n al ysis visit will be dis pla y e d b el o w t h e x-a xis.   
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
T he a nal yses will be p erf or me d f or t h e later o nset st u dies w here H F M S E w as c a pt ure d i n t h e i n d e x 
st u d y or c olle cte d fr o m t he i nitiati o n of C S 1 1.  A d diti o n all y, H F M S E will b e s u m m ariz e d f or all 
s u bje cts fr o m M M D R Da y 1. 
 
6. 4. 6     
U p pe r Li m b M o d ule ( U L M) a n d Re vis e d U p per Li m b M o d ule ( R U L M) Tests 
T he U p per Li m b M o d ule Test ( U L M) is a n o utc o m e m eas ure s p ecificall y de vel o pe d t o assess u p per 
li m b f u ncti o nal a bilities i n patie nts wit h S M A, i ncl u di n g y o u n g c hil dre n a n d patie nts wit h se v ere 
c o ntra ct ures i n t h e l o wer li m bs i n w h o m t h e p ossi bilit y t o dete ct f u n cti o nal c h a n ges, s uc h as r olli n g 
or l o n g sitti n g, is li mite d. T w o v ersi o ns of t h e test were a d mi nistere d t o C S 1 1 p artici p a nts wit h 
s u bje cts pre vi o usl y e nr olle d i n C S 1 2 w h o were n o n-a m b ulat or y perf or mi n g t h e 9 ite m test ( U L M) 
( Ma zz o n e et al. 2 0 1 1) a n d s u bjects e nr olle d i n C S 4 pre vi o usl y, p erf or mi n g t h e re vis e d 1 9 ite m test 
( R U L M: Re vise d U p p er Li m b M o d ule) test ( Maz z o n e et al. 2 0 1 6). As p art of t h e pr ot oc ol v ersi o n 2 
a me n d me nt t he re vise d 1 9 ite m test will b e a d mi nistere d t o all n o n-a m b ulat or y s u bje cts.
 
A d eri v e d t otal s c ore will b e c alc ulate d b y s u m mi n g t he sc ores fr o m t h es e i n di vi d u al ite ms.  If, f or 
a n i n di vi d u al ite m, a res p o nse is rec or de d f or b ot h t h e left a n d ri g ht si de t he hi g hest s c ore will b e 
use d i n calc ulati n g t he t otal. F or t h e 1 9 ite m test, if 3 or fe wer ite ms are missi n g t h e n t hese ite ms will 
b e i m p ute d t o b e 0 w h e n s u m mi n g all ite ms. F or t he 9 ite ms test if 1 ite m is missi n g t h e n t his will be 
i m p ute d t o be 0 w h e n s u m mi n g all 9 ite ms.   
 
A n u m ber of pres e ntati o ns will b e m a d e t o e x pl ore t h e u p per li m b sc ore o v er ti m e a n d prese ntati o ns 
will b e m a de usi n g t h e 1 9 ite ms a n d 9 ite ms s cale se p aratel y.  I n or der t o all o w t h e C S 2 s u bje cts t o 
b e f oll o we d o v er ti m e as t he y tra nsiti o n b et wee n sc ale a n     
 a n al ysis will b e perf or m e d 
w here t otal R U L M s c ore is m a p pe d t o b e o n t he U L M sc ale ( Re vis e d u p p er li m b m o d ule f or s pi nal 
m usc ular atr o p h y: De vel o p me nt of a n e w m o d ule, Maz z o ne et al 2 0 1 7). 
 
I n or der t o f urt h er e x pl ore t he res p o ns e as meas ure d b y u p p er li m b sc ore a n u m b er of t hres h ol ds will 
b e e v al u ate d:  T he pr o p orti o n of s u bjects a c hie vi n g: w orse ni n g of > = 1 0, > = 5, > = 3, > = 2, > = 1 p oi nts, 
a n y w orse ni n g, n o c ha n g e, a n y i m pr o ve m e nt, > = 1, > = 2, > = 3, > = 5, > = 1 0 p oi nts i m pr o ve m e nt will be 
pres e nte d. 
A n alyses 
 
 R U L M at b aseli n e  
 U L M/ R U L M C ha n g e fr o m baseli ne a n d act ual sc ore b y visit 
 R U L M T hres h ol ds of c ha n ge fr o m baseli n e b y visit 
 Pl ots of R U L M t otal s c ore a n d c ha n g e fr o m baseli ne.  
 F or C S 4 s u bje cts (i n d e x st u d y + S HI N E i nte grate d), a mi x m o d el of re p eate d m eas ure m e nts 
( M M R M) will b e use d t o a n al y ze c ha n g e fr o m baseli ne b y visits wit h a g e gr o u p, visit a n d 
t h eir i nteracti o n as m ai n fact ors, a n d b aseli n e R U L M a n d a ge at first- d ose as c o v ariates. 
Baseli n e H F M S E b y visit i nteracti o ns will als o be i ncl u d e d i n m o del. U nstr u ct ure d 
c o v aria nce matri x will b e us e d. Le ast s q uare ( L S) m ea ns a n d 9 5 % c o nfi de nce i nter vals ( CI) 
will b e esti m ate d. M o del c o n ver ge nc e will b e c hec ke d a n d if n o n-c o n v er ge nce e xists, it will 
b e i n vesti g ate d b y statisticia n a n d a p pr o priate a dj ust m e nts m a y b e i m ple m e nte d.  
 T he sa m e M M R M m o d el will b e us e d b ut e xcl u di n g d ata f oll o wi n g i nitiati o n of ris di pla m.  


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 F or C S 3 B or C S 4 s u bjects (i n de x st u d y + C S 1 1 i nte grate d) a n d a ge at first d os e dis pla y, 
s p a g h etti pl ots of t otal sc ore vs. a g e at visit will be pres e nte d wit h fitte d li n es dis pla y e d. 
 
T he a nal yses will be p erf or me d f or t h e i nfa ntile a n d later o ns et st u dies w here a vaila ble i n t h e i n d e x 
st u d y or c olle cte d fr o m t h e i nitiati o n of C S 1 1.  A d diti o nall y, R U L M will b e s u m m arize d f or all 
s u bje cts w h o ha ve re cei v e d a d os e at M M D R Da y 1, fr o m M M D R Da y 1. 
 
6. 4. 7     
6 Mi n ute- W al k Test  
T he 6 Mi n ute- Wal k Test ( 6 M W T) is a n o bjecti ve e val u ati o n of f u ncti o nal e x ercise c a p a bilit y w hic h 
m eas ures t h e dista nc e a pers o n ca n wal k q uic kl y i n 6 mi n utes.  T h e 6 M W T ca n be perf or m e d safel y 
i n a m b ulat or y pati e nts wit h S M A a n d c orrelates wit h sta n d ar d S M A o utc o m e m e as ures, i n cl u di n g 
ti m e d wal ki n g tests ( M o ntes et al. 2 0 1 0).  I n S M A, t h e 6 M W T m a y be m ore se nsiti v e t o cli nic all y 
m ea ni n gf ul c ha n ges i n patie nts wit h T y pe 3 S M A as it is a direct m e as ure of t h eir f u n cti o nal m o bilit y.  
T he 6 M W T h as als o be e n us e d as a pri m ar y o utc o m e m eas ure i n s e v eral cli nical trials i n 
n e ur o m usc ular dis ease i ncl u di n g D uc he n ne 
M usc ular D ystr o p h y ( Mc D o nal d et al. 2 0 1 0) a n d 
late- o nset P o m pe dis ease ( v a n der Pl o e g et al. 2 0 1 0).  
 
As p art of t he n usi nerse n cli nic al de vel o p m e nt pr o gra m, t his test was o nl y a d mi nistere d t o 
a m b ulat or y s u bjects a n d o nl y c ollecte d i n C S 2 a n d C S 1 2 a n d t he n i ntr o d uce d f or C S 4 s u bje cts i n 
C S 1 1.  I n C S 1/ 2 a n d C S 4, a s u bje ct was c o nsi dere d a m b ulat or y if h e/s h e was a ble t o wal k 1 5 feet 
i n d e p e n de ntl y ( wit h o ut s u p p ort or braces). I n C S 1 1, a m b ulat or y is defi n e d as a n y s u bject w h o h as 
a c hie ve d i n de pe n d e nt wal ki n g as d efi n e d b y t h e W H O M ot or Milest o nes criteria ( Test Ite m # 6 
 
Wal ki n g Al o n e).  If a s u bje ct was c o nsi dere d t o be n o n-a m b ulat or y at b as eli n e a n d pr o vi d e d a 6 M W T 
res ult p ost- baseli n e t he n b aseli n e will be i m p ute d as 0. 
 
T he dista nc e wal k e d i n t he first a n d si xt h mi n ute will be use d t o calc ulate P er ce nt a ge F ati g u e  as: 
 
% F ati g ue = 1 0 0 *( dista n c e wal k e d i n 1 st mi n ute  dista nc e wal k e d i n 6t h mi n ute)/ dista nc e wal ke d i n 
t h e 1st mi n ute
If t he dista n ce wal k e d is rec or de d f or t h e 1 st mi n ute a n d t h e 6
t h mi n ute is missi n g t he n % Fati g ue will 
b e s et t o 1 0 0.   
 
I n t h e c o nte xt of o ne si n gle test, a p ositi v e val ue i n dic ates a n i ncrease i n fati g ue o ver t he 6 mi n utes. 
 
T he f oll o wi n g will be pres e nte d:
 
 S u m m ar y of p erce nta ge of fati g ue a n d c ha n ge fr o m baseli ne o ver ti m e  
 S u m m ar y of t otal dista n c e a n d c ha n ge fr o m b aseli n e o v er ti m e   
 T he pr o p orti o n of s u bje cts w h o i n creas e w al ki n g dista n ce > = 3 0 meters fr o m b aseli n e  o ver 
ti m e   
 Pl ot of b ot h t otal dista n c e a n d c h a n ge fr o m b aseli ne  o ver ti m e 
 Me dia n c ha n g e fr o m baseli ne o ver ti m e f or fati g ue a n d dista n ce 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
T he f o c us wit h t h es e a n al yses will b e f or t he s u bje cts i n C S 2/ C S 1 w h o were a ble t o wal k at b aseli n e 
or ac hie ve d wal ki n g d uri n g t h e C S 2/ C S 1 or C S 1 2 st u d y.  F or s u bje cts w h o e ntere d fr o m ot h er st u dies 
t h e data will b e liste d.    
 
6. 4. 8     
Perf or m a nce Li miti n g  C o ntr a ct ur e Assess m e nt 
M ot or p erf or ma n ce i n S M A is defi ne d as a de m o nstrate d a bilit y t o p erf or m a s kill u n d er c ertai n 
test c o n diti o ns. T his perf or m a nce c ha n ges wit h diseas e pr o gressi o n a n d/ or i nter ve nti o n (i n cl u di n g 
s ur g er y) a n d is base d o n t he o bs er ve d res p o nse o n t he d a y of t he assess m e nt. M ot or perf or m a n ce will 
b e affecte d b y m uscle stre n gt h, c o g niti ve a bilit y, c o ntra ct ures, a n d m at urati o nal de vel o p me nt 
( p u b ert y). All s u bje cts will be e v al u ate d f or c o ntract ures fr o m versi o n 3 of t he pr ot o c ol. 
A s u m m ar y of t h e n u m b er of s u bjects e x perie nci n g perf or m a nc e li miti n g c o ntra ct ures b y l oc ati o n, 
d e gree of c o ntract ure i m p act o n t he p erf or ma n ce of m ot or assess m e nt ( n o, mi ni m al, m o d erate or 
se v ere) a n d visit will b e pres e nte d. 
 
6. 4. 9     
C h a n ge i n G r o wt h P a r a m eters 
Gr o wt h p ara m eters c o m prise le n gt h f or a ge, wei g ht f or a g e, wei g ht f or le n gt h, he a d circ u mfere n ce 
f or a ge, c hest circ u mfere nce, h e a d t o c hest circ u mfere n ce rati o, a n d ar m circ u mfere n ce 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 wt h Sta n dar ds, 2 0 0 6) will b e us e d t o deter mi n e 
t h e perce ntil es f or e ac h para m eter f or s u bjects < 5 ye ars ol d. I n p arallel t h e 2 0 0 0 C D C Gr o wt h C h arts 
(a ges 0 t o < 2 0 y ears) will b e us e d t o ass ess t h e gr o wt h c h a n g e f or ol der s u bje cts ( > 5 ye ars ol d.) It 
m ust be n ote d t hat t h es e s cales are desi g ne d f or healt h y c hil dre n. Patie nts wit h S M A h a v e l o wer 
m uscle m ass a n d are t h eref ore e x pecte d t o ha ve l o wer wei g ht f or h ei g ht a n d a ge. T he W H O pr o vi d es 
a S A S m a cr o ( S A S i gr o w u p pa c k a g e) w hic h c a n be d o w nl o a de d fr o m a we bsite [ W H O A nt hr o] a n d 
t his will be utiliz e d t o c alc ulate t he perce ntiles f or e ac h c hil d. T he C D C c h art a n d S A S m acr o c a n b e 
d o w nl oa d e d fr o m a we b site [ C D C]. T h e t w o s cales were d e vel o pe d usi n g differe nt met h o ds a n d 
p o p ulati o ns, f or t his re as o n t h e wei g ht perce ntile s h o ul d n ot b e mi x e d usi n g b ot h sc ales. T he C D C 
c hart will be use d o nl y t o calc ulate t h e wei g ht perce ntile s.  
 
T he c ha n ge fr o m baseli n e t o e ac h wi n d o we d a nal ysis visit ( usi n g t h e Safet y wi n d o ws) will be 
s u m m arize d usi n g descri pti v e statistics f or t he f oll o wi n g gr o wt h p ara m eters: wei g ht f or a g e 
p erce ntile ( usi n g 
W H O a n d C D C sc ales), wei g ht f or le n gt h/ hei g ht, he a d circ u mfere n c e, c hest 
circ u mfere nce, h ea d t o c hest circ u mfere n ce rati o n a n d ar m circ u mfere n ce. Prese ntati o ns will b e m a de 
f or all st u dies. 
 
A n alyses  
 
 Gr o wt h p ara m eters at baseli ne   
 C h a n ge fr o m baseli ne 
 
T he gr o wt h p ara m eters at M M D R da y 1 a n d t he c ha n g e fr o m M M D R da y 1 will be s u m mariz e d f or 
all s u bje cts w h o ha ve rec ei ve d a d os e at M M D R Da y 1. 


     
   
 
 
   
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6. 4. 1 0    
Pe ds Q L  
S u bje cts i n C S 1 1 will b e e v al uate d usi n g t he Pe diatric Q ualit y of Life I n v e nt or y ( Pe ds Q L
) 
Me as ure m e nt 4. 0 Ge n eric C ore Sc ales a n d 3. 0 Ne ur o m usc ular M o d ule ( Var ni et al. 1 9 9 9) at  
Scree ni n g a n d/ or pre d ose ( wit hi n 7 d a ys of d osi n g) at M M D R Da y 1, a p pr o xi m at el y a n n uall y 
t h ereafter (i.e., M M D R Da ys 3 6 0, 7 2 0, 1 0 8 0, a n d 1 4 4 0), a n d at t he E O S E v al uati o n/ E T Visit. 
T he q uesti o n n aires are s pecific t o t h e a ge of t he s u bje ct, a n d sites are i nstr u cte d t o get b ot h s u bje cts 
a n d c are gi v ers t o c o m plete t h e sa m e a ge s p ecific q uesti o n n aire as was c ollecte d at b aseli n e 
irres pe cti v e of w het h er or n ot t he s u bjects cr oss a n a ge b o u n d ar y at a s u bse q u e nt visit.  Fr o m Pr ot o c ol 
A m e n d me nt Versi o n 2, t his g ui d a n c e was c ha n ge d a n d t h e sites were i nstr u cte d t o use t h e Pe ds Q L 
v ersi o n ac c or di n g t o t h e a g e of t he s u bje ct at t he visit.    
T he Pe ds Q L pare nt q u esti o n n aire is c olle cte d f or c hil dr e n a n d tee na g ers i n t h e f oll o wi n g a g e 
c ate g ories: 2- 4, 5- 7, 8- 1 2 a n d 1 3- 1 8.  F o ur di m e nsi o ns are c olle cte d: P h ysic al, E m oti o nal, S o cial a n d 
Sc h o ol f u n cti o ni n g a n d e ac h ite m is sc ore d o n a 5 p oi nt or di nal sc ale ( 0 = N e ver, 1 = Al m ost Ne ver, 
2 = S o m eti m es, 3 = Ofte n, 4 = Al m ost Al wa ys).   
I n t h e n e ur o m usc ular m o d ule, o n e pare nt q u esti o n n aire is c ollecte d f or all s u bje cts irres p ecti v e of 
- p oi nt or di nal sc ale is c olle cte d f or e ac h q u esti o n. 
A ps yc h os o cial h ealt h s u m m ar y sc ore, c o nstr ucte d fr o m t hree di m e nsi o ns, will b e calc ulate d as t he 
s u m of ite ms o v er t he n u m b er of ite ms a ns were d i n t h e e m oti o nal, s o cial a n d sc h o ol f u n cti o ni n g 
sc ales. A t otal sc ore will be c alc ulate d as t h e s u m of all t he ite ms o v er t he n u m b er of ite ms a ns were d 
o n all t h e sc ales.  If greater t h a n 5 0 perce nt of t h e ite ms are missi n g, t h e n t he s u m m ar y s c ore or t otal 
sc ore will be set t o be missi n g.  
F or t h e ne ur o m usc ular m o d ule, a s c ore f or e ac h di m e nsi o n a n d t he n t otal s c ore will b e c alc ulate d i n 
t h e sa m e m a n ner, n o healt h s u m m ar y s c ores are e v al uate d.   
D ue t o t h e a g e s p ecific nat ure of t h es e q u esti o n n aires, s u bje cts a ge d 2- 4 years w o ul d n ot b e e x pecte d 
t o c o m plete t h e self-e v al uati o n. 
A n alysis
 T otal c h a n ge a n d perce nta g e c h a n g e fr o m b aseli ne sc ore (ea c h t otal sc ore a n d pare nt/s u bject 
e val u ati o n s e paratel y) t o ea c h visit will b e pres e nte d 
 T otal c h a n ge a n d p erce nta ge c h a n g e fr o m M M D R da y 1 will be s u m mariz e d f or all s u bjects 
w h o h a ve re cei v e d a d ose at M M D R Da y 1. 
 
6. 4. 1 1    
A C E N D 
Pare nts of s u bje cts will c o m plete t h e Ass ess m e nt of Care gi v er E x p erie nc e wit h Ne ur o m usc ular 
Dis ease ( A C E N D) q u esti o n n aire at s pe cific visits.   T his assess m e nt i nstr u m e nt h as b ee n desi g n e d 
t o q ua ntif y t he c are gi v er i m p act e x perie nce d b y pare nts of c hil dre n affecte d wit h se v ere 
n e ur o m usc ular dis eases, i n cl u di n g c hil dre n wit h S M A ( Mats u m ot o et al. 2 0 1 1). S u bjects s h o ul d n ot 
c o m plete q u alit y of life q u esti o n n aires i nte n de d f or c o m pleti o n b y a c are gi ver. 
T he 
A C E N D i ncl u des a t otal of se ve n d o m ai ns ass essi n g p h ysic al i m pa ct (i n cl u di n g 
fe e 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 g e n eral c are gi ver i m p act 
(i n cl u di n g ti m e, e m oti o n, a n d fi n a n ce) a n d e ac h d o m ai n c o m pris es se veral it e ms.  T h e t otal s c ore f or 


     
   
 
 
   
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a d o m ai n wit h n ite ms, ea c h ite m ass esse d o n or di nal sc ale fr o m 1 t o z, is deri v e d as f oll o ws: 1 0 0 
m ulti plie d b y ( Me a n of t h e n ite ms i n t h e d o m ai n - 1) di vi d e d b y ( z- 1).  T his t otal s c ore will b e o n a 
sc ale 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 c are gi v er.  At le ast t w o ite ms 
f or t h e ti me d o m ai n a n d o ne ite m f or t he re m ai ni n g d o mai ns ne e d t o b e n o n- missi n g f or a d o m ai n 
t otal t o be calc ulate d; else t he t otal sc ore will b e set t o be missi n g. 
A n alyses: 
 T otal sc ores i n ea c h d o m ai n at b aseli ne  
 T otal sc ores b y d o m ai n a n d visit  
 C h a n ge fr o m baseli ne i n t otal s c ore b y d o m ai n a n d visit  
F or s u bje cts w h o start t his fr o m M M D R Da y 1 t h e f oll o wi n g a n al ysis will b e p erf or m e d:
 
 
S u m m ar y of t otal s c ore b y d o m ai n fr o m M M D R Da y 1 b y visit
 
 
 
6. 4. 1 3   
X- R a y of S pi ne
treate d at Ger m a n sites) will h a ve a n X-ra y of t h e t h orac ol u m bar s pi n e o n Scree ni n g a n d/ or 
pre d ose ( wit hi n 7 d a ys of visit) at M M D R Da y 1, a p pr o xi m atel y a n n uall y t hereafter (i.e., M M D R 
Da ys 3 6 0, 7 2 0, 1 0 8 0, a n d 1 4 4 0), a n d at t he E O S E val uati o n/ E T Visit. T he X-ra ys will be use d t o 
d eter mi n e t he s e v erit y of s c oli osis b y m e as uri n g t he C o b b a n gle. T h e s pi ne X-ra y was p erf or m e d at 
scre e ni n g of C S 4 i n de x st u d y a n d fr o m t h e be gi n ni n g of C S 1 1, a n d t he i m a ge ac q uisiti o n g ui deli nes 
will re m ai n c o nsiste nt b et wee n t he C S 4 a n d t h e c urre nt e xte nsi o n st u d y. 
Wit h Pr ot oc ol A m e n d m e nt Versi o n 1, t he X-ra y was i ntr o d u ce d o nl y f or t he s u bje cts i n C S 4, a n d 
wit h Versi o n 2, X-ra y was i ntr o d u ce d t o all t h e rest of t h e s u bjects e nteri n g C S 1 1 fr o m ot h er i n de x 
st u dies.  
A n alyses f or gr o u p C S 4 s u bjects: 
 


     
   
 
 
   
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 Me a n c o b b a n gle b y visit 
 Me a n c ha n g e fr o m baseli n e b y visit 
 Pl ots of m ea n a n d m ea n c ha n g e fr o m b aseli n e b y visit 
 Pr o p orti o n of s u bje cts w h o h a v e pr oce d ures f or gr o wi n g r o ds or sc oli osis fi x ati o n (s pi n al 
f usi o n a n d s pi n al c orre cti o n s ur g eries) as i d e ntifie d b y st u d y Me dical Direct or, will b e 
pres e nte d usi n g Ka pla n- Meier pr o d uct-li mit m et h o d f or t h e s u bjects wit h c o b b a n gle d ata.  
 
F or s u bje cts w h o start t his assess m e nt aft er Pr ot o c ol A m e n d m e nt Versi o n 2, t h e f oll o wi n g a nal ysis 
will b e perf or m e d: 
 
S u m m ar y of C o b b a n gle a n d c h a n ge fr o m M M D R Da y 1 b y visit.
 Pr o p orti o n of s u bje cts w h o h a v e pr oce d ures f or gr o wi n g r o ds or sc oli osis fi x ati o n (s pi n al 
f usi o n a n d s pi n al c orre cti o n s ur g eries) as i d e ntifie d b y st u d y Me dical Direct or, will b e 
pres e nte d usi n g Ka pla n- Meier pr o d uct-li mit m et h o d f or p atie nts wit h c o b b a n gle d ata.  
 
6. 4. 1 4    
N u m be r a n d Le n gt h of H os pit aliz ati o ns  
 
Details o n h os pitalizati o ns are c olle cte d i n t h e e C R F h os pitaliz ati o n f or m. T his f or m was c olle cte d 
as p art of t he C S 3 B a n d 2 3 2 S M 2 0 2 st u d y a n d f or t h es e s u bjects c o nti n u e d t o b e use d i n C S 1 1.   
 
I n t h e C S 4, C S 3 A a n d C S 1 2 st u dies, n o h os pitaliz ati o n f or m wa s c ollecte d.  
 
A n u p d ate d e C R F f oll o wi n g Pr ot o c ol A me n d me nt Versi o n 2 i n cl u d e d a h os pitaliz ati o n f or m f or all 
s u bje cts a n d t heref ore a s u m m ar y of h os pitaliz ati o ns d ata will be starti n g fr o m M M D R Da y 1.  
 
Base d o n starti n g p oi nt of data a vaila bilit y, t he f oll o wi n g a n al ys es will be pres e nte d.  
 
N u m b er a n d a n n u aliz e d r ate of h os pit aliz ati o ns d ue t o seri o us a d vers e eve nts ( S A E) over 3 6 0- d a y 
i nterv al 
  
T he pr o p orti o n of s u bjects wit h n u m ber of h os pitaliz ati o ns 0, 1, 2, 3, 4, > = 5 will be pres e nte d.  
 
A n n u alize d rate f or t h e peri o d will b e calc ulate d as t otal n u m b er of h os pitali z ati o ns di vi d e d b y t otal 
n u m b er of s u bje ct- years f oll o we d i n t h e 3 6 0- da y peri o d f or eac h c o h ort of s u bje cts w hic h are liste d 
b el o w.  
 C S 3 B or C S 4 i n d e x st u d y pl us C S 1 1:  pre vi o us c o ntr ol or n usi nerse n dis pla y.  
 C S 3 B or C S 4 i n d e x st u d y pl us C S 1 1: a ge at first n usi n erse n d ose dis pla y.  
 Fr o m baseli n e of C S 1 1, i nfa ntile, later S M A o ns et a n d all S M A s u bje cts dis pla ys.  
 
T he n u m b er of h os pitaliz ati o ns was d eter mi n e d b y c o u nti n g t he n u m b er of S A Es w hic h 
re q uire d h os pitaliz ati o n.  If m ulti ple S A Es w hic h oc c urre d o n t h e sa m e date a n d le d t o 
h os pitaliz ati o n, it will b e c o u nte d as o ne h os pitaliz ati o n.  
             
D ur ati o n a n d ti me of h os pit aliz ati o n b y 3 6 0- d ay i nter v al 
 


     
   
 
 
   
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F or e ac h s u bject t h e pr o p orti o n of ti m e i n h os pital will be d eter mi ne d, f or a gi v e n 3 6 0- da y i nter val. 
T he n u merat or will b e t h e t otal n u m b er of d a ys i n h os pital a n d t he d e n o mi n at or will be t h e ti m e t he 
s u bje ct was f oll o we d i n t h e i nter val.  T he f oll o wi n g will b e prese nte d: 
 
 0 % of ti m e i n h os pital 
 > 0 % t o < 1 0 % of ti m e i n h os pital 
 > = 1 0 % t o < 2 0 % of ti m e i n h os pital 
 > = 2 0 % t o < 3 0 % of ti m e i n h os pital 
 > = 3 0 % t o < 4 0 % of ti m e i n h os pital 
 > = 4 0 % t o < 5 0 % of ti m e i n 
> = 5 0 % t o < 6 0 % of ti m e i n h os pital
> = 6 0 % of ti m e i n h os pital
S u m m ar y statistics f or e ac h i nter val will b e prese nte d. 
 
T he a nal yses will be pres e nte d f or all s u bje cts fr o m M M D R Da y 1 a n d C S 3 B s u bjects fr o m t h e start 
of C S 1 1.  
      
If a s u bje ct e nters h os pitaliz ati o n i n o ne 3 6 0- da y i nter val a n d le a ves h os pital i n t h e ne xt 3 6 0- da y 
i nter val t he n t h e da ys i n h os pital will b e c o u nte d i n t h e first i nter val. 
 
6. 4. 1 5    
N u m be r of H os pit aliz ati o ns D ue t o Se ri o us Res pir at or y A d verse E v e nt  
T he n u m b er a n d a n n ualize d rate of seri o us res pirat or y e ve nts (ie e v e nts c o d e d i nt o t h e S O C of 
res pirat or y, t h oracic, a n d m e diasti n al dis or d ers) will b e s u m mariz e d as descri b e d i n Se cti o n 6. 4. 1 4.   
 
6. 4. 1 6    
Dis e ase-rel ate d ( S M A) H os pit aliz ati o ns a n d A Es 
Ma n y A Es ca n p ossi bl y b e relate d t o eit h er S M A or t o n or m al c hil d h o o d ill ness, f urt h er c o nte xt 
w o ul d b e re q uire d t o differe ntiate t h e preci pitati n g fact ors. Wit h refere n ce t o t he 2 0 1 7 Sta n d ar ds of 
Care p u blic ati o ns [ Fi n kel 2 0 1 7, Merc uri 2 0 1 7], t h e St u d y Me dical Direct or create d a list of preferre d 
ter ms t h at relate t o s p e cific e v e nts t h at are hi g hl y li kel y t o be res ulta nt fr o m S M A. T h ese are liste d 
i n A p pe n di x B.   T h e i n ci d e nc e of dise ase relate d a d v erse e ve nts will be s u m m arize d fr o m t h e start 
of C S 1 1.  Si milarl y, t h e s u bs et of disease relate d S A Es lea di n g t o h os pitaliz ati o n will als o be 
pres e nte d.  
 
6. 4. 1 7    
Si g ns a n d S y m pt o ms of D ys p h a gi a 
T he Pare nt Assess m e nt of S wall o wi n g A bilit y ( P A S A) q uesti o n n aire was de v el o pe d b y a Bi o ge n 
te a m i n or der t o assess t he si g ns a n d s y m pt o ms of d ys p h a gia a n d c olle cte d fr o m t he i nitiati o n of 
Pr ot oc ol A m e n d m e nt Versi o n 3.  T his q uesti o n n aire c o nsists of 3 3 ite ms a cr oss 4 d o m ai ns c o v eri n g: 
g e n eral fe e di n g, dri n ki n g li q ui ds, eati n g s oli d f o o ds a n d assess me nt of s wall o wi n g c o nc er ns.  T he 
first t hree of t h es e d o m ai ns are ge n erall y ass esse d wit h 5 le vels of res p o nse: Ne ver, Rarel y, 
S o m eti m es, Ofte n a n d Al wa ys, alt h o
I n t h e fi n al d o mai n t he ass ess m e nt of s wall o wi n g c o n cer ns has 4 le v els of res p o nse: Str o n gl y a gree, 


     
   
 
 
   
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A gree, Dis a gre e a n d Str o n gl y disa gree.  I n a ns weri n g ea c h ite m, t h e p are nt is directe d t o c o nsi der 
t h e pre vi o us 7 d a ys. 
 
T he n u m b er a n d p erce nta ge of s u bje cts sc ori n g e ac h c ate g or y i n t h e P A S A i n e ac h d o mai n will b e 
pres e nte d b y visit. F or all s u bjects, m e a n s c ores of ite ms b y d o m ai n o v er ti m e f or d o mai ns of ge n eral 
fe e di n g, dri n ki n g li q ui ds a n d eati n g s oli d f o o ds will b e pres e nte d fr o m M M D R Da y 1 b y S M A o nset, 
wit h ite m sc ore defi n e d as 4 = Ne v er, 3 = Rarel y, 2 = S o m eti m es, 1 = Ofte n a n d 0 = Al wa ys. Si milarl y, 
t h e m ea n sc ore will be prese nte d f or t h e d o m ai n of ass ess m e nt of s wall o wi n g c o nc er ns ( 3 = Str o n gl y 
disa gree, 2 = Disa gree, 1 = A gree a n d 0 = Str o n gl y a gree) will be prese nte d fr o m M M D R Da y 1. 
S pa g h etti pl ots of ite m s c ore v ers us M M D R visit will b e g e n erate d b y d o mai ns. 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
  






     
   
 
 
   
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Baseli n e c o nc e ntrati o ns will b e s u m m ariz e d o verall, b y a ge of o ns et usi n g des cri pti v e statistics.   
 
S u m m ar y ta bles will be prese nte d f or m ea n c o n ce ntrati o n, g e o m etric m ea n c o n ce ntrati o n, ge o m etric 
m ea n rati o b y visit. A pl ot of m e a n o ver ti m e will be prese nte d f or c o n ce ntrati o n o n t he se mi-
l o g arit h mic sc ale. T he g e o m etric m ea n rati o will b e prese nte d o n t h e ori gi nal s cale.  
 
F or t h e later o ns et p o p ulati o n, t h e y are rec ei vi n g d oses e ver y 4 m o nt hs fr o m M M D R Da y 1. I n or der 
t o e x pl ore t h e tra nsiti o n fr o m 6 m o nt hl y t o 4 m o nt hl y d osi n g, s u m maries of M M D R Da y 1 t o 
s u bse q ue nt M M D R visits will b e pres e nte d f or s u bjects w h o rec ei ve d 1 2 m g l o a di n g d oses (i.e. C S 4 
a n d s o m e C S 2 s u bje cts).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


     
   
 
 
   
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6. 4. 2 2    
S u b g r o u p A n al yses 
 
S u b gr o u p a n al yses b y a g e are alr ea d y c o v ere d f or t h e C S 3 B a n d C S 4 gr o u ps of p atie nts base d o n 
t h e pla n ne d dis pla ys. 
  
7. 0  
    
S A F E T Y D A T A 
 
A nal yses of safet y d ata will i ncl u d e a d verse e ve nts a n d seri o us a d verse e ve nts, la b orat or y data, 
E C Gs, vital si g ns, a n d n e ur ol o gical e x a mi nati o ns. 
W ors e ni n g or n e w fi n di n gs n ote d fr o m t he 
p h ysical or n e ur ol o gical e x a mi nati o ns will b e re p orte d as A Es as a p pr o priate. 
 
7. 1  A d ve rse E v e nts 
 
All a d v erse e v e nts ( A Es) will be a nal y ze d base d o n t h e pri nci ple of treat m e nt e mer g e n ce. A n a d verse 
e ve nt will be re g ar de d as treat m e nt-e m er ge nt if it was prese nt pri or t o rec ei vi n g t he first d os e of 
n usi n erse n or first s ha m pr oc e d ure i n t h e i n de x st u d y a n d s u bs e q ue ntl y w orse ne d i n se verit y, or was 
n ot prese nt pri or t o rec ei vi n g t he first d os e of n usi nerse n or first s ha m pr oce d ure i n t h e i n de x st u d y 
b ut s u bse q ue ntl y a p pe are d. F or s u bje cts rec ei vi n g t h e s ha m pr oc e d ure i n t h e i n de x st u d y, a n 
a d diti o nal tre at m e nt e m er ge nt defi niti o n will b e use d t o defi n e if t h e a d verse e ve nt is treat m e nt 
e mer g e nt t o t h e first d ose of n usi n erse n i n C S 1 1. 
 
Of n ote, e ve nts t h at are d u plic ate d i n b ot h i n de x a n d C S 1 1 t h e data f or t h at A E will be ta ke n fr o m 
C S 1 1. T h ese d u plic ates will be d efi n e d b as e d o n t he c o d e d ter ms a n d start d ates. Ot her varia bles will 
b e us e d as n ee d e d. 
 
F or e ve nts wit h missi n g start or st o p dates, t h e f oll o wi n g criteria will b e use d f or t h e p ur p ose of 
i d e ntif yi n g treat m e nt-e m er g e nt a d v erse e ve nts ( T E A Es): 
 
if b ot h t h e start a n d st o p d ates f or a p artic ular e v e nt are missi n g, t he n t h e e ve nt is 
c o nsi dere d t o ha ve o cc urre d o n or after t h e first d ose or s ha m pr oc e d ure; 
 
 if t h e start d ate f or a p artic ular e ve nt is missi n g a n d t h e st o p d ate/ti m e falls after t h e first 
d os e or first s ha m pr oc e d ure date/ti m e, t h e n t h e e v e nt is c o nsi d ere d t o ha ve occ urre d o n or 
after t h e first d ose or s ha m pr oc e d ure; 
 
 if t he start ti m e is missi n g a n d t h e start date is sa m e as t h e first d osi n g or first s ha m 
pr oc e d ure date, t he n t h e e v e nt is c o nsi d ere d t o ha ve o cc urre d o n or after t he first d ose or 
s h a m pr oc e d ure;
 
 if it ca n n ot b e deter mi n e d w het her a n e v e nt h as o cc urre d o n or after d osi n g d u e t o a missi n g 
or p artial d ate, t h e n t he e v e nt will be ass u m e d t o h a v e oc c urre d o n or after t h e first d os e 
f or t h e p ur p ose of i d e ntif yi n g treat m e nt-e m er g e nt a d verse e ve nts. 
 


     
   
 
 
   
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S pe cific all y, let A E S T D T de n ote t h e start d ate of a n a d verse e v e nt a n d T R T S T D T b e t h e start d ate of 
treat m e nt/s h a m pr oce d ure. F or t h e p ur p ose of i de ntif yi n g treat m e nt e mer ge nt a d v erse e ve nts, t h e 
f oll o wi n g al g orit h m will b e us e d f or t h e i m p utati o n of missi n g or partial d ate: 
 
 
If A E S T D T is c o m pletel y missi n g or t h e ye ar is missi n g, t h e n i m p ute A E S T D T t o 
T R T S T D T. 
 
 
If, i n A E S T D T, ye ar is pres e nt a n d m o nt h/ d a y are missi n g a n d ye ar is e q u al t o t he y e ar 
p orti o n of T R T S T D T, t he n i m p ute t h e m o nt h/ d a y p orti o n of A E S T D T t o t h e m o nt h/ d a y 
p orti o n of T R T S T D T.
 
 
If, i n A E S T D T, year is pres e nt a n d m o nt h/ d a y are missi n g a n d ye ar is n ot e q u al t o t h e 
y ear p orti o n of T R T S T D T, t he n i m p ute t he m o nt h/ da y p orti o n of A E S T D T t o Ja n uar y 
0 1. 
 
 
C o nsi d er t he sit u ati o n i n A E S T D T w here ye ar a n d m o nt h are pres e nt wit h o nl y d a y 
missi n g. If t h e ye ar a n d m o nt h are t he s a m e as t h ose f or T R T S T D T, t h e n i m p ute da y i n 
A E S T D T wit h d a y i n T R T S T D T. Ot h er wise, i m p ute t he d a y i n A E S T D T wit h t he first 
d a y of t h e m o nt h.
 
It is i m p orta nt t o e m p h asiz e t h at t h e i m p ute d date will n ot b e us e d f or calc ul ati o ns s uc h as o ns et a n d 
d urati o n of a n a d v erse e v e nt.
 
D ue t o t he l o n g h alf-life of n usi n ers e n, a nal yses of treat m e nt-e m er ge nt a d verse e ve nts will i n cl u de 
all e v e nts re p orte d d uri n g t h e st u d y. 
 
I n or der t o all o w safet y t o be prese nte d i n a si milar m a n n er t o t he effic ac y dis pla ys fr o m M M D R Da y 
1, t he d ate a n d ti m e of t h e M M D R Da y 1 d ose will b e use d t o defi n e e ve nts w hic h are c o nsi d ere d 
treat m e nt e mer g e nt t o M M D R Da y 1. 
A d v erse e v e nts will be c o de d usi n g t he Me d D R A dicti o n ar y. T his c o di n g s yste m pr o vi d es m ore t h a n 
fi v e le vels t o classif y a d verse e v e nts. I n ge neral, a d verse e ve nts will b e prese nte d b y s yste m or ga n 
class a n d preferre d ter ms b ut ot h er classific ati o ns m a y be use d if warra nte d. 
 
T he i n ci d e nce or fre q u e nc y (e ve nt c o u nt) of treat m e nt-e m er ge nt a d v erse e ve nts will be s u m m ariz e d 
b y i nfa ntile a n d later o ns et gr o u ps a n d o v erall. A s u bject h a vi n g t h e sa m e a d verse e ve nt m ore t h a n 
o nc e will b e c o u nte d o nl y o n ce i n t he i nci d e n ce f or t h at a d v erse e v e nt; m ulti ple oc c urre n ces of t h e 
sa m e a d v erse e v e nt f or t he sa m e s u bject will all be c o u nte d i n t h e fre q ue n c y f or t h at a d v erse e ve nt. 
T he s u m m ar y ta bles will i n cl u d e i n ci de nc e or fre q ue n c y esti m ates f or o verall s yste m or ga n cl ass as 
well as f or preferre d ter ms wit hi n ea c h s yste m or ga n class. I nci d e n ce will be pres e nte d b y d ecreasi n g 
or der b y s yste m or ga n class a n d b y d ecre asi n g or der b y preferre d ter m wit hi n ea c h s yste m or g a n 
class. T he m ost c o m m o n a d verse e ve nts, i.e., t h os e t h at o cc urre d i n at least 5 % of s u bjects i n eit h er 
gr o u p, will b e pres e nte d. U p o n e x a mi n ati o n of t h e act u al data, differe nt c ut- offs m a y b e us e d if it is 
d ee m e d m ore a p pr o priate. 
 




     
   
 
 
   
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T he i n ci d e nce of a d v erse e ve nts t hat le d t o disc o nti n u ati o n of st u d y treat m e nt will b e pres e nte d. All 
a d v erse e ve nts t hat le d t o disc o nti n u ati o n of st u d y treat m e nt will b e liste d. 
7. 1. 8     
De at hs 
 
T he i n ci d e nce of d eat h will be s u m m ariz e d b y gr o u p a n d o verall. All d eat hs will be liste d i ncl u di n g 
c a use of d eat h. T he i n ci d e nce of e v e nts t h at le d t o de at h will b e prese nte d.
 
7. 1. 9     
Prese nt ati o ns 
T he f oll o wi n g pres e ntati o ns will b e s h o w n f or treat m e nt e m er ge nt a d v erse e ve nts ( T E A Es):
 
A n o v erall s u m m ar y s h o wi n g, f or ea c h gr o u p, t he n u m b er a n d p erce nta g e of s u bje cts wit h
a n a d verse e ve nt, a m o derate or s e v ere e v e nt, a s e v ere e v e nt, a p ossi bl y or relate d e v e nt, a 
relate d e v e nt, a p ote ntial L P relate d e ve nt, a n e v e nt t h at le d t o deat h, a seri o us e ve nt 
(i n cl u di n g fatalities), a relate d seri o us e ve nt, a n e v e nt t h at 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 v e nt t hat le d t o wit h dra wal fr o m t h e st u d y 
 
 
I nci d e n ce b y s yste m or ga n class a n d preferre d ter m 
 
I nci d e n ce, b y preferre d ter m, i n at le ast 5 % of s u bjects i n eit h er gr o u p 
 
 
I nci d e n ce of mil d, m o d erate a n d se vere e v e nts b y s yste m or ga n class a n d preferre d 
ter m 
 
 
I nci d e n ce of s e v ere e v e nts b y s yste m or ga n class a n d preferre d ter m 
 
 
I nci d e n ce of n ot relate d, u nli k el y t o b e relate d, p ossi bl y relate d, a n d relate d e v e nts b y 
s yste m or ga n class a n d preferre d ter m 
 
 
I nci d e n ce of dr u g-relate d e ve nts b y s yste m or ga n class a n d preferre d ter m 
 
 
I nci d e n ce a n d fre q u e n c y of seri o us a d verse e ve nts b y s yste m or ga n class a n d preferre d 
ter m a n d a listi n g of seri o us a d v erse e v e nts 
 
 
I nci d e n ce of dr u g-relate d s eri o us a d v erse e ve nts b y s yste m or g a n class a n d preferre d ter m 
a n d a listi n g of s eri o us a d verse e ve nts 
 
 
I nci d e n ce of d eat h a n d a listi n g of ea c h d e at h 
 
 
I nci d e n ce of e ve nts t hat le d t o de at h 
 
 
I nci d e n ce a n d fre q u e n c y of e ve nts le a di n g t o disc o nti n uati o n of St u d y Dr u g b y s yste m 
or ga n class a n d preferre d ter m a n d a listi n g of s u c h e v e nts 
 
 
I nci d e n ce of e ve nts lea di n g t o wit h dra wal fr o m t h e st u d y b y s yste m or ga n class a n d 
preferre d ter m a n d a listi n g of s u c h e ve nts 
 
 
I nci d e n ce a n d fre q u e n c y of a d v erse e v e nts o v er ti m e b y s yste m or ga n class a n d preferre d 
ter m a n d a listi n g of s u c h e v e nts. 
 
I n ci de nce of p ote ntiall y L P relate d e v e nts f oll o wi n g d osi n g/s h a m pr oc e d ure. 
 


     
   
 
 
   
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I nci d e n ce of a d v erse e v e nts a nti b o d y stat us b y s yste m or g a n class a n d preferre d ter m a n d a 
listi n g of s u c h e v e nts.
 
S o m e of t he a b o v e dis pla ys will b e re p e ate d fr o m M M D R Da y 1. 
 
T o a v oi d t he p ote ntial f or misle a di n g i nter pretati o n of a n al ysis of a d v erse e v e nts, n o statistical testi n g 
will b e perf or m e d. 
 
7. 2  Cli nic al L a b or at or y D at a 
T he f oll o wi n g cli nic al la b orat or y para meters are t o b e assesse d:
  
 He m at ol o g y: he m o gl o bi n, h e m at o crit, re d bl o o d cell c o u nt, W B C c o u nt wit h differe ntial 
b ot h as a bs ol ute v al ues a n d as a p er ce nta g e ( ne utr o p hils, e osi n o p hils, bas o p hils, 
l y m p h oc ytes, a n d m o n oc ytes), a n d platelet c o u nt 
 
 Bl o o d c h e mistr y: li ver f u n cti o n (t otal bilir u bi n ( dire ct a n d i n dire ct), al k ali n e p h os p hatase, 
A L T/ S G P T, A S T/ S G O T), ki d n e y f u n cti o n a n d electr ol ytes ( B U N, creati ni n e, c ystati n C, 
s o di u m, p otassi u m, c hl ori d e), t otal pr otei n, al b u mi n, c alci u m, p h os p h or o us, gl u c ose, a n d 
C P K 
 
 Uri n al ysis: s p ecific gra vit y, p H, pr otei n, gl u c ose, ket o nes, bilir u bi n, bl o o d, R B C, 
W B C, 
e pit h elial c ells, b acteria, c asts, cr ystals a n d uri n e t otal pr otei n 
 C o a g ulati o n: a P T T, I N R  
 
C o a g ulati o n a n d uri n e t otal pr otei n testi n g was c ollecte d at e v er y visit fr o m t h e i ntr o d ucti o n of 
Pr ot oc ol A m e n d m e nt Versi o n 2 at sites. 
 
F or a para m eter, if t he l oc al a n d c e ntral res ults are a vaila ble wit h t he sa me d ate a n d ti m e, t he n o nl y 
t h e ce ntral a n al ysis res ult will be c o nsi dere d f or pres e ntati o ns b y visit. I n a sit u ati o n w h ere t w o or 
m ore c e ntral la b res ults h a v e t h e sa m e date a n d ti me t h e n t h e earliest L B R E FI D will b e sele cte d. 
 
La b orat or y tests, i n cl u di n g c h e mistr y p a nel a n d c o m plete bl o o d c o u nt wit h differe ntial, will b e 
s u m m arize d b y st u d y visit. At t he ti m e of de v el o p m e nt of t his d o c u m e nt, it has be e n f o u n d t hat a fe w 
e xtre m e la b res ults are err o n e o us d u e t o i nc orrect la b u nit w hic h is i m p ossi ble t o res ol ve pri or t o d ata 
b as e l o c k d u e t o cl ose d sites etc. T hese res ults will b e e x cl u de d fr o m t he s u m m aries. T he j ustific ati o n 
of t h e e xcl usi o ns will be d o c u m e nte d i n a n ote t o file pr o vi de d b y St u d y Me dical Direct or a n d 
re vie we d b y m e m b ers of S M T. 
 
Eac h    
 la b orat or y v al ues will b e classifie d a cc or di n g t o w h et h er t he test res ult is    
 
b el o w t he l o wer li mit of n or m al [ L L N]), n or m
 ( wit hi n t h e n or m al ra n ge), 
 a b o v e 
t h e u p p er li mit of n or m al [ U L N]).  If a s u bject is missi n g a b as eli ne v al ue b ut h a d a p ost- baseli ne 
v al u e, t he n t h e baseli ne ass ess m e nt is la bele d 
 P ost- bas eli ne la b orat or y res ults are 
d efi ne d as a n y ass ess m e nt ta ke n after t he first d ose, i ncl u di n g d ata c olle cte d fr o m l oc al la b orat ories. 
T he s hifts (relati v e t o t h e n or m al ra n ge) fr o m baseli n e t o t h e mi ni m u m a n d m a xi m u m p ost- b as eli ne 


     
   
 
 
   
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classifie d val u es (ie n or mal, l o w or hi g h) will be pres e nte d. If a s u bject ha d a b as eli n e val u e b ut h a d n o 
p ost- b as eli n e v al ues, t h e n t he mi ni m u m a n d ma xi m u m are la bele d 
 S h o ul d a treat m e nt 
affect a la b orat or y para meter, t hat para m eter c o ul d be affecte d at differe nt ti m es f or differe nt s u bjects. 
T heref ore, t h es e a nal yses prese nt t he m ost e xtre me val u es f or e ac h s u bject. F or ma n y la b orat or y 
p ara meters, t h e effe ct c o ul d be i n eit h er directi o n, (i.e., a n i ncrease or a de crease), s o b ot h t he m a xi m u m 
a n d mi ni m u m val ues ha ve b ee n a n al yze d. I n a d diti o n, t he s hifts (relati ve t o t he n or mal ra n ge) fr o m 
b aseli ne t o l o w a n d hi g h will be calc ulate d. If a s u bject's v al ue s hifts, it c a n c h a n ge fr o m n or m al t o 
eit her l o w or hig h, fr o m l o w t o n or m al or hi g h, fr o m hi g h t o n or m al or l o w, or fr o m u n k n o w n t o l o w, 
n or m al, or hi g h. F or eac h para meter, t h e i nci de nc e 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- b aseli n e val ues. S hift t o l o w i ncl u des s u bje cts wit h a n or m al, hi g h, or u n k n o w n baseli ne 
v al u e a n d at le ast o n e 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 
b e s u m mariz e d usi n g t he m a xi m u m p ost- baseli ne v al u es. S hift t o hi g h i ncl u des s u bjects wit h a l o w, 
n or m al, or u n k n o w n baseli ne val ue a n d at least o ne p ost- b aseli ne val ue. All bl o o d a n d uri n e sa m ples 
will b e use d i n t he s hift a nal yses.
 
Base d o n t h e pr ot o c ol, c o a g ulati o n la b tests (a P P T a n d I N R) a n d uri n t otal pr otei n are ass esse d b y 
l o cal la b orat ories. L oc al la b orat ories ha v e hist oric al iss u es, s u c h as n o n or m al ra n g e esta blis h e d or 
n ot pr o vi di n g n or m al ra n g es. T o alle viate t h e iss u es f or t h es e pr ot oc ol- d efi n e d l o cal la b tests, te xt-
b o o k refere nc e ra n g es f or I N R a n d uri n t otal pr otei n will b e pr o vi de d b y cli nic al d e v el o p me nt 
m e dic al direct or. T heir s hift ta bles will be pres e nte d b y i nc or p orati n g te xt- b o o k n or mal ra n g es. 
 
 
F or li v er f u ncti o n tests, t h e a d diti o n al c ate g ories will be d efi n e d t o prese nt t h e baseli n e a n d p ost- 
b as eli n e v al ues as wit hi n t h e u p per li mit of n or m al, > 1 x U L N, > 3 x U L N,
 5 x U L N, 
1 0 x U L N, a n d > 2 0 x U L N f or A L T/ A S T, > 1 x U L N, > 1. 5 x U L N, a n d
2 x U L N f or t otal bilir u bi n 
(i n cl u di n g direct a n d i n direct bilir u bi n), a n d > 1 x U L N a n d 1. 5 x U L N f or al k ali n e p h os p hatase. I n 
a d diti o n, i n ci de n ce of p ost baseli ne A L T or A S T i n crease ( > = 3 x U L N) will b e s u m m ariz e d b y 
c o n c urre nt ele vati o n i n bilir u bi n ( m a xi m u m p ost- b as eli n e bilir u bi n > 1. 5 x U L T, > 2 x U L N). 
 
Me dia n, mi ni m u m a n d ma xi m u m la b res ults vs. visit f or certai n la b t ests will be prese nte d 
gra p hicall y.  
7. 3  E C Gs 
E C Gs are t o be rec or de d at Scree ni n g d uri n g t he i n de x st u dies, scree ni n g i n C S 1 1 a n d/ or pre d os e 
( wit hi n 7 da ys of d osi n g) at M M D R Da y 1, a p pr o xi m at el y a n n uall y t h ereafter, (i.e., M M D R Da ys 
3 6 0, 7 2 0, 1 0 8 0, 1 4 4 0), a n d at t h e E O S E val uati o n/ E T Visit. After t h e E C G is c o m plete d, a n i nitial 
l o cal rea d of t h e E C G s h o ul d o cc ur b ef ore t h e E C G is se nt f or a c e ntral rea d (all E C Gs will b e 
c e ntrall y rea d). T h e vari o us p ossi ble rea di n gs ( n or m al, a b n or m al, cli nicall y si g nific a nt) will als o be 
s u m m arize d.  
 
A d diti o nal E C Gs m a y b e perf or m e d p er t h e j u d g me nt of t h e I n vesti g at or, as d ee m e d cli nic all y 
n ec essar y. 
 
E C Gs will b e a n al yz e d usi n g t w o a p pr oa c hes. 
 




     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 Diast olic blo o d press ure < 5 0 m m H g, > 9 0 m m H g a n d > 1 0 0 m m H g           
 P ulse rate < 6 0 a n d > 1 0 0 
 B o d y te m perat ure < 3 6 a n d > 3 8 
 Res pirat or y rate < 1 2 breat hs/ mi n a n d > 2 0 breat hs/ mi n   
 
7. 5  Ne ur ol o gic al E x a mi n ati o ns 
7. 5. 1     
HI N E Se cti o ns 1 a n d 3 
Secti o ns 1 a n d 3 of t h e HI N E will be c o n d ucte d o n all s u bjects 
2 4 m o nt hs of a g e. T his sta n d ar d 
e xa mi n ati o n ( d e v el o p e d b y [ D u b o witz a n d D u b o witz 1 9 8 1]) is a q u a ntitati v e s c ora ble m et h o d f or 
assessi n g t h e ne ur ol o gic al de v el o p m e nt of i nfa nts b et wee n 2 a n d 2 4 m o nt hs of a ge. T h e e x a mi nati o n 
i n cl u des ass ess m e nt of cra nial n er ve f u ncti o ns, p ost ure, m o v e m e nts, t o n e, a n d refle x es. 
 
T he n e ur ol o gical ite ms c o m prise cra nial n er ve f u ncti o n (facial a p p e ara nc e, e y e a p pe ara nc e, a u dit or y 
res p o nse, vis u al res p o nse, s uc ki n g/s wall o wi n g), p ost ure ( h ea d i n sitti n g p ositi o n, tr u n k i n sitti n g 
p ositi o n, ar ms at rest, ha n ds, le gs i n sitti n g p ositi o n, le gs i n s u pi n e a n d sta n di n g p ositi o ns, fe et i n 
s u pi n e a n d sta n di n g p ositi o ns), m o v e me nts ( q u a ntit y, q ualit y), t o ne (sc arf si g n, p assi v e s h o ul d er 
ele v ati o n, pr o nati o n/s u pi n ati o n, a d d uct ors, p o pliteal a n gle, a n kle d orsifle xi o n, p ulle d t o sit, v e ntral 
s us pe nsi o n), a n d refle x es a n d rea cti o ns (te n d o n refle x es, ar m pr otecti o n, vertic al s us p e nsi o n, lateral 
tilti n g, f or war d parac h ute). Be ha vi or is c o m pris e d of state of c o nsci o us ness, e m oti o n al state, a n d 
s o cial orie ntati o n. 
 
F or e ac h ite m a n d s u bject, t he w orst p ost- baseli ne a n d t h e best p ost- baseli n e o ut c o m es will b e 
 fr o m baseli n e t o t he 
b est p ost- baseli ne val ue will be prese nte d. I n t his a n al ysis, all ass ess me nts after t h e first d os e at 
b as eli n e will b e c o nsi d eri n g p ost b aseli n e visits. 
7. 5. 2     
Ne ur ol o gic al a n d F oc use d Ne ur ol o gic al E x a mi n ati o ns 
Starti n g Pr ot o c ol A m e n d m e nt 5, f oc us e d n e ur ol o gic al e xa mi n ati o ns were i m ple m e nte d t o re pla ce 
sta n d ar d ne ur ol o gic al e xa mi nati o ns. F oc use d ne ur ol o gical e xa mi nati o ns ha ve less ite ms t ha n 
sta n d ar d n e ur ol o gic al e xa mi nati o ns.  
 
F or all s u bjects > 2 4 m o nt hs of a ge, f oc use d ne ur ol o gic al e xa mi n ati o ns, w hic h i ncl u d e assess m e nts 
of m e ntal stat us, le vel of c o ns ci o us n ess, s e ns or y f u ncti o n, m ot or f u n cti o n, cra nial n er ve f u n cti o n, 
c o or di nati o n a n d c ere bellar f u n cti o n, pla ntar res p o nse a n d refle xes, will be c o n d ucte d. T hese 
assess me nts will be d o n e pre- d ose a n d 1 h o ur p ost- d ose at e ver y o nsite visit t hr o u g h o ut t h e st u d y.   
 
T he f oll o wi n g ta ble s u m m arizes t h e res ults fr o m ea c h assess m e nt se cti o n/test ( N ote: it alics 
re pres e nts f oc use d n e ur ol o gic al e x a mi nati o ns).  
 
 
Secti o ns     
Tests 
O utc o m es of r es ult 
C o or di nati o n 
a n d c ere bellar 
f u ncti o n 
Fi n ger t o n ose, G ait, Tre m or  
N or m al, a b n or m al  


     
   
 
 
   
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Versi o n N o. 5. 0  
 
Cra nial 
Ner ves 
Eye 
m o ve me nt , Facial 
m oti o n, 
Ga g refle x, 
Heari n g, J a w m o v e m e nt a n d facial se ns ati o n, 
( S C M, Tra p ezi us), T o n g ue, Visi o n  
Ge n eral     
A p p eara nc e/ Fa cial/ M ot or E x pressi o n, 
M e nt al 
st at us, S p ee c h/la n g ua ge, 
N or m al, a b n or m al  
 
Lev el of C o ns ci o us ness 
0 
N o res p o ns e 
1   
Res p o n ds 
after pai nf ul 
sti m uli  
2 
Res p o n ds after pr o d di n g  
3  Res p o n ds after n a m e calle d  
4 
Let h ar gic res p o nse  
5 
Res p o n ds rea dil y  
 
M o o d 
1 - Ha p p y 
2 - Ne utral 
3 - Irrita ble 
M ot or     
M uscle t o ne
N or m al, a b n or m al  
 
C h g i n M uscle T o n e fr o m Pre E xa m  
N or Y  
Pla ntar 
res p o nse 
Refle x (left t oe, ri g ht t o e) 
N or mal, a b n or m al  
Refle x es    
Reflex (left/ri g ht 
a n kle, left/ri g ht 
bic e ps, 
left/ri g ht 
br ac hi or a di alis, 
left/ri g ht 
k n ee, 
left/ri g ht tric e p) 
0 - U n a ble t o elicit refle x 
1 
H y p orefle xia 
2 - N or m al 
3 
H y p errefle xi a 
4 - H y p errefle xia wit h cl o n us  
Se nsati o n    
Te m p er at ur e (left/ri g ht fi n ger ti p, left/ri g ht 
l o wer t o e); Vi br ati o n (left/ri g ht fi n g er ti p, 
left/ri g ht l o wer t o e) 
Pres e nt, a bs e nt 
 
 
F or ea c h a b n or m al test res ult, it is rec or de d w h et h er or n ot it is se c o n d ar y t o S M A.  
 
A w orse ni n g s hift will be s u m m ariz e d f or f o c us e d n e ur ol o gi cal e xa ms: 
 
 
p ost b aseli n e at a n y ti m e will b e pres e nte d. 
 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 F or le v el of c o nsci o us n ess a n d m o o d assess m e nts, t he n u m ber a n d pr o p orti o n of s u bjects 
w h os e s c ores d ecre ase or i ncre ase fr o m baseli n e will b e pres e nte d, res pecti vel y.  
 
I n a d diti o n, f or refle xes a n d le vel of c o nsci o us ness, t h e m e a n s c ores vers us a n al ysis visit will b e 
pres e nte d.   
 
O nl y c ha n ges n ot d ee m e d s ec o n dar y t o S M A will b e pres e nte d. 
 
A n u p date d e C R F f oll o wi n g t h e Pr ot oc ol A m e n d me nt Versi o n 2 i ncl u de d ne ur ol o gic al e x a m 
assess me nt f or all s u bje cts a n d t h eref ore a s u m mar y will b e p ossi ble fr o m M M D R Da y 1. 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 


     
   
 
 
   
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St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 
 
 I n se cti o n 4. 2 Effic ac y dis pla ys, f or t he re- e v al uate d s u bje cts e q ualit y a d de d t o b
H F M S E  
 Ne w effic ac y a n al yses a d de d utilizi n g M M D R Da y 1   
 
Secti o n 7. 1 i n t h e pre vi o us S A P, d escri b e d a n a p pr o ac h t o li n k a d v erse e v e nt ter ms w h ere t h e 
se v erit y ha d lesse ne d at a s u bse q u e nt ti m e p oi nt a n d t o o nl y c o u nt t he first i nsta nc e of t h es e 
i n s u m maries of t h e n u m ber of e v e nts.  N o w t he te xt h as b ee n re m o ve d i n or der t o si m plif y 
t h e re p orti n g of t he a d v erse e ve nts a n d t o us e a c o nsiste nt a p pr oa c h t o t hat utilize d i n pre vi o us 
i nte grate d safet y a n al yses. 
 
Fr o m S A P Versi o n 3: 
 A b bre viati o ns h a v e b e e n u p date d. 
 M M D R d osi n g sc he d ule has b e e n u p d ate d t o M M D R Da ys 1, 1 2 0, 2 4 0, 3 6 0, 4 8 0, 6 0 0, 7 2 0, 
8 4 0, 9 6 0, 1 0 8 0 1 2 0 0, 1 3 2 0, 1 4 4 0, 1 5 6 0, a n d 1 6 8 0 ( ± 1 4 d a ys) u ntil t h e E O S E val uati o n/ Earl y 
Ter mi n ati o n ( E T) Visit. 
 C o ntract ure assess me nts ha ve b ee n a d de d t o m ot or f u n cti o n assess m e nts. 
 Dis all o we d c o nc o mita nt m e dicati o n were re m o ve d. 
 A d diti o nal e x a m ples h a v e be e n pr o vi de d f or c o nc o mita nt pr o ce d ures. 
 U p d ates t o i m p utati o n m et h o ds f or C H O P I N T E N D fr o m M M D R Da y 1. 
 Effica c y ass ess m e nt f or m ot or f u n cti o ns occ ur at s cree ni n g a n d/ or pre d ose at M M D R Da y 1, 
e ver y 8 m o nt hs u ntil M M D R Da y 7 2 0, i n cl usi ve (i.e., M M D R Da ys 2 4 0, 4 8 0, 7 2 0), a n d e ver y 
1 2 m o nt hs t here after (i.e. pre d os e at M M D R Da ys 1 0 8 0 a n d 1 4 4 0), a n d at t h e E O S E v al u ati o n 
( M M D R Da y 1 8 0 0 [ ± 1 4 da ys)/ E T Visit. 
 Pe ds Q L sc h e d ule u p d ate d t o Scre e ni n g a n d/ or pre d ose ( wit hi n 7 d a ys of d osi n g) at M M D R 
Da y 1, a p pr o xi m atel y a n n u all y t hereafter (i.e., M M D R Da ys 3 6 0, 7 2 0, 1 0 8 0, a n d 1 4 4 0), a n d 
at t h e E O S E val u ati o n/ E T Visit. 
 C GI h as b ee n re m o ve d fr o m t his S A P d u e t o diffic ult y i n relia ble i nter pretati o n. 
 X-ra y of t he s pi ne sc h e d ule u p date d t o Scree ni n g a n d/ or pre d ose ( wit hi n 7 da ys of d osi n g) at 
M M D R Da y 1, a p pr o xi m atel y a n n u all y t h ereafter (i.e., M M D R Da ys 3 6 0, 7 2 0, 1 0 8 0, a n d 
1 4 4 0), a n d at t h e E O S E v al uati o n/ E T Visit. 
 
 
 U p d ates t o A p pe n di x A wi n d o wi n g f or effica c y b ase d o n u p d ate d M M D R s c h e d ule 
 La n g u a ge was u p d ate d o n Ne ur ol o gic al E xa mi n ati o ns t o e ns ure c o nsiste n c y wit h Pr ot oc ol 
Versi o n 5. 
 Secti o n o n a nal yses t o assess t h e i m p act of C O VI D- 1 9 was a d de d. 
 
Fr o m S A P Versi o n 4 
 
 S u m m ar y of g a p b et wee n e n d of i n d e x st u dies a n d first d os e i n C S 1 1 is a d d e d.  
 A ge at First N usi n erse n D os e Dis pla y is a d de d.  
 De n o mi nat or d eter mi n ati o n f or C H O P I N T E N D a n d 
W H O M M res p o n der a n al yses are 
u p d ate d. 


     
   
 
 
   
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St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
 A nal ysis f or W H O M M are u p date d, m aj orl y a d d e d res p o n d er a nal ysis a n d s hift pres e ntati o ns 
a n d re m o ve d s o m e f or b etter pres e ntati o n of data. 
 HI N E/ W H O M M c o m bi ne d a n al ys es o n ti m e t o a c hi v e first milest o ne are a d d e d. 
 Gr o wt h fail ure a n al ys es are re m o ve d.  
 C o b b a n gle a nal ysis is si m plifie d t o pres e nt m e a n or c h a n ge o ver ti m e a n d a s u m m ar y t o 
pres e nt pr o p orti o n of s u bje cts wit h gr o wi n g r o d or s c oli osis fi x ati o n pr o ce d ures o cc urre d o ver 
ti m e usi n g Ka pla n- Meier m et h o d.  
 N u m b er a n d le n gt h of h os pitaliz ati o n is u p d ate d t o b e m ore s p ecific o n a nal ys es t o be d o n e.  
 Seri o us res pirat or y e v e nt, seri o us dis ease ( S M A)-relate d A Es le a di n g h os pitaliz ati o n a n d 
dise as e ( S M A)-relate d A Es  are a d de d.  
 
 
 
  
 
  
 Safet y la b orat or y is u p d ate d t o a d d a nal yses usi n g te xt- b o o k n or m al ra n g e. I n a d diti o n, 
s u m m ar y of la b res ults o v er visit per pr ot o c ol are a d de d.  
 Vital si g n is u p d ate d t o a d d s u m m ar y o ver ti m e per pr ot oc ol.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
A p pe n di x A 
 
T he e n d of st u d y da y will f oll o w t he m a xi m u m wi n d o w i n pr ot o c ol a m e n d m e nt Versi o n 6. 0 as 
M M D R Da y 1 8 0 0 + 1 4 da ys. De p e n di n g o n w he n last assess m e nts are a ct uall y fi nis he d f or t he st u d y, 
t h e f oll o wi n g wi n d o wi n g m a y b e e xte n d e d be y o n d t h e pr ot oc ol- defi n e E O S da y.  
 
Des cri pti o n of t he wi n d o wi n g f o r effic ac y (I nte g r ate d dis pl a y): 
 
 
S u bje cts ori gi n ati n g i n i n de x st u d y C S 4: 
 
 St u d y da ys > 1 t o < = 5 0 will be la b elle d Da y 2 5
St u d y da ys > 5 0 t o < = 1 3 1 will b e la belle d Da y 9 2
 St u d y da ys > 1 3 1 t o < = 2 1 1 will be la belle d Da y 1 6 9
 St u d y da ys > 2 1 1 t o < = 3 0 2 will b e la belle d Da y 2 5 3
 St u d y da ys > 3 0 2 t o < = 4 0 0 will b e la belle d Da y 3 5 0
 St u d y da ys > 4 0 0 t o < = 5 7 0 will b e la belle d Da y 4 5 0
 St u d y da ys > 5 7 0 t o < = 8 1 0 will b e la belle d Da y 6 9 0
 St u d y da ys > 8 1 0 t o < = 1 0 5 0 will be la belle d Da y 9 3 0
 St u d y da ys > 1 0 5 0 t o < = 1 2 9 0 will b e la belle d Da y 1 1 7 0 
 St u d y da ys > 1 2 9 0 t o < = 1 5 3 0 will b e la b elle d Da y 1 4 1 0 
 St u d y da ys > 1 5 3 0 t o < = 1 8 9 0 will b e la b elle d Da y 1 7 1 0 
 
F or st u d y d a ys > X- 1 8 0 t o < = X +- 1 8 0 will be la belle d Da y X w h ere X b e gi ns at 2 0 7 0 a n d i n cre ases 
b y 3 6 0 u ntil t h e E O S E val u ati o n/ E T Visit. F or C S 4 s u bje cts w h o were ra n d o mize d t o s h a m pr oc e d ure 
i n C S 4 t he n t his wi n d o wi n g sc he m e will als o be a p plie d fr o m t h e start of C S 1 1. St u d y da y will b e 
re calc ulate d t h e d ate of first d ose i n C S 1 1. 
 
S u bje cts ori gi n ati n g i n i n de x st u d y C S 1 or C S 2: 
 
St u d y da ys > 5 0 t o < = 1 3 1 will b e la belle d Da y 9 2
St u d y da ys > 1 3 1 t o < = 2 1 1 will be la belle d Da y 1 6 9
 St u d y da ys > 2 1 1 t o < = 3 0 2 will b e la belle d Da y 2 5 3
 St u d y da ys > 3 0 2 t o < = 4 0 0 will b e la belle d Da y 3 5 0
 St u d y da ys > 4 0 0 t o < = 5 0 0 will b e la belle d Da y 4 5 0
 St u d y da ys > 5 0 0 t o < = 6 0 0 will b e la belle d Da y 5 5 0
 St u d y da ys > 6 0 0 t o < = 7 0 0 will b e la belle d Da y 6 5 0
 St u d y da ys > 7 0 0 t o < = 8 0 0 will b e la belle d Da y 7 5 0
 St u d y da ys > 8 0 0 t o < = 9 0 0 will b e la belle d Da y 8 5 0
 St u d y d a ys > 9 0 0 t o < = 1 0 0 0 will be la belle d Da y 9 5 0
 St u d y da ys > 1 0 0 0 t o < = 1 1 7 0 will b e la b elle d Da y 1 0 5 0 
 
T he n f or st u d y d a ys > X- 1 2 0 t o < = X + 1 2 0 will b e la belle d Da y X w h ere X be gi ns at 1 2 9 0 a n d 
i n creases b y 2 4 0 u ntil Da y 2 0 1 0. F or st u d y d a ys > Y- 1 8 0 t o < = Y- 1 8 0 will be la belle d Da y Y w h ere 
Y b e gi ns at 2 3 1 0 a n d i ncre ases b y 3 6 0 u ntil t h e E O S E val u ati o n/ E T Visit.  
 


     
   
 
 
   
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St atistical A nal ysis Pl a n  
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S u bje cts ori gi n ati n g i n i n de x st u d y C S 3 B a n d C S 3 A 
 
 St u d y da ys > 1 t o < = 2 2 will be la b ele d Da y 1 5 
 St u d y da ys > 2 2 t o < = 4 7 will b e la b ele d Da y 2 9 
 St u d y d a ys > 4 7 t o < = 1 2 3 will b e la bele d Da y 6 4 
 St u d y da ys > 1 2 3 t o < = 2 4 2 will b e la bele d Da y 1 8 3 
 St u d y da ys > 2 4 2 t o < = 3 4 8 will b e la bele d Da y 3 0 2 
 St u d y da ys > 3 4 8 t o < = 4 8 6 will b e la bele d Da y 3 9 4 
 St u d y da ys > 4 8 6 t o < = 6 9 8 will be la bele d Da y 5 7 8 
 St u d y da ys > 6 9 8 t o < = 9 3 8 will be la b ele d Da y 8 1 8 
St u d y da ys > 9 3 8 t o < = 1 1 7 8 will b e la b ele d Da y 1 0 5 8
 St u d y da ys > 1 1 7 8 t o < = 1 4 1 8 will b e la bele d Da y 1 2 9 8 
 St u d y da ys > 1 4 1 8 t o < = 1 6 5 8 will b e la bele d Da y 1 5 3 8 
 St u d y da ys > 1 6 5 8 t o < = 2 0 1 8 will b e la bele d Da y 1 8 3 8 
 
F or st u d y da ys > Y- 1 8 0 t o < = Y + 1 8 0 will b e la b elle d Da y Y w here Y b e gi ns at 2 1 9 8 a n d i ncre as es 
b y 3 6 0 u ntil t h e E O S E val uati o n/ E T Visit. 
 
F or C S 3 B s u bjects w h o were ra n d o mize d t o s ha m pr oce d ure i n C S 3 B t h e n t he s a m e wi n d o wi n g 
sc h e m e will als o be a p plie d fr o m t h e start of C S 1 1. St u d y da y will be re calc ulate d fr o m t h e date of 
first d os e i n C S 1 1. 
 
S u bje cts ori gi n ati n g i n i n de x st u d y 2 3 2 S M 2 0 2 Part 1 a n d 2 
 
 St u d y da ys < = 1 will be la belle d Baseli n e  
 St u d y da ys > 1 t o < = 2 2 will be la b elle d Da y 1 5 
 St u d y d a ys > 2 2 t o < = 4 7 will b e la b elle d Da y 2 9 
 St u d y da ys > 4 7 t o < = 1 2 3 will be la b elle d Da y 6 4 
 St u d y da ys > 1 2 3 t o < = 2 4 2 will b e la belle d Da y 1 8 3 
 St u d y da ys > 2 4 2 t o < = 3 6 2 will b e la belle d Da y 3 0 2 
 St u d y da ys > 3 6 2 t o < = 4 8 2 will b e 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 b elle 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
 
 
T he n f or st u d y da ys > X- 1 2 0 t o < = X + 1 2 0 will b e la belle d Da y X w h ere X be gi ns at 9 5 8 a n d i ncreases 
b y 2 4 0 da ys u ntil Da y 1 6 7 8. F or st u d y d a ys > Y- 1 8 0 t o < = Y- 1 8 0 will b e l a belle d Da y Y w here Y 
b e gi ns at 1 9 7 8 a n d i ncre ases b y 3 6 0 u ntil t he E O S E v al u ati o n/ E T Visit.  
 
 
Des cri pti o n of t he wi n d o wi n g f o r effic ac y (si nce M M D R D a y 1): 
 
Wi n d o wi n g will be a p plie d t o u nsc he d ule d 
M M D R visits f or effic acies (e x c e pt f or c o g niti ve 
assess me nts). T h e a n al ysis wi n d o wi n g will be defi n e d as:  
 
Baseli n e - M M D R Da y 1:   


     
   
 
 
   
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N o n- missi n g ass ess m e nt at M M D R Da y 1 or a n y ot h er visit wit hi n 6 0 da ys pri or t o M M D R Da y 1 
d osi n g d ate   
 
M M D R Da y 1 2 0:   6 0 < st u d y d a ys < = 1 8 0 
M M D R Da y 2 4 0:   1 8 0 < st u d y d a ys < = 3 0 0 
M M D R Da y X: X- 6 0 < st u d y d a ys < = X + 6 0, w here X be gi ns at 3 6 0 a n d i ncre as es b y 1 2 0 till e arl y 
ter mi n ati o n or E O S ( M M D R Da y 1 8 0 0). I de all y, t he last wi n d o wi n g will be M M D R Da y 1 8 0 0: 1 7 4 0 
< st u d y d a ys < = 1 8 6 0, a n d it c a n g o b e y o n d t h at if d ata e xist. T he wi n d o wi n g ca n g o b e y o n d.   
 
 
  
 
St u d y da ys calc ulate d as (ass ess me nt date 
 M M D R Da y 1 d osi n g date) + 1 f or p ost M M D R Da y 1 
assess me nts.   
 
Des cri pti o n of t he wi n d o wi n g f o r s afet y: 
 
F or safet y assess m e nts f or s u bjects ori gi n ati n g i n C S 1, C S 2, C S 4 a n d 2 3 2 S M 2 0 2 (later o nset) t he 
f oll o wi n g wi n d o wi n g will b e us e d: 
 
 St u d y da ys > 1 t o < = 1 6 will be la b ele d Da y 1 
 St u d y da ys > 1 6 t o < = 5 7 will b e la b ele d Da y 2 9 
 St u d y da ys > 5 7 t o < = 1 2 7 will be la b ele d Da y 8 5 
 St u d y da ys > 1 2 7 t o < = 2 1 1 will b e la bele d Da y 1 6 9 
 St u d y da ys > 2 1 1 t o < = 3 0 2 will b e la bele d Da y 2 5 3 
 St u d y da ys > 3 0 2 t o < = 4 0 0 will b e la bele d Da y 3 5 0 
 St u d y da ys > 4 0 0 t o < = 5 4 0 will be la bele d Da y 4 5 0 
 St u d y da ys > 5 4 0 t o < = 6 9 0 will be la bele d Da y 6 3 0 
 St u d y da ys > 6 9 0 t o < = 8 1 0 will be la bele d Da y 7 5 0 
 
T he n f or st u d y d a ys > X- 6 0 t o < = X + 6 0 will be la belle d Da y X w h ere X b e gi ns at 8 7 0 a n d i ncreases 
b y 1 2 0 da ys.  
 
F or safet y assess m e nts f or s u bje cts ori gi nati n g i n C S 3 B, C S 3 A a n d 2 3 2 S M 2 0 2 (i nfa ntile o nset) t h e 
f oll o wi n g wi n d o wi n g will be use d: 
 
 St u d y d a ys > 1 t o < = 2 2 will be la b ele d Da y 1 5 
 St u d y da ys > 2 2 t o < = 4 7 will b e la b ele d Da y 2 9 
 St u d y da ys > 4 7 t o < = 1 2 3 will be la b ele d Da y 6 4 
 St u d y da ys > 1 2 3 t o < = 2 4 3 will b e la bele d Da y 1 8 3 
 St u d y da ys > 2 4 3 t o < = 3 6 2 will b e la bele d Da y 3 0 2 
 
 
T he n f or st u d y d a ys > X- 6 0 t o < = X + 6 0 will be la belle d Da y X w h ere X b e gi ns at 4 2 2 a n d i ncreases 
b y 1 2 0 da ys.   
 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
A p pe n di x B 
 
T he f oll o wi n g ta ble lists a d verse e ve nts w hic h are m ost li k el y S M A- dise as e relate d e ve nts at t h e 
ti m e of t his d o c u m e nt d e v el o p me nt. T he e ve nts are s u bject t o u p d ate after d ata b ase l o c k a n d a fi n al 
sele cte d e v e nts  will b e us e d f or prese ntati o ns.  
 
B o d y S yste m or O r g a n Cl ass 
Dicti o n a r y- De ri v e d Ter m 
C o n g e nital, fa milial a n d ge netic dis or ders     
De v el o p m e ntal hi p d ys plasia 
 
S pi n al m usc ular atr o p h y 
 
Tali pes 
Gastr oi ntesti n al dis or ders
C o nsti p ati o n  
Ge n eral dis or ders a n d a d mi nistrati o n site 
c o n diti o ns 
Gait dist ur ba nc e
M usc ul os keletal a n d c o n n ecti ve tiss ue dis or d ers 
B o n e def or mit y 
 
J oi nt c o ntract ure
 
J oi nt ra n ge of m oti o n d ecreas e d 
 
J oi nt stiff ness 
 
K y p h osc oli osis
 
K y p h osis 
 
Li m b as y m m etr y
 
Li m b disc o mf ort
 
M us cle atr o p h y
 
M us cle c o ntract ure
 
M us cle s pas ms 
 
M us cle ti g ht ness
 
M us cle t witc hi n g 
 
M us c ular wea k ness 
 
Ne ur o m usc ular s c oli osis 
 
Oste o p or osis 
 
Oste o p or otic fra ct ure 
 
Ri b def or mit y 
Ner v o us s yste m dis or ders
M ot or d e v el o p m e ntal d ela y  
Ner v o us s yste m dis or ders
M ot or d ysf u ncti o n  
 
 
 
 
Ps y c hiatric dis or ders  
E nc o presis  
Res pirat or y, t h oracic a n d me diasti n al dis or ders   
Ac ute res pirat or y distress s y n dr o me 
 
Ac ute res pirat or y fail ure 
 
Atelectasis 
 
Res pirat or y m uscle we a k ness 
 
 
 
 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
R E F E R E N C E S 
 
C D C 
 
D u b o witz L, D u b o witz V. T he n e ur ol o gic al assess me nt of t he preter m a n d f ull-ter m n e w b or n 
i nfa nt. L o n d o n ( U K): Willia m Hei ne m a n n Me dic al b o o ks Lt d; 1 9 8 1.
Fi n e, J. P., a n d Gra y, R. 
 J o ur n al of t h e A m eric a n Statistic al Ass o ciati o n 9 4: 4 9 6 5 0 9. 
 
 
 
Ma zz o n e E S, Ma y he w A, M o ntes J, et al. Re vise d u p per li m b m o d ule f or s pi n al m usc ular 
atr o p h y: De v el o p m e nt of a ne w m o d ule. M uscle Ner v e. 2 0 1 6 E p u b 2 0 1 6/ 1 0/ 0 4. 
 
Ma zz o n e E S 1, Ma y he w A 2, M o ntes J 3, Ra mse y D 4, Fa n elli L 1, Y o u n g S D 3, Salaz ar R 3, De Sa nctis 
R 1, Paster na k A 5, Gla nz m a n A 6, C oratti G 1, Ci vitell o M 7, F orci na N 1, G e e R 8, D u o n g T 8, Pa ne 
M 1, Sc ot o M 4, Pera M C 1, Messi n a S 9, Te n n e k o o n G 6, Da y J W 8, Darras B T 5, De Vi v o D C 3, Fi n k el 
R 7, M u nt o ni F 4, Merc uri E 1. M uscle Ner ve. 2 0 1 7 J u n; 5 5( 6): 8 6 9- 8 7 4. E p u b 2 0 1 7 Fe b 6. 
 
M o ntes J, Mc Der m ott M P, Marte ns W B, et al. Si x- Mi n ute Wal k Test d e m o nstrates m ot or fati g ue 
i n s pi nal m us c ular atr o p h y. Ne ur ol o g y. 2 0 1 0; 7 4( 1 0): 8 3 3- 8. 
 
Fi n kel R S, Merc uri E, Me y er O H, Si m o n ds A K, Sc hr ot h M K, Gra h a m RJ, Kirsc h n er J, Ia n n ac c o ne 
S T, Cra wf or d T O, W o o ds S, M u nt o ni F, Wirt h B, M o ntes J, Mai n M, Maz z o n e E S, Vitale M, S n y d er 
B, Q uija n o- R o y S, Berti ni E, Da vis R H, Qia n Y, Sejerse n T; S M A Car e gr o u p. Dia g n osis a n d 
m a n a ge me nt of s pi nal m us c ular atr o p h y: Part 2: P ul m o n ar y a n d ac ute c are; m e dic ati o ns, s u p ple m e nts 
a n d i m m u nizati o ns; ot h er or ga n s yste ms; a n d et hics. Ne ur o m usc ul Dis or d. 2 0 1 8 M ar; 2 8( 3): 1 9 7- 2 0 7. 
d oi: 1 0. 1 0 1 6/j. n m d. 2 0 1 7. 1 1. 0 0 4. E p u b 2 0 1 7 N o v 2 3. P MI D: 2 9 3 0 5 1 3 7.
 
Merc uri E, Fi n kel R S, M u nt o ni F, Wirt h B, M o ntes J, Mai n M, Maz z o n e E S, Vitale M, S n y der B, 
Q uija n o- R o y S, Berti ni E, Da vis R H, Me yer O H, Si m o n ds A K, Sc hr ot h M K, Gra h a m RJ, Kirsc h ner 
J, Ia n nac c o n e S T, Cra wf or d T O, W o o ds S, Qia n Y, Sejerse n T; S M A C ar e Gr o u p. Dia g n osis a n d 
m a n a ge me nt of s pi nal m us c ular atr o p h y: Part 1: Rec o m m e n d ati o ns f or dia g n osis, re h a bilitati o n, 
ort h o p e dic 
a n d 
n utriti o nal 
care. 
Ne ur o m usc ul 
Dis or d. 
2 0 1 8 
Fe b; 2 8( 2): 1 0 3- 1 1 5. 
d oi: 
1 0. 1 0 1 6/j. n m d. 2 0 1 7. 1 1. 0 0 5. E p u b 2 0 1 7 N o v 2 3. P MI D: 2 9 2 9 0 5 8 0.  
 
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/ 
 
W H O 
M ot or De vel o p m e nt St u d y: 
Wi n d o ws of a c hie v e m e nt f or si x gr oss m ot or d e v el o p me nt 
milest o nes, Acta P æ diatrica, 2 0 0 6; S u p pl 4 5 0: 8 6/ 9 5 
 
S pr o ule D M, Has n ai n R, K oe ni qs ber ger D, et al. A ge at dis ease o ns et pre dicts li k eli h o o d a n d ra pi dit y 
of gr o 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 n al m usc ular atr o p h y t y pes 1 a n d 2. J 
C hil d Ne ur ol 2 0 1 2 J ul; 2 7( 7): 8 4 5- 8 5 1. 


     
   
 
 
   
St u d y N u m ber: I SI S 3 9 6 4 4 3- C S 1 1                                 
St atistical A nal ysis Pl a n  
Versi o n N o. 5. 0  
 
Va n d er Pl oe g A T, Cle m e ns P R, C orz o D, et al. A Ra n d o miz e d St u d y of Al gl u c osi dase Alfa i n 
Late- O ns et P o m p e's Dise as e. Ne w E n gla n d J o ur nal of Me dici n e. 2 0 1 0; 3 6 2( 1 5): 1 3 9 6- 1 4 0 6
 
 




Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
9/ 7/ 2 0 2 3 1: 0 8: 0 4 P M
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
9/ 8/ 2 0 2 3 6: 0 6: 3 0 A M
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
9/ 8/ 2 0 2 3 6: 0 7: 2 3 A M
C o m pl et e d
S e c urit y C h e c k e d
9/ 8/ 2 0 2 3 9: 1 1: 5 4 A M
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s