Clinical trial NCT04089566
Conditions: Muscular Atrophy, Spinal
Sponsor: Biogen
Start date: 2020-03-26; Completion date: 2024-05-30
Enrollment: 145 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score (Part B); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C).

The secondary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A, B and C); to examine the effect of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA, to examine the effect of nusinersen administered intrathecally at higher doses compared to the currently approved dose in participants with SMA (Part B).

Detailed description:

Arms: arm 1: Part A: Participants with later-onset SMA will receive loading doses of 28 mg of nusinersen intrathecally on Days 1, 15 and 29 followed by maintenance doses of 28 mg on Days 149 and 269. arm 2: Part B: Participants with infantile- or later-onset SMA will receive loading doses of 12 mg of nusinersen intrathecally on Days 1, 15, 29, and 64 followed by maintenance doses of 12 mg on Days 183 and 279. Sham procedure will be administered on Day 135. arm 3: Part B: Participants with infantile- or later-onset SMA will receive loading doses of 50 mg of nusinersen intrathecally on Days 1 and 15 followed by maintenance doses of 28 mg on Days 135 and 279. Sham procedure will be administered on Days 29, 64 and 183. arm 4: Part C: Participants who have been receiving the approved dose of 12 mg for at least 1 year prior to entry, will receive a single bolus dose of 50 mg of nusinersen intrathecally on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by maintenance doses of 28 mg on Days 121 and 241.
Interventions: intervention 1: Nusinersen
Intervention descriptions: intervention 1: Administered as specified in the treatment arm

Protocol documents:
Prot_000.pdf: 
COVER PAGE 
Official Title: 
Escalating Dose and Randomized, Controlled Study of Nusinersen 
(BIIB058) in Participants With Spinal Muscular Atrophy 
NCT Number: NCT04089566 
Document date: 11 Jun 2024 


CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA 02142 
United States 
PROTOCOL NUMBER: 
232SM203 
Biogen Idec Research Limited 
5 Foundation Park 
Roxborough Way 
Maidenhead, Berkshire 
SL6 3UD 
United Kingdom 
PHASE OF DEVELOPMENT: 
2/3 
PROTOCOL TITLE: Escalating Dose and Randomized, Controlled Study of Nusinersen 
(BIIB058) in Participants With Spinal Muscular Atrophy 
EUDRA CT NUMBER: 
2019-002663-10 
IND NUMBER:  
110011 
DATE:  
11 June 2024 
Version 7 
FINAL 
Supersedes previous Version 6 dated 05 May 2022. 


Protocol 232SM203, Version 7 
Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
2 
SPONSOR INFORMATION 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA 02142 
United States 
 
Biogen Idec Research Limited 
5 Foundation Park 
Roxborough Way 
Maidenhead, Berkshire  
SL6 3UD 
United Kingdom 
Biogen Japan Ltd. 
Nihonbashi 1-chome Mitsui 
Building 14F 
4-1 Nihonbashi 1-chome 
Chuo-ku, Tokyo 
103-0027 Japan 
 
Biogen Australia PTY Ltd. 
Level 4 
2 Banfield Road 
Macquarie Park, NSW 2113 
Australia 
 
For urgent medical issues in which the study Medical Director should be contacted, refer to the 
Study Reference Guide’s Official Study Contact List for complete contact information. 
 
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization and other third parties; however, Biogen retains overall accountability for these 
activities. 
 
 


Protocol 232SM203, Version 7 
Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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3 
SPONSOR SIGNATURE PAGE 
 
Protocol 232SM203 was approved by: 
 
 
__________________________________________ 
 
______________ 
 PharmD 
Date 
  
Biogen


Protocol 232SM203, Version 7 
Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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TABLE OF CONTENTS 
SPONSOR INFORMATION...........................................................................................................2 
SPONSOR SIGNATURE PAGE ....................................................................................................3 
1. 
KEY STUDY ELEMENTS ........................................................................................10 
1.1. 
Synopsis ......................................................................................................................10 
1.2. 
Study Design Schematic .............................................................................................25 
1.3. 
Schedule of Activities .................................................................................................26 
2. 
LIST OF ABBREVIATIONS .....................................................................................49 
3. 
INTRODUCTION ......................................................................................................51 
3.1. 
Study Rationale ...........................................................................................................51 
3.1.1. 
Rationale for Study Population ...................................................................................52 
3.1.2. 
Rationale for Dosing Regimen ...................................................................................52 
3.2. 
Background .................................................................................................................54 
3.2.1. 
Overview of SMA .......................................................................................................54 
3.2.2. 
Current Therapies for SMA ........................................................................................55 
3.2.3. 
Profile of Previous Experience With Nusinersen .......................................................55 
3.3. 
Benefit-Risk Assessment ............................................................................................56 
4. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................57 
5. 
STUDY DESIGN .......................................................................................................64 
5.1. 
Study Overview ..........................................................................................................64 
5.2. 
Study Duration for Participants ..................................................................................66 
 
67 
5.4. 
Unscheduled Visits .....................................................................................................67 
5.5. 
End of Study ...............................................................................................................68 
6. 
STUDY POPULATION .............................................................................................69 
6.1. 
Inclusion Criteria ........................................................................................................69 
6.2. 
Exclusion Criteria .......................................................................................................72 
6.3. 
Screening, Retesting, and Screen Failures ..................................................................77 
6.3.1. 
Screening ....................................................................................................................77 
6.3.2. 
Retesting and Rescreening ..........................................................................................78 
6.3.3. 
Screen Failures ............................................................................................................78 
7. 
STUDY TREATMENT ..............................................................................................79 


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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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7.1. 
Regimen ......................................................................................................................79 
7.2. 
Modification of Dose ..................................................................................................80 
7.3. 
Study Treatment Management ....................................................................................80 
7.3.1. 
Nusinersen ..................................................................................................................80 
7.4. 
Blinding Procedures ....................................................................................................81 
7.5. 
Compliance .................................................................................................................82 
7.6. 
Concomitant Therapy and Procedures ........................................................................82 
7.6.1. 
Concomitant Therapy .................................................................................................82 
7.6.2. 
Concomitant Procedures .............................................................................................83 
7.7. 
Continuation of Treatment ..........................................................................................83 
8. 
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF PARTICIPANTS FROM THE STUDY ...............................................................84 
8.1. 
Discontinuation of Study Treatment ...........................................................................84 
8.2. 
Lost to Follow-Up .......................................................................................................84 
8.3. 
Withdrawal of Participants From the Study ...............................................................85 
9. 
EFFICACY, 
 AND PHARMACODYNAMIC 
ASSESSMENTS .........................................................................................................86 
9.1. 
Clinical Efficacy Assessments ....................................................................................86 
9.1.1. 
Motor Milestones ........................................................................................................89 
9.1.2. 
Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease ............91 
9.1.3. 
Hammersmith Functional Motor Scale Expanded ......................................................91 
9.1.4. 
Revised Upper Limb Module .....................................................................................91 
 
92 
 
92 
 
93 
9.1.8. 
Clinical Global Impression of Change .......................................................................93 
9.1.9. 
Parent Assessment of Swallowing Ability .................................................................93 
9.1.10. 
Quality-of-Life Questionnaires ...................................................................................94 
 
95 
 
95 
 
95 
9.1.14. 
Ventilator Use .............................................................................................................96 
9.1.15. 
Standard of Care .........................................................................................................96 


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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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.96 
9.3. 
Pharmacodynamic Assessments .................................................................................96 
 
96 
9.5. 
Pharmacogenetic and Genetic Assessments ...............................................................96 
9.6. 
Future Scientific Research Assessments ....................................................................97 
10. 
SAFETY ASSESSMENTS ........................................................................................98 
10.1. 
Clinical Safety Assessments .......................................................................................98 
10.2. 
Laboratory Safety Assessments ..................................................................................99 
10.3. 
Telephone Assessments ..............................................................................................99 
11. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES ...............................................................................................100 
11.1. 
Definitions ................................................................................................................100 
11.1.1. 
Adverse Event ...........................................................................................................100 
11.1.2. 
Serious Adverse Event ..............................................................................................100 
11.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ..............101 
11.2. 
Safety Classifications ................................................................................................101 
11.2.1. 
Investigator Assessment of Events ...........................................................................101 
11.2.2. 
Relationship of Events to Study Treatment or LP/Sham Procedure .........................102 
11.2.3. 
Severity of Events .....................................................................................................102 
11.2.4. 
Expectedness of Events ............................................................................................102 
11.3. 
Monitoring and Recording Events ............................................................................103 
11.3.1. 
Adverse Events .........................................................................................................103 
11.3.2. 
Serious Adverse Events ............................................................................................103 
11.3.3. 
Immediate Reporting of Serious Adverse Events .....................................................103 
11.3.4. 
Suspected Unexpected Serious Adverse Reactions ..................................................104 
11.4. 
Procedures for Handling Special Situations .............................................................104 
11.4.1. 
Pregnancy .................................................................................................................104 
11.4.2. 
Overdose ...................................................................................................................105 
11.4.3. 
Medical Emergency ..................................................................................................105 
11.5. 
Contraception Requirements ....................................................................................105 
11.6. 
Safety Responsibilities ..............................................................................................107 
11.6.1. 
The Investigator ........................................................................................................107 


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11.6.2. 
The Sponsor ..............................................................................................................107 
12. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .........108 
12.1. 
General Considerations .............................................................................................108 
12.2. 
Analysis Sets .............................................................................................................108 
12.3. 
Definition of Baseline ...............................................................................................108 
12.4. 
Methods of Analysis for Efficacy Endpoints ............................................................109 
12.4.1. 
Analysis of the Primary Endpoint in Part B .............................................................109 
12.4.2. 
Analysis of the Secondary Endpoints in Part B ........................................................110 
12.4.3. 
Analysis of the Remaining Endpoints ......................................................................113 
 
113 
12.6. 
Methods of Analysis for Pharmacodynamic Endpoints ...........................................113 
12.7. 
Methods of Analysis for Biomarkers/Pharmacogenetics .........................................113 
12.8. 
Methods of Analysis for Safety Endpoints ...............................................................114 
12.8.1. 
Adverse Events .........................................................................................................114 
12.8.2. 
Clinical Laboratory Results ......................................................................................114 
12.8.3. 
Vital Signs ................................................................................................................115 
12.8.4. 
Neurological Examinations ......................................................................................115 
 
115 
12.10. 
Interim Analyses .......................................................................................................115 
12.11. 
Sample Size Considerations .....................................................................................115 
13. 
ETHICAL AND REGULATORY REQUIREMENTS ............................................117 
13.1. 
Declaration of Helsinki .............................................................................................117 
13.2. 
Ethics Committee ......................................................................................................117 
13.3. 
Changes to the Final Protocol ...................................................................................118 
13.4. 
Informed Consent .....................................................................................................118 
13.5. 
Participant Data Protection .......................................................................................119 
13.6. 
Compensation for Injury ...........................................................................................119 
13.7. 
Conflict of Interest ....................................................................................................119 
13.8. 
Study Report Signatory .............................................................................................119 
13.9. 
Registration of Study and Disclosure of Study Results ............................................120 
13.10. 
Retention of Study Data ............................................................................................120 
14. 
KEY ROLES AND STUDY GOVERNANCE COMMITTEES .............................121 


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14.1. 
Vendors .....................................................................................................................121 
14.1.1. 
Contract Research Organization ...............................................................................121 
14.1.2. 
Interactive Response Technology .............................................................................121 
14.1.3. 
Electronic Data Capture ............................................................................................121 
14.1.4. 
Central Laboratories for Laboratory Assessments ...................................................121 
14.2. 
Study Committees .....................................................................................................122 
14.2.1. 
Endpoint Adjudication Committee ...........................................................................122 
14.2.2. 
Independent Data Monitoring Committee ................................................................122 
15. 
ADMINISTRATIVE PROCEDURES .....................................................................123 
15.1. 
Study Site Initiation ..................................................................................................123 
15.2. 
Quality Control and Quality Assurance ....................................................................123 
15.3. 
Monitoring of the Study ............................................................................................123 
15.4. 
Travel Policy .............................................................................................................124 
15.5. 
Study Funding ...........................................................................................................124 
15.6. 
Publications ...............................................................................................................124 
16. 
REFERENCES .........................................................................................................125 
17. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .......................................128 
18. 
APPENDICES ..........................................................................................................129 
APPENDIX A. PERMANENT VENTILATION DEFINITION CRITERIA: ACUTE 
REVERSIBLE EVENT ............................................................................................130 
APPENDIX B. LABORATORY ANALYTES ........................................................................132 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities for Part A ................................................................................27 
Table 2: 
Schedule of Activities for Part B ................................................................................32 
Table 3: 
Schedule of Activities for Part C Cohort 1 .................................................................37 
Table 4: 
Schedule of Activities for Part C Cohort 2 .................................................................42 
Table 5: 
Schedule of Activities for Participants in Part B Who Discontinue Study 
Treatment but Agree to Remain in the Study .............................................................47 
Table 6: 
Part B Blinded Dosing Schedule ................................................................................79 
Table 7: 
Hammersmith Infant Neurological Examination Section 2 - Motor 
Milestones ...................................................................................................................90 
Table 8: 
Primary and Secondary Endpoints ............................................................................112 


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Table 9: 
Number of Participants in Each Study Part, by Symptom Onset .............................116 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................25 
 


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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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1. 
KEY STUDY ELEMENTS 
1.1. 
Synopsis 
Protocol Title: 
Escalating Dose and Randomized, Controlled Study of Nusinersen 
(BIIB058) in Participants With Spinal Muscular Atrophy 
Protocol Number: 
232SM203 
Version Number: 
7 
Name of Study 
Treatment: 
Research Name: 
BIIB058 
Generic Name: 
Nusinersen 
Trade Name:  
Spinraza 
Study Phase: 
2/3 
Study Indication: 
Spinal muscular atrophy (SMA) 
Study Rationale: 
Efficacy and safety results across the nusinersen clinical development 
program have demonstrated an overall positive benefit-risk profile of 
nusinersen across a broad range of SMA phenotypes and patient 
populations. Nusinersen is approved in the United States, Europe, 
and other countries and regions for the treatment of SMA in pediatric 
and adult patients at a recommended dosage of 12 mg administered in 
3 loading doses at 14-day intervals, a fourth loading dose 30 days 
after the third dose, and maintenance doses every 4 months 
thereafter. Pharmacokinetic (PK) and pharmacodynamic (PD) 
analyses indicate that nusinersen drug exposure higher than that 
achieved with 12 mg in patients with SMA may produce an even 
greater benefit in motor function. Additionally, PK modeling and 
simulations identified dosing regimens that achieve higher drug 
exposure more rapidly. Therefore, this study is being conducted to 
investigate the efficacy, safety, tolerability, 
 of a 50/28-mg 
dose of nusinersen (50-mg loading dose; 28-mg maintenance dose) 
and a dosing regimen targeted to achieve higher drug exposure more 
rapidly. This study will be conducted in participants with genetically 
confirmed SMA. 
Rationale for Dose 
and Schedule 
Selection: 
The clinical PK, safety, and efficacy of nusinersen have been 
evaluated in a number of patient populations (infantile-onset [SMA 
symptom onset ≤ 6 months (≤ 180 days) of age], later-onset [SMA 
symptom onset > 6 months (> 180 days) of age], and 
presymptomatic). The approved dosing regimen of nusinersen is 
12 mg administered in 4 loading doses during a 2-month period 


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followed by maintenance doses every 4 months thereafter. In the 
original development program, 2 different dosing regimens 
(4 loading doses followed by maintenance doses every 4 months and 
3 loading doses followed by maintenance doses every 6 months) 
were evaluated in sham-controlled studies. Results from these 
studies, the population PK and exposure-response modeling, and the 
nonhuman primate safety studies were used as the basis for selecting 
dosing regimens in this study. 
An exploratory exposure-response analysis performed in participants 
with infantile-onset SMA (Study CS3A, n = 20, age 38 days to 
8 months) showed a statistically significant positive correlation 
between nusinersen cerebrospinal fluid (CSF) exposure and motor 
function (e.g., Children’s Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders [CHOP-INTEND] scores).  
Previous PK modeling predicted that the median concentration of 
nusinersen within the CSF immediately prior to the administration of 
the subsequent maintenance dose (i.e., trough concentration [Ctrough]) 
would be approximately 10 ng/mL at steady state with the 
label-approved maintenance dosing regimen (i.e., 12 mg 
administered every 4 months) and approximately 20 ng/mL at steady 
state with the proposed maintenance dosing regimen for Study 
232SM203 (i.e., 28 mg administered every 4 months). This model 
was subsequently updated to include additional data from 
Studies 232SM201 and CS11 not previously modeled, resulting in an 
adjustment of CSF Ctrough predictions in all patient populations, which 
are still consistent with the prior predictions. As a consequence, 
population PK modeling now predicts that with increasing the 
maintenance dose from 12 to 28 mg administered every 4 months, 
CSF Ctrough should increase from 5 to 12 ng/mL at steady state. The 
exposure-response (PK/PD) relationship between steady-state CSF 
Ctrough and CHOP-INTEND response continuously increases as a 
function of PK and is on an upward trajectory at concentrations 
consistent with the 12 mg maintenance dose (i.e., 5 ng/mL). It is 
predicted that additional clinical benefit (i.e., a 5-point increase in 
CHOP-INTEND score) could be achieved by increasing CSF 
exposures to 12 ng/mL. Therefore, administration of this higher dose 
of nusinersen may lead to meaningful clinical benefit to patients. At 
this time, no dose-limiting toxicity has been identified with 
nusinersen. The PK modeling therefore suggests that it is unlikely 
that the higher doses of nusinersen would have a less favorable 
risk-benefit profile compared with standard dose nusinersen. 
The PK/PD relationship has thus far been demonstrated primarily in 
the infantile-onset SMA population. However, the same positive 


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PK/PD relationship is expected across SMA types and patient age 
groups because they share the same disease mechanism. This is 
supported by the preliminary correlation analysis from 
Study 232SM202, which showed a positive relationship between CSF 
Ctrough and total motor milestones scores in patients with infantile- 
and later-onset SMA who received 12 mg of nusinersen as 4 loading 
doses followed by maintenance doses every 4 months. 
Using 12 ng/mL as the clinical CSF Ctrough target concentration and 
the predicted CSF PK profiles from 28 mg of nusinersen 
(maintenance doses every 4 months) as the reference dosing regimen, 
simulations were performed to evaluate additional dosing scenarios 
with higher doses and reduced loading-dose frequency. Additional 
evaluation of the maintenance dosing frequency was not performed 
because previous modeling showed that a dosing frequency of every 
4 months best maintained the CSF concentration achieved at steady 
state.  
The assumption of PK linearity is supported by nusinersen 
toxicokinetic results in nonhuman primates, which showed nearly 
dose-proportional PK in the plasma and central nervous system 
tissues (target site of action) up to 15 mg (human equivalent dose of 
150 mg). Assuming PK linearity, PK simulations were performed in 
both infantile- and later-onset SMA populations after 2 years of 
treatment using a population PK model developed from patients 
across the age range of ≤ 6 months to 18 years old. Based on the most 
recent PK modeling performed, relative to the approved 12-mg label 
regimen (CSF Ctrough of approximately 5 ng/mL), 28 mg administered 
as 3 loading doses (biweekly) or 50 mg administered as 2 loading 
doses (biweekly), each followed by maintenance doses of 28 mg 
every 4 months, were identified to achieve the desired CSF Ctrough 
(approximately 12 ng/mL) more rapidly at the end of the loading 
dose period. Nusinersen 28 mg administered as 3 loading doses 
(biweekly) had a comparable predicted CSF maximum concentration 
(Cmax) to the reference dosing regimen, whereas the 50-mg dosing 
regimen surpassed the predicted Cmax from the reference dosing 
regimen. Moreover, the 28-mg maintenance dosing regimen 
adequately maintained the higher CSF Ctrough target (approximately 
12 ng/mL) during the maintenance dose period. Toxicology studies in 
nonhuman primates evaluating the nonhuman primate equivalent of 
the 28- and 50-mg doses have been conducted and support the safety 
of these doses in a clinical study (see Section 3.3). Therefore, the 
28-mg dose (administered as 3 loading doses at biweekly intervals), 
50-mg dose (administered as 2 loading doses at biweekly intervals), 


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and 28-mg maintenance dose were recommended for additional 
clinical evaluation. 
The single bolus dose in Part C is supported by PK simulations 
showing that a titration dosing regimen of a single loading dose 
(50 mg) followed by maintenance doses of 28 mg every 4 months 
thereafter achieved and maintained the higher CSF Ctrough target 
concentration (approximately 12 ng/mL) in the representative 
populations for later-onset and infantile-onset SMA, respectively. 
The predicted exposures of the proposed titration dosing regimens are 
covered by the levels demonstrated to be safe in nonhuman primates. 
Study Objectives and Endpoints 
 
Part B Primary Objective 
Primary Endpoint 
To examine the clinical efficacy of 
nusinersen administered intrathecally at 
higher doses to participants with SMA 
in the 232SM203 50/28 mg Group 
compared to the CS3B Matched Sham 
Control Group, as measured by change 
in CHOP-INTEND total score. 
Infantile-Onset SMA 
• Change from baseline to Day 183 in 
CHOP-INTEND total score, accounting 
for mortality/dropout using the 
joint-rank test (comparison of higher 
dose to matched sham control) 
Part B Secondary Objectives 
Secondary Endpoints 
To examine the clinical efficacy of 
nusinersen administered intrathecally at 
higher doses to participants with SMA 
in the 232SM203 50/28 mg Group 
compared to: 
• CS3B Matched Sham 
Control Group 
AND 
• 232SM203 nusinersen 12 mg 
Group 
Infantile-Onset SMA 
• Proportion of Hammersmith Infant 
Neurological Examination (HINE) 
Section 2 motor milestone responders at 
Day 183 (comparison of higher dose to 
matched sham control) 
• Change from baseline to Day 183 in 
HINE Section 2 motor milestones total 
score (comparison of higher dose to 
matched sham control) 
• Change from baseline to Day 183 in 
plasma concentration of NF-L 
(comparison of higher dose to matched 
sham control) 
• Change from baseline to Day 302 in 
CHOP-INTEND total score 


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(comparison of higher dose to 12 mg 
dose) 
• Change from baseline to Day 302  in 
HINE Section 2 motor milestones total 
score (comparison of higher dose to 12 
mg dose) 
• Change from baseline to Day 29 in 
plasma concentration of NF-L 
(comparison of higher dose to 12 mg 
dose) 
• Time to death or permanent ventilation 
(tracheostomy or ≥ 16 hours of 
ventilation/day continuously for 
> 21 days in the absence of an acute 
reversible event [Appendix A]) 
(comparison of higher dose to matched 
sham control) 
• Time to death (overall survival) 
(comparison of higher dose to matched 
sham control) 
• Time to death or permanent ventilation 
(tracheostomy or ≥ 16 hours of 
ventilation/day continuously for 
> 21 days in the absence of an acute 
reversible event [Appendix A]) 
(comparison of higher dose to 12 mg 
dose) 
• Time to death (overall survival) 
(comparison of higher dose to 12 mg 
dose) 
To examine the clinical efficacy of 
nusinersen administered intrathecally at 
higher doses compared to the currently 
approved 12 mg dose in participants 
with SMA 
 
Later-Onset SMA 
• Change from baseline in Hammersmith 
Functional Motor Scale Expanded 
(HFMSE) score 
• Change from baseline in Revised Upper 
Limb Module (RULM) score 


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• Total number of new World Health 
Organization (WHO) motor milestones 
• Change from baseline in Assessment of 
Caregiver Experience with 
Neuromuscular Disease (ACEND) 
• Change from baseline in Pediatric 
Quality of Life Inventory™ (PedsQL) 
• Change from baseline in CSF 
concentration of NF-L 
• Change from baseline in plasma 
concentration of NF-L 
To examine the safety and tolerability of 
nusinersen administered intrathecally at 
higher doses to participants with SMA  
• Incidence of adverse events (AEs), 
including serious adverse events (SAEs) 
• Shifts from baseline in clinical 
laboratory parameters, 
electrocardiograms (ECGs), and vital 
signs 
• Change in growth parameters 
• Shifts from baseline in coagulation 
parameters (activated partial 
thromboplastin time [aPTT], 
prothrombin time [PT], and 
international normalized ratio [INR]) 
• Change in urine total protein 
• Change from baseline in neurological 
examination outcomes 
• The proportion of participants with a 
postbaseline platelet count below the 
lower limit of normal on at least 
2 consecutive measurements 
• The proportion of participants with a 
postbaseline corrected QT interval using 
Fridericia’s formula (QTcF) of 
> 500 msec and an increase from 


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baseline to any postbaseline timepoint 
in QTcF of > 60 msec 
To examine the effect of nusinersen 
administered intrathecally at higher 
doses compared to the currently 
approved 12 mg dose in participants 
with SMA 
Infantile-Onset and Later-Onset SMA 
• Number and duration of hospitalizations  
• Clinical Global Impression of Change 
(CGIC) [physician, caregiver] at 
Day 302 
• Number of serious respiratory events 
• Proportion of time on ventilation 
(infantile-onset SMA population) 
• Ventilator use 
• Change in the Parent Assessment of 
Swallowing Ability (PASA) scale 
Infantile-Onset SMA only 
 
• Change from baseline in CSF 
concentration of NF-L 
Parts A and C Primary Objective 
Primary Endpoints 
To examine the safety and tolerability of 
nusinersen administered intrathecally at 
higher doses to participants with SMA 
• Incidence of AEs, including SAEs 
• Shifts from baseline in clinical 
laboratory parameters, ECGs, and vital 
signs 
• Change in growth parameters 
• Shifts from baseline in coagulation 
parameters (aPTT, PT, and INR) 
• Change in urine total protein 
• Change from baseline in neurological 
examination outcomes 
• The proportion of participants with a 
postbaseline platelet count below the 


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lower limit of normal on at least 
2 consecutive measurements 
• The proportion of participants with a 
postbaseline QTcF of > 500 msec and 
an increase from baseline to any 
postbaseline timepoint in QTcF of 
> 60 msec 
Parts A and C Secondary Objectives 
Secondary Endpoints 
To examine the clinical efficacy of 
nusinersen administered intrathecally at 
higher doses to participants with SMA 
Parts A and C: 
• Change from baseline in HFMSE score 
• Change from baseline in RULM score 
• Total number of new WHO motor 
milestones 
• Change from baseline in ACEND 
• Change from baseline in PedsQL (Part 
A and Part C Cohort 1 only) 
Part C (Cohort 1 only): 
• Change from baseline in 
CHOP-INTEND  
• Change from baseline in HINE 
Section 2 motor milestones 
To examine the effect of nusinersen 
administered intrathecally at higher 
doses to participants with SMA 
Parts A and C: 
• Number and duration of hospitalizations 
• CGIC (physician, caregiver) at Day 302 
• Number of serious respiratory events 
• Ventilator use 
• Change in the PASA scale (Part A only) 
  


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Study Design: 
This is a 3-part (Parts A, B, and C) study in which participants will 
be followed for approximately 10 to 13 months after the first dose of 
study treatment. Following the completion of this study, all eligible 
participants may elect to enroll in a separate long-term extension 
study (232SM302), pending study approval by ethics committees and 
the appropriate regulatory authorities. In regard to participants rolling 
over from Part B, this will be done without unblinding the 
participant’s treatment group. 
Part A is an open-label safety evaluation. Six participants with 
later-onset SMA who are 2 to ≤ 15 years of age, inclusive, at the 
signing of informed consent will receive 3 loading doses of 28 mg of 
nusinersen on Days 1, 15, and 29, followed by 2 maintenance doses 
of 28 mg on Days 149 and 269. Participants will remain at the clinic 
for at least 24 hours after each dose. A sentinel dosing approach will 
be used, in which the first participant will be enrolled and dosed with 
28 mg of nusinersen. Following the availability of 72 hours of safety 
data after the first loading dose in the first participant, data for this 
participant will be reviewed by the Investigator and the Sponsor 
before the next 5 participants are enrolled. Only 1 participant can 
receive their first dose of study treatment on a given day.  
After 6 participants have completed the loading period (i.e., when the 
last participant has available safety data through the Day 64 visit), an 
independent data monitoring committee (IDMC) will review the 
available safety data to recommend whether Part B can be initiated. If 
deemed necessary by the Sponsor, additional participants may be 
enrolled in Part A to ensure sufficient data are available for the safety 
evaluation prior to enrollment of participants in Part B. Details 
regarding the IDMC review of data may be found in the IDMC 
charter. Meanwhile, participants in Part A will proceed to 
maintenance dosing without interruption. Note that the IDMC can 
recommend to stop the study based on the safety findings. 
Part B will consist of a pivotal, double-blind, active-controlled 
treatment period with either 2 or 4 loading doses of nusinersen (for 
the 50/28-mg and Control Groups, respectively) administered 
intrathecally followed by maintenance doses approximately every 
4 months thereafter. Approximately 99 participants with infantile- or 
later-onset SMA will be randomized in a 1:2 ratio to receive either 
the currently approved dosing regimen of 4 loading doses of 12 mg 
of nusinersen administered intrathecally (Days 1, 15, 29, and 64) 
followed by 2 maintenance doses of 12 mg on Days 183 and 279 
(Control Group) or 2 loading doses of 50 mg of nusinersen 
administered intrathecally (Days 1 and 15) followed by 


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2 maintenance doses of 28 mg on Days 135 and 279 (50/28-mg 
Group). In order to maintain blinding, 1 sham procedure will be 
administered in the Control Group on Day 135 and 3 sham 
procedures will be administered in the 50/28-mg Group on Days 29, 
64, and 183 to ensure the same dosing visit schedule as the Control 
Group. Participants will remain at the clinic for at least 24 hours after 
study treatment administration on Days 1 and 15; inpatient stays at 
other visits may occur based on the Investigator’s discretion. If the 
primary reason for the inpatient stay is due to an AE or SAE, 
reporting requirements per Section 11.3 must be followed. 
Once the fifteenth participant in Part B has been enrolled and 
administered the first dose of study treatment, no new participants 
will be dosed in Part B until after an IDMC review. The IDMC will 
review unblinded data from the first 15 participants in Part B who 
have completed the Day 29 visit (in order to achieve 6 or more 
participants who have received 50 mg in the 50/28-mg Group, while 
maintaining the blind for the rest of the study team). This review will 
include safety data through the Day 29 visit at a minimum and all 
available individual CSF and plasma nusinersen concentration data 
for these participants, including the Day 15 samples at a minimum. 
Dosing of the remaining participants in Part B and dosing in Part C 
will occur only after this review has completed, provided that no 
safety concerns are identified. Note that the IDMC can recommend to 
stop the study based on the safety findings. By the time of 
implementation of Protocol Version 6, the IDMC reviewed these data 
and recommended that the study may continue with dosing of the 
remaining participants in Part B and initiating dosing in Part C 
without any modifications to the study. 
In Part C, up to approximately 40 participants who have already 
initiated treatment with nusinersen and have been receiving the 
approved dose of 12 mg for at least 1 year prior to entry will be 
enrolled. The initial cohort in Part C (i.e., Cohort 1) consists of up to 
approximately 20 participants of any age or SMA status. For Cohort 
1, an attempt will be made to enroll at least 8 but no more than 
12 participants ≥ 18 years of age (participants in Cohort 1 ≥ 18 years 
of age must be ambulatory). Up to 5 participants with severe scoliosis 
and/or severe contractures may be enrolled in Cohort 1 of Part C after 
consultation with the Medical Monitor. An additional cohort (i.e., 
Cohort 2) consisting of up to approximately 20 adult participants (≥ 
18 years of age) was subsequently added to Part C in Protocol 
Version 5 in order to enable collection of data in adults transitioning 
from the currently approved nusinersen dosing regimen to higher 


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dose. Participants in Cohort 2 can be either ambulatory on 
nonambulatory. 
All participants in Part C will receive a single bolus dose of 50 mg 
(which should be administered 4 months ± 14 days after their most 
recent maintenance dose of 12 mg) followed by 2 maintenance doses 
of 28 mg on Days 121 and 241. Participants in Part C will remain at 
the clinic for at least 24 hours after the first (bolus) dose for the 
purpose of completing study assessments. 
Study Location: 
Approximately 65 sites globally are planned. 
Study Population: 
This study will be conducted in participants who meet the following 
criteria: 
• Parts A, B, and C: 
− Genetic documentation of 5q SMA (homozygous gene 
deletion, mutation, or compound heterozygote) 
• Part A: 
− Participants with later-onset SMA, aged 2 to 
≤ 15 years, inclusive, at the time of informed consent 
• Part B: 
− Participants with infantile-onset SMA, aged > 1 week 
to ≤ 7 months (≤ 210 days) at the time of informed 
consent 
− Participants with later-onset SMA, aged 2 to 
< 10 years at the time of informed consent 
• Part C: 
Cohort 1: 
− Males and females of any age (individuals ≥ 18 years 
of age at Screening must be ambulatory) 
− Have been receiving treatment with nusinersen for at 
least 1 year prior to entry in this study 
Cohort 2: 


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− Males and females ≥ 18 years of age (can be 
ambulatory or nonambulatory) 
− Have been receiving treatment with nusinersen for at 
least 1 year prior to entry in this study 
Detailed criteria are described in Section 6. 
Number of Planned 
Participants: 
Including all 3 parts (A, B, and C), approximately 145 participants 
may be enrolled. 
Treatment Groups: 
• Part A: Six participants with later-onset SMA will receive 
3 loading doses of 28 mg of nusinersen administered 
intrathecally on Days 1, 15, and 29. Maintenance doses of 
28 mg of nusinersen will be administered on Days 149 
and 269. 
• Part B: 
− Control Group: A total of 33 participants (25 with 
infantile-onset SMA and 8 with later-onset SMA) will 
receive 4 loading doses of 12 mg of nusinersen 
administered intrathecally (Days 1, 15, 29, and 64), 
followed by maintenance doses of 12 mg on Days 183 
and 279 (and a sham procedure on Day 135). 
− 50/28-mg Group: A total of 66 participants (50 with 
infantile-onset SMA and 16 with later-onset SMA) 
will receive 2 loading doses of 50 mg of nusinersen 
administered intrathecally (Days 1 and 15) and 2 sham 
procedures on Days 29 and 64, followed by 
maintenance doses of 28 mg on Days 135 and 279 
(and a sham procedure on Day 183). 
• Part C: Up to approximately 40 participants (i.e., up to 
approximately 20 participants each in Cohorts 1 and 2) 
who have already been receiving treatment with 
nusinersen for at least 1 year prior to entry in this study 
will receive a single bolus dose of 50 mg of nusinersen 
administered intrathecally on Day 1 in this study (which 
should be administered 4 months ± 14 days after their 
most recent maintenance dose of 12 mg), followed by 
2 maintenance doses of 28 mg of nusinersen on Days 121 
and 241. 


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Sample Size 
Determination: 
A total sample size of approximately 145 participants is planned for 
this study (Table 9). The justification for the sample size for the 
infantile-onset SMA population in Part B is detailed below. The 
sample sizes for the remaining groups are not based on statistical 
considerations. 
A minimum of 6 participants with later-onset SMA will be enrolled 
in Part A to characterize the safety, tolerability,
 of a 
28/28 mg dose of nusinersen (28-mg loading dose; 28-mg 
maintenance dose). A total of 24 participants with later-onset SMA 
will be randomized to the Control Group and 50/28-mg Group in 
Part B in a ratio of 1:2; this will allow the exploration of the safety, 
tolerability, 
, and efficacy of a 50/28 mg dose of 
nusinersen in this population. A total of up to approximately 
40 participants will be enrolled in Part C (i.e., up to approximately 20 
participants each in Cohorts 1 and 2) to characterize the safety, 
tolerability, 
 of a 50/28-mg dose of nusinersen in 
participants transitioning from maintenance dosing at the currently 
approved dose of 12 mg of nusinersen. 
For the infantile-onset SMA population in Part B, a sample size of 
approximately 50 participants in the 50/28-mg Group and a minimum 
of N=20 sham participants will provide at least approximately 99% 
power for the primary endpoint to detect an improvement of 
24 points on CHOP-INTEND and 23% survival rate benefit 
(compared to that observed in Study CS3B participants receiving 
sham control) at Day 183 based on the joint-rank test at a 2-sided 
significance level of 0.05. This power calculation is based on 
simulations using data generated from a joint model of survival and 
functional change. The model used a difference of 24 points for the 
Day 183 change from baseline in CHOP-INTEND total score (50/28-
mg Group – Study CS3B Sham Control Group) and a population 
standard deviation of 8.8 for change from baseline. 
For Part B, the randomization will be stratified as follows: 
• For participants with infantile-onset SMA by disease 
duration: ≤ 12 weeks and > 12 weeks (time from age at 
symptom onset to age at informed consent) 
• For participants with later-onset SMA by age at informed 
consent: < 6 years and ≥ 6 years 


Protocol 232SM203, Version 7 
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Visit Schedule: 
Participants will have up to 10 visits during the study. The number of 
visits for each part is as follows: 
• Part A: 8 to 9 visits 
• Part B: 9 to 10 visits 
• Part C: 5 to 6 visits 
Visits during Days 1, 15, and 29 of the loading periods of Parts A and 
B, and Day 1 of the loading period of Part C should be performed ± 1 
day from the nominal visit day. Visits during Day 64 of the loading 
period of Parts A and B and the maintenance period of Parts A, B, 
and C should be performed ± 7 days from the nominal visit day. Visit 
days are calculated with respect to Day 1 (the date of first dose). 
Study assessments conducted at each visit are listed in the Schedule 
of Activities (Table 1, Table 2, Table 3, and Table 4). 
Duration of Study 
Participation: 
Study duration for each participant will be as follows: 
Part A: approximately 323 to 410 days 
• Screening: 21 days 
• Loading period: 64 days 
• Maintenance period: 205 days 
• Follow-up: 33 to 120 days 
Part B: approximately 323 to 420 days 
• Screening: 21 days 
• Loading period: 64 days 
• Maintenance period: 215 days 
• Follow-up: 23 to 120 days 
Part C: approximately 323 to 382 days 
• Screening: 21 days 
• Loading period: 1 day 


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• Maintenance period: 240 days 
• Follow-up: 61 to 120 days 
Benefit-Risk Analysis: Nusinersen (Spinraza) 12 mg has a positive benefit-risk profile, with 
more than 4 years of postmarketing experience and more than 
11,000 patients treated. The safety profile to date does not preclude 
study of higher doses in any population. 
Detailed information about the known and expected benefits and 
risks, reasonably expected AEs, and nonclinical toxicology studies 
supporting investigation of higher doses of nusinersen in the clinic 
are provided in the Investigator’s Brochure and informed consent 
form. A high-level summary of the benefits and risks known during 
study design is provided here. 
Anticipating a potential enhancement of benefit with the dosing 
regimens proposed for Study 232SM203, substantiated by PK/PD 
modeling described in Section 3.1.2, the safety of the loading period 
for Study 232SM203 is supported by a nonclinical study conducted 
in monkeys (Study P058-17-03). In this study, the 
no-observed-adverse-effect level (NOAEL) was 15 mg (human 
equivalent dose of 150 mg). As such, dosing for Study 232SM203 
has a safety margin of at least 4.5-fold for cumulative doses during 
the loading period and a 3-fold margin for a single loading dose of 50 
mg.  
The safety of long-term exposure during the Study 232SM203 
maintenance period is supported by a 53-week monkey study 
(Study 396443-AS06). Monkeys received a cumulative dose of 3.9, 
13, and 52 mg at each dose level (0.3, 1, and 4 mg per dose, 
respectively) during the 52-week treatment duration. The overall 
NOAEL was determined to be 4 mg. Tissue concentrations measured 
in monkeys from the 53-week toxicology study at the NOAEL (4 mg) 
were compared to the estimated tissue concentrations in patients with 
SMA. The exposure-based safety margin is at least 1.4-fold based on 
exposure in the spinal cord (safety margins are higher for other 
tissues). 


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1.2. 
Study Design Schematic 
A schematic of the study design is shown in Figure 1. 
Figure 1: 
Study Schematic 
 
 
1 + 5 = Sentinel dosing of the first participant in Part A will be followed by a review of the safety data before the 
remaining 5 participants in Part A are dosed; 28/28 = 28-mg loading doses and 28-mg maintenance doses; 
12/12 = 12-mg loading doses and 12-mg maintenance doses; 50/28 = 50-mg loading doses and 28-mg maintenance 
doses; 12/50/28 = 12-mg loading doses and initial maintenance doses followed by a single 50-mg dose and 
subsequent 28-mg maintenance doses; LD = loading dose; MD = maintenance dose; N = number of participants; 
pts = participants; R = randomization; SMA = spinal muscular atrophy 
Infantile-onset: SMA symptom onset ≤ 6 months (≤ 180 days) of age 
Later-onset: SMA symptom onset > 6 months (> 180 days) of age 
1 Participants who do not meet the criteria for contraception use will have their last visit on Day 302. Participants 
who meet the criteria for contraception use (see Section 11.5) will have a Day 302 visit and a Day 389, Day 399, 
or Day 361 visit for Part A, Part B, or Part C, respectively. Male participants who meet the criteria may complete 
the Day 389 (Part A), Day 399 (Part B), or Day 361 (Part C) visit via a telephone interview; female participants 
who meet the criteria will return to the site for these visits. For participants in Parts B and C who meet the criteria 
for contraception use and enroll into the long-term extension study (232SM302) at the Day 302 visit, that will be 
their final visit in Study 232SM203.  


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1.3. 
Schedule of Activities 
Study assessments conducted at each visit are listed in Table 1, Table 2, Table 3, and Table 4. 
Participants in Part B who discontinue treatment may remain in the study to continue the 
protocol-required tests and assessments described in Table 5 (unless the reason for 
discontinuation is to initiate treatment with a disallowed concomitant therapy per 
Section 7.6.1.2). 


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27 
Table 1: 
Schedule of Activities for Part A 
 
Screening 
Visit1 
Treatment 
Follow-Up2 
EOS 
Assessments 
D-21 to 
D-1 
D1, D15 (± 1 day),  
D29 (± 1 day) 
D64 
(± 7 days) 
D149 (± 7 days), 
D269 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D389 
(+ 14 days) 
 
 
Predose 
LP 
Postdose 
 
Predose 
LP 
Postdose 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Local Urine/Serum 
Pregnancy Test for 
Females of Childbearing 
Potential3 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Medical (including SMA) 
History 
X 
 
 
 
 
 
 
 
 
 
 
SMA Genetic Testing4 
X 
 
 
 
 
 
 
 
 
 
 
X-ray Examination (with 
the participant supine, not 
in a supported sitting 
position)5 
X 
 
 
 
 
 
 
 
 
 
 
LP Opening Pressure 
 
 
X 
 
 
 
X 
 
 
 
 
Study Treatment Injection6 
 
 
X 
 
 
 
X 
 
 
 
 
Inpatient Stay (at least 
24 hours) 
 
 
 
X 
 
 
 
X 
 
 
 
Vital Signs and Pulse 
Oximetry7 
 
X 
 
X8 
 
X 
 
X8 
 
X 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
 


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Screening 
Visit1 
Treatment 
Follow-Up2 
EOS 
Assessments 
D-21 to 
D-1 
D1, D15 (± 1 day),  
D29 (± 1 day) 
D64 
(± 7 days) 
D149 (± 7 days), 
D269 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D389 
(+ 14 days) 
 
 
Predose 
LP 
Postdose 
 
Predose 
LP 
Postdose 
 
 
 
Growth Parameters 
(including height/ulnar 
length) 
X 
X 
 
 
 
X9 
 
 
 
X 
 
Physical Examination10 
X 
X 
 
 
 
X 
 
 
 
X 
 
Neurological 
Examination11 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
ECG12 
 
X 
 
X 
X 
 
 
X 
 
X 
 
Safety Laboratory Tests13 
X 
X 
 
 
X 
X 
 
 
 
X 
 
Local Coagulation 
Laboratory Tests14 
X 
X 
 
 
 
X 
 
 
 
 
 
Safety Follow-Up 
Telephone Contact 
 
 
 
X15 
 
 
 
 
X 
 
 
CSF Local Laboratory 
Sample (cell count, total 
protein, and glucose) 
 
X 
 
 
 
X 
 
 
 
 
 


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Screening 
Visit1 
Treatment 
Follow-Up2 
EOS 
Assessments 
D-21 to 
D-1 
D1, D15 (± 1 day),  
D29 (± 1 day) 
D64 
(± 7 days) 
D149 (± 7 days), 
D269 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D389 
(+ 14 days) 
 
 
Predose 
LP 
Postdose 
 
Predose 
LP 
Postdose 
 
 
 
Efficacy Assessments18 
(HFMSE, RULM, WHO 
Motor Milestones, 
 
19) 
X20 
X21 
 
 
X9 
X9 
 
 
 
X 
 
CGIC22 
 
X 
 
 
X 
X 
 
 
 
X 
 
PedsQL and ACEND23 
 
X 
 
 
 
X 
 
 
 
X 
 
Dysphagia Assessment 
(PASA) 
X 
 
 
 
X 
X 
 
 
 
X 
 
Ventilator Use24 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
AE Recording 
X-------------------------------------------------------------------------------------------------------------------------------------------X 
SAE Recording 
X-------------------------------------------------------------------------------------------------------------------------------------------X 
Concomitant Therapy and 
Procedures Recording 
X-------------------------------------------------------------------------------------------------------------------------------------------X 
; ACEND = Assessment of Caregiver Experience with Neuromuscular Disease; 
AE = adverse event; CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; EOS = end of study; 
ET = early termination; HFMSE = Hammersmith Functional Motor Scale Expanded; ICF = informed consent form; LP = lumbar puncture; PASA = Parent 
Assessment of Swallowing Ability; PedsQL = Pediatric Quality of Life Inventory™; 
; RULM = Revised Upper Limb Module; 
SAE = serious adverse event; SMA = spinal muscular atrophy; SMN1 = survival motor neuron-1 gene; SMN2 = survival motor neuron-2 gene; WHO = World 
Health Organization 
1 If the Screening visit occurs within 7 days before Day 1, screening assessments can be used for Day 1 predose assessments. During the Screening period, 
participants who have an out-of-range result that is not clinically significant can be retested 1 time only at the discretion of the Investigator. The Screening 
period may be extended for up to 10 days for individuals who cannot complete the Day 1 visit within 21 days of signing the ICF, as long as they continue to 
meet other eligibility criteria. 
2 Participants who meet the criteria for contraception use (see Section 11.5) will have a Day 302 and a Day 389 visit. Male participants who meet the criteria may 
complete the Day 389 visit via a telephone interview. Female participants who meet the criteria will return to the site to complete this assessment. Participants 
who do not meet the criteria for contraception use will have their last visit on Day 302. Day 389 will take place at least 120 days after the final dose. 


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3 A serum pregnancy test will be performed locally in female participants of childbearing potential in the event of a positive or equivocal urine pregnancy test 
result. 
4 A blood sample will be collected at Screening for SMN2 copy number for those participants without acceptable historical genetic documentation of SMN2 copy 
number. For all other participants, a blood sample will be collected during the study (preferably before or on Day 149) for analysis of both SMN1 copy number 
and deletion/mutation and SMN2 copy number by the central laboratory. 
5 Eligibility based on scoliosis severity at Screening will be determined by local analysis of the X-ray results. The results of the central X-ray read will be 
documented and used for subsequent data analyses. For sites with local regulation on use of X-ray (e.g., Germany), the Investigator may assess scoliosis based 
on physical examination without imaging.  
6 Spinal ultrasound, fluoroscopy, or similar techniques may be used for the LP procedure, if deemed necessary, but are not required. Anesthesia (local or general) 
and/or sedation may be used for the LP procedure, at the discretion of the Investigator and/or study center. 
7 Vital signs will include temperature, pulse rate, systolic and diastolic blood pressure, respiratory rate, and pulse oximetry.  
8 Vital signs will be collected at 1, 2, 4, 6, and 8 hours (± 15 minutes) postdose and 24 hours (± 2 hours) postdose. 
9 These assessments may be performed up to 7 days prior to dosing/study visit. 
10 Videotaping of physical examinations is optional. 
11 On dosing visits, a neurological examination will be performed predose, at 3 and 6 hours (± 15 minutes) postdose, and at 24 hours (± 2 hours) postdose, or 
when anesthesia/sedation (if used) has worn off. Predose neurological examinations should be repeated when the assessment falls outside the protocol-specified 
window because of a delay in dosing. 
12 ECGs will be performed predose, at 5 hours (± 1 hour) postdose, and at 24 hours (± 2 hours) postdose on Days 1, 15, and 29; at the Day 64 visit; at 5 hours (± 
1 hour) postdose on Days 149 and 269; and at Day 302/ET. Predose ECGs should be repeated when the assessment falls outside the protocol-specified window 
because of a delay in dosing. If a postdose ECG result is abnormal and clinically significant, a repeat ECG should be performed within 2 hours. 
13 Blood chemistry, hematology, and urinalysis samples will be analyzed by a central laboratory. These assessments may be performed up to 7 days prior to 
dosing/study visit, if necessary. Urine total protein will be analyzed by local laboratory; however, if local analysis is not possible without a 24-hour urine 
collection, then samples will be analyzed by central laboratory (Appendix B). Predose clinical safety laboratory assessments should be repeated when the 
assessment falls outside the protocol-specified window because of a delay in dosing. 
14 Coagulation testing will be conducted locally at Screening and predose (within 7 days prior to dosing) at each dosing visit; results must be reviewed prior to 
dosing. Predose coagulation parameters should be repeated when the assessment falls outside the protocol-specified window because of a delay in dosing. 
15 A safety follow-up telephone call will be made 2 weeks (± 3 days) after the Day 29 dose. 
 
 
 
 
 
18 Videotaping of all motor milestone and motor function assessments is optional. 
19 When assessing efficacy, HFMSE and RULM will be performed first, followed by remaining assessments. 
 
 
 
 
 


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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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31 
20 Two baseline assessments are required for HFMSE and RULM. At least 1 assessment must be conducted during the Screening period. The second assessment 
may be conducted either during the Screening period or at Day 1 predose. If both baseline assessments are conducted during the Screening period, the 
assessments do not need to be repeated on Day 1. 
21 During the loading period, the efficacy assessments will be performed on Day 29 predose only. The Day 29 efficacy assessments may be performed up to 
3 days prior to dosing, if necessary. 
22 CGIC will be collected on Days 29, 64, and 149 (predose), and Day 302. 
23 Assessments will be performed on Day 1, Day 149, and at Day 302/ET. 
24 Ventilator use will be collected at every study visit (see Section 9.1.14). 
 


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32 
Table 2: 
Schedule of Activities for Part B 
 
Screening 
Visit1 
Treatment 
Follow-Up2 
EOS 
Assessments 
D-21 to 
D-1 
D1, D15 (± 1 day),  
D29 (± 1 day), D64 (± 7 days) 
D135 (± 7 days),  
D183 (± 7 days),  
D279 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D399 
(+ 14 days)
 
 
Predose 
LP/ 
SP 
Postdose 
Predose 
LP/ 
SP 
Postdose 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Standard of Care 
X 
 
 
 
 
 
 
 
X 
 
Local Urine/Serum Pregnancy Test 
for Females of Childbearing 
Potential3 
X 
X 
 
 
X 
 
 
 
X 
X 
Medical (including SMA) History 
X 
 
 
 
 
 
 
 
 
 
SMA Genetic Testing4 
X 
 
 
 
 
 
 
 
 
 
X-ray Examination for Participants 
With Later-Onset SMA (with the 
participant in a sitting or supported 
sitting position)5 
X 
 
 
 
 
 
 
 
 
 
Randomization (Day 1 only) 
 
X 
 
 
 
 
 
 
 
 
LP Opening Pressure6 
 
 
X6 
 
 
X6 
 
 
 
 
Study Treatment Injection/Sham 
Procedure7 
 
 
X 
 
 
X 
 
 
 
 
Inpatient Stay 
 
 
 
X8 
 
 
 
 
 
 
Vital Signs and Pulse Oximetry9 
X 
X 
 
X10 
X 
 
X10 
 
X 
 
Weight 
X 
X 
 
 
X 
 
 
 
X 
 


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Screening 
Visit1 
Treatment 
Follow-Up2 
EOS 
Assessments 
D-21 to 
D-1 
D1, D15 (± 1 day),  
D29 (± 1 day), D64 (± 7 days) 
D135 (± 7 days),  
D183 (± 7 days),  
D279 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D399 
(+ 14 days)
 
 
Predose 
LP/ 
SP 
Postdose 
Predose 
LP/ 
SP 
Postdose 
 
 
 
Growth Parameters (including 
height/body length/ulnar length, and 
head/chest/arm circumference)11 
X 
X 
 
 
X12 
 
 
 
X 
 
Physical Examination13 
X 
X 
 
 
X 
 
 
 
X 
 
Neurological Examination14 
X 
X 
  
X 
X 
 
X 
 
X 
 
ECG15 
 
X 
 
X 
 
 
X 
 
X 
 
Safety Laboratory Tests16 
X 
X 
 
 
X 
 
 
 
X 
 
Local Coagulation Laboratory 
Tests17 
X 
X 
 
 
X 
 
 
 
 
 
Safety Follow-Up Telephone Contact 
 
 
 
X18 
 
 
 
X 
 
 
CSF Local Laboratory Sample (cell 
count, total protein, and glucose)6 
 
X 
 
 
X 
 
 
 
 
 
CSF Biomarker 
 
X 
 
 
X 
 
 
 
 
 
Plasma Biomarker 
 
X 
 
 
X12 
 
 
 
X 
 
Efficacy Assessments21 for 
Participants With Infantile-Onset 
SMA (CHOP-INTEND and HINE 
Section 2 Motor Milestones) 
X22 
X23 
 
 
X12 
 
 
 
X 
 


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Screening 
Visit1 
Treatment 
Follow-Up2 
EOS 
Assessments 
D-21 to 
D-1 
D1, D15 (± 1 day),  
D29 (± 1 day), D64 (± 7 days) 
D135 (± 7 days),  
D183 (± 7 days),  
D279 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D399 
(+ 14 days)
 
 
Predose 
LP/ 
SP 
Postdose 
Predose 
LP/ 
SP 
Postdose 
 
 
 
Efficacy Assessments21 for 
Participants With Later-Onset SMA 
(HFMSE, RULM, WHO Motor 
Milestones, 
 
) 
X22 
X23 
 
 
X12 
 
 
 
X 
 
CGIC25 
 
X 
 
 
X 
 
 
 
X 
 
PedsQL and ACEND26 
 
X 
 
 
X12 
 
 
 
X 
 
Dysphagia Assessment (PASA) 
X 
X27 
 
 
X12, 27 
 
 
 
X 
 
Ventilator Use28 
X 
X 
 
 
X 
 
 
X 
X 
 
Ventilator Use Diary (for 
Participants with Infantile-Onset 
SMA) 
X--------------------------------------------------------------------------------------------------------------------X 
 
AE Recording 
X---------------------------------------------------------------------------------------------------------------------------------X 
SAE Recording 
X---------------------------------------------------------------------------------------------------------------------------------X 
Concomitant Therapy and 
Procedures Recording 
X---------------------------------------------------------------------------------------------------------------------------------X 
 ACEND = Assessment of Caregiver Experience with Neuromuscular Disease; 
AE = adverse event; CGIC = Clinical Global Impression of Change; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders; COVID-19 = coronavirus disease 2019; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; EOS = end of study; ET = early termination; 
HFMSE = Hammersmith Functional Motor Scale Expanded; HINE = Hammersmith Infant Neurological Examination; ICF = informed consent form; 
LP = lumbar puncture; PASA = Parent Assessment of Swallowing Ability; PedsQL = Pediatric Quality of Life Inventory™; 
; 
RULM = Revised Upper Limb Module; SAE = serious adverse event; SMA = spinal muscular atrophy; SMN1 = survival motor neuron-1 gene; 
SMN2 = survival motor neuron-2 gene; SP = sham procedure; WHO = World Health Organization 


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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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35 
1 If the Screening visit occurs within 7 days before Day 1, screening assessments can be used for Day 1 predose assessments. The Screening period may be 
extended for up to 10 days for individuals who cannot complete the Day 1 visit within 21 days of signing the ICF, as long as they continue to meet other 
eligibility criteria. 
2 Participants who do not meet the criteria for contraception use will have their last visit on Day 302. Participants who meet the criteria for contraception use (see 
Section 11.5) will have a Day 302 and a Day 399 visit. Male participants who meet the criteria may complete the Day 399 visit via a telephone interview. 
Female participants who meet the criteria will return to the site for the Day 399 visit. Day 399 will take place at least 120 days after the final dose. For 
participants who meet the criteria for contraception use and enroll into the long-term extension study (232SM302) at the Day 302 visit, that will be their final 
visit in Study 232SM203. 
3 A serum pregnancy test will be performed locally in female participants of childbearing potential in the event of a positive or equivocal urine pregnancy test 
result. 
4 For all participants, a blood sample will be collected during the study to evaluate SMN1 status (copy number, deletion, and mutation where necessary to 
confirm 5q SMA) and SMN2 copy number by the central laboratory. For participants without acceptable documentation of these genetic testing results before 
Screening, a blood sample must be collected during the Screening period to determine eligibility (preferably for analysis by the central laboratory but may be 
determined by local laboratory genetic testing, if needed). For participants with documentation of these genetic testing results before Screening or whose 
sample was analyzed locally during the Screening period (with documentation of these genetic testing results), a blood sample will be collected (preferably at 
Screening or by Day 29 but must be collected by the Day 135 visit) for confirmatory testing through the central laboratory. 
5 Eligibility based on scoliosis severity at Screening will be determined by local analysis of the X-ray results. Results of the central X-ray read will be 
documented and used for subsequent data analyses. For sites with local regulation on use of X-ray (e.g., Germany), the Investigator may assess scoliosis based 
on physical examination without imaging.  
6 LP opening pressure will only be evaluated for participants with later-onset SMA. Only measure LP opening pressure and assess CSF local laboratory sample 
on Days 1, 15, and 279 to avoid potential unblinding. 
7 Spinal ultrasound, fluoroscopy, or similar techniques may be used for the LP procedure, if deemed necessary, but are not required. Local anesthesia and/or 
sedation may be used for the LP procedure in participants with infantile-onset SMA, and anesthesia (local or general) and/or sedation may be used for the LP 
procedure in participants with later-onset SMA, at the discretion of the Investigator and/or study center. If anesthesia and/or sedation is used for the LP 
procedure for an individual participant, in order to maintain the blind, that participant will receive equivalent anesthesia and/or sedation (according to 
institutional procedures) for all of the sham procedures and LP injections. For participants with infantile-onset SMA, LP injections/sham procedures may not 
occur within 72 hours after an immunization. 
8 Participants will remain at the clinic for at least 24 hours after study treatment administration on Days 1 and 15; inpatient stays at other visits may occur based 
on the Investigator’s discretion. If the primary reason for the inpatient stay is due to an AE or SAE, reporting requirements per Section 11.3 must be followed. 
9 Vital signs will include temperature, pulse rate, systolic and diastolic blood pressure, respiratory rate, and pulse oximetry.  
10 On Days 1 and 15, postdose vital signs will be collected at 1, 2, 4, 6, and 8 hours (± 15 minutes) postdose and at 24 hours (± 2 hours) postdose. On Days 29, 64, 
135, 183, and 279, postdose vital signs will be collected at 1 hour (± 30 minutes) and 6 hours (± 1 hour) postdose. 
11 Length and head, chest, and arm circumference will be measured in participants with infantile-onset SMA, and height or body length (for participants who are 
not able to stand independently) and ulnar length will be measured in participations with later-onset SMA. The same measurement (height or body length) 
should be evaluated at all study visits wherever possible. 
12 These assessments may be performed up to 7 days prior to dosing. 
13 Videotaping of physical examinations is optional. 
14 HINE Sections 1 and 3 will be administered to participants with infantile-onset SMA, and a neurological examination will be performed in participants with 
later-onset SMA. A neurological examination will be performed at Screening; predose, at 3 and 6 hours (± 15 minutes) postdose, and at 24 hours (± 2 hours) 


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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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36 
postdose or when anesthesia/sedation (if used) has worn off on Days 1 and 15; predose and at 1 and 3 hours (± 30 minutes) postdose on Days 29, 64, 135, 183, 
and 279; and at Day 302/ET. Predose neurological examinations should be repeated when the assessment falls outside the protocol-specified window because 
of a delay in dosing. 
15 ECGs will be performed predose, at 5 hours (± 1 hour) postdose, and at 24 hours (± 2 hours) postdose on Days 1 and 15; predose and at 5 hours (± 1 hour) 
postdose on Days 29 and 64; at 5 hours (± 1 hour) postdose on Days 135, 183, and 279; and at Day 302/ET. Predose ECGs should be repeated when the 
assessment falls outside the protocol-specified window because of a delay in dosing. If a postdose ECG result is abnormal and clinically significant, a repeat 
ECG should be performed within 2 hours later. 
16 Blood chemistry, hematology, and urinalysis samples will be analyzed by a central laboratory. For the Screening visit only, a local laboratory may be used 
instead for analysis, if needed, for the timely treatment of the participant at the discretion of the Investigator. If a local laboratory is used for the Screening visit, 
the samples should be collected on Day 1 for central laboratory evaluation (even if within 7 days of Screening). These assessments may be performed up to 7 
days prior to dosing/study visit, if necessary. Urine total protein will be analyzed by local laboratory; however, if local analysis is not possible without a 24-
hour urine collection, then samples will be analyzed by central laboratory. (Appendix B). Predose clinical safety laboratory assessments should be repeated 
when the assessment falls outside the protocol-specified window because of a delay in dosing. When the safety laboratory sample analysis is at risk due to 
logistical difficulties or issues with access to the central laboratory (e.g., due to COVID-19–related disruptions or humanitarian emergencies), these samples 
may be analyzed by the local laboratory. Any use of a local laboratory under these circumstances must be approved by the Sponsor prior to being implemented. 
17 Coagulation testing will be conducted locally at Screening and predose (within 7 days prior to dosing) at each dosing visit; results should be reviewed prior to 
dosing. Predose coagulation parameters should be repeated when the assessment falls outside the protocol-specified window because of a delay in dosing. 
18 A safety follow-up telephone call will be made 2 weeks (± 3 days) after the Day 29 dose for the first 20 participants. 
 
 
 
21 Videotaping of all motor milestone and motor function assessments is optional; however, if the participant/caregiver consents to video recording, all 
assessments should be recorded. 
22 Two baseline assessments are required for CHOP-INTEND, HFMSE, and RULM. At least 1 assessment must be conducted during the Screening period. The 
second assessment may be conducted either during the Screening period or at Day 1 predose. If both baseline assessments are conducted during the Screening 
period, they should be completed on different days and the assessments do not need to be repeated on Day 1. 
23 During the loading period, the efficacy assessments will be performed on Days 29 and 64 predose only. The Day 29 efficacy assessments may be performed up 
to 3 days prior to dosing, if necessary. The Day 64 efficacy assessments may be performed up to 7 days prior to dosing, if necessary. 
 
 
 
  
25 CGIC will be assessed on Days 29, 64, and 183 (predose), and Day 302. 
26 PedsQL and ACEND will be assessed only in participants with later-onset SMA. Assessments will be performed on Day 1, Day 183, and at Day 302/ET. 
27 PASA will be assessed only on Days 64 and 183. 
28 Ventilator use will be collected at every study visit (see Section 9.1.14). 


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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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37 
Table 3: 
Schedule of Activities for Part C Cohort 1 
 
Screening 
Visit1 
Treatment 
Follow-up2 
EOS 
Assessments 
D-21 to  
D-1 
D13 
D121 (± 7 days),  
D241 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D361 
(+ 14 days) 
 
 
Predose 
LP 
Postdose 
Predose 
LP 
Postdose 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Local Urine/Serum Pregnancy Test 
for Females of Childbearing 
Potential4 
X 
X 
 
 
X 
 
 
 
X 
X 
Medical (including SMA) History 
X 
 
 
 
 
 
 
 
 
 
SMA Genetic Testing5 
X 
 
 
 
 
 
 
 
 
 
X-ray Examination for Participants 
with Later-Onset SMA (with the 
participant in a sitting or supported 
sitting position)6 
X 
 
 
 
 
 
 
 
 
 
LP Opening Pressure 
 
 
X 
 
 
X 
 
 
 
 
Study Treatment Injection7 
 
 
X 
 
 
X 
 
 
 
 
Inpatient Stay 
 
 
 
X 
 
 
 
 
 
 
Vital Signs and Pulse Oximetry8 
X 
X 
 
X9 
X 
 
X9 
 
X 
 
Weight 
X 
X 
 
 
X 
 
 
 
X 
 
Growth Parameters (including 
height/body length/ulnar length, 
and head/chest/arm 
circumference)10 
X 
X 
 
 
X11 
 
 
 
X 
 
Physical Examination12 
X 
X 
 
 
X 
 
 
 
X 
 


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Screening 
Visit1 
Treatment 
Follow-up2 
EOS 
Assessments 
D-21 to  
D-1 
D13 
D121 (± 7 days),  
D241 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D361 
(+ 14 days) 
 
 
Predose 
LP 
Postdose 
Predose 
LP 
Postdose 
 
 
 
Neurological Examination13 
X 
X 
 
X 
X 
 
X 
 
X 
 
ECG14 
 
X 
 
X 
 
 
X 
 
X 
 
Safety Laboratory Tests15 
X 
X 
 
 
X 
 
 
 
X 
 
Local Coagulation Laboratory 
Tests16 
X 
X 
 
 
X 
 
 
 
 
 
Safety Follow-Up Telephone 
Contact 
 
 
 
X17 
 
 
 
X 
 
 
CSF Local Laboratory Sample 
(cell count, total protein, and 
glucose) 
 
X 
 
 
X 
 
 
 
 
 
CGIC20 
 
 
 
 
X 
 
 
 
X 
 


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39 
 
Screening 
Visit1 
Treatment 
Follow-up2 
EOS 
Assessments 
D-21 to  
D-1 
D13 
D121 (± 7 days),  
D241 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D361 
(+ 14 days) 
 
 
Predose 
LP 
Postdose 
Predose 
LP 
Postdose 
 
 
 
Efficacy Assessments Based on 
Clinical Status21 (CHOP-INTEND, 
HINE Section 2 Motor Milestones, 
HFMSE, RULM, WHO Motor 
Milestones, 
 
) 
X23 
X23 
 
 
X11 
 
 
 
X 
 
PedsQL and ACEND24 
 
X 
 
 
X11 
 
 
 
X 
 
Ventilator Use25 
X 
X 
 
 
X 
 
 
X 
X 
 
AE Recording 
X-----------------------------------------------------------------------------------------------------------------------------------X 
SAE Recording 
X-----------------------------------------------------------------------------------------------------------------------------------X 
Concomitant Therapy and 
Procedures Recording 
X-----------------------------------------------------------------------------------------------------------------------------------X 
; ACEND = Assessment of Caregiver Experience with Neuromuscular Disease; 
AE = adverse event; CGIC = Clinical Global Impression of Change; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; EOS = end of study; ET = early termination; HFMSE = Hammersmith Functional 
Motor Scale Expanded; HINE = Hammersmith Infant Neurological Examination; ICF = informed consent form; LP = lumbar puncture; PedsQL = Pediatric 
Quality of Life Inventory™; 
; RULM = Revised Upper Limb Module; SAE = serious adverse event; SMA = spinal muscular atrophy; 
SMN1 = survival motor neuron-1 gene; SMN2 = survival motor neuron-2 gene; WHO = World Health Organization 
1 If the Screening visit occurs within 7 days before Day 1, screening assessments can be used for Day 1 predose assessments. The Screening period may be 
extended for up to 10 days for individuals who cannot complete the Day 1 visit within 21 days of signing the ICF, as long as they continue to meet other 
eligibility criteria. 
2 Participants who do not meet the criteria for contraception use will have their last visit on Day 302. Participants who meet the criteria for contraception use (see 
Section 11.5) will have a Day 302 and a Day 361 visit. Male participants who meet the criteria may complete the Day 361 visit via a telephone interview. 
Female participants who meet the criteria will return to the site for the Day 361 visit. Day 361 will take place at least 120 days after the final dose. For 
participants who meet the criteria for contraception use and enroll into the long-term extension study (232SM302) at the Day 302 visit, that will be their final 
visit in Study 232SM203. 
3 Day 1 should be 4 months ± 14 days after the participant’s most recent nusinersen maintenance dose of 12 mg. 


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4 A serum pregnancy test will be performed locally in female participants of childbearing potential in the event of a positive or equivocal urine pregnancy test 
result. 
5 For all participants, a blood sample will be collected to evaluate SMN1 status (copy number, deletion, and mutation where necessary to confirm 5q SMA) and 
SMN2 copy number by the central laboratory. For participants without acceptable documentation of these genetic testing results before Screening, a blood 
sample must be collected during the Screening period to determine eligibility (preferably for analysis by the central laboratory but may be determined by local 
laboratory genetic testing, if needed). For participants with documentation of genetic testing results before Screening or whose sample was analyzed locally 
during the Screening period (with documentation of these genetic testing results), a blood sample will be collected (preferably at Screening but must be 
collected by the Day 121 visit) for confirmatory testing through the central laboratory. 
6 Up to 5 participants with severe scoliosis and/or severe contractures will be enrolled in Cohort 1. Scoliosis severity at Screening will be determined by local 
analysis of the X-ray results. Results of the central X-ray read will be documented and used for subsequent data analyses. For sites with local regulation on use 
of X-ray (e.g., Germany), the Investigator may assess scoliosis based on physical examination without imaging. 
7 Spinal ultrasound, fluoroscopy, or similar techniques may be used for the LP procedure, if deemed necessary, but is not required. Local anesthesia and/or 
sedation may be used for the LP procedure in participants < 2 years of age, and anesthesia (local or general) and/or sedation may be used for the LP procedure 
in participants ≥ 2 years of age, at the discretion of the Investigator and/or study center. LP injections may not occur within 72 hours after an immunization. 
8 Vital signs will include temperature, pulse rate, systolic and diastolic blood pressure, respiratory rate, and pulse oximetry.  
9 On Day 1, postdose vital signs will be collected at 1, 2, 4, 6, and 8 hours (± 15 minutes) postdose and at 24 hours (± 2 hours) postdose. On Days 121 and 241, 
postdose vital signs will be collected at 1 hour (± 30 minutes) and 6 hours (± 1 hour) postdose. 
10 Length and head, chest, and arm circumference will be measured in participants with infantile-onset SMA, and height or body length (for participants who are 
not able to stand independently) and ulnar length will be measured in participants with later-onset SMA. The same measurement (height or body length) should 
be evaluated at all study visits whenever possible. 
11 These assessments may be performed up to 7 days prior to dosing. 
12 Videotaping of physical examinations is optional. 
13 HINE Sections 1 and 3 will be administered to participants < 2 years of age at the time of informed consent, and a neurological examination will be performed 
in participants ≥ 2 years of age at the time of informed consent. A neurological examination will be performed at Screening; predose, at 3 and 6 hours 
(± 15 minutes) postdose, and at 24 hours (± 2 hours) postdose or when anesthesia/sedation (if used) has worn off on Day 1; predose and at 1 and 3 hours (± 30 
minutes) postdose on Days 121 and 241; and at Day 302/ET. Predose neurological examinations should be repeated when the assessment falls outside the 
protocol-specified window because of a delay in dosing. 
14 ECGs will be performed predose, at 5 hours (± 1 hour) postdose, and at 24 hours (± 2 hours) postdose on Day 1; at 5 hours (± 1 hour) postdose on Days 121 
and 241; and at Day 302/ET. Predose ECGs should be repeated when the assessment falls outside the protocol-specified window because of a delay in dosing. 
If a postdose ECG result is abnormal and clinically significant, a repeat ECG should be performed within 2 hours. 
15 Blood chemistry, hematology, and urinalysis samples will be analyzed by a central laboratory. For the Screening visit only, a local laboratory may be used 
instead for analysis if needed for the timely treatment of the participant at the discretion of the Investigator. If a local laboratory is used for the Screening visit, 
the samples should be collected on Day 1 for central laboratory evaluation (even if within 7 days of Screening). These assessments may be performed up to 7 
days prior to dosing/study visit, if necessary. Urine total protein will be analyzed by local laboratory only; however, if local analysis is not possible without a 
24-hour urine collection, then samples will be analyzed by central laboratory. (Appendix B). Predose clinical safety laboratory assessments should be repeated 
when the assessment falls outside the protocol-specified window because of a delay in dosing. 
16 Coagulation testing will be conducted locally at Screening and predose (within 7 days prior to dosing) at each dosing visit; results should be reviewed prior to 
dosing. Predose coagulation parameters should be repeated when the assessment falls outside the protocol-specified window because of a delay in dosing. 
17 A safety follow-up telephone call will be made 2 weeks (± 3 days) after the Day 1 bolus dose. 


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41 
 
 
20 Adult participants who do not require a caregiver during the study visits will only have the CGIC assessed by the Investigator. 
21 The Investigator will select the appropriate efficacy assessments based on criteria in Section 9.1. Videotaping of all motor milestone and motor function 
assessments is optional; however, if the participant/caregiver consents to video recording, all assessments should be recorded. 
 
 
 
 
23 Two baseline assessments are required for CHOP-INTEND, HFMSE, and RULM. At least 1 assessment must be conducted during the Screening period. The 
second assessment may be conducted either during the Screening period or at Day 1 predose. If both baseline assessments are conducted during the Screening 
period, they should be completed on different days and the assessments do not need to be repeated on Day 1. 
24 PedsQL and ACEND will be assessed only in participants ≥ 2 years of age at Screening. The ACEND questionnaire will not be collected for adult participants 
who do not require a caregiver during the study visits. Assessments will be performed on Day 1, Day 241, and at Day 302/ET. 
25 Ventilator use will be collected at every study visit (see Section 9.1.14). 
 


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42 
Table 4: 
Schedule of Activities for Part C Cohort 2 
 
Screening 
Visit1 
Treatment 
Follow-up2 
EOS 
Assessments 
D-21 to  
D-1 
D13 
D121 (± 7 days),  
D241 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D361 
(+ 14 days) 
 
 
Predose 
LP 
Postdose 
Predose 
LP 
Postdose 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Local Urine/Serum Pregnancy Test 
for Females of Childbearing 
Potential4 
X 
X 
 
 
X 
 
 
 
X 
X 
Medical (including SMA) History 
X 
 
 
 
 
 
 
 
 
 
SMA Genetic Testing5 
X 
 
 
 
 
 
 
 
 
 
X-ray Examination (with the 
participant in a sitting or supported 
sitting position)6 
X 
 
 
 
 
 
 
 
 
 
LP Opening Pressure 
 
 
X 
 
 
X 
 
 
 
 
Study Treatment Injection7 
 
 
X 
 
 
X 
 
 
 
 
Inpatient Stay 
 
 
 
X 
 
 
 
 
 
 
Vital Signs and Pulse Oximetry8 
X 
X 
 
X9 
X 
 
X9 
 
X 
 
Weight 
X 
X 
 
 
X 
 
 
 
X 
 
Growth Parameters (including 
height/body length/ulnar length, 
and head/chest/arm 
circumference)10 
X 
X 
 
 
X11 
 
 
 
X 
 
Physical Examination12 
X 
X 
 
 
X 
 
 
 
X 
 


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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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43 
 
Screening 
Visit1 
Treatment 
Follow-up2 
EOS 
Assessments 
D-21 to  
D-1 
D13 
D121 (± 7 days),  
D241 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D361 
(+ 14 days) 
 
 
Predose 
LP 
Postdose 
Predose 
LP 
Postdose 
 
 
 
Neurological Examination13 
X 
X 
 
X 
X 
 
X 
 
X 
 
ECG14 
 
X 
 
X 
 
 
X 
 
X 
 
Safety Laboratory Tests15 
X 
X 
 
 
X 
 
 
 
X 
 
Local Coagulation Laboratory 
Tests16 
X 
X 
 
 
X 
 
 
 
 
 
Safety Follow-Up Telephone 
Contact 
 
 
 
X17 
 
 
 
X 
 
 
CSF Local Laboratory Sample 
(cell count, total protein, and 
glucose) 
 
X 
 
 
X 
 
 
 
 
 
CGIC20 
 
 
 
 
X 
 
 
 
X 
 
HFMSE21 
X22 
X22 
 
 
X11 
 
 
 
X 
 
RULM21 
X22 
X22 
 
 
X11 
 
 
 
X 
 
WHO Motor Milestones21 
X 
 
 
 
X11 
 
 
 
X 
 


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Screening 
Visit1 
Treatment 
Follow-up2 
EOS 
Assessments 
D-21 to  
D-1 
D13 
D121 (± 7 days),  
D241 (± 7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(± 7 days) 
D361 
(+ 14 days) 
 
 
Predose 
LP 
Postdose 
Predose 
LP 
Postdose 
 
 
 
ACEND23 
 
X 
 
 
 
 
 
 
X 
 
Ventilator Use26 
X 
X 
 
 
X 
 
 
X 
X 
 
AE Recording 
X-----------------------------------------------------------------------------------------------------------------------------------X 
SAE Recording 
X-----------------------------------------------------------------------------------------------------------------------------------X 
Concomitant Therapy and 
Procedures Recording 
X-----------------------------------------------------------------------------------------------------------------------------------X 
 ACEND = Assessment of Caregiver Experience with Neuromuscular Disease; 
AE = adverse event; CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; EOS = end of study; 
; ET = early termination; 
 
HFMSE = Hammersmith Functional Motor Scale Expanded; ICF = informed consent form; LP = lumbar puncture; 
; RULM = Revised 
Upper Limb Module; SAE = serious adverse event; SMA = spinal muscular atrophy; 
; 
SMN1 = survival motor neuron-1 gene; SMN2 = survival motor neuron-2 gene; 
 WHO = World Health Organization 
1 If the Screening visit occurs within 7 days before Day 1, screening assessments can be used for Day 1 predose assessments. The Screening period may be 
extended for up to 10 days for individuals who cannot complete the Day 1 visit within 21 days of signing the ICF, as long as they continue to meet other 
eligibility criteria. 
2 Participants who do not meet the criteria for contraception use will have their last visit on Day 302. Participants who meet the criteria for contraception use (see 
Section 11.5) will have a Day 302 and a Day 361 visit. Male participants who meet the criteria may complete the Day 361 visit via a telephone interview. 
Female participants who meet the criteria will return to the site for the Day 361 visit. Day 361 will take place at least 120 days after the final dose. For 


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participants who meet the criteria for contraception use and enroll into the long-term extension study (232SM302) at the Day 302 visit, that will be their final 
visit in Study 232SM203. 
3 Day 1 should be 4 months ± 14 days after the participant’s most recent nusinersen maintenance dose of 12 mg. 
4 A serum pregnancy test will be performed locally in female participants of childbearing potential in the event of a positive or equivocal urine pregnancy test 
result. 
5 For all participants, a blood sample will be collected to evaluate SMN1 status (copy number, deletion, and mutation where necessary to confirm 5q SMA) and 
SMN2 copy number by the central laboratory. For participants without acceptable documentation of these genetic testing results before Screening, a blood 
sample must be collected during the Screening period to determine eligibility (preferably for analysis by the central laboratory but may be determined by local 
laboratory genetic testing, if needed). For participants with documentation of genetic testing results before Screening or whose sample was analyzed locally 
during the Screening period (with documentation of these genetic testing results), a blood sample will be collected (preferably at Screening but must be 
collected by the Day 121 visit) for confirmatory testing through the central laboratory. 
6 Eligibility based on scoliosis severity at Screening will be determined by local analysis of the X-ray results. Results of the central X-ray read will be 
documented and used for subsequent data analyses. For sites with local regulation on use of X-ray (e.g., Germany), the Investigator may assess scoliosis based 
on physical examination without imaging. 
7 Spinal ultrasound, fluoroscopy, or similar techniques may be used for the LP procedure, if deemed necessary, but is not required. Local anesthesia and/or 
sedation may be used for the LP procedure in participants < 2 years of age, and anesthesia (local or general) and/or sedation may be used for the LP procedure 
in participants ≥ 2 years of age, at the discretion of the Investigator and/or study center. LP injections may not occur within 72 hours after an immunization. 
8 Vital signs will include temperature, pulse rate, systolic and diastolic blood pressure, respiratory rate, and pulse oximetry.  
9 On Day 1, postdose vital signs will be collected at 1, 2, 4, 6, and 8 hours (± 15 minutes) postdose and at 24 hours (± 2 hours) postdose. On Days 121 and 241, 
postdose vital signs will be collected at 1 hour (± 30 minutes) and 6 hours (± 1 hour) postdose. 
10 Length and head, chest, and arm circumference will be measured in participants with infantile-onset SMA, and height or body length (for participants who are 
not able to stand independently) and ulnar length will be measured in participants with later-onset SMA. The same measurement (height or body length) should 
be evaluated at all study visits whenever possible. 
11 These assessments may be performed up to 7 days prior to dosing. 
12 Videotaping of physical examinations is optional. 
13 A neurological examination will be performed at Screening; predose, at 3 and 6 hours (± 15 minutes) postdose, and at 24 hours (± 2 hours) postdose or when 
anesthesia/sedation (if used) has worn off on Day 1; predose and at 1 and 3 hours (± 30 minutes) postdose on Days 121 and 241; and at Day 302/ET. Predose 
neurological examinations should be repeated when the assessment falls outside the protocol-specified window because of a delay in dosing. 
14 ECGs will be performed predose, at 5 hours (± 1 hour) postdose, and at 24 hours (± 2 hours) postdose on Day 1; at 5 hours (± 1 hour) postdose on Days 121 
and 241; and at Day 302/ET. Predose ECGs should be repeated when the assessment falls outside the protocol-specified window because of a delay in dosing. 
If a postdose ECG result is abnormal and clinically significant, a repeat ECG should be performed within 2 hours. 
15 Blood chemistry, hematology, and urinalysis samples will be analyzed by a central laboratory. For the Screening visit only, a local laboratory may be used 
instead for analysis if needed for the timely treatment of the participant at the discretion of the Investigator. If a local laboratory is used for the Screening visit, 
the samples should be collected on Day 1 for central laboratory evaluation (even if within 7 days of Screening). These assessments may be performed up to 7 
days prior to dosing/study visit, if necessary. Urine total protein will be analyzed by local laboratory only; however, if local analysis is not possible without a 
24-hour urine collection, then samples will be analyzed by central laboratory (Appendix B). Predose clinical safety laboratory assessments should be repeated 
when the assessment falls outside the protocol-specified window because of a delay in dosing. 
16 Coagulation testing will be conducted locally at Screening and predose (within 7 days prior to dosing) at each dosing visit; results should be reviewed prior to 
dosing. Predose coagulation parameters should be repeated when the assessment falls outside the protocol-specified window because of a delay in dosing. 


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17 A safety follow-up telephone call will be made 2 weeks (± 3 days) after the Day 1 bolus dose. 
20 Adult participants who do not require a caregiver during the study visits will only have the CGIC assessed by the Investigator. 
 
 
22 Two baseline assessments are required for HFMSE and RULM. At least 1 assessment must be conducted during the Screening period. The second assessment 
may be conducted either during the Screening period or at Day 1 predose. If both baseline assessments are conducted during the Screening period, they should 
be completed on different days and the assessments do not need to be repeated on Day 1. 
23 The ACEND questionnaire will not be collected for adult participants who do not require a caregiver during the study visits. 
24 Assessment will be performed on Day 121 only. 
 
 
 
 
26 Ventilator use will be collected at every study visit (see Section 9.1.14). 
 


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Table 5: 
Schedule of Activities for Participants in Part B Who Discontinue Study Treatment but Agree to Remain in the 
Study 
Assessment1 
Follow-Up Visits2 
Weight 
X 
Growth Parameters 
X 
Physical Examination 
X 
Vital Signs (temperature, pulse rate, systolic and diastolic blood pressure, respiratory rate, and pulse oximetry) 
X 
Neurological Examination3 
X 
Urine/Serum Pregnancy Test for Females of Childbearing Potential4 
X 
Safety Laboratory Tests 
X 
WHO Motor Milestones 
X 
HINE Section 2 Motor Milestones (as appropriate) 
X 
Motor Function Assessments (as appropriate, including CHOP-INTEND, HFMSE, RULM, 
)  
X 
Plasma Biomarker Assessment (optional) 
X 
Ventilator Use 
X 
Ventilator Use Diary (participants with infantile-onset SMA) 
X 
Concomitant Therapy and Procedure Recording 
X 
AE and SAE Recording 
X 
; AE = adverse event; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders; HFMSE = Hammersmith Functional Motor Scale Expanded; HINE = Hammersmith Infant Neurological Examination; 
PD = pharmacodynamic(s); 
 RULM = Revised Upper Limb Module; SAE = serious adverse event; SMA = spinal muscular atrophy; 
WHO = World Health Organization 
Note: See Section 9 for additional details regarding efficacy, 
, and PD assessments. 
1 Participants who initiate treatment with a disallowed concomitant therapy (see Section 7.6.1.2) must be withdrawn from Study 232SM203; they are not eligible 
to remain in the study for follow-up visits per Table 5. 
2 Participants should return to the clinic according to the original visit schedule per Table 2 (i.e., Days 1, 15, 29, 64, 135, 183, 279, and 302) for follow-up visits 
after discontinuing treatment but will follow a reduced Schedule of Activities at these visits. 
3 HINE Sections 1 and 3 will be administered to participants with infantile-onset SMA, and a neurological examination will be performed in participants with 
later-onset SMA. 


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4 A serum pregnancy test will be performed locally in females of childbearing potential in the event of a positive or equivocal urine pregnancy test result. 


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2. 
LIST OF ABBREVIATIONS 
 
 
 
 
ACEND 
Assessment of Caregiver Experience with Neuromuscular Disease 
AE 
adverse event 
aPTT 
activated partial thromboplastin time 
 
 
ASO 
antisense oligonucleotide 
BLQ 
below limit of quantification 
CGIC 
Clinical Global Impression of Change 
CHOP-INTEND 
Children’s Hospital of Philadelphia-Infant Test of Neuromuscular 
Disorders 
Cmax 
maximum concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
Ctrough 
trough concentration 
DHA 
Directions for Handling and Administration 
EAC 
endpoint adjudication committee 
ECG 
electrocardiogram 
EOS 
end of study 
 
 
ET 
early termination 
EU 
European Union 
GCP 
Good Clinical Practice 
HFMSE 
Hammersmith Functional Motor Scale Expanded 
HINE 
Hammersmith Infant Neurological Examination 
HRQOL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
 
 
INR 
international normalized ratio 
IRT 
interactive response technology 
ITT 
Intent-to-Treat 
LLOQ 
lower limit of quantification 
LP 
lumbar puncture 
MI 
multiple imputation 
NF-L 
neurofilament light chain 
NOAEL 
no-observed-adverse-effect level 


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PASA 
Parent Assessment of Swallowing Ability 
PD 
pharmacodynamic(s) 
PedsQL 
Pediatric Quality of Life Inventory™ 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
QoL 
Quality of Life 
QTcF 
corrected QT interval using Fridericia’s formula 
RSV 
respiratory syncytial virus 
RULM 
Revised Upper Limb Module 
SAE 
serious adverse event 
SMA 
spinal muscular atrophy 
 
 
SMN 
survival motor neuron protein 
SMN1 
survival motor neuron-1 gene 
SMN2 
survival motor neuron-2 gene 
SUSAR 
suspected unexpected serious adverse reaction 
US 
United States 
 
 
WHO 
World Health Organization 


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3. 
INTRODUCTION 
Nusinersen is an ASO administered intrathecally via LP; it increases SMN expression and 
significantly improves motor function in patients with SMA. Nusinersen was approved for the 
treatment of SMA under the tradename Spinraza™ in the US, EU, and 15 other countries. The 
population for this study includes participants with infantile-onset and later-onset SMA. 
3.1. 
Study Rationale 
Efficacy and safety results across the nusinersen clinical development program have 
demonstrated an overall positive benefit-risk profile of nusinersen across a broad range of SMA 
phenotypes and patient populations. Nusinersen is approved in the US, Europe, and other 
countries and regions for the treatment of SMA in pediatric and adult patients at a recommended 
dosage of 12 mg administered in 3 loading doses at 14-day intervals, a fourth loading dose 
30 days after the third dose, and maintenance doses every 4 months thereafter. PK and PD 
analyses indicate that nusinersen drug exposure higher than that achieved with 12 mg in patients 
with SMA may produce an even greater benefit in motor function. Additionally, PK modeling 
and simulations identified dosing regimens that achieve higher drug exposure more rapidly. 
Therefore, this study is being conducted to investigate the efficacy, safety, tolerability, and 
 of 
a 50/28-mg dose of nusinersen (50-mg loading dose/28-mg maintenance dose) and a dosing 
regimen targeted to achieve higher drug exposure more rapidly. This study will be conducted in 
participants with genetically confirmed SMA. 
Part A of the study will evaluate the safety of a higher loading dose and maintenance dosing 
regimen (28-mg loading/28-mg maintenance) than the approved regimen (12-mg loading/12-mg 
maintenance) prior to exposing participants to the target higher dosing regimen (50-mg 
loading/28-mg maintenance) in the pivotal portion of the study. 
In Part B, in order to evaluate the proposed higher dosing regimen, an active-controlled design is 
being used, with participants randomized either to the investigational dosing regimen (50-mg 
loading/28-mg maintenance) or to the currently approved dosing regimen (12-mg loading/12-mg 
maintenance). In order to supplement the number of participants available for the analysis in 
Part B of this study, historical data from the existing data set for Study CS3B, a Phase 3 efficacy 
and safety study of nusinersen in participants with infantile-onset SMA, may be borrowed to 
augment the control arm (see Section 12.4 for details). Enrollment in Part B will begin after 
6 participants in Part A have completed the loading period (i.e., when the last participant reaches 
the Day 64 visit) and after an IDMC has reviewed the available safety data to recommend 
whether Part B can be initiated. If deemed necessary by the Sponsor, additional participants may 
be enrolled in Part A to ensure sufficient data are available for the safety evaluation prior to 
enrollment of participants in Part B. Details regarding the IDMC review of data may be found in 
the IDMC charter. Note that the IDMC can recommend to stop the study based on the safety 
findings. 
Part C of the study will allow safety evaluation of transitioning participants who are on the 
currently approved dose of nusinersen (12-mg maintenance for at least 1 year after the initiation 
of treatment) to the proposed higher dosing regimen via the administration of a single bolus dose 


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of 50 mg of nusinersen (which should be administered 4 months ± 14 days after their most recent 
maintenance dose of 12 mg), with maintenance dosing at 28 mg thereafter. Enrollment in Part C 
will be staggered with that in Part B such that at least 29 days of safety follow-up for at least 
15 participants in Part B will be available, with no safety concerns identified by the IDMC, 
before the first participants will be enrolled in Part C. Note that the IDMC can recommend to 
stop the study based on the safety findings. 
3.1.1. 
Rationale for Study Population 
Part A will be conducted in participants with later-onset SMA who are 2 to ≤ 15 years of age, 
inclusive, for the purpose of evaluating AEs. 
Part B will include participants with both infantile-onset SMA (≤ 7 months of age) and 
later-onset SMA (2 to < 10 years of age). The infantile-onset SMA population was selected as 
the main population to evaluate efficacy based on the following considerations: 
• The results of 
 modeling and simulations showed that an improvement in 
CHOP-INTEND, which is administered in participants with infantile-onset SMA, 
may be possible with a higher dose. 
• Data from Studies CS3B and CS4 show that improvement in efficacy occurs more 
quickly in younger participants with shorter disease duration. 
Therefore, the infantile-onset SMA population may be more sensitive to a higher dose, and thus 
efficacy in Part B can be assessed at an earlier timepoint compared to participants with 
later-onset SMA. In addition, the choice of the infantile-onset SMA population allows the 
opportunity to leverage data from Study CS3B, which used the approved dose of 12 mg, as does 
the Control Group in this study. 
Part C will enroll participants with SMA who have been receiving nusinersen treatment for at 
least 1 year prior to entry in this study across participants of all ages (Cohort 1) and participants 
≥ 18 years of age (Cohort 2). Participants should be receiving nusinersen as per local label and 
have no missed doses in the last year prior to Screening. This part is designed to evaluate the 
safety of transitioning participants from the currently approved dosing regimen to the higher 
dosing regimen in a representative patient population. 
3.1.2. 
Rationale for Dosing Regimen 
The clinical PK, safety, and efficacy of nusinersen have been evaluated in a number of patient 
populations (infantile-onset [SMA symptom onset ≤ 6 months (≤ 180 days) of age], later-onset 
[SMA symptom onset > 6 months (> 180 days) of age], and presymptomatic). The approved 
dosing regimen of nusinersen is 12 mg administered in 3 loading doses at 14-day intervals, a 
fourth loading dose 30 days after the third dose, and maintenance doses every 4 months 
thereafter. In the original development program, 2 different dosing regimens (4 loading doses 
followed by maintenance doses every 4 months and 3 loading doses followed by maintenance 
doses every 6 months) were evaluated in sham-controlled studies. Results from these studies, 


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population PK and exposure-response modeling, and nonhuman primate safety studies were used 
as the basis for selecting dosing regimens in this study. 
An exploratory exposure-response analysis performed in participants with infantile-onset SMA 
(Study CS3A, n = 20, age 38 days to 8 months) showed a statistically significant positive 
correlation between nusinersen CSF exposure and motor function (e.g., CHOP-INTEND scores).  
Previous PK modeling predicted that the median concentration of nusinersen within the CSF 
immediately prior to the administration of the subsequent maintenance dose (i.e., Ctrough) would 
be approximately 10 ng/mL at steady state with the label-approved maintenance dosing regimen 
(i.e., 12 mg administered every 4 months) and approximately 20 ng/mL at steady state with the 
proposed maintenance dosing regimen for Study 232SM203 (i.e., 28 mg administered every 
4 months). This model was subsequently updated to include additional data from 
Studies 232SM201 and CS11 not previously modeled, resulting in an adjustment of CSF Ctrough 
predictions in all patient populations, which are still consistent with the prior predictions. As a 
consequence, population PK modeling now predicts that with increasing the maintenance dose 
from 12 to 28 mg administered every 4 months, CSF Ctrough should increase from 5 to 12 ng/mL 
at steady state. The exposure-response (PK/PD) relationship between steady-state CSF Ctrough 
and CHOP-INTEND response continuously increases as a function of PK and is on an upward 
trajectory at concentrations consistent with the 12 mg maintenance dose (i.e., 5 ng/mL). It is 
predicted that additional clinical benefit (i.e., a 5-point increase in CHOP-INTEND score) could 
be achieved by increasing CSF exposures to 12 ng/mL. Therefore, administration of this higher 
dose of nusinersen may lead to meaningful clinical benefit to patients. At this time, no 
dose-limiting toxicity has been identified with nusinersen. The PK modeling therefore suggests 
that it is unlikely that the higher doses of nusinersen would have a less favorable risk-benefit 
profile compared with standard dose nusinersen. 
The PK/PD relationship has thus far been demonstrated primarily in the infantile-onset SMA 
population. However, the same positive PK/PD relationship is expected across SMA types and 
patient age groups because they share the same disease mechanism. This is supported by the 
preliminary correlation analysis from Study 232SM202, which showed a positive relationship 
between CSF Ctrough and total motor milestones scores in participants with infantile- and 
later-onset SMA who received 12 mg of nusinersen as 4 loading doses followed by maintenance 
doses every 4 months. 
Using 12 ng/mL as the clinical CSF Ctrough target concentration and the predicted CSF PK 
profiles from 28 mg of nusinersen (maintenance doses every 4 months) as the reference dosing 
regimen, simulations were performed to evaluate additional dosing scenarios with higher doses 
and reduced loading-dose frequency. Additional evaluation of the maintenance dosing frequency 
was not performed because previous modeling showed that a dosing frequency of every 
4 months best maintained the CSF concentration achieved at steady state.  
The assumption of PK linearity is supported by nusinersen toxicokinetic results in nonhuman 
primates, which showed nearly dose-proportional PK in the plasma and CNS tissues (target site 
of action) up to 15 mg (human equivalent dose of 150 mg). Assuming PK linearity, PK 
simulations were performed in both infantile- and later-onset SMA populations after 2 years of 


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treatment using a population PK model developed from patients across the age range of 
≤ 6 months to 18 years old. Based on the most recent PK modeling performed, relative to the 
approved 12-mg label regimen (CSF Ctrough of approximately 5 ng/mL), 28 mg administered as 
3 loading doses (biweekly) or 50 mg administered as 2 loading doses (biweekly), each followed 
by maintenance doses of 28 mg every 4 months, were identified to achieve the desired CSF 
Ctrough (approximately 12 ng/mL) more rapidly at the end of the loading dose period. Nusinersen 
28 mg administered as 3 loading doses (biweekly) had a comparable predicted CSF Cmax to the 
reference dosing regimen, whereas the 50-mg dosing regimen surpassed the predicted Cmax from 
the reference dosing regimen. Moreover, the 28-mg maintenance dosing regimen adequately 
maintained the higher CSF Ctrough target (approximately 12 ng/mL) during the maintenance dose 
period. Toxicology studies in nonhuman primates evaluating the nonhuman primate equivalent 
of the 28- and 50-mg doses have been conducted and support the safety of these doses in a 
clinical study (see Section 3.3). Therefore, the 28-mg dose (administered as 3 loading doses at 
biweekly intervals), 50-mg dose (administered as 2 loading doses at biweekly intervals), and 
28-mg maintenance dose were recommended for additional clinical evaluation. 
The single bolus dose in Part C is supported by PK simulations showing that a titration dosing 
regimen of a single loading dose (50 mg) followed by maintenance doses of 28 mg every 
4 months thereafter achieved and maintained the higher CSF Ctrough target concentration 
(approximately 12 ng/mL) in the representative populations for later-onset and infantile-onset 
SMA, respectively. The predicted exposures of the proposed titration dosing regimens are 
covered by the levels demonstrated to be safe in nonhuman primates. 
3.2. 
Background 
3.2.1. 
Overview of SMA  
SMA is an autosomal recessive neuromuscular disease characterized by degeneration of the 
motor neurons in the anterior horn of the spinal cord, resulting in atrophy of the voluntary 
muscles of the limbs and trunk. With an incidence of 8.5 to 10.3 per 100,000 live births, it is the 
most common monogenetic cause of infant mortality and a major cause of childhood morbidity 
due to weakness in the US [Arkblad 2009; Jedrzejowska 2010]. Historically, the natural history 
of SMA includes 4 major recognized phenotypes that are dependent on age of onset and 
achieved motor abilities. Type I SMA has a disease onset within the first few months of life; 
these children are never able to sit or walk and usually die from respiratory failure by 2 years of 
age. Patients with Type II SMA are able to sit but never walk unaided, with symptoms presenting 
between 6 and 18 months of age. Patients with Type III SMA are able to sit and walk but may 
become severely and increasingly disabled. Patients with Type IV SMA typically have disease 
onset after the age of 18 years and have normal life expectancies.  
Humans have a variable copy number of the SMN2 (0 to 8 copies) [Wirth 2006]. The number of 
SMN2 copies and the resulting amount of full-length SMN expressed in patients with SMA (10% 
to 40% of normal SMN levels) correlate with SMA disease severity; thus, SMN2 is a key 
modifier of disease phenotype [Coovert 1997; Feldkötter 2002; Lefebvre 1997; Prior 2004]. 


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3.2.2. 
Current Therapies for SMA  
In countries where nusinersen and/or other SMA therapies are not approved, current medical care 
is limited to supportive care, focused on respiratory support, nutritional support, and 
management of resulting musculotendinous contractures and neuromuscular scoliosis through 
bracing, physical therapy, and surgery, with specific guidelines according to age of SMA onset 
[Finkel 2017; Mercuri 2018]. 
A gene transfer agent, Zolgensma®, an adeno-associated virus vector expressing a SMN1 
delivered intravenously, was approved in the US in 2019 and Japan in 2020 for the treatment of 
SMA Type 1 in patients younger than 2 years of age, and in the EU in May 2020 for the 
treatment of patients with 5q SMA with dosing guidance for body weight up to 21 kg. Risdiplam 
(Evrysdi™, formerly RG7916) is an oral SMN2-directed splicing modifier indicated for the 
treatment of SMA in patients ≥ 2 months of age. It was first approved in the US in 2020 and has 
since received approval in at least 5 other markets.  
3.2.3. 
Profile of Previous Experience With Nusinersen 
Nusinersen is an ASO administered intrathecally via LP and increases SMN expression and 
significantly improves motor function in patients with SMA.  
The primary support for the efficacy of nusinersen in the treatment of SMA derives from 
sham-controlled studies in participants with infantile-onset SMA (primarily Type I SMA) and 
later-onset SMA (may include Type II and Type III SMA). Results from uncontrolled studies in 
genetically diagnosed, presymptomatic infants, participants with infantile-onset SMA, and 
participants with later-onset SMA are highly supportive of the results of the pivotal 
sham-controlled efficacy studies and provide evidence of long-term benefit. Nusinersen has been 
administered to 352 unique participants with SMA in 10 clinical studies to date, with safety data 
available for 346 participants during 665 person-years of exposure. Treatment with nusinersen 
has been well tolerated, and the SAE profile is consistent with the events seen in infants and 
children with SMA.  
Nusinersen was first approved for the treatment of SMA under the tradename Spinraza™ in the 
US on 23 December 2016 (New Drug Application 209531). Subsequently, it was approved in the 
EU (5q SMA) [May 2017] and other major markets (5q SMA, infantile SMA, and all other 
SMAs). 
As of December 2020, more than 11,000 patients with SMA have been treated with nusinersen 
worldwide, in the postmarketing setting, expanded access programs, and clinical trials. 
See the Investigator’s Brochure for detailed information on relevant nonclinical and clinical 
studies. 


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3.3. 
Benefit-Risk Assessment 
Nusinersen (Spinraza) 12 mg has a positive benefit-risk profile, with more than 4 years of 
postmarketing experience and more than 11,000 patients treated. The safety profile to date does 
not preclude study of higher doses in any population. 
Detailed information about the known and expected benefits and risks, reasonably expected AEs, 
and nonclinical toxicology studies supporting investigation of higher doses of nusinersen in the 
clinic are provided in the Investigator’s Brochure and ICF. A high-level summary of the benefits 
and risks known during study design is provided here. 
Anticipating a potential enhancement of benefit with the dosing regimens proposed for 
Study 232SM203, substantiated by PK/PD modeling described in Section 3.1.2, the safety of the 
loading period for Study 232SM203 is supported by a nonclinical study conducted in monkeys 
(Study P058-17-03). In this study, the NOAEL was 15 mg (human equivalent dose of 150 mg). 
As such, dosing for Study 232SM203 has a safety margin of at least 4.5-fold for cumulative 
doses during the loading period and a 3-fold margin for a single loading dose of 50 mg. 
The safety of long-term exposure during the Study 232SM203 maintenance period is supported 
by a 53-week monkey study (Study 396443-AS06). Monkeys received a cumulative dose of 3.9, 
13, and 52 mg at each dose level (0.3, 1, and 4 mg per dose, respectively) during the 52-week 
treatment duration. The overall NOAEL was determined to be 4 mg. Tissue concentrations 
measured in monkeys from the 53-week toxicology study at the NOAEL (4 mg) were compared 
to the estimated tissue concentrations in patients with SMA. The exposure-based safety margin is 
at least 1.4-fold based on exposure in the spinal cord (safety margins are higher for other tissues). 




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• Change from baseline to Day 29 in 
plasma concentration of NF-L 
(comparison of higher dose to 12 mg 
dose) 
• Time to death or permanent 
ventilation (tracheostomy or 
≥ 16 hours of ventilation/day 
continuously for > 21 days in the 
absence of an acute reversible event 
[Appendix A]) (comparison of 
higher dose to matched sham 
control) 
• Time to death (overall survival) 
(comparison of higher dose to 
matched sham control) 
• Time to death or permanent 
ventilation (tracheostomy or 
≥ 16 hours of ventilation/day 
continuously for > 21 days in the 
absence of an acute reversible event 
[Appendix A]) (comparison of 
higher dose to 12 mg dose) 
• Time to death (overall survival) 
(comparison of higher dose to 12 mg 
dose) 
To examine the clinical efficacy of 
nusinersen administered intrathecally at 
higher doses compared to the currently 
approved 12 mg dose in participants with 
SMA 
Later-Onset SMA 
• Change from baseline in HFMSE 
score 
• Change from baseline in RULM 
score 
• Total number of new WHO motor 
milestones 
• Change from baseline in ACEND 
• Change from baseline in PedsQL  


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• Change from baseline in CSF 
concentration of NF-L 
• Change from baseline in plasma 
concentration of NF-L 
To examine the safety and tolerability of 
nusinersen administered intrathecally at 
higher doses to participants with SMA 
• Incidence of AEs, including SAEs 
• Shifts from baseline in clinical 
laboratory parameters, ECGs, and 
vital signs 
• Change in growth parameters 
• Shifts from baseline in coagulation 
parameters (aPTT, PT, and INR) 
• Change in urine total protein 
• Change from baseline in 
neurological examination outcomes 
• The proportion of participants with a 
postbaseline platelet count below the 
lower limit of normal on at least 
2 consecutive measurements 
• The proportion of participants with a 
postbaseline QTcF of > 500 msec 
and an increase from baseline to any 
postbaseline timepoint in QTcF of 
> 60 msec 
To examine the effect of nusinersen 
administered intrathecally at higher doses 
compared to the currently approved 12 mg 
dose in participants with SMA 
Infantile-Onset and Later-Onset SMA 
• Number and duration of 
hospitalizations 
• CGIC (physician, caregiver) at 
Day 302 
• Number of serious respiratory events 
• Proportion of time on ventilation 
(infantile-onset SMA population) 






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• CGIC (physician, caregiver) at 
Day 302 
• Number of serious respiratory events 
• Ventilator use 
• Change in the PASA scale (Part A 
only) 


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Residual samples collected in this clinical study may be used for future scientific and genetic 
research if participants provide separate optional consent or as allowed by local regulations. 
Objectives related to this future research have not been determined. 


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5. 
STUDY DESIGN 
5.1. 
Study Overview 
This 3-part study will evaluate the efficacy and safety of a higher dosing regimen of nusinersen 
in approximately 145 participants. The study will be conducted at approximately 65 sites 
globally. Following the completion of this study, all eligible participants may elect to enroll in a 
separate long-term extension study (232SM302), pending study approval by ethics committees 
and the appropriate regulatory authorities. In regard to participants rolling over from Part B, this 
will be done without unblinding the participant’s treatment group. 
Participants will be followed for approximately 323 to 420 days in Parts A, B, and C. 
The study consists of an open-label safety evaluation of a regimen consisting of nusinersen 
administered intrathecally at loading doses of 28 mg followed by maintenance dosing at 28 mg 
(Part A); a pivotal, double-blind, active-controlled portion (Part B) in which participants will be 
randomized to 1 of 2 regimens (loading doses of nusinersen at 50 mg followed by maintenance 
dosing at 28 mg [50/28-mg regimen] or loading and maintenance dosing at 12 mg [control 
dosing regimen]); and a third open-label portion (Part C) in which participants who have already 
been treated with nusinersen for at least 1 year prior to entry in this study will receive a single 
50-mg bolus of nusinersen followed by maintenance dosing at 28 mg.  
Part A will enroll a minimum of 6 participants with later-onset SMA, from 2 to ≤ 15 years of 
age, inclusive, at the signing of informed consent. Participants will receive 3 loading doses of 
28 mg (Days 1, 15, and 29) followed by 2 maintenance doses of 28 mg (Days 149 and 269). 
Participants will remain at the clinic for at least 24 hours after each dose. A sentinel dosing 
approach will be used, in which the first participant will be enrolled and dosed with 28 mg of 
nusinersen. Following the availability of 72 hours of safety data after the first loading dose in the 
first participant, data for this participant will be reviewed by the Investigator and the Sponsor 
before the next 5 participants are enrolled. Only 1 participant can receive their first dose of study 
treatment on a given day.  
After 6 participants have completed the loading period (i.e., when the last participant has 
available safety data through the Day 64 visit), an IDMC will review the available safety data to 
recommend whether Part B can be initiated. If deemed necessary by the Sponsor, additional 
participants may be enrolled in Part A to ensure sufficient data are available for the IDMC 
review prior to enrollment of participants in Part B. Details regarding the IDMC review of data 
may be found in the IDMC charter. Meanwhile, participants in Part A will proceed to 
maintenance dosing without interruption. Note that the IDMC can recommend to stop the study 
based on the safety findings. 
Part B will consist of a pivotal, double-blind, active-controlled treatment period with either 2 or 
4 loading doses of nusinersen (for the 50/28-mg Group and Control Group, respectively) 
administered intrathecally followed by maintenance doses approximately every 4 months 


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thereafter. Approximately 99 participants with infantile- or later-onset SMA will be randomized 
in a 1:2 ratio to receive either the currently approved dosing regimen of 4 loading doses of 12 mg 
of nusinersen administered intrathecally (Days 1, 15, 29, and 64) followed by 2 maintenance 
doses of 12 mg on Days 183 and 279 (Control Group) or 2 loading doses of 50 mg of nusinersen 
administered intrathecally (Days 1 and 15) followed by 2 maintenance doses of 28 mg on 
Days 135 and 279 (50/28-mg Group). In order to maintain blinding, 1 sham procedure will be 
administered in the Control Group on Day 135 and 3 sham procedures will be administered in 
the 50/28-mg Group on Days 29, 64, and 183 to ensure the same dosing visit schedule as the 
Control Group. Participants will remain at the clinic for at least 24 hours after study treatment 
administration on Days 1 and 15; inpatient stays at other visits may occur based on the 
Investigator’s discretion. If the primary reason for the inpatient stay is due to an AE or SAE, 
reporting requirements per Section 11.3 must be followed. 
Randomization in Part B will be performed using IRT. For Part B, the randomization will be 
stratified as follows: 
• For participants with infantile-onset SMA by disease duration: ≤ 12 weeks and 
> 12 weeks (time from age at symptom onset to age at informed consent) 
• For participants with later-onset SMA by age at informed consent: < 6 years and 
≥ 6 years 
Once the fifteenth participant in Part B has been enrolled and administered the first dose of study 
treatment, no new participants will be dosed in Part B until after an IDMC review. The IDMC 
will review unblinded data from the first 15 participants in Part B who have completed the 
Day 29 visit (in order to achieve 6 or more participants who have received 50 mg in the 
50/28-mg Group while maintaining the blind for the rest of the study team). This review will 
include safety data through the Day 29 visit at a minimum and all available individual CSF and 
plasma nusinersen concentration data for these participants, including the Day 15 samples at a 
minimum. Dosing of the remaining participants in Part B and dosing in Part C will occur only 
after this review has completed, provided that no safety concerns are identified. Note that the 
IDMC can recommend to stop the study based on the safety findings. By the time of 
implementation of Protocol Version 6, the IDMC reviewed these data and recommended that the 
study may continue with dosing of the remaining participants in Part B and initiating dosing in 
Part C without any modifications to the study.  
In Part C, up to approximately 40 participants who have already initiated treatment with 
nusinersen and have been receiving the approved dose of 12 mg for at least 1 year prior to entry 
will be enrolled in Part C. The initial cohort in Part C (i.e., Cohort 1) consists of up to 
approximately 20 participants of any age and of any SMA status. For Cohort 1, an attempt will 
be made to enroll at least 8 but no more than 12 participants ≥ 18 years of age (participants in 
Cohort 1 ≥ 18 years of age must be ambulatory). Up to 5 participants with severe scoliosis and/or 
severe contractures may be enrolled in Cohort 1 of Part C after consultation with the Medical 
Monitor. An additional cohort (i.e., Cohort 2) consisting of up to approximately 20 adult 
participants (≥ 18 years of age) was subsequently added to Part C in Protocol Version 5 in order 


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to enable collection of data in adults transitioning from the currently approved nusinersen dosing 
regimen to a higher dose. Participants in Cohort 2 can be either ambulatory or nonambulatory. 
All participants in Part C will receive a single bolus dose of 50 mg (which should be 
administered 4 months ± 14 days after their most recent maintenance dose of 12 mg) followed by 
2 maintenance doses of 28 mg on Days 121 and 241. Participants in Part C will remain at the 
clinic for at least 24 hours after the first (bolus) dose for the purpose of completing study 
assessments.  
See Figure 1 for a schematic of the study design. 
5.2. 
Study Duration for Participants 
The total study duration for each participant will be approximately up to 420 days, divided as 
follows: 
• Part A: approximately 323 to 410 days 
− Screening: 21 days 
− Loading period: 64 days 
− Maintenance period: 205 days 
− Follow-up: 33 to 120 days 
• Part B: approximately 323 to 420 days 
− Screening: 21 days 
− Loading period: 64 days 
− Maintenance period: 215 days 
− Follow-up: 23 to 120 days 
• Part C: approximately 323 to 382 days 
− Screening: 21 days 
− Loading period: 1 day 
− Maintenance period: 240 days 
− Follow-up: 61 to 120 days 


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Participants will have the following numbers of visits during the study:  
• Part A: 8 to 9 visits 
• Part B: 9 to 10 visits 
• Part C: 5 to 6 visits 
Visits during Days 1, 15, and 29 of the loading periods of Parts A and B and Day 1 of the 
loading period of Part C should be performed ± 1 day from the nominal visit day. Visits during 
Day 64 of the loading period of Parts A and B and the maintenance period of Parts A, B, and C 
should be performed ± 7 days from the nominal visit day. Visit days are calculated with respect 
to Day 1 (the date of first dose). 
The end-of-study date for a participant may be the last study visit, last follow-up telephone 
conversation, last protocol-specified assessment, or, if the participant has ongoing SAEs that are 
being followed, the date of SAE resolution. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
The Sponsor may terminate this study at any time, after informing Investigators. The Sponsor (or 
designee) will notify Investigators when the study is to be placed on hold, completed, or 
terminated. 
5.4. 
Unscheduled Visits 
Data collected during unscheduled visits should be recorded on CRFs only if the data support 
protocol objectives and/or are required for safety monitoring. This includes laboratory 
assessments collected locally for the purposes of safety monitoring.  


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5.5. 
End of Study 
The EOS is last participant, last visit (either in-person visit or telephone contact) for final 
collection of data. 


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6. 
STUDY POPULATION 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening or at the timepoint specified in the individual eligibility criterion listed. 
6.1. 
Inclusion Criteria 
Inclusion criteria are presented separately for each study part. 
Part A 
1. Signed informed consent of parent or guardian and signed informed assent of the 
participant, if indicated per participant’s age and institutional guidelines 
2. Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound 
heterozygote) 
3. Onset of clinical signs and symptoms consistent with SMA at > 6 months (> 180 days) of 
age (i.e., later-onset SMA) 
4. Age 2 to ≤ 15 years, inclusive, at the time of informed consent 
5. Able to complete all study procedures, measurements, and visits and parent(s) or legal 
guardian(s)/participant has adequately supportive psychosocial circumstances, in the 
opinion of the Investigator 
6. Must be compliant with the study travel policy (see Section 15.4) 
7. Estimated life expectancy > 2 years from Screening, in the opinion of the Investigator 
8. Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is 
planned for study procedures (as assessed by the Investigator and either anesthesiologist 
or pulmonologist) 
9. Ability of the participant and/or his/her legally authorized representative (e.g., parent, 
spouse, or legal guardian), as appropriate and applicable, to understand the purpose and 
risks of the study, to provide informed consent, and to authorize the use of confidential 
health information in accordance with national and local privacy regulations 
10. All female participants of childbearing potential (defined as any female physiologically 
capable of becoming pregnant) and all male participants of reproductive age must 
practice contraception as described in Section 11.5 


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Part B 
All Participants 
1. Signed informed consent of parent or guardian and signed informed assent of the 
participant, if indicated per participant’s age and institutional guidelines 
2. Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound 
heterozygote) 
3. Ability of the participant and/or his/her legally authorized representative (e.g., parent, 
spouse, or legal guardian), as appropriate and applicable, to understand the purpose and 
risks of the study, to provide informed consent, and to authorize the use of confidential 
health information in accordance with national and local privacy regulations 
4. Able to complete all study procedures, measurements, and visits and parent(s) or legal 
guardian(s)/participant has adequately supportive psychosocial circumstances, in the 
opinion of the Investigator 
5. Must be compliant with the study travel policy (see Section 15.4) 
6. Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is 
planned for study procedures (as assessed by the Investigator and either anesthesiologist 
or pulmonologist) 
7. All female participants of childbearing potential (defined as any female physiologically 
capable of becoming pregnant) and all male participants of reproductive age must 
practice contraception as described in Section 11.5 
Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) 
8. Age > 1 week to ≤ 7 months (≤ 210 days) at the time of informed consent 
9. SMN2 copy number = 2 
10. Onset of clinical signs and symptoms consistent with SMA at ≤ 6 months (≤180 days) of 
age 
11. At Screening, receiving adequate nutrition and hydration, in the opinion of the 
Investigator 
12. Body weight in at least the third percentile for age using appropriate country-specific 
guidelines 
13. Gestational age of 37 to 42 weeks for singleton births and 34 to 42 weeks for twins. 
Infants with a lower gestational age may be considered for enrollment if there are no 
complications due to prematurity and approval by the Medical Monitor has been granted. 


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Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset) 
14. Onset of clinical signs and symptoms consistent with SMA at > 6 months (> 180 days) of 
age 
15. Age 2 to < 10 years at the time of informed consent 
16. Can sit independently but has never had the ability to walk independently 
17. HFMSE score ≥ 10 and ≤ 54 at Screening 
18. Estimated life expectancy > 2 years from Screening, in the opinion of the Investigator 
Part C 
All Participants 
1. Signed informed consent of parent or guardian and signed informed assent of the 
participant, if indicated per participant’s age and institutional guidelines 
2. Currently on nusinersen treatment at the time of Screening, with the first dose being at 
least 1 year prior to Screening 
3. Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound 
heterozygote) 
4. Ability of the participant and/or his/her legally authorized representative (e.g., parent, 
spouse, or legal guardian), as appropriate and applicable, to understand the purpose and 
risks of the study, to provide informed consent, and to authorize the use of confidential 
health information in accordance with national and local privacy regulations 
5. Able to complete all study procedures, measurements, and visits and parent(s) or legal 
guardian(s)/participant has adequately supportive psychosocial circumstances, in the 
opinion of the Investigator 
6. Must be compliant with the study travel policy (see Section 15.4) 
7. Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is 
planned for study procedures (as assessed by the Investigator and either anesthesiologist 
or pulmonologist) 
8. All female participants of childbearing potential (defined as any female physiologically 
capable of becoming pregnant) and all male participants of reproductive age must 
practice contraception as described in Section 11.5 
9. Postmenopausal female participants must be amenorrheic without an alternative medical 
cause and have a serum follicle-stimulating hormone level > 40 mIU/mL for ≥ 12 months 


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prior to Screening or ≥ 6 weeks postsurgical bilateral oophorectomy (with or without 
hysterectomy) prior to Screening 
Participants in Cohort 1  
10. Males and females of any age (individuals ≥ 18 years of age at Screening must be 
ambulatory) 
Participants in Cohort 2 
11. Males and females ≥ 18 years of age at Screening (can be ambulatory or nonambulatory) 
12. HFMSE total score ≥ 4 points at Screening 
13. RULM entry item A score ≥ 3 points at Screening 
6.2. 
Exclusion Criteria 
Exclusion criteria are presented separately for each study part. 
Part A 
1. Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive 
ventilation for > 6 hours during a 24-hour period, at Screening 
2. Medical necessity for a gastric feeding tube, where the majority of feeds are given by this 
route, as assessed by the Investigator 
3. Severe scoliosis evident on X-ray examination at Screening (with the participant supine, 
not in a supported sitting position). For sites with local regulation on use of X-ray 
(e.g., Germany), the Investigator may assess scoliosis based on physical examination 
without imaging. 
• Cobb’s angle > 40.0°: exclusionary for severe scoliosis 
• Cobb’s angle < 33.0°: not exclusionary for severe scoliosis 
• For participants with a Cobb’s angle between 33.0° and 40.0°, inclusive, discussion 
with the Medical Monitor must occur before determining eligibility. 
4. Severe contractures evident at Screening, as determined by clinical judgment of the 
Investigator (with the participant supine, not in a supported sitting position) 
5. Hospitalization for surgery (i.e., scoliosis surgery or other surgery), pulmonary event, or 
nutritional support within 2 months prior to Screening or planned within 12 months after 
the participant’s first dose 


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6. Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy at any time during the Screening period 
7. History of brain or spinal cord disease that would interfere with the LP procedures, CSF 
circulation, or safety assessments 
8. Presence of an implanted shunt for the drainage of CSF or of an implanted CNS catheter 
9. History of bacterial meningitis, viral encephalitis, or hydrocephalus 
10. Clinically significant abnormalities in hematology or blood chemistry parameters, as 
assessed by the Investigator, at Screening that would render the participant unsuitable for 
inclusion 
11. Prior scoliosis surgery that would interfere with the LP injection procedure 
12. Participants who are pregnant or currently breastfeeding and those intending to become 
pregnant during the study 
13. Treatment with an investigational drug given for the treatment of SMA (e.g., oral 
albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, and 
hydroxyurea), biological agent, or device within 30 days or 5 half-lives of the agent, 
whichever is longer, prior to Screening or anytime during the study; any prior or current 
treatment with any SMN2-splicing modifier or gene therapy; or prior ASO treatment or 
cell transplantation 
14. The participant’s parent(s) or legal guardian(s) is unable to understand the nature, scope, 
and possible consequences of the study or does not agree to comply with the protocol-
defined Schedule of Activities. 
15. The participant’s parent(s) or legal guardian(s) is not willing or able to meet guidelines in 
the consensus statement for standard of care in SMA [Finkel 2018; Mercuri 2018] (see 
Study Reference Guide) or provide nutritional and respiratory support throughout the 
study, per the Investigator’s judgment. Note: Routine vaccinations and RSV prophylaxis 
are recommended per consensus guidelines on standard of care [Finkel 2018; Mercuri 
2018] but are not required for study enrollment. Participants who are not currently on 
vaccinations or who are not receiving RSV prophylaxis but otherwise meet study 
inclusion criteria will be considered eligible for study enrollment. 
16. Ongoing medical condition that, according to the Investigator, would interfere with the 
study conduct and assessments. Examples are medical disability other than SMA that 
would interfere with the assessment of safety or would compromise the ability of the 
participant to undergo study procedures. 
17. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the 
participant unsuitable for enrollment. 


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Part B 
All Participants 
1. Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy at any time during the Screening period 
2. History of brain or spinal cord disease that would interfere with the LP procedures, CSF 
circulation, or safety assessments 
3. History of bacterial meningitis, viral encephalitis, or hydrocephalus 
4. Presence of an implanted shunt for the drainage of CSF or of an implanted CNS catheter 
5. Permanent tracheostomy or on permanent ventilation at Screening 
6. Clinically significant abnormalities in hematology or blood chemistry parameters, as 
assessed by the Investigator, at Screening that would render the participant unsuitable for 
inclusion 
7. History of systemic hypersensitivity reaction to the excipients contained in the 
formulation, and if appropriate, any diagnostic agents to be administered during the study 
8. Prior scoliosis surgery that would interfere with the LP injection procedure 
9. Prior injury (e.g., upper or lower limb fracture) or surgical procedure that affects the 
participant’s ability to perform any of the outcome measure testing required in the 
protocol and from which the participant has not fully recovered or achieved a stable 
baseline 
10. Treatment with an investigational drug including but not limited to the treatment of SMA 
(e.g., oral albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, and 
hydroxyurea), biological agent, or device within 30 days or 5 half-lives of the agent, 
whichever is longer, prior to Screening or anytime during the study; any prior or current 
treatment with any SMN2-splicing modifier or gene therapy; or prior ASO treatment 
(e.g., nusinersen) or cell transplantation  
11. The participant’s parent(s) or legal guardian(s) is unable to understand the nature, scope, 
and possible consequences of the study or does not agree to comply with the 
protocol-defined Schedule of Activities. 
12. The participant’s parent(s) or legal guardian(s) is not willing or able to meet guidelines in 
the consensus statement for standard of care in SMA [Finkel 2018; Mercuri 2018] (see 
Study Reference Guide) or provide nutritional and respiratory support throughout the 
study, per the Investigator’s judgment. Note: Routine vaccinations and RSV prophylaxis 
are recommended per consensus guidelines on standard of care [Finkel 2018; Mercuri 
2018] but are not required for study enrollment. Participants who are not currently on 


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vaccinations or who are not receiving RSV prophylaxis but otherwise meet study 
inclusion criteria will be considered eligible for study enrollment. 
13. Ongoing medical condition that, according to the Investigator, would interfere with the 
conduct and assessments of the study. Examples are medical disability other than SMA 
that would interfere with the assessment of safety or would compromise the ability of the 
participant to undergo study procedures. 
14. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the 
participant unsuitable for enrollment. 
Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) 
15. Hypoxemia (O2 saturation [awake or asleep, without ventilation support] ˂ 96% at an 
altitude of < 1500 meters, < 92% at an altitude of 1500 to 2000 meters, or < 90% at an 
altitude > 2000 meters) at Screening 
16. Signs or symptoms of SMA present at birth or within the first week after birth 
Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset) 
17. Hospitalization for surgery (i.e., scoliosis surgery or other surgery), pulmonary event, or 
nutritional support within 2 months prior to Screening or planned within 12 months after 
the participant’s first dose  
18. Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive 
ventilation for > 6 hours during a 24-hour period, at Screening  
19. Medical necessity for a gastric feeding tube, where the majority of feeds are given by this 
route, as assessed by the Investigator  
20. Severe scoliosis evident on X-ray examination at Screening (with the participant in a 
sitting or supported sitting position). For sites with local regulation on use of X-ray 
(e.g., Germany), the Investigator may assess scoliosis based on physical examination 
without imaging. 
• Cobb’s angle > 40.0°: exclusionary for severe scoliosis 
• Cobb’s angle < 33.0°: not exclusionary for severe scoliosis 
• For participants with a Cobb’s angle between 33.0° and 40.0°, inclusive, discussion 
with the Medical Monitor must occur before determining eligibility. 
21. Severe contractures evident at Screening, as determined by clinical judgment of the 
Investigator (with the participant supine, not in a supported sitting position) 


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22. Participants who are pregnant or currently breastfeeding, and those intending to become 
pregnant during the study 
Part C 
All Participants 
1. Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy at any time during the Screening period 
2. History of brain or spinal cord disease that would interfere with the LP procedures, CSF 
circulation, or safety assessments 
3. History of bacterial meningitis, viral encephalitis, or hydrocephalus 
4. Presence of an implanted shunt for the drainage of CSF or of an implanted CNS catheter 
5. Permanent tracheostomy or on permanent ventilation at Screening 
6. Clinically significant abnormalities in hematology or blood chemistry parameters, as 
assessed by the Investigator, at Screening that would render the participant unsuitable for 
inclusion 
7. History of systemic hypersensitivity reaction to nusinersen, the excipients contained in 
the formulation, and if appropriate, any diagnostic agents to be administered during the 
study 
8. Prior scoliosis surgery that would interfere with the LP injection procedure 
9. Prior injury (e.g., upper or lower limb fracture) or surgical procedure that affects the 
participant’s ability to perform any of the outcome measure testing required in the 
protocol and from which the participant has not fully recovered or achieved a stable 
baseline 
10. Hospitalization for surgery (i.e., scoliosis surgery or other surgery), pulmonary event, or 
nutritional support within 2 months prior to Screening or planned within 12 months after 
the participant’s first dose 
11. Participants who are pregnant or currently breastfeeding, and those intending to become 
pregnant during the study 
12. Concurrent or previous participation and/or administration of nusinersen in another 
clinical study. 
13. Concomitant or previous administration of any SMN2-splicing modifier (excluding 
nusinersen) or gene therapy, either in a clinical study or as part of medical care. 


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14. Concurrent or previous participation in any interventional investigational study for any 
other drug or device within 30 days or 5 half-lives of the agent, whichever is longer, prior 
to Screening. 
15. Ongoing medical condition that, according to the Investigator, would interfere with the 
conduct and assessments of the study. Examples are medical disability other than SMA 
that would interfere with the assessment of safety or would compromise the ability of the 
participant to undergo study procedures. 
16. The participant or the participant’s parent(s) or legal guardian(s) is unable to understand 
the nature, scope, and possible consequences of the study or does not agree to comply 
with the protocol-defined Schedule of Activities. 
17. The participant or the participant’s parent(s) or legal guardian(s) is not willing or able to 
meet guidelines in the consensus statement for standard of care in SMA [Finkel 2018; 
Mercuri 2018] (see Study Reference Guide) or provide nutritional and respiratory support 
throughout the study, per the Investigator’s judgment. Note: Routine vaccinations and 
RSV prophylaxis are recommended per consensus guidelines on standard of care [Finkel 
2018; Mercuri 2018] but are not required for study enrollment. Participants who are not 
currently on vaccinations or who are not receiving RSV prophylaxis but otherwise meet 
study inclusion criteria will be considered eligible for study enrollment. 
18. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the 
participant unsuitable for enrollment. 
Participants in Cohort 2 
19. Severe scoliosis evident on X-ray examination at Screening (with the participant in a 
sitting or supported sitting position). For sites with local regulation on use of X-ray 
(e.g., Germany), the Investigator may assess scoliosis based on physical examination 
without imaging. 
• Cobb’s angle > 40.0°: exclusionary for severe scoliosis 
• Cobb’s angle < 33.0°: not exclusionary for severe scoliosis 
• For participants with a Cobb’s angle between 33.0° and 40.0°, inclusive, discussion 
with the Medical Monitor must occur before determining eligibility. 
6.3. 
Screening, Retesting, and Screen Failures 
6.3.1. 
Screening 
Once informed consent is obtained, screening assessments can occur. At this time, a unique 
identification number is assigned that will be used on study-related documents pertaining to the 
participant. Any identification numbers that are assigned will not be reused even if the 


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participant does not receive treatment. Study sites are required to document all screened 
participants initially considered for inclusion in the study.  
6.3.2. 
Retesting and Rescreening 
During the Screening period, participants who have an out-of-range result may be retested 1 time 
only at the discretion of the Investigator within the Screening process, without the need for a 
repeat full Screening. The Screening period may be extended for up to 10 days for individuals 
who cannot complete the Day 1 Visit within 21 days of signing the ICF, as long as they continue 
to meet other eligibility criteria. 
Participants who fail Screening (see Section 6.3.3) may be rescreened once at the discretion of 
the Investigator. Participants who are rescreened will be assigned a new identification number. 
6.3.3. 
Screen Failures 
Screen failures are defined as participants who sign the ICF but are not subsequently dosed or 
randomized. If a participant is considered a screen failure, the reasons for exclusion must be 
documented in the participant’s source documents and on the screening log. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAEs. 


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7. 
STUDY TREATMENT  
7.1. 
Regimen 
Participants will receive treatment as follows: 
• Part A: Six participants with later-onset SMA will receive 3 loading doses of 28 mg 
of nusinersen administered intrathecally on Days 1, 15, and 29. A sentinel dosing 
approach will be used, in which the first participant will be enrolled and dosed with 
28 mg of nusinersen. Following the availability of 72 hours of safety data after the 
first loading dose in the first participant, data for this participant will be reviewed by 
the Investigator and the Sponsor before the next 5 participants are enrolled. Only 
1 participant can receive their first dose of study treatment on a given day. 
Maintenance doses of 28 mg of nusinersen will be administered on Days 149 and 
269. 
• Part B: 
− Control Group: A total of 33 participants (25 with infantile-onset SMA and 8 with 
later-onset SMA) will receive 4 loading doses of 12 mg of nusinersen 
administered intrathecally (Days 1, 15, 29, and 64), followed by maintenance 
doses of 12 mg on Days 183 and 279 (and a sham procedure on Day 135). See 
Table 6 for the blinded dosing schedule. 
− 50/28-mg Group: A total of 66 participants (50 with infantile-onset SMA and 
16 with later-onset SMA) will receive 2 loading doses of 50 mg of nusinersen 
administered intrathecally (Days 1 and 15) and 2 sham procedures on Days 29 
and 64, followed by maintenance doses of 28 mg on Days 135 and 279 (and a 
sham procedure on Day 183). See Table 6 for the blinded dosing schedule. 
Table 6: 
Part B Blinded Dosing Schedule 
Arm 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Dose 6 
Dose 7 
50/28-mg 
Group 
D1 
(50 mg) 
D15 
(50 mg) 
D29 
(sham) 
D64 
(sham) 
D135 
(28 mg) 
D183 
(sham) 
D279 
(28 mg)1 
Control 
Group 
(12/12 mg) 
D1 
(12 mg) 
D15 
(12 mg) 
D29 
(12 mg) 
D64 
(12 mg) 
D135 
(sham) 
D183 
(12 mg) 
D279 
(12 mg)2 
D = day 
1 Delayed by 24 days from targeted dosing day of D255 
2 Moved up 24 days from the targeted dosing day of D303 
• Part C: Up to approximately 40 participants (i.e., up to approximately 20 participants 
each in Cohorts 1 and 2) who have already been receiving treatment with nusinersen 
for at least 1 year prior to entry in this study will receive a single bolus dose of 50 mg 
of nusinersen administered intrathecally on Day 1 of this study (which should be 


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administered 4 months ± 14 days after their most recent maintenance dose of 12 mg), 
followed by 2 maintenance doses of 28 mg of nusinersen on Days 121 and 241. 
If a loading dose is delayed or missed (as per the Schedule of Activities), a protocol deviation 
should be recorded and nusinersen should be administered as soon as possible, with at least 
14 days between doses, and dosing should be continued according to the Schedule of Activities. 
In the maintenance phase, if a planned dose is delayed or missed, nusinersen should be 
administered as soon as possible and dosing should be continued according to the Schedule of 
Activities. 
7.2. 
Modification of Dose 
The dosage cannot be modified. 
7.3. 
Study Treatment Management 
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice. 
Site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment. The DHA aligns with all other references, 
including the protocol. 
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff. Study 
treatment is to be dispensed only to participants enrolled in this study. Once study treatment is 
prepared for a participant, it can be administered only to that participant. Study treatment is for 
1-time use only; do not use any study treatment remaining in the vial for another participant. 
7.3.1. 
Nusinersen 
Nusinersen will be supplied as specified in the DHA. The study treatment is supplied as a 
formulation that contains nusinersen, sodium dihydrogen phosphate dihydrate, sodium phosphate 
dibasic anhydrous, sodium chloride, potassium chloride, calcium chloride dihydrate, and 
magnesium chloride hexahydrate in water for injection, adjusted, if necessary, to a target pH of 
7.2 with hydrochloric acid or sodium hydroxide during compounding. Further details on drug 
preparation and administration may be found in the DHA. 
The contents of the nusinersen label will be in accordance with all applicable regulatory 
requirements. At a minimum, the label will include a study reference code, study treatment 
identifier, quantity of dosage units, lot number, and other pertinent information in accordance 
with local law. The expiry or use-by date is stored in the IRT system, and printable assignment 
reports are available to site staff. Study treatment should not be used after the expiry or use-by 
date. 


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7.3.1.1. 
Preparation 
The individual preparing nusinersen should carefully review the instructions provided in the 
DHA. 
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vial(s) or study treatment, do not use the study treatment. The vial(s) in question should be 
saved at the study site and the problem immediately reported to the Sponsor (or designee). 
Contact information for reporting a problem is provided in the Study Reference Guide. 
7.3.1.2. 
Storage 
Study treatment must be stored in a secure location.  
Nusinersen is to be protected from light and is to be stored at 2C to 8C, in a locked refrigerator 
with limited access. For the most up-to-date storage requirements, follow the instructions 
provided in the DHA. 
7.3.1.3. 
Handling and Disposal 
The Investigator must return all used and unused vials of nusinersen as instructed by the Sponsor 
(or designee) unless approved for onsite destruction. 
If any used nusinersen supplies are to be destroyed at the study site, the institution or appropriate 
site staff must obtain prior approval from the Sponsor (or designee), by providing, in writing, the 
destruction policy or details of the method of destruction. After such destruction, the Sponsor (or 
designee) must be notified, in writing, of the details of the study treatment destroyed (e.g., lot or 
kit numbers, quantities), the date of destruction, and proof of destruction. 
7.3.1.4. 
Accountability 
Accountability for study treatment is the responsibility of the Investigator. The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (participant-by-participant accounting), and accounts of any study treatment 
accidentally or deliberately destroyed or lost.  
Unless otherwise notified, all vials, both used and unused, must be saved for study treatment 
accountability. Ongoing reconciliation must be made between the amount of nusinersen and, if 
applicable, diluent (artificial CSF), supplied, dispensed, and subsequently destroyed or returned 
to the Sponsor (or designee). A written explanation must be provided for any discrepancies. 
Please refer to the DHA for additional details and instructions. 
7.4. 
Blinding Procedures 
Part B is the only study part that will be blinded; Parts A and C will be open-label.  


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To maintain the study blind in Part B, the procedure will be performed in a dedicated room by 
dedicated study personnel who are unblinded to the treatment group; this will not include any of 
the key study site personnel (i.e., the Investigator, Study Coordinator, or Outcomes Assessors). 
The key study site personnel and the parent/guardians (if applicable) will not be present during 
the procedure to ensure blinding. 
The sham procedure will consist of a small needle prick on the lower back at the location where 
the LP injection is normally made. The needle will break the skin, but no LP injection or needle 
insertion will occur. The site of the needle prick will be covered in the same manner as that of 
the LP injection, thus simulating the appearance of an LP injection. If anesthesia and/or sedation 
is used for the LP procedure for an individual participant, in order to maintain the blind, that 
participant will receive equivalent anesthesia and/or sedation (according to institutional 
procedures) for all of the sham procedures and LP injections. Participants who receive the sham 
procedure will be kept in the procedure room for the same amount of time as that for participants 
who were administered study treatment, thus simulating the time period of a study treatment 
administration procedure. 
Study treatment and sham kits will be packaged in a blinded fashion. Blinded kits for sham 
procedures will contain artificial CSF that will not be injected but will be used to simulate CSF 
samples for a participant who has undergone sham procedure at a specific visit, as described in 
the DHA. 
At the end of the study, if unblinding of Part B will not jeopardize the results of ongoing related 
studies, the Sponsor will provide the randomization codes to Investigators, who then can inform 
their participants about the treatment received.  
In the event of a medical emergency that requires unblinding of a participant’s treatment 
assignment, refer to Section 11.4.3. 
7.5. 
Compliance 
Study treatment will be administered by the site staff. 
7.6. 
Concomitant Therapy and Procedures 
7.6.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between Screening and the final 
study visit/telephone call. 
Participants should be instructed to contact their Investigators before taking any new 
medications, including nonprescription drugs and herbal preparations. 


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7.6.1.1. 
Allowed Concomitant Therapy 
Throughout the study, Investigators or designated licensed physicians involved in the study may 
prescribe concomitant therapies or treatments deemed necessary for AEs or to provide adequate 
supportive care. 
7.6.1.2. 
Disallowed Concomitant Therapy 
Participants are prohibited from receiving other experimental or approved agents for the 
treatment of SMA, including gene therapy, SMN2-splicing modifier, biological agent, or device, 
during the study. This includes marketed agents at experimental doses that are being tested for 
the treatment of SMA (oral albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, 
valproate, hydroxyurea, etc.). In addition, participants will not be allowed to enroll in other 
interventional studies during Study 232SM203. 
7.6.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
Screening and the final study visit/telephone call. 
7.7. 
Continuation of Treatment  
Following completion of this study, all eligible participants may elect to enroll in a separate 
long-term extension study (232SM302), pending study approval by ethics committees and the 
appropriate regulatory authorities. In regard to participants rolling over from Part B, this will be 
done without unblinding the participant’s treatment group.  


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8. 
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY 
8.1. 
Discontinuation of Study Treatment 
A participant must permanently discontinue study treatment for any of the following reasons: 
• The participant becomes pregnant. Study treatment must be discontinued 
immediately. Report the pregnancy according to the instructions in Section 11.4.1. 
• The participant or the participant’s parent(s)/legal guardian(s) withdraws consent to 
continue study treatment.  
• The participant experiences an AE that necessitates permanent discontinuation of 
study treatment. 
• The participant is not tolerating a given dose. 
• The participant experiences a medical emergency that necessitates permanent 
discontinuation of study treatment (or unblinding of the participant’s treatment 
assignment in Part B). 
• At the discretion of the Investigator for medical reasons. 
• At the discretion of the Investigator or Sponsor for noncompliance. 
The primary reason for discontinuation of study treatment must be recorded in the participant’s 
CRF. 
Participants in Part B who discontinue treatment may remain in the study to continue the 
protocol-required tests and assessments described in Table 5 (unless the reason for 
discontinuation is to initiate treatment with a disallowed concomitant therapy per 
Section 7.6.1.2). Participants should return to the clinic according to the original visit schedule 
per Table 2 until the Day 302 study visit but will follow a reduced Schedule of Activities at these 
visits. 
8.2. 
Lost to Follow-Up 
Participants will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the study site for a required 
study visit: 
• The study site staff must attempt to contact the participant and reschedule the missed 
visit as soon as possible and counsel the participant on the importance of maintaining 


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the assigned visit schedule and ascertain whether the participant wishes to and/or 
should continue in the study. 
• In cases in which the participant is deemed lost to follow-up, the Investigator or 
designee must make every effort to regain contact with the participant. These contact 
attempts should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, that participant will be considered 
to have withdrawn from the study with the primary reason of “lost to follow-up.” 
8.3. 
Withdrawal of Participants From the Study 
Participants must be withdrawn from the study for any one of the following reasons: 
• The participant or the participant’s parent(s)/legal guardian(s) withdraws consent for 
participation in the study.  
• The participant enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered 
or initiates treatment with a disallowed concomitant therapy as described in 
Section 7.6.1.2. 
• The participant is unwilling or unable to comply with the protocol. 
The primary reason for the participant’s withdrawal from the study must be recorded in the 
participant’s CRF. 
Participants should undergo an ET visit unless withdrawal is due to death or withdrawal of 
consent. 
Participants who withdraw from the study may not be replaced. 


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9. 
EFFICACY, 
, AND 
PHARMACODYNAMIC ASSESSMENTS 
See Section 1.3 for the timing of all assessments. 
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged. In these cases, participants will be asked to return to the 
study site to have the evaluations repeated. 
9.1. 
Clinical Efficacy Assessments 
The following clinical assessments will be performed to evaluate the efficacy of nusinersen in all 
study participants. 
All Participants 
• Number of serious respiratory events 
• Number and duration of hospitalizations 
• CGIC (physician and caregiver assessment) 
• Ventilator use 
The following clinical assessments will be performed to evaluate the efficacy of nusinersen in 
participants enrolled in specific parts of the study. 
Sitting independently will be defined as able to sit without support per WHO motor milestone 
(Test Item No. 1 – sitting without support), and ambulatory will be defined as any participant 
who has achieved independent walking as defined by the WHO motor milestone criteria (Test 
Item No. 6 – Walking Alone). 
Videotaping of all motor milestone and motor function assessments will be optional; however, if 
the participant/caregiver consents to video recording, all assessments should be recorded. 
Part A 
Participants with Later-Onset SMA: 
• HFMSE 
• RULM 
• WHO motor milestones 
 
 
 


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• QoL questionnaires (PedsQL and ACEND) 
• Dysphagia assessments (PASA) 
Part B 
Participants with Infantile-Onset SMA: 
• CHOP-INTEND 
• HINE Section 2 motor milestones 
• Daily ventilator use (number of hours/day), using a daily ventilator use diary 
• Dysphagia assessments (PASA) 
• 
 
Participants with Later-Onset SMA: 
• HFMSE 
• RULM 
• WHO motor milestones 
 
 
 
 
 
 
• QoL questionnaires (PedsQL and ACEND) 
• Dysphagia assessment (PASA) 
• 
 


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Part C 
The Investigator will select efficacy assessments based on criteria described below. The 
assessments selected at Screening will be used to evaluate the participant throughout the entire 
duration of the trial, from Screening to follow-up. 
Cohort 1: 
• CHOP-INTEND and HINE Section 2 motor milestones should be performed by the 
following participants: 
− Participants 1 to < 2 years of age at the time of informed consent. 
− Participants 2 to ≤ 5 years of age at the time of informed consent if they did not 
achieve independent sitting prior to screening. 
• HFMSE and RULM should be performed by the following participants: 
− Participants ≥ 2 years of age at the time of informed consent. If unable to sit 
independently, CHOP-INTEND and HINE Section 2 motor milestones will also 
be performed. 
− Participants ≥ 2 years of age after informed consent obtained while in the study. 
HFMSE and RULM should start to be collected for participants ≥ 2 years of age 
while continuing to collect CHOP-INTEND and HINE Section 2 motor 
milestones until the end of study.  
• WHO motor milestones 
 should be collected for all 
participants.  
 
 
  
 
 
 
• QoL questionnaires (PedsQL and ACEND) should be assessed for participants 
≥ 2 years of age at the time of informed consent. 
Cohort 2: 
• HFMSE, RULM, WHO motor milestones, QoL questionnaires (ACEND and 
), 
, 
 should be evaluated for all 
participants. 


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9.1.1. 
Motor Milestones 
The assessments to be performed will depend on the participant’s age at enrollment and current 
motor abilities. Videotaping of the WHO and/or HINE motor milestone assessments will be 
optional. 
Motor milestones will be assessed using the WHO motor milestone criteria [WHO Multicentre 
Growth Reference Study Group 2006; Wijnhoven 2004] and/or Section 2 of the HINE, as per the 
Schedule of Activities (Table 1, Table 2, Table 3, and Table 4). Section 2 of the HINE is 
composed of the following 8 motor milestone categories: voluntary grasp, ability to kick in 
supine position, head control, rolling, sitting, crawling, standing, and walking. Within each 
motor milestone category, 3 to 5 levels can be achieved. All 8 motor milestones will be tested 
during each assessment. A participant 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 7 
to the right side of the table, as denoted by the Milestone Level Progression arrow in the table 
[Haataja 1999]. 
WHO motor milestones will be assessed by the site clinical evaluator and caregiver. Adult 
participants who do not require a caregiver during the study visit may self-report WHO motor 
milestone achievement. 
Whenever possible, for each participant, motor milestone assessments across all study visits 
should be conducted consistently by the same clinical evaluator. 


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Table 7: 
Hammersmith Infant Neurological Examination Section 2 - Motor 
Milestones 
Motor 
Milestone 
Category 
Milestone Level Progression Score 
(Age Expected in Heathy Infants1) 
Improvement 
0 
1 
2 
3 
4 
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 
Rolls to side 
(4 months) 
Prone to 
supine 
(6 months) 
Supine to 
prone 
(7 months) 
 
Sitting 
Cannot sit 
Sits with 
support at the 
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) 
Crawls flat on 
the 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] 
Walks 
independently 
(15 months) 
 
1 Values for healthy infants in [De Sanctis 2016; Haataja 1999] 
The definition of a motor milestone responder is based on the motor milestones categories in 
Section 2 of the HINE, with the exclusion of voluntary grasp, as follows: 
• Participant demonstrates at least a 2-point increase in the category of ability to kick or 
increase to the maximal score on that category (touching toes) or a 1-point increase in 
the motor milestones category of head control, rolling, sitting, crawling, standing, or 
walking AND 


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• Among the 7 motor milestone categories (with the exclusion of voluntary grasp), the 
participant demonstrates improvement in more categories than worsening. 
Note: For the category of ability to kick, similar to the definition of improvement in (1), 
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. 
Participants 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. 
9.1.2. 
Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease 
CHOP-INTEND will be assessed in participants in Part B with infantile-onset SMA. Participants 
in Part C will have CHOP-INTEND assessed as described in Section 9.1. 
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. CHOP-INTEND has been established as a safe and reliable infant motor measure in 
infantile-onset SMA and has been validated [Glanzman 2011]. 
Whenever possible, for each participant, CHOP-INTEND assessments across all study visits 
should be conducted consistently by the same clinical evaluator. 
9.1.3. 
Hammersmith Functional Motor Scale Expanded 
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 II and Type III 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 the evaluation of ambulatory patients with SMA [O'Hagen 
2007]. The HFMSE has been shown to be highly correlated with other clinical assessments and 
has shown good test-retest reliability. 
Whenever possible, for each participant, HFSME assessments across all study visits should be 
conducted consistently by the same clinical evaluator. 
9.1.4. 
Revised Upper Limb Module 
Participants with later-onset SMA will be evaluated using the RULM [Mazzone 2016]. The 
RULM will continue to be performed should participants 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 of detecting 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 the mouth as if drinking, take a coin and place it in a box, and remove the lid 


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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 the change that occurs in the 
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 (e.g., puberty), and the RULM aims to incorporate 
the performance of the shoulder, elbow, wrist, and hand. 
Whenever possible, for each participant, RULM assessments across all study visits should be 
conducted consistently by the same clinical evaluator. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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9.1.8. 
Clinical Global Impression of Change 
The CGIC rating scale was developed as a brief standalone assessment of the clinician’s view of 
the patient’s global functioning after initiating a study medication [Guy 1976]. The CGIC 
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. The 
CGIC 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 the illness, the patient’s level of distress and other aspects 
of impairment, and the impact of the illness on functioning. The CGIC 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 CGIC is a 7-point scale that requires the clinician to assess how much the patient’s illness 
has changed 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. 
CGIC should be assessed consistently by the same rater for each study participant. A separate 
CGIC assessment will be performed by the Investigator (Principal Investigator or 
Subinvestigator) and caregiver. Adult participants who do not require a caregiver during the 
study visits will only have the CGIC assessment assessed by the Investigator. 
9.1.9. 
Parent Assessment of Swallowing Ability 
Dysphagia will be assessed in Parts A and B at the timepoints specified in the Schedule of 
Activities (Table 1 and Table 2) using the PASA questionnaire. Caregivers will be asked a series 
of questions regarding the mealtime behavior of the participant. 
The PASA questionnaire was developed by a Biogen team in order to assess the signs and 
symptoms of dysphagia. This questionnaire consists of 33 items across 4 domains that cover 


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general feeding, drinking liquids, eating solid foods, and assessment of swallowing concerns. 
The first 3 of these domains are generally assessed with 5 levels of response (Never, Rarely, 
Sometimes, Often, and Always), although 2 items are assessed with a simple “Yes”/“No” 
answer. In the final domain, the assessment of swallowing concerns has 4 levels of response: 
Strongly Agree, Agree, Disagree, and Strongly Disagree. In answering each item, the caregiver is 
directed to consider the previous 7 days. 
9.1.10. 
Quality-of-Life Questionnaires 
QoL questionnaires include the PedsQL, ACEND, 
. QoL questionnaires will 
be collected on the days specified in Table 1, Table 2, Table 3, and Table 4. 
9.1.10.1. Pediatric Quality of Life Inventory (Generic Core Scales and Neuromuscular 
Module) 
Participants with later-onset SMA will be evaluated using the age-appropriate modules of the 
PedsQL Measurement 4.0 Generic Core Scales and 3.0 Neuromuscular Module [Varni 1999], 
which include age 2 to 4 years, 5 to 7 years, 8 to 12 years, 13 to 18 years, 18 to 25 years, and 
≥ 26 years. 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 HRQOL in children, 
adolescents, and adults. The PedsQL consists of brief, practical, generic core scales, as well as 
condition-specific modules for use in designated clinical populations. The PedsQL 4.0 Generic 
Core Scales include an assessment of physical functioning, emotional functioning, social 
functioning, and school functioning and will be assessed for participants 2 to ≥ 26 years of age. 
The PedsQL 3.0 Neuromuscular Module was designed to measure HRQOL dimensions specific 
to patients with neuromuscular disorders, including SMA, and will be assessed in participants 2 
to 25 years of age. Patient self-report will be measured in participants starting at 5 years of age, 
while parent proxy-report of HRQOL will be measured for participants starting at 2 years of age. 
In Parts A and B, all participants with later-onset SMA will be evaluated using the PedsQL. In 
Part C Cohort 1, the PedsQL (in addition to ACEND) will be evaluated in participants who are 
≥ 2 years of age at Screening. The PedsQL will not be evaluated for participants in Part C 
Cohort 2. 
If a participant is assessed on PedsQL at baseline, then the age range of the scale used at 
Screening for that participant will continue to be used up to Day 302, regardless of changes in 
the participant’s age. 
9.1.10.2. Assessment of Caregiver Experience With Neuromuscular Disease 
Parents/caregivers of participants will complete the ACEND questionnaire. The ACEND 
questionnaire will not be collected for adult participants who do not require a caregiver. This 
assessment instrument has been designed to quantify the caregiver impact experienced by 
parents/caregivers of children affected with severe neuromuscular diseases, including children 


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with SMA [Matsumoto 2011]. ACEND includes domains assessing physical impact (including 
feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact 
(including time, emotion, and finance). 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  


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9.1.14. 
Ventilator Use 
9.1.14.1. All Participants 
The participant’s ventilator use will be collected at every study visit. If ventilation is used daily, 
the average number of hours per day for the past 7 days will be recorded (except for participants 
with infantile-onset SMA enrolled in Part B; see Section 9.1.14.2). 
9.1.14.2. Participants With Infantile-Onset SMA in Part B 
The participant’s ventilator use (number of hours/day) will be recorded daily by the caregiver 
using a daily ventilator use diary for the duration of the study, regardless of whether or not a 
ventilator is being utilized. This information will be obtained by the site during study visits and 
telephone contacts and entered into the CRF. 
9.1.15. 
Standard of Care 
All participants are expected to follow standard of care as referenced in Section 6.2 throughout 
the entire duration of the study. Investigators will document standard of care information for Part 
B participants at Screening and Day 302. 
 
 
  
9.3. 
Pharmacodynamic Assessments 
The PD properties of nusinersen will be assessed (where data are available) by evaluating the 
plasma and CSF levels of NF-L to explore its role as a potential biomarker of treatment response 
in SMA. 
 
 
 
 
9.5. 
Pharmacogenetic and Genetic Assessments 
All participants will undergo genetic testing through a central laboratory to confirm SMN1 status 
(copy number, deletion, and mutation where necessary to confirm 5q SMA) and SMN2 copy 
number. For the purpose of determining study eligibility, historical genetic testing results may be 
acceptable with appropriate documentation or analysis may be performed at a local laboratory if 
needed, but confirmatory testing through a central laboratory will also be performed. 
Deoxyribonucleic acid is to be collected from all participants to assess sequence variations at the 
SMN1 and SMN2 loci that might affect SMN1 and SMN2 activity or the binding of nusinersen. 


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9.6. 
Future Scientific Research Assessments 
 
 
 
The samples collected may be utilized to identify or verify putative, prognostic, and predictive 
markers associated with disease and markers of therapeutic response to treatment, and/or to 
develop diagnostic and analytical tests. Background and dynamic clinical disease characteristics 
and associated biomarker data may be utilized to predict subsequent disease worsening 
(severity), identify high-risk patient subgroups, and identify predictors of response to treatment. 
 


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10. 
SAFETY ASSESSMENTS 
See Section 1.3 for the timing of all safety assessments. 
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged. In these cases, participants will be asked to return to the 
study site to have the evaluations repeated. 
10.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to evaluate the safety profile of nusinersen: 
• AE and SAE recording 
• Medical (including SMA) history. 
 
• Vital sign measurements: temperature, pulse rate, systolic and diastolic blood 
pressure, respiratory rate, and pulse oximetry 
• Growth parameters: body length/height (for all participants; body length will be 
measured for participants who are not able to stand independently), head, chest, and 
arm circumference (for participants with infantile-onset SMA), and ulnar length (for 
participants with later-onset SMA) will be measured. Additional parameters of 
weight-for-age, weight-for-length, and head-to-chest circumference ratio will be 
calculated. 
• Neurological examinations: HINE Sections 1 and 3 will be administered to 
participants in Part B with infantile-onset SMA, and participants in Part C < 2 years 
of age at the time of informed consent. A neurological examination will be performed 
in participants in Parts A and B with later-onset SMA and participants in Part C 
≥ 2 years of age at the time of informed consent.  
• Physical examinations (videotaping of physical examinations is optional) 
• ECGs 
• LP opening pressure: Details available in the DHA. LP opening pressure will be 
evaluated for all participants in Parts A and C, but only for participants with 
later-onset SMA in Part B. 
• Concomitant therapy and procedure recording 


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10.2. 
Laboratory Safety Assessments 
Samples will be analyzed using Good Laboratory Practice-validated assays. 
The following laboratory assessments will be performed to evaluate the safety profile of 
nusinersen: 
• Hematology: complete blood cell count, with differential and platelet count, and 
absolute neutrophil count 
• Coagulation parameters (by local laboratory): aPTT, PT, and INR 
• Blood chemistry: total protein, albumin, creatinine, blood urea nitrogen, bilirubin 
(total and direct), alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, 
bicarbonate, chloride, sodium, potassium, cystatin C, creatine phosphokinase, and 
creatine kinase 
• Urinalysis: urine total protein (by local laboratory except if local analysis is not 
possible without a 24-hour urine collection, in which case samples will be analyzed 
by a central laboratory); specific gravity, pH, protein, glucose, ketones, bilirubin, 
blood, red blood cells, white blood cells, epithelial cells, bacteria, casts, and crystals 
• CSF local laboratory sample: cell count, total protein, and glucose 
The laboratory analytes to be measured are shown in Appendix B. 
When the safety laboratory sample analysis is at risk due to logistical difficulties or issues with 
access to the central laboratory (e.g., due to COVID-19–related disruptions or humanitarian 
emergencies), these samples may be analyzed by the local laboratory. Any use of a local 
laboratory under these circumstances must be approved by the Sponsor prior to being 
implemented.  
10.3. 
Telephone Assessments 
For all study parts, from 2 to 14 days after each maintenance dose, participants will be contacted 
via a telephone call to capture any clinical changes, such as new AEs, ventilator use/status 
updates, and changes in concomitant therapies. Telephone calls will also be made in Part A 
2 weeks (± 3 days) after the Day 29 dose, in Part B 2 weeks (± 3 days) after the Day 29 dose for 
the first 20 participants, and in Part C 2 weeks (± 3 days) after the Day 1 bolus dose. 


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11. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs. If 
an AE occurs, the first concern should be for the safety of the participant. If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each participant and/or his/her legally authorized representative and/or 
main caregiver must be given the names and telephone numbers of site staff for reporting SAEs, 
pregnancies, overdoses, and medical emergencies. Throughout the protocol, the Sponsor is 
named, but reporting may be done through a CRO. 
11.1. 
Definitions 
11.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
(participant) administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal assessment such as an abnormal laboratory value), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product. 
Determination of whether an abnormal assessment (e.g., laboratory value, vital sign, and ECG) 
result meets the definition of an AE will be made by the Investigator. Abnormal results are not 
considered AEs unless one or more of the following criteria are met: 
• The result meets the criteria for an SAE. 
• The result requires the participant to receive specific corrective therapy. 
• The result is considered by the Investigator to be clinically significant. 
11.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death. 
• In the view of the Investigator, places the participant at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 


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• Results in a congenital anomaly/birth defect. 
• Is a medically important event. 
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
participant or may require intervention to prevent one of the other outcomes listed in the 
definition above. (Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or convulsions occurring at home that do not require 
an inpatient hospitalization.) 
11.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the participant is hospitalized. The study site must document all of the 
following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the 
participant’s consent to be in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of the 
Investigator, between the participant’s consent to be in the study and the time of the 
procedure or treatment. 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission. 
− If a participant is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless one 
of the requirements in Section 11.1.2 is met. 
11.2. 
Safety Classifications 
11.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
• If the event meets the criteria for an SAE as defined in Section 11.1.2 
• The relationship of the event to study treatment as defined in Section 11.2.2 
• The severity of the event as defined in Section 11.2.3 




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11.3. 
Monitoring and Recording Events 
11.3.1. 
Adverse Events 
Any AE experienced by the participant between the time of signing of the ICF and the last study 
visit/telephone contact is to be recorded on the CRF, regardless of the severity of the event or its 
relationship to study treatment. At each study visit, the Investigator will assess the participant for 
AEs and will record any new AEs or updates to previously reported AEs on the CRF. 
AEs that are ongoing when the participant completes or discontinues the study will be followed 
by the Investigator until the event has resolved or become stable. AE outcome will be recorded 
on the CRF, as applicable. 
11.3.2. 
Serious Adverse Events 
Any SAE experienced by the participant between the time of the signing of the ICF and the last 
study visit/telephone contact is to be recorded on an SAE form, regardless of the severity of the 
event or its relationship to study treatment. SAEs must be reported to the Sponsor within 
24 hours or according to national law, as described in Section 11.3.3. Follow-up information 
regarding an SAE also must be reported within 24 hours or according to national law. 
Participants will be followed for all SAEs until the last study visit/telephone contact. Thereafter, 
the event should be reported to the Sponsor only if the Investigator considers the SAE to be 
related to study treatment. 
Any SAE that is ongoing when the participant completes or discontinues the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status. 
11.3.3. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify the Sponsor within 24 hours of the site staff becoming aware of the SAE or 
according to national law. It is the Investigator’s responsibility to ensure that the SAE reporting 
information and procedures are used and followed appropriately. 




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Investigator or site staff must report the outcome of the pregnancy to the Sponsor. A pregnancy 
is not considered an AE and should not be recorded on the AE CRF. 
Congenital abnormalities and birth defects in the offspring of male or female participants should 
be reported as an SAE if conception occurred during the study treatment period or 120 days from 
their last dose of study treatment. 
11.4.2. 
Overdose 
An overdose is any dose of study treatment administered to a participant or taken by a participant 
that exceeds the dose assigned to the participant according to the protocol. Overdoses are not 
considered AEs and should not be recorded as an AE on the CRF; however, all overdoses must 
be recorded on an Overdose form and faxed or emailed to the Sponsor within 24 hours of the site 
becoming aware of the overdose. An overdose must be reported to the Sponsor even if the 
overdose does not result in an AE. If an overdose results in an AE, the AE must be recorded. If 
an overdose results in an SAE, both the SAE and Overdose forms must be completed and faxed 
or emailed to the Sponsor. All study treatment-related dosing information must be recorded on 
the dosing CRF. 
11.4.3. 
Medical Emergency 
In a medical emergency requiring immediate attention, site staff will apply appropriate medical 
intervention, according to current standard 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. 
11.4.3.1. Unblinding for Medical Emergency 
Part B is the only part of the study that is blinded. In a medical emergency when knowledge of 
the participant’s treatment assignment may influence the participant’s clinical care, the 
Investigator may access the participant’s treatment assignment by IRT. The Investigator must 
document the reasons for unblinding in the participant’s source documents. The Investigator is 
strongly advised not to divulge the participant’s treatment assignment to any individual who is 
not directly involved in managing the medical emergency or to personnel involved with the 
analysis and conduct of the study. The Investigator can contact the Sponsor to discuss such 
situations. 
11.5. 
Contraception Requirements 
All female participants of childbearing potential and all male participants of reproductive age 
must ensure that effective contraception is used for the duration of the study. In addition, 
participants should not donate sperm or eggs for the duration of the study. 
For the purposes of this study, females of childbearing potential are defined as all females 
physiologically capable of becoming pregnant, unless they meet one of the following conditions:  


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• Postmenopausal 
− 52 continuous weeks of natural (spontaneous) amenorrhea without an alternative 
medical cause and a serum follicle-stimulating hormone level > 40 mIU/mL 
− 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Posthysterectomy 
For the purposes of the study, effective contraception is defined as the use of one of the 
following: 
For females: 
• Female surgical sterilization (e.g., bilateral tubal ligation), where applicable, 
according to local guidelines. 
• Established use of oral, intravaginal, or transdermal combined (estrogen and 
progestogen containing) hormonal methods of contraception associated with the 
inhibition of ovulation 
• Established use of oral, injected, or implanted hormonal methods of contraception  
• Placement of an intrauterine device or intrauterine hormone-releasing system 
• Barrier methods of contraception, where applicable according to local guidelines 
• Bilateral tubal occlusion 
• Sex with a male who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate) 
For males: 
• Vasectomy with negative semen analysis at follow-up. If documentation is not 
available, the participant must use contraception. 
• Condoms with spermicide, where applicable according to local guidelines 
• Sex with a woman who uses the methods described for females if she is of 
childbearing potential 
True abstinence, when this is consistent with the preferred and usual lifestyle of the participant, 
can be considered an acceptable method of contraception based on the evaluation of the 
Investigator who should also take into consideration the duration of the clinical study. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are 
not considered acceptable methods of contraception. 


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Pregnancy reporting is described in Section 11.4.1. 
11.6. 
Safety Responsibilities 
11.6.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
• Monitor and record all AEs, including SAEs, on the CRF regardless of the severity or 
relationship to study treatment. 
• Determine the seriousness, relationship, and severity of each event. 
• Determine the onset and resolution dates of each event. 
• Monitor and record all pregnancies in female participants and follow up on the 
outcome of all pregnancies. 
• Complete an SAE form for each SAE and fax or email it to the Sponsor within 
24 hours of the site staff becoming aware of the event or according to national law. 
• Pursue SAE follow-up information actively and persistently. Follow-up information 
must be reported to the Sponsor within 24 hours of the site staff becoming aware of 
new information or according to national law. 
• Ensure all AE and SAE reports are supported by documentation in the participants’ 
medical records. 
• Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. Record AE follow-up information, including resolution, on the CRF, as 
applicable. 
• Report SAEs to local ethics committees, as required by local law. 
11.6.2. 
The Sponsor  
The Sponsor’s responsibilities include the following: 
• Before a site can enroll any participants, the Medical Monitor is responsible for 
reviewing with site staff the definitions of AE and SAE, as well as the instructions for 
monitoring, recording, and reporting AEs and SAEs. 
• The Sponsor is to notify all appropriate regulatory authorities, central ethics 
committees, and Investigators of SAEs, as required by local law, within required time 
frames. 


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12. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
12.1. 
General Considerations 
The objectives of the study, the endpoints to be analyzed, and the statistical hypotheses are listed 
in Section 4.  
In Part B, the primary endpoint and a subset of the secondary endpoints will compare the 50/28-
mg Group to participants who received sham control in Study CS3B; these analyses will be 
performed using the 50/28-mg Group within this study and the data from the Study CS3B Sham 
Control Group. A matching algorithm will be used to select a group of participants who are 
similar to the 232SM203 higher dose group. The remaining secondary endpoints will compare 
the arms within Study 232SM203 Part B (50/28 mg Group versus 12 mg Group). This is detailed 
further in the following sections. 
12.2. 
Analysis Sets 
The ITT Set is defined as all participants who are randomized (or enrolled, as in Parts A and C) 
and receive nusinersen; participants will be analyzed in the treatment group to which they are 
randomized.  
The Safety Set is defined as all participants who receive nusinersen; participants will be analyzed 
in the treatment group based on what they actually received. 
 
 
The ITT, Safety, 
 Sets will be defined separately for each of the following populations: 
Part A, Part B infantile-onset, Part B later-onset, and Part C. 
A Per-Protocol Set will be defined for the Part B infantile-onset SMA population and will 
include the subset of the ITT Set who complete at least the initial 4 doses of drug/sham 
procedure, have a baseline assessment and at least a Day 183 efficacy assessment, and have no 
significant protocol deviations that would be expected to affect efficacy assessments. 
The Matched Sham Set will be defined for the analysis of the primary and secondary endpoints 
comparing to sham. This will comprise of sham participants identified by the matching algorithm 
and all 50/28 mg participants in the ITT Set. 
12.3. 
Definition of Baseline 
The baseline for all assessments except CHOP-INTEND is defined as the last nonmissing 
assessment prior to the first dose of study treatment. The baseline for CHOP-INTEND is defined 
as the average of the assessments taken during the Screening/Baseline period. 


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12.4. 
Methods of Analysis for Efficacy Endpoints 
Within Part B to control the overall Type 1 error at a 2 sided alpha level of 0.05, a sequential 
testing procedure ranked in the order of the primary and secondary endpoints will be utilized. In 
this procedure, the primary endpoint of change in CHOP-INTEND total score from baseline to 
Day 183 for the Study CS3B Sham Control Group compared to the 50/28-mg Group will be 
tested. If this is statistically significant, then the first secondary endpoint of the proportion of 
motor milestone responders at Day 183 for the Study CS3B Sham Control Group compared to 
the 50/28-mg Group will be tested and so forth in the order of the remaining endpoints as 
detailed in Table 8. Inferential conclusions about each successive analysis require statistical 
significance of the prior one. 
The statistical testing of the primary endpoint and a subset of secondary endpoints will use the 
Sham Control Group from Study CS3B. Within Study CS3B, there are 37 participants with an 
opportunity to attend the Day 183 visit.  
An algorithm will be used to select a group of sham participants from the pool of 37. The 
algorithm will attempt to match the largest number of participants and if unsuccessful, smaller 
pools will be selected and the minimum matched will be 20 participants.  
 
 
 
 
 
 
 
 
    
The main analysis for the primary endpoint and secondary endpoints comparing nusinersen 
50/28 mg to sham will be performed using the 50/28 mg participants in the ITT Set and the set of 
at least 20 sham participants selected via the matching algorithm. 
The main analyses for secondary endpoints comparing 50/28 mg to 12 mg will be performed 
using the ITT Set. 
  
 
 
12.4.1. 
Analysis of the Primary Endpoint in Part B 
CHOP-INTEND 
The primary efficacy endpoint of change from baseline to Day 183 in CHOP-INTEND total 
score will be analyzed using the joint-rank methodology to account for mortality [Berry 2013]. 
This joint-ranking procedure allows for a statistical test of the treatment effect on the 
CHOP-INTEND total score while accounting for loss of data due to deaths. In this analysis, a 
participant’s Combined Assessment of Function and Survival score will be calculated by 
comparing each participant to every other participant in the study, resulting in a score of +1 if the 


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outcome was better than the participant being compared, -1 if worse, and 0 if the same. The 
participant’s score will then be calculated by summing up their comparison to all the other 
participants in the study. For example, if 2 participants complete the study up to Day 183, their 
comparison score will be based on the change from baseline in CHOP-INTEND total score at 
Day 183. A participant who dies prior to the Day 183 visit will rank lower than any participant 
who completes the study up to Day 183. Two participants who both die prior to the Day 183 visit 
will be ranked based on the time of death with longer time to death corresponding to the higher 
rank. Hence, in general, these comparisons will result in participants who die being assigned the 
worst scores and ranked according to the time of death. Multiple imputation will be utilized to 
impute a missing Day 183 value of CHOP-INTEND for participants who discontinued for a 
reason other than death or where it was not assessed.  Participants who have an imputed or 
available Day 183 score will be ranked more favorably than participants who die. The ranked 
scores will be analyzed using an analysis of covariance model with treatment included as a fixed 
effect and adjusted for baseline CHOP-INTEND total score and disease duration. 
The trimmed-means method [Permutt and Li 2017] will be performed as a supplementary 
analysis. The analysis will be performed treating all dropouts and deaths as bad outcomes and 
trimming them out with other observed bad outcomes to form balanced comparison groups. In 
the trimmed mean approach, response scores are ranked from best to worst, and participants who 
died are considered as having worse outcomes than those who survived and completed the study. 
All response scores in the treatment group with high mortality/dropout rate will be retained. In 
the treatment group with the higher survival/completion rate, only the same proportion (as the 
survival rate in the high-mortality group) of the top response scores will be retained. The 
trimmed-mean difference can be interpreted as the difference between the top fraction of 
responses between the 2 groups. An analysis of covariance model will be fitted to the trimmed 
sample, with treatment as a factor and adjusting for covariates of baseline score and disease 
duration to obtain the adjusted mean difference. The pvalue associated with the adjusted-
difference test statistic will be calculated using a reference distribution generated by a 
rerandomization procedure. 
12.4.2. 
Analysis of the Secondary Endpoints in Part B 
HINE Motor Milestone Responders 
The difference in the proportion of responders between treatment groups will be compared using 
logistic regression with the number of motor milestones at Baseline, age at symptom onset, and 
disease duration at Screening as covariates. Should the number of responders be less than 5 in 
either group, Fisher’s exact test will be used instead. If Fisher’s exact test is used, the 
unconditional confidence interval for the difference in response rates will be provided [Santner 
and Snell 1980]. 
The proportion of HINE Section 2 motor milestone responders will be assessed at Day 183 for 
50/28 mg versus sham. 


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Total HINE Section 2 – Motor Milestones 
Change from baseline to Day 183 for 50/28 mg versus sham and change from baseline to Day 
302 for 50/28 mg versus 12 mg will be analyzed using the same methodology as described for 
the primary endpoint. 
Plasma Neurofilament  
For plasma NF-L, if the baseline assessment is missing, then the first available assessment post 
dose within Day 2 will be used instead as baseline. 
Values that are BLQ will be set to half of the diluted LLOQ. 
Change in plasma NF-L from (ratio to) baseline to Day 183 will be analyzed for 50/28 mg versus 
sham, and change in plasma NF-L from baseline to Day 29 will be analyzed for 50/28 mg versus 
12 mg using the same method as for the primary endpoint. 
CHOP-INTEND 
Change in CHOP-INTEND from baseline to Day 302 will be analyzed for 50/28 mg versus 12 
mg using the same methodology as described for the primary endpoint. 
Time to Death or Permanent Ventilation 
Permanent ventilation is defined as tracheostomy or ≥ 16 hours of ventilation/day continuously 
for > 21 days in the absence of an acute reversible event (Appendix A). 
An independent EAC will determine, in a blinded fashion, the date at which a participant is 
considered to have met the definition of an event. The procedures for reviewing and adjudicating 
events will be described in a charter. 
The time to death or permanent ventilation (tracheostomy or ≥ 16 hours of ventilation/day 
continuously for > 21 days in the absence of an acute reversible event) and time to death (overall 
survival) will be analyzed using the log-rank test stratified by disease duration at Screening. The 
null hypothesis is that the comparison groups (ie., sham and 50/28 mg dose) have the same 
“survival” function. Participants who do not meet the endpoint definition will be censored at the 
last occasion the participant was seen (either in-person visit or by telephone contact), irrespective 
of whether the participant has completed the full course of treatment and whether the participant 
has completed the study or permanently withdrawn. The exception is time to death or permanent 
ventilation in cases in which a participant has begun a ventilator diary, in which case the latest 
entry in the diary will be used as the date of censoring. The proportion of participants meeting an 
event at timepoints of interest will be estimated using the Kaplan-Meier method. 
The analysis will also be perfomed for the comparison of sham versus 50/28 mg doses and the 
comparison of 12 mg versus 50/28 mg doses. 


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Time to Death 
Overall survival will be analyzed in the same way as time to death or permanent ventilation. 
Table 8 summarizes the planned statistical testing. 
Table 8: 
Primary and Secondary Endpoints 
Rank Endpoint and Comparison 
Analysis Method 
Comparison of higher dose (50/28 
mg) to 
1 
Change in CHOP-INTEND 
from baseline to Day 183 
total score 
Joint rank using MI 
CS3B Matched Sham Control  
2 
Proportion of HINE 
Section 2 motor milestone 
responders at Day 183 
Logistic regression or 
Fisher’s Exact Test 
CS3B Matched Sham Control 
3 
Change from baseline to 
Day 183 in HINE Section 2 
total score 
Joint rank using MI 
CS3B Matched Sham Control 
4 
Change from baseline to 
Day 183 in plasma NF-L 
from baseline to Day 183 
Joint rank using MI 
CS3B Matched Sham Control 
5 
Change from baseline to 
Day 302 in CHOP-INTEND 
total score 
Joint rank using MI 
232SM203 12 mg Control 
6 
Change from baseline to 
Day 302 in HINE Section 2 
Motor Milestones total score  
Joint rank using MI 
232SM203 12 mg Control 
7 
Change from baseline to 
Day 29 in plasma NF-L  
Joint rank using MI 
232SM203 12 mg Control 
8 
Time to death or permanent 
ventilation 
Log-rank test stratified 
by disease duration at 
Screening 
CS3B Matched Sham Control 
9 
Time to death 
Log-rank test stratified 
by disease duration at 
Screening 
CS3B Matched Sham Control 
10 
Time to death or permanent 
ventilation 
Log-rank test stratified 
by disease duration at 
Screening 
232SM203 12 mg Control 
11 
Time to death 
Log-rank test stratified 
by disease duration at 
Screening 
232SM203 12 mg Control 
 


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12.4.3. 
Analysis of the Remaining Endpoints 
For Parts A, B, and C, summary statistics will be presented to characterize the efficacy data over 
time. For continuous endpoints, the summary statistics will generally include the number of 
participants with data, mean, standard deviation, median, minimum, and maximum. For 
categorical endpoints, the summary statistics will generally include the number of participants 
with data and the percentage of those with data in each category. Frequency distributions will be 
presented as appropriate. The change from baseline to each visit will be summarized. The 
number of hospitalizations will be analyzed using the rate at which they occur, and the time on a 
ventilator will be prorated based on the time on study. Further details will be provided in the 
Statistical Analysis Plan. 
 
 
 
 
 
 
 
 
 
12.6. 
Methods of Analysis for Pharmacodynamic Endpoints 
The analysis population for PD will include all participants with available PD data. 
Plasma and CSF NF-L levels will be summarized using available results. The baseline 
concentrations and the actual score and change (including absolute and percentage) will be 
presented by visit. In addition, the correlation between the baseline level and measurements, 
including weight, disease duration, and age at the first dose, will be presented. 
 
 
 
 
 
For Part B, plasma NF-L and CSF NF-L levels will be analyzed as secondary endpoints 
(Section 12.4.2).   
12.7. 
Methods of Analysis for Biomarkers/Pharmacogenetics 
Plasma and CSF samples (collected as specified in Section 1.3) may be assayed for NF-L and 
data will be summarized using descriptive statistics and will be presented by dose group. 


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Sampling for this analysis will be approved at the discretion of each site’s ethics committee. If a 
site’s ethics committee does not approve the sampling for the analysis, this section will not be 
applicable to that site. 
12.8. 
Methods of Analysis for Safety Endpoints 
The analysis of safety will be performed separately for the Safety Set for Part A, Part B 
infantile-onset, Part B later-onset, and Part C. In addition, the Part B participants will be 
presented by treatment group. The duration of treatment and the amount of study treatment will 
be summarized. 
12.8.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities. 
The incidence of treatment-emergent AEs and SAEs will be presented for Parts A, B, and C. All 
AEs will be analyzed based on the principle of treatment emergence. An AE will be regarded as 
treatment-emergent if it was present prior to receiving the first dose of nusinersen and 
subsequently worsened in severity or was not present prior to receiving the first dose of 
nusinersen but subsequently appeared. 
The number and percentage of participants who experienced SAEs, AEs, and discontinuation 
from nusinersen due to an AE will be summarized. Additionally, AEs will be summarized by 
severity and relationship to nusinersen.  
A participant having the same AE more than once will be counted only once in the incidence for 
that event. The occurrence of the AE with the greatest severity will be used in the calculation of 
incidence by severity; the occurrence of the AE with the strongest relationship to nusinersen will 
be used in the calculation of incidence by relationship to nusinersen. 
AEs will be further tabulated by subgroup (e.g., age, race, sex, administration status of 
nusinersen [90-day intervals], and SMA history).  
12.8.2. 
Clinical Laboratory Results 
Clinical laboratory evaluations, including coagulation, hematology, blood chemistry, and 
urinalysis parameters, will be summarized using shift tables, presenting changes relative to each 
parameter’s normal range. Summary statistics for actual values and changes from baseline will 
also be presented. 


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12.8.3. 
Vital Signs 
The analysis of vital signs will focus on clinically significant abnormalities. Changes from 
baseline in vital signs and ECGs will be summarized. 
12.8.4. 
Neurological Examinations 
Changes from baseline in neurological examinations will be summarized. 
 
 
 
 
 
 
12.10. 
Interim Analyses 
Interim and final analyses for Parts A and C may occur prior to completion of Part B of the 
study. 
An interim analysis of the primary endpoint in Part B may be performed when all participants 
with infantile-onset SMA have had the opportunity to reach the Day 183 visit. 
Full details of the analyses and controlled access to the unblinded data will be documented in the 
Statistical Analysis Plan, the unblinding plan, and the IDMC charter. 
12.11. 
Sample Size Considerations 
A total sample size of approximately 145 participants is planned for this study (Table 9). The 
justification for the sample size for the infantile-onset SMA population in Part B is detailed as 
follows. The sample sizes for the remaining groups are not based on statistical considerations.  
A minimum of 6 participants with later-onset SMA will be enrolled in Part A to characterize the 
safety, tolerability, and 
 of a 28/28-mg dose of nusinersen (28-mg loading dose; 28mg 
maintenance dose). A total of 24 participants with later-onset SMA will be randomized to the 
Control Group and 50/28-mg Group in Part B in a ratio of 1:2; this will allow the exploration of 
the safety, tolerability, 
, and efficacy of the 50/28 mg dose of nusinersen in this 
population. A total of up to approximately 40 participants will be enrolled in Part C (i.e., up to 
approximately 20 participants each in Cohorts 1 and 2) to characterize the safety, tolerability, 
and 
 of a 50/28 mg dose of nusinersen in participants transitioning from maintenance 
dosing at the currently approved dose of 12 mg of nusinersen. 


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Table 9: 
Number of Participants in Each Study Part, by Symptom Onset 
Part/Dose 
Number of Participants 
Later 
Onset 
Infantile 
Onset 
Total 
Part A (28-mg loading dose; 28-mg maintenance dose) 
6 
 
6 
Part B 
 
 
 
Control Group (12-mg loading dose; 12-mg 
maintenance dose) 
8 
25 
33 
50/28-mg Group (50-mg loading dose; 28-mg 
maintenance dose) 
16 
50 
66 
Part C (50-mg loading dose; 28-mg maintenance dose) 
 
 
401 
Total 
 
 
1451 
1 The sample size is an estimate that may be up to approximately the stated number. 
For the infantile-onset SMA population in Part B, a sample size of approximately 50 participants 
in the 50/28-mg Group and at least N= 20 sham participants from CS3B will provide at least 
approximately 99% power for the primary endpoint to detect an improvement of 24 points on 
CHOP-INTEND and 23% survival rate benefit (compared to that observed in Study CS3B 
participants receiving sham control) at Day 183 based on the joint-rank test at a 2 -sided 
significance level of 0.05. This power calculation is based on simulations using data generated 
from a joint model of survival and functional change. The model used a difference of 24 points 
for the Day 183 change from baseline in CHOP-INTEND total score (50/28-mg Group – 
Study CS3B Sham Control Group) and a population standard deviation of 8.8 for change from 
baseline.  
A secondary endpoint for this study is that the efficacy in the 50/28 mg Group compared to the 
12 mg Control Group will be different based on the change from baseline to Day 302 in CHOP-
INTEND.  
For Part B, the randomization will be stratified as follows: 
• For participants with infantile-onset SMA by disease duration: ≤ 12 weeks and 
> 12 weeks (time from age at symptom onset to age at informed consent) 
• For participants with later-onset SMA by age at informed consent: < 6 years and 
≥ 6 years 
For Cohort 1 of Part C, an attempt will be made to enroll at least 8 but no more than 
12 participants ≥ 18 years of age (participants ≥ 18 years of age must be ambulatory). For 
Cohort 2 of Part C, all participants must be ≥ 18 years of age and can be either ambulatory or 
nonambulatory. 


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13. 
ETHICAL AND REGULATORY REQUIREMENTS 
The Sponsor, any contracted third party, and the Investigator must comply with all instructions, 
regulations, and agreements in this protocol and applicable ICH and GCP guidelines and conduct 
the study according to local regulations. 
The Investigators are responsible for demonstrating timely oversight of all clinical trial data from 
their site, including data external to the electronic data capture system, such as laboratory, 
imaging, and electronic clinical outcomes assessment data. Investigators must approve all their 
data on completed CRFs by signing electronically, at the participant, visit, or casebook level, at 
any time prior to an interim lock or database lock, as well as before any subsequent relock. The 
electronic data capture system does not prohibit Investigator approval or signing in any way. 
The Investigator may delegate responsibilities for study-related tasks, where appropriate, to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines. The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated. 
13.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
13.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study. The Sponsor or designee will submit documents on 
behalf of the study sites in countries other than the US. 
If the Investigator makes any changes to the ICF, the Sponsor must approve the changes before 
the ICF is submitted to the ethics committee. A copy of the approved ICF must be provided to 
the Sponsor. After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and the Sponsor. 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
The Sponsor must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study. Protocol 
amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. 


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At the completion or termination of the study, where required, the study site must submit a 
close-out letter to the ethics committee and the Sponsor. 
13.3. 
Changes to the Final Protocol 
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law. Protocol modifications that affect participant safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study. If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, the Sponsor may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a participant. In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 13.4). 
13.4. 
Informed Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, informed consent with the approved ICF must be obtained. 
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the participant must be explained to the participant and/or 
the participant’s legally authorized representative. The participant and/or the participant’s legally 
authorized representative must be given sufficient time to consider whether to participate in the 
study. 
In addition, participants who have the capacity should provide their assent to participate in the 
study. The level of information provided to participants should match their level of 
understanding, as determined by the Investigator and in accordance with applicable regulations 
and guidelines. 
A copy of the signed and dated ICF and assent must be given to the participant and/or the 
participant’s legally authorized representative. The original signed and dated ICF will be retained 
with the study records. Local regulations must be complied with regarding the final disposition 
of the original and copies of the signed and dated ICFs. 
Confirmation of informed consent and assent must also be documented in the participant’s 
medical record. 
When additional information that may affect participants’ willingness to continue in the study 
becomes available, the Investigators will be notified in a timely manner, according to all local 
and applicable law. An updated ICF may be required. 


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13.5. 
Participant Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by applicable national and local privacy regulations 
(e.g., Protected Health Information authorization in North America). 
During the study, participants’ race, ethnicity, and full date of birth will be collected. These data 
will be used in the analysis of the safety and/or 
 of the study treatment. SMA is caused 
by the loss of SMN due to a homozygous deletion or mutation or a compound heterozygous 
mutation in the SMN1 on chromosome 5q11-q13. Thus, patients with SMA are completely 
dependent on the amount of SMN produced by the SMN2. Genetic modifiers, such as the number 
of copies of the SMN2, 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 participants 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 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 participant will not be identified by 
name in CRFs, study-related forms, study reports, or any related publications. The Sponsor, its 
partners and designees, ethics committees, and various government health agencies may inspect 
the records of this study. Every effort will be made to keep the participant’s personal medical 
data confidential. 
13.6. 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws. 
13.7. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor) with the participant before the participant makes a decision to participate in the study. 
13.8. 
Study Report Signatory 
The Sponsor will designate one or more of the participating Investigators as a signatory for the 
study report. This determination will be made by several factors, including but not limited to, the 
Investigator’s experience and reputation in the studied indication; the Investigator’s contribution 
to the study in terms of design, management, and/or participant enrollment; or other factors 
determined to be relevant by the Sponsor. 


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13.9. 
Registration of Study and Disclosure of Study Results 
The Sponsor will register the study and post study results, regardless of outcome, on a publicly 
accessible website in accordance with the applicable laws and regulations. 
The Sponsor also will notify, when required, the regulatory authorities and ethics committees 
about the completion or termination of this study and send a copy of the study synopsis in 
accordance with necessary timelines. 
13.10. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations. Prior to proceeding with destruction of records, the Investigator must notify the 
Sponsor in writing and receive written authorization from the Sponsor to destroy study records. 
In addition, the Investigator must notify the Sponsor of any changes in the archival 
arrangements, including but not limited to archival at an offsite facility or transfer of ownership 
if the Investigator leaves the site. 


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14. 
KEY ROLES AND STUDY GOVERNANCE COMMITTEES 
14.1. 
Vendors 
Biogen will ensure oversight of any study-related duties and functions carried out on its behalf 
and will specify in writing all duties and functions that are transferred.  
14.1.1. 
Contract Research Organization 
A CRO will be responsible for the administrative aspects of the study, including but not limited 
to study initiation, management of SAE reports, monitoring, and data management. 
14.1.2. 
Interactive Response Technology 
IRT will be used in this study. Before participants are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system. 
14.1.3. 
Electronic Data Capture 
Participant information will be captured and managed by study sites on electronic CRFs by a 
web-based electronic data capture tool configured by the CRO and hosted by Medidata. 
14.1.4. 
Central Laboratories for Laboratory Assessments 
A central laboratory will be selected by the Sponsor to analyze hematology, blood chemistry, 
urinalysis, and CSF samples (except for local analysis of CSF total protein, cell count, and 
glucose) collected for this study. Analysis of urine total protein will be conducted by local 
laboratories; however, if local analysis is not possible without a 24-hour urine collection, then 
samples will be analyzed by a central laboratory. Analysis of coagulation, pregnancy tests, and 
CSF total protein/cell count/glucose will be conducted by local laboratories. 
, 
, and NF-L samples will be analyzed at a laboratory selected by the Sponsor 
(Appendix B). 
When the safety laboratory sample analysis is at risk due to logistical difficulties or issues with 
access to the central laboratory (e.g., due to COVID-19–related disruptions or humanitarian 
emergencies), these samples may be analyzed by the local laboratory. Any use of a local 
laboratory under these circumstances must be approved by the Sponsor prior to being 
implemented.  
For all participants, a blood sample will be collected during the study to evaluate SMN1 status 
(copy number, deletion, and mutation where necessary to confirm 5q SMA) and SMN2 copy 
number by the central laboratory. For participants without acceptable documentation of these 
genetic testing results before Screening, a blood sample must be collected during the Screening 
period to determine eligibility (preferably for analysis by the central laboratory but may be 
determined by local laboratory genetic testing, if needed). For participants with documentation of 
these genetic testing results before Screening or whose sample was analyzed locally during the 


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Screening period (with documentation of these genetic testing results), a blood sample will be 
collected (preferably at Screening but must be collected by the first maintenance dosing visit) for 
confirmatory testing through the central laboratory. 
Sample analysis for participants from China will be performed within China. 
14.2. 
Study Committees 
14.2.1. 
Endpoint Adjudication Committee 
Time to death or permanent ventilation will be determined in a blinded fashion by a central, 
independent EAC. Procedures for reviewing and adjudicating events are described in the charter 
that governs the operation of the EAC. 
14.2.2. 
Independent Data Monitoring Committee  
An IDMC will be formed to review ongoing safety and tolerability data. An IDMC review of 
participant data through Day 64 of Part A will occur prior to enrollment of participants into 
Part B. An IDMC review of unblinded data from the first 15 participants in Part B (Section 5.1) 
will occur prior to dosing of the remaining participants in Part B and dosing in Part C of the 
study. Note that the IDMC can recommend to stop the study based on the safety findings. 
An IDMC charter will provide full guidance on the function and practices to be followed by the 
IDMC. 


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15. 
ADMINISTRATIVE PROCEDURES 
15.1. 
Study Site Initiation 
The Investigator must not screen any participants prior to the Sponsor completing a study 
initiation visit. This initiation visit with the Investigator and other site staff, as appropriate, will 
include a detailed review of the protocol, study procedures, and study responsibilities. 
15.2. 
Quality Control and Quality Assurance 
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate. The Investigator is responsible for endorsing 
all CRF data prior to any interim or final database lock. 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits or inspections. The Investigator will 
be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested. 
15.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the participants’ medical histories. Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail). The 
Investigator should maintain a record of the location(s) of essential documents. 
The Site Monitor will visit the study site at regular intervals during the study and after the study 
has completed, as appropriate, or may perform monitoring activities remotely (where permitted 
by local regulations) only during the COVID-19 pandemic where on-site monitoring is not 
allowed per local/regional restrictions. A clinical site monitoring plan will detail who performs 
the monitoring, how often, and the extent of the review. It also will provide the monitoring 
strategy, with emphasis on participant safety, data integrity, and critical data and processes. 
CRFs, supporting documentation, and essential documentation related to the study will be 
reviewed, and any discrepancies or omissions will be resolved. Documentation of results will be 
provided to the Sponsor in a timely fashion to allow follow-up and verification of compliance 
with the monitoring plan. Remote evaluation of data may also be conducted and reported as 
defined in the monitoring plan. 
Monitoring must be conducted according to the applicable ICH and GCP guidelines to ensure the 
protection of participants’ rights and well-being, protocol adherence, quality of data (accurate, 
complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities. 


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15.4. 
Travel Policy 
Sites must review the study travel policy prior to screening any study participants. Consultation 
and/or approval may be required from the Medical Monitor depending on the study participant’s 
place of residence and travel distance to the site. Please refer to the Study Travel Policy for 
specific details and guidelines. 
15.5. 
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, the Investigator, and Biogen. 
15.6. 
Publications 
Details are included in the clinical trial agreement for this study. 
 


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16. 
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. 
 
 
 
Berry JD, Miller R, Moore DH, et al. The Combined Assessment of Function and Survival 
(CAFS): a new endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal 
Degener. 2013;14(3):162-8. Epub 2013/01/17. 
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. 
De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular 
atrophy. Neuromuscul Disord. 2016;26(11):754-759. Epub 2016/10/05. 
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. 
Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: 
Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ 
systems; and ethics. Neuromuscul Disord. 2017 Epub 2017/11/23. 
Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: 
Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ 
systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207. Epub 2017/11/23. 
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. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. 
Department of Health, Education, and Welfare; 1976. 


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126 
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. 
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. 
 
 
 
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. 
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. 
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. 
 
 
Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: 
Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. 
Neuromuscul Disord. 2018;28(2):103-115. Epub 2017/11/23. 
 
 
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. 
Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat. 2017;16(1):20-
28. Epub 2016/08/15. 


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127 
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. 
Santner TJ, Snell MK. Small-Sample Confidence Intervals for p 1 - p 2 and p 1 /p 2 in 2 × 2 
Contingency Tables. J Am Statist Assoc. 1980;75:386-94. 
 
 
 
 
 
 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
inventory. Med Care. 1999;37(2):126-39. 
WHO Multicentre Growth Reference Study Group. Assessment of differences in linear growth 
among populations in the WHO Multicentre Growth Reference Study. Acta Paediatr Suppl. 
2006;450:56-65. 
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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17. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “Escalating Dose and Randomized, Controlled Study of 
Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy,” and agree to conduct the 
study according to the protocol and the applicable ICH guidelines and GCP regulations, and to 
inform all who assist me in the conduct of this study of their responsibilities and obligations. 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 
 


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18. 
APPENDICES 


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APPENDIX A. PERMANENT VENTILATION DEFINITION CRITERIA: 
ACUTE REVERSIBLE EVENT 
Purpose: Acute, intercurrent events may result in transient utilization of increased respiratory 
support for participants with spinal muscular atrophy (SMA) in this study. Such events may not 
reflect irreversible SMA disease progression and may complicate the ability to detect the effects 
of nusinersen on SMA disease progression. 
A secondary endpoint is defined as the time to death or permanent ventilation (tracheostomy or 
≥ 16 hours of ventilation/day continuously for > 21 days in the absence of an acute reversible 
event). 
The purpose of this appendix is to define an acute reversible event and to indicate how this 
prespecified definition will be used in this study. 
Any one of the following that occur between 7 days before and 7 days after the onset of 
threshold-level respiratory support (≥ 16 hours/day) meet the definition of an acute reversible 
event: 
1. Fever ≥ 102°F/38.9°C (tympanic, rectal, axillary, skin, sublingual) 
2. Infection 
• Blood, sputum, throat, or cerebrospinal fluid (CSF) culture positive × 2 for virus, 
bacteria, or fungus 
• Blood, throat, sputum, or CSF viral polymerase chain reaction positive 
• Blood, throat, sputum, or CSF for infectious antigen diagnostic (e.g., streptococcus+ 
or hepatitis B surface antigen positive) 
• Blood, throat, sputum, or CSF positive for direct microscopic visualization 
(e.g., bronchoalveolar lavage or Gram stain revealing the presence of bacteria by 
tissue biopsy) 
3. Surgical procedure 
• Operation (i.e., gastrostomy/jejunostomy tube or an orthopedic procedure) 
• Any procedure in which regional or general anesthesia is administered 
If any of the above is verified by appropriate source documents (e.g., emergency room visit 
summary, outpatient clinic note, inpatient hospital summary, operative report, etc.), the endpoint 
is NOT met until the participant requires threshold-level ventilation (≥ 16 hours/day) 
continuously for > 21 days beginning 14 days after the acute reversible event. The rationale is 
that, in the context of an acute reversible event, the SMA participant is given a “grace period” of 


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14 days to clear the event or recover from surgery/anesthesia. Once the grace period has expired, 
if the participant requires threshold-level ventilation for > 21 consecutive days, this respiratory 
dependence is likely to be due to SMA disease progression, and the endpoint is met. 


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APPENDIX B. LABORATORY ANALYTES 
Clinical Safety Assessments (Minimum Requirements) 
Other Assessments 
Blood Chemistry1 
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 
GGT 
Urinalysis1 
Specific gravity 
pH 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Red blood cells 
White blood cells 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Hematology1 
Red blood cells 
Hemoglobin 
Hematocrit 
Platelets 
WBCs 
WBC differential (% and 
absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
 
Pharmacodynamics 
NF-L 
 
 
 
The following are to be assessed 
by local laboratory only: 
Urine total protein (quantitative)2  
Coagulation (aPTT, PT, and INR) 
CSF Local Laboratory Sample 
Cell count 
Total protein 
Glucose  
Pregnancy 
Urine hCG 
Serum pregnancy test 
; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CK = creatine kinase; COVID-19 = coronavirus disease 2019; 
CPK = creatine phosphokinase; CSF = cerebrospinal fluid; GGT = gamma glutamyl transferase; hCG = human 
chorionic gonadotropin; INR = international normalized ratio; 
 NF-L =  neurofilament 
light chain; PT = prothrombin time; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic 
pyruvic transaminase; WBC = white blood cell 
1 Blood chemistry, hematology, and urinalysis samples will be analyzed by a central laboratory. For the Screening 
visit only, a local laboratory may be used instead for analysis if needed for the timely treatment of the participant 
at the discretion of the Investigator. When the safety laboratory sample analysis is at risk due to logistical 
difficulties or issues with access to the central laboratory (e.g., due to COVID-19–related disruptions or 
humanitarian emergencies), these samples may be analyzed by the local laboratory. Any use of a local laboratory 
under these circumstances must be approved by the Sponsor prior to being implemented.  


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2 Quantitative urine total protein should be prioritized if there is not enough urine sample for all tests. For urinary 
protein concentration > 0.2 g/L, repeat testing and further evaluation should be considered. Urine total protein will 
be analyzed by local laboratory; however, if local analysis is not possible without a 24-hour urine collection, then 
samples will be analyzed by a central laboratory. 








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higher dose to matched sham 
control) 
• Time to death (overall survival) 
(comparison of higher dose to 
matched sham control) 
• Time to death or permanent 
ventilation (tracheostomy or 
≥ 16 hours of ventilation/day 
continuously for > 21 days in the 
absence of an acute reversible 
event [Appendix A]) (comparison 
of higher dose to 12 mg dose) 
• Time to death (overall survival) 
(comparison of higher dose to 12 
mg dose) 
To examine the clinical efficacy of 
nusinersen administered intrathecally at 
higher doses compared to the currently 
approved 12 mg dose in participants with 
SMA 
Later-Onset SMA 
• Change from baseline in HFMSE 
score 
• Change from baseline in RULM 
score 
• Total number of new WHO motor 
milestones 
• Change from baseline in ACEND 
• Change from baseline in PedsQL  
• Change from baseline in CSF 
concentration of NF-L 
• Change from baseline in plasma 
concentration of NF-L 
… 
To examine the effect of nusinersen 
administered intrathecally at higher doses 
Infantile-Onset and Later-Onset SMA 
• Number and duration of 
hospitalizations 




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3. The hazard ratio (50/28 mg Group over Study CS3B Sham Control Group) for time to 
death is different from 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
Section 12.4, Methods of Analysis for Efficacy Endpoints 
Now reads: 
Within Part B to control the overall Type 1 error at a 2- sided alpha level of 0.05, a sequential 
testing procedure ranked in the order of the primary, and secondary, and then exploratory 
hypotheses endpoints will be utilized. In this procedure, the primary hypothesisendpoint of 
mean change in CHOP-INTEND total score from baseline to Day 183 for the Study CS3B Sham 
Control Group compared to the 50/28-mg Group will be tested once, when all of the infantile-
onset participants have reached Day 183. If this is statistically significant, no further statistical 
testing will be performed until all infantile-onset participants have reached Day 302. Thenthen 
the first secondary endpoint of the proportion of motor milestone responders at Day 302183 for 
the Study CS3B Sham Control Group compared to the 50/28-mg Group will be tested and so 
forth in the order of the remaining endpoints as detailed in Table 8. Inferential conclusions about 
each successive analysis require statistical significance of the prior one. 
Use of Historical Data 
The statistical testing of the primary endpoint and a subset of secondary hypotheses endpoints 
will use the Sham Control Group from Study CS3B. Within Study CS3B, there are 41 
participants in the ITT set, 37 participants with an opportunity to attend the Day 183 visit, and 
28 participants with an opportunity to attend the Day 302 visit. No prospective formal 


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assessment of the similarity in baseline characteristics is planned for these analyses between 
Study CS3B and the present study, since the natural history of infantile onset SMA is well 
established, the 12 mg dose has been demonstrated to be highly efficacious versus sham, and it is 
reasonable to expect a similar or better result for a 50 mg dose. 
 
 
  
 
 
 
 
 
  
 
    
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
  
 
 
The main analysis for the primary endpoint and secondary endpoints comparing 
nusinersen 50/28 mg to sham will be performed using the 50/28 mg participants in the ITT 
Set and the set of at least 20 sham participants selected via the matching algorithm. 


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The main analyses for secondary endpoints comparing 50/28 mg to 12 mg will be 
performed using the ITT Set. 
 
 
 
… 
Table 8: 
Primary and Secondary Hypotheses  Comparing the 50/28 mg Group to 
Study CS3B Sham Control Endpoints 
Rank Endpoint and Comparison 
Analysis Method 
Population Comparison of higher dose 
(50/28 mg) to  
1 
Change in CHOP-INTEND 
from baseline to Day 183 
total score 
Joint rank using 
MI 
50/28 mg ITT population versus 
Study CS3B Matched Sham Control 
Day 183 efficacy set 
2 
Proportion of HINE 
Section 2 motor milestone 
responders at Day 302183 
Logistic 
regression or 
Fisher’s Exact 
Test 
50/28 mg ITT population versus 
Study CS3B Matched Sham Control 
Day 302 efficacy set 
3 
Change from baseline to 
Day 183 in HINE Section 2 
total score 
Joint rank using 
MI 
CS3B Matched Sham Control 
4 
Change from baseline to 
Day 183 in plasma NF-L 
from baseline to Day 183 
Joint rank using 
MI 
CS3B Matched Sham Control 
5 
Change from baseline to 
Day 302 in CHOP-
INTEND total score 
Joint rank using 
MI 
232SM203 12 mg Control 
6 
Change from baseline to 
Day 302 in HINE Section 2 
Motor Milestones total 
score  
Joint rank using 
MI 
232SM203 12 mg Control 
7 
Change from baseline to 
Day 29 in plasma NF-L  
Joint rank using 
MI 
232SM203 12 mg Control 
83 
Time to death or permanent 
ventilation 
Log-rank test 
stratified by 
disease duration 
at Screening 
50/28 mg ITT population (additional 
follow up from extension study) versus 
Study CS3B Matched Sham Control ITT 
Set 
94 
Time to death 
Log-rank test 
stratified by 
disease duration 
at Screening 
50/28 mg ITT population (additional 
follow up from extension study) versus 
Study CS3B Matched Sham Control ITT 
Set 


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Rank Endpoint and Comparison 
Analysis Method 
Population Comparison of higher dose 
(50/28 mg) to  
10 
Time to death or 
permanent ventilation 
Log-rank test 
stratified by 
disease duration 
at Screening 
232SM203 12 mg Control 
11 
Time to death 
Log-rank test 
stratified by 
disease duration 
at Screening 
232SM203 12 mg Control 
 
 
 
 
Rationale:  
CS3B Matched Sham Control Group: 
For analysis of the primary and secondary endpoints comparing nusinersen 50/28 mg versus 
sham in infantile-onset SMA, the control group was updated from all 37 sham participants that 


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completed a Day 183 visit in Study CS3B to a Matched Sham Group of 20 or more participants 
selected from the CS3B sham arm using a matching algorithm. Compared to using all CS3B 
sham participants, the matching algorithm will minimize the potential bias caused by the time 
gap of when Studies 232SM203 and CS3B were conducted and provide a robust analysis in the 
context of well-characterized natural history of untreated SMA. Analysis of the remaining 
secondary endpoints comparing nusinersen 50/28 mg versus 12 mg will utilize only the 
participants within 232SM203 Part B. 
Comparisons of nusinersen 50/28 mg versus 12 mg: 
Given the clinical importance of understanding the relative benefit of the higher dose (50/28 mg) 
versus standard dose (12 mg) nusinersen regimens, formal comparisons between these regimens 
 to secondary analyses. The methods of analysis in the protocol 
describe the updated sequential testing order and comparison populations of the efficacy 
endpoints for participants with infantile-onset SMA in Part B. The primary and secondary 
endpoints will be tested sequentially with a 2-sided alpha of 0.05. Statistical significance needs 
to be declared for an endpoint before testing the next endpoint in the sequence.  
Neurofilament biomarker: 
Neurofilaments are a nonspecific marker of axonal injury and neurodegeneration. Across 
neurodegenerative diseases, including SMA, higher levels of NF have been found to be 
prognostic for faster disease progression. As such, a treatment-driven reduction in NF levels 
provides objective evidence of a slowing of the neurodegenerative process that is central to the 
underlying pathophysiology of SMA. As such, NF levels will be measured as a secondary 
measure of treatment response in participants with infantile-onset SMA and later-onset SMA. 
The NF biomarker was changed from 
 to NF-L due to recent technical issues with the 
. Internally, assays for 
 NF-L have been fully qualified for 
SMA research, and samples collected from other Biogen studies on nusinersen have been 
analyzed for both NF proteins. 
Proportion of HINE Section 2 responders (higher dose vs. sham): 
The secondary endpoint of proportion of HINE Section 2 responders (higher dose vs. sham) was 
changed to the same timepoint as the primary endpoint (Day 183) to allow use of the same set of 
matched sham participants/data for the primary endpoint and to increase the likelihood of closest 
match given the greater sample size of CS3B sham participants from which to match. Follow-up 
to Day 183 is considered sufficient to see a clear separation for higher dose versus sham control. 
CHOP-INTEND (higher dose vs. 12 mg): 
The endpoint of change from baseline in CHOP-INTEND (higher dose vs. 12 mg), 
 
 to a secondary endpoint, was changed to a timepoint of 
Day 302 to provide a greater opportunity to show a difference between the higher dose compared 
to the approved, highly efficacious 12 mg dose. 


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These changes also affect Section 1.1, Synopsis; Section 9.3, Pharmacodynamic Assessments; 
Section 12.1, General Considerations; Section 12.2, Analysis Sets; Section 12.4.2, Analysis of 
the Secondary Endpoints in Part B; Section 12.6, Methods of Analysis for Pharmacodynamic 
Endpoints; Section 12.7, Methods of Analysis for Biomarkers/Pharmacogenetics; Section 12.11, 
Sample Size Considerations; Section 14.1.4, Central Laboratories for Laboratory Assessments; 
and Appendix B, Laboratory Analytes. 
 


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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. 
Section 1.1, Synopsis 
The synopsis was revised to reflect changes made throughout the protocol. 
 
Section 9.1.15, Standard of Care 
Change: A standard of care assessment was added to the clinical efficacy assessments. 
Now reads: 
All participants are expected to follow standard of care as referenced in Section 6.2 
throughout the entire duration of the study. Investigators will document standard of care 
information for Part B participants at Screening and Day 302. 
Rationale: A new section was added for a standard of care assessment to reflect the 
implementation of a Standard of Care CRF. The CRF was added to further understand access to 
health care specialists in the many countries that enrolled. 
This change also affects Section 1.3, Schedule of Activities. 
 
Section 10.2, Laboratory Safety Assessments 
Change: Text was added to clarify whether urine total protein analysis will be performed by the 
local or central laboratory. 
Now reads: 
… 
• Urinalysis: urine total protein (by local laboratory except if local analysis is not 
possible without a 24-hour urine collection, in which case samples will be 
analyzed by a central laboratory); specific gravity, pH, protein, glucose, ketones, 
bilirubin, blood, red blood cells, white blood cells, epithelial cells, bacteria, casts, and 
crystals 
… 


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Rationale: As some sites (e.g., sites in China) are unable to perform local urine total protein 
analysis without collecting urine over a 24-hour period, accommodations have been set up for 
central laboratory analysis for these affected sites only. 
This change also affects Section 1.3, Schedule of Activities; Section 14.1.4, Central Laboratories 
for Laboratory Assessments; and Appendix B, Laboratory Analytes. 
 
Section 16, Public Health or Humanitarian Emergencies 
Change: Section 16, Public Health or Humanitarian Emergencies was removed from the 
protocol. 
Now reads: 
In the event of public health or humanitarian emergencies that result in site closure, travel 
restrictions, and/or clinical research activities being deprioritized at the site such that clinic 
visit(s) cannot occur, a protocol deviation would be incurred for any deviation from the 
protocol specified visits and assessments, with additional notation that this protocol deviation is 
due to the public health or humanitarian emergency. If a protocol specified clinical visit cannot 
occur due to a public health or humanitarian emergency, the following mitigating options should 
be pursued: 1) transfer to another active study site that is open and 2) local laboratory visit. 
These mitigating options only apply in the setting of a public health or humanitarian emergency 
in which a protocol specified clinic visit cannot occur and should not be pursued solely due to 
the participant’s preference. If the participant does not participate in one of these options, a 
safety telephone call must be conducted within 14 days of the last dosing visit. 
If any participants with later onset SMA enrolled in Part B are unable to comply with study visits 
in areas affected by public health or humanitarian emergencies and are withdrawn early from the 
study (prior to the Day 183 dose and assessments), up to 4 additional participants may be 
enrolled at the Sponsor’s discretion. 
Rationale: Section 16 was previously removed as a country-specific protocol amendment for 
Germany (dated 07 November 2022) to comply with local regulations. After review, text 
elsewhere in the protocol sufficiently captures key mitigation activities related to 
COVID‑19‑related disruptions or humanitarian emergencies. Therefore, this section was 
removed from the global protocol. 
This change also affects Section 1.1, Synopsis; and Section 12.11, Sample Size Considerations. 


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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. 
• Typographical errors and formatting were corrected throughout the protocol. 
• Section numbers and table numbers were updated where applicable. 
• Sponsor Information was updated. 
• The Sponsor Signature Page was updated to change the signatory. 
• Section 2, List of Abbreviations, was updated. 
• In Section 4, Objectives and Endpoints, clarification was added that the Part B 
Primary Objective and Endpoint will compare the 232SM203 50/28 mg Group to the 
CS3B Matched Sham Control Group. 
• In Section 12.4.1, Analysis of the Primary Endpoint in Part B, clarification was added 
that MI will be utilized to impute a missing Day 183 value of CHOP-INTEND for 
participants who discontinued for a reason other than death or where it was not 
assessed.   
• In Section 12.4.2, Analysis of the Secondary Endpoints in Part B, clarification was 
added that for plasma NF-L, if the baseline assessment is missing, then the first 
available assessment postdose within Day 2 will be used instead as baseline, and that 
values that are BLQ will be set to half of the diluted LLOQ. 
 
 


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LIST OF ABBREVIATIONS 
 
ACEND 
Assessment of Caregiver Experience with Neuromuscular Disease 
 
 
BLQ 
below limit of quantification 
CHOP-INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders 
CGIC 
Clinical Global Impression of Change 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CSF 
cerebrospinal fluid 
HFMSE 
Hammersmith Functional Motor Scale Expanded 
HINE 
Hammersmith Infant Neurological Examination 
ITT 
Intent-to-Treat 
LLOQ 
lower limit of quantification 
MI 
multiple imputation 
NF 
neurofilament 
NF-L 
neurofilament light chain 
PASA 
Parent Assessment of Swallowing Ability 
PedsQL 
Pediatric Quality of Life Inventory™ 
 
 
RULM 
Revised Upper Limb Module 
SMA 
spinal muscular atrophy 
WHO 
World Health Organization 
 


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Biogen MA Inc. 
225 Binney Street 
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Biogen Idec Research Limited 
Innovation House 
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Maidenhead, Berkshire 
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United Kingdom 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol 232SM203 
Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants 
With Spinal Muscular Atrophy 
Version 6 
Date: 05 May 2022 
EUDRA CT Number: 2019-002663-10 
Version 6 of the protocol has been prepared for this amendment, which supersedes Version 5. 


Amendment Summary for Protocol 232SM203, Version 6 
 
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TABLE OF CONTENTS 
PRIMARY REASON FOR AMENDMENT...................................................................................3 
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL .......................................................6 
SUMMARY OF MINOR CHANGES TO THE PROTOCOL .....................................................14 
LIST OF ABBREVIATIONS ........................................................................................................16 
 


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PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 232SM203 is to reduce the sample size for 
Part B infantile onset participants to 75. As a result, the total sample size for the study was 
adjusted to 145 participants. 
 
New text is shown in bold type; deleted text is shown with a strikethrough. 
 
Section 12.11, Sample Size Considerations 
Now reads:  
A total sample size of up to approximately 172 145 participants is planned for this study, with a 
possibility of stopping recruitment in the infantile onset SMA population in Part B based on the 
interim analysis (Table 10). The justification for the sample size for the infantile-onset SMA 
population in Part B is detailed as follows. The sample sizes for the remaining groups are not 
based on statistical considerations. 
… 
Table 10: 
Number of Participants in Each Study Part, by Symptom Onset 
Part/Dose 
Number of Participants 
Later Onset 
Infantile 
Onset 
Total 
Part A (28-mg loading dose; 28-mg maintenance dose) 
6 
 
6 
Part B 
 
 
 
Control Group (12-mg loading dose; 12-mg 
maintenance dose) 
8 
34 25 
42 33 
50/28-mg Group (50-mg loading dose; 28-mg 
maintenance dose) 
16 
68 50 
84 66 
Part C (50-mg loading dose; 28-mg maintenance dose) 
 
 
401 
Total 
 
 
172 1451 
1 The sample size is an estimate that may be up to approximately the stated number. 
For the infantile-onset SMA population in Part B, a sample size of up to 68 approximately 
50 participants in the 50/28-mg Group will provide at least approximately 99% power for the 
primary endpoint to detect an improvement of 24 points on CHOP- INTEND and 23% survival 
rate benefit (compared to that observed in Study CS3B participants receiving sham control) at 


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Day 183 based on the joint-rank test at a 2-sided significance level of 0.05. This power 
calculation is based on simulations using data generated from a joint model of survival and 
functional change. The model used a difference of 24 points for the Day 183 change from 
baseline in CHOP- INTEND total score (50/28-mg Group – Study CS3B Sham Control Group) 
and a population standard deviation of 8.8 for change from baseline.  
 
 
 
 
 
 
 
 
… 
Rationale: Part B of the DEVOTE study design includes primary and secondary hypotheses that 
compare the high-dose nusinersen arm from DEVOTE to the historical sham-control arm from 
Study CS3B (ENDEAR). 
 
 
 
With 75 participants, the primary and secondary hypotheses that compare the higher dose of 
nusinersen to sham from ENDEAR all have a power of ≥ 95%, as shown in the table below. 
Enrolling an additional 27 participants (as planned in the original design based on initial 
determination of borrowing) does not meaningfully increase the power for the primary and 
secondary hypothesis testing, since these are already high.  


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Summary of Power for Testing Statistical Hypotheses in Part B of DEVOTE With a Total of 75 
or 102 Participants and Assuming No Borrowing 
Order 
Endpoint 
Comparison 
Assumptions for 
Higher-Dose 
Nusinersen 
Power 
DEVOTE Enrolled 
Sample Size 
N = 75 
N = 102 
1P 
Change from baseline to 
Day 183 in CHOP-INTEND 
total score, accounting for 
mortality/dropout using the 
joint-rank test 
DEVOTE high 
dose (n = 50/68) 
versus ENDEAR 
sham (n = 37) 
At Day 183, high dose 
4.5 points better AND 
survival 3% better than 
12 mg in ENDEAR 
> 99% 
> 99% 
2S 
Proportion of HINE Section 2 
motor milestone responders at 
Day 302 
DEVOTE high 
dose (n = 50/68) 
versus ENDEAR 
sham (n = 28) 
At Day 302, high dose 
proportion of 
responders same as 
12 mg from ENDEAR 
> 99% 
> 99% 
3S 
Time to death or permanent 
ventilation (tracheostomy or 
≥ 16 hours of ventilation/day 
continuously for > 21 days in 
the absence of an acute 
reversible event) 
DEVOTE high 
dose (n = 50/68) 
versus ENDEAR 
sham (n = 41) 
At Day 302, 40% of 
participants reach 
death or permanent 
ventilation in 
high-dose arm 
98% 
>99% 
4S 
Time to death (overall survival) 
DEVOTE high 
dose (n = 50/68) 
versus ENDEAR 
sham (n = 41) 
At Day 302, 15% of 
subjects die 
95% 
>99% 
Two-sided alpha = 0.05 used for all endpoints 
Hypotheses to test: P = primary; S = secondary. 
Power determined by simulations: for the primary and secondary hypotheses, data from simulated high-dose 
participants were compared to actual sham-control data from ENDEAR. 
 
This change also affects Section 1.1, Synopsis; Section 1.2, Study Design Schematic; 
Section 5.1, Study Overview; Section 7.1, Regimen; and Section 12.10, Interim Analyses. 


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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. 
Section 1.1, Synopsis 
The Synopsis was revised to reflect changes made throughout the protocol. 
 
Section 3.1.2, Rationale for Dosing Regimen 
Change: Additional details regarding the revision of the target CSF Ctrough and the clinical 
relevance of this change were included. 
Now reads: 
Previous PK modeling predicted that the median concentration of nusinersen within the 
CSF immediately prior to the administration of the subsequent maintenance dose (i.e., 
Ctrough) would be approximately 10 ng/mL at steady state with the label-approved 
maintenance dosing regimen (i.e., 12 mg administered every 4 months) and approximately 
20 ng/mL at steady state with the proposed maintenance dosing regimen for 
Study 232SM203 (i.e., 28 mg administered every 4 months). This model was subsequently 
updated to include additional data from Studies 232SM201 and CS11 not previously 
modeled, resulting in an adjustment of CSF Ctrough predictions in all patient populations, 
which are still consistent with the prior predictions. As a consequence, Ppopulation PK 
modeling now predicts that with increasing the maintenance dose from 12 to 28 mg administered 
every 4 months, CSF Ctrough should increase from 5 to 12 ng/mL at steady state. The 
exposure-response (PK/PD) relationship between steady-state CSF Ctrough and CHOP- INTEND 
response continuously increases as a function of PK, and is on an upward trajectory at 
concentrations consistent with the 12 mg maintenance dose (i.e., 5 ng/mL). It is therefore 
predicted that additional clinical benefit (i.e., a 5-point increase in CHOP- INTEND score) could 
be achieved by increasing CSF exposures to 12 ng/mL. This assumption is supported by 
nusinersen toxicokinetic results in nonhuman primates, which showed nearly dose proportional 
PK in the plasma and CNS tissues (target site of action) up to 15 mg (human equivalent dose of 
150 mg). Therefore, administration of this higher dose of nusinersen may lead to 
meaningful clinical benefit to patients. At this time, no dose-limiting toxicity has been 
identified with nusinersen. The PK modeling therefore suggests that it is unlikely that the 
higher doses of nusinersen would have a less favorable risk-benefit profile compared with 
standard dose nusinersen. 
… 


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The assumption of PK linearity is supported by nusinersen toxicokinetic results in 
nonhuman primates, which showed nearly dose-proportional PK in the plasma and CNS 
tissues (target site of action) up to 15 mg (human equivalent dose of 150 mg). Assuming PK 
linearity, PK simulations were performed in both infantile- and later onset SMA populations 
after 2 years of treatment using a population PK model developed from patients across the age 
range of ≤ 6 months to 18 years old. Based on the most recent PK modeling performed, relative 
to the approved 12-mg label regimen (CSF Ctrough of approximately 5 ng/mL), 28 mg 
administered as 3 loading doses (biweekly) or 50 mg administered as 2 loading doses (biweekly), 
each followed by maintenance doses of 28 mg every 4 months, were identified to achieve the 
desired CSF Ctrough (approximately 12 ng/mL) more rapidly at the end of the loading dose period. 
Nusinersen 28 mg administered as 3 loading doses (biweekly) had a comparable predicted CSF 
Cmax to the reference dosing regimen, whereas the 50-mg dosing regimen surpassed the predicted 
Cmax from the reference dosing regimen. Moreover, the 28-mg maintenance dosing regimen 
adequately maintained the higher CSF Ctrough target (approximately 12 ng/mL) during the 
maintenance dose period. Toxicology studies in nonhuman primates evaluating the nonhuman 
primate equivalent of the 28- and 50-mg doses have been conducted and support the safety of 
these doses in a clinical study (see Section 3.3). Therefore, the 28-mg dose (administered as 
3 loading doses at biweekly intervals), 50-mg dose (administered as 2 loading doses at biweekly 
intervals), and 28-mg maintenance dose were recommended for additional clinical evaluation. 
Rationale: Since the development of the original protocol for Study 232SM203, more recent PK 
modeling data have become available. These data have impacted the predicted steady-state CSF 
Ctrough values for the different nusinersen dosing regimens used in this study. Additional 
information describing the change in CSF Ctrough predictions was added to this protocol 
amendment for clarity and to further explain why the target CSF Ctrough has changed. In addition, 
text was added to show that the potential predicted clinical benefit (in the form of an increase in 
CHOP-INTEND score) is also greater now based on the new PK modeling data available. 
This change also affects Section 1.1, Synopsis. 
 
Section 5.1, Study Overview 
Change: Details regarding the IDMC review of safety and PK data for the first 15 participants in 
Part B were added to the protocol. 
Now reads: 
… 
Once the fifteenth participant in Part B has been enrolled and administered the first dose of study 
treatment, no new participants will be dosed in Part B until after an IDMC review. The IDMC 
will review unblinded data from the first 15 participants in Part B who have completed the 
Day 29 visit (in order to achieve 6 or more participants who have received 50 mg in the 
50/28-mg Group while maintaining the blind for the rest of the study team). This review will 


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include safety data through the Day 29 visit at a minimum and all available individual CSF and 
plasma nusinersen concentration data for these participants, including the Day 15 samples at a 
minimum. Dosing of the remaining participants in Part B and dosing in Part C will occur only 
after this review has completed, provided that no safety concerns are identified. Note that the 
IDMC can recommend to stop the study based on the safety findings. By the time of 
implementation of Protocol Version 6, the IDMC reviewed these data and recommended 
that the study may continue with dosing of the remaining participants in Part B and 
initiating dosing in Part C without any modifications to the study. 
Rationale: The prespecified IDMC review of the first 15 participants enrolled in Part B has now 
occurred. As such, a statement was added to the protocol to acknowledge that this review has 
been completed and that no study design changes were required as a result. This enabled dosing 
to continue in Part B and for participants to begin enrolling in Part C of the study. 
This change also affects Section 1.1, Synopsis. 
 
Section 6.2, Exclusion Criteria 
Change: For Part B, exclusion criterion 10 was revised to apply only to participants with SMA 
symptom onset > 6 months (> 180 days) of age (later onset). 
Now reads: 
… 
Part B 
All Participants 
… 
9. 
Prior injury (e.g., upper or lower limb fracture) or surgical procedure that affects the 
participant’s ability to perform any of the outcome measure testing required in the protocol and 
from which the participant has not fully recovered or achieved a stable baseline 
10. 
Hospitalization for surgery (i.e., scoliosis surgery or other surgery), pulmonary event, or 
nutritional support within 2 months prior to Screening or planned within 12 months after the 
participant’s first dose 
11. 
Treatment with an investigational drug including but not limited to the treatment of SMA 
(e.g., oral albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, and 
hydroxyurea), biological agent, or device within 30 days or 5 half-lives of the agent, whichever 
is longer, prior to Screening or anytime during the study; any prior or current treatment with any 
SMN2-splicing modifier or gene therapy; or prior ASO treatment (e.g., nusinersen) or cell 
transplantation 


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… 
Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset) 
17. 
Hospitalization for surgery (i.e., scoliosis surgery or other surgery), pulmonary 
event, or nutritional support within 2 months prior to Screening or planned within 
12 months after the participant’s first dose  
18. 
Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive 
ventilation for > 6 hours during a 24-hour period, at Screening 
Rationale: For the primary endpoint analysis, participants in this study will be compared to 
participants who received sham treatment in the ENDEAR study. As such, this change was 
implemented to ensure consistency with participant selection criteria in the ENDEAR study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 9.1.10.1, Pediatric Quality of Life Inventory (Generic Core Scales and Neuromuscular 
Module) 
Change: The PedsQL Measurement 4.0 Generic Core Scales and 3.0 Neuromuscular Module for 
participants ≥ 26 years of age were added. 
Now reads: 
Participants with later-onset SMA will be evaluated using the age-appropriate modules of the 
PedsQL Measurement 4.0 Generic Core Scales and 3.0 Neuromuscular Module [Varni 1999], 
which include age 2 to 4 years, 5 to 7 years, 8 to 12 years, 13 to 18 years, 18 to 25 years, and 
≥ 26 years. 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 HRQOL in children, and 
adolescents, and adults. The PedsQL consists of brief, practical, generic core scales, as well as 
condition-specific modules for use in designated clinical populations. Patient self report is 
measured in children and adolescents 5 to 25 years of age, and parent proxy report of child 
HRQOL is measured for children and adolescents 2 to 25 years of age. Patient self report and 
parent proxy report are available for participants who are ≥ 26 years of age for the Generic Core 
Scale. The PedsQL 4.0 Generic Core Scales include an assessment of physical functioning, 
emotional functioning, social functioning, and school functioning and will be assessed for 
participants 2 to ≥ 26 years of age. The PedsQL 3.0 Neuromuscular Module was designed to 
measure HRQOL dimensions specific to children 2 to 18 years of age patients with 
neuromuscular disorders, including SMA, and will be assessed in participants 2 to 25 years of 
age. Patient self-report will be measured in participants starting at 5 years of age, while 
parent proxy-report of HRQOL will be measured for participants starting at 2 years of age. 
Rationale: Details regarding the available modules by age for the PedsQL Measurement 
4.0 Generic Core Scales and 3.0 Neuromuscular Module were included for completeness. In 
addition, assessment requirements by age were updated for the study in order to enable 
assessment for participants up to 25 and ≥ 26 years of age, which is applicable for participants in 
Cohort 1 of Part C. 
 
Section 10.2, Laboratory Safety Assessments 
Change: The CSF local laboratory sample protein was updated to “total protein.” 
Now reads: 
… 
• CSF local laboratory sample: cell count, total protein, and glucose 


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Rationale: This change was implemented to further specify that total protein would be measured 
for the CSF local laboratory sample. 
This change also affects Table 1, Schedule of Activities for Part A; Table 2, Schedule of 
Activities for Part B; Table 3, Schedule of Activities for Part C Cohort 1; Table 4, Schedule of 
Activities for Part C Cohort 2; Section 14.1.4, Central Laboratories for Laboratory Assessments; 
and Appendix B, Laboratory Analytes. 
 
Section 10.2, Laboratory Safety Assessments 
Change: Language was added to allow use of a local laboratory when necessary (e.g., difficult 
transportation of samples to the central laboratory). 
Now reads: 
… 
The laboratory analytes to be measured are shown in Appendix B. 
When the safety laboratory sample analysis is at risk due to logistical difficulties or issues 
with access to the central laboratory (e.g., due to COVID-19–related disruptions or 
humanitarian emergencies), these samples may be analyzed by the local laboratory. Any 
use of a local laboratory under these circumstances must be approved by the Sponsor prior 
to being implemented.  
Rationale: For various clinical sites globally (e.g., Saudi Arabia and Russia), transporting safety 
laboratory samples to the central laboratory could take longer than usual and result in the 
samples arriving outside the stability period. Allowing these samples to be sent to the local 
laboratory offers the flexibility to have the samples processed and evaluated in a timely manner, 
ensuring the safety of trial participants and analysis of these important study data.  
This change also affects footnote 16 of Table 2, Schedule of Activities for Part B; Section 14.1.4, 
Central Laboratories for Laboratory Assessments; and footnote 1 of Appendix B, Laboratory 
Analytes. 
 
Section 12.10, Interim Analyses 
 
 
 


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Now reads: 
Interim and final analyses for Parts A and C may occur prior to completion of Part B of the 
study. 
An interim analysis 
 
 
 
 
 
 
 
 
 of the primary endpoint 
in Part B 
 may be performed when all participants with infantile-onset SMA have had the 
opportunity to reach the Day 183 visit. 
 
 
 
  
This change also affects Section 12.4, Methods of Analysis for Efficacy Endpoints; 
Section 12.11, Sample Size Considerations; and Section 14.2.2, Independent Data Monitoring 
Committee. 
 
Section 12.11, Sample Size Considerations 
Change: 
 
 
 
Now reads: 
… 
 
 
 
 
 
 
 
 
Rationale: 
 
 


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This change also affects Section 3.1, Study Rationale. 
 
Section 16, Public Health or Humanitarian Emergencies 
Change: This section was added to address contingencies in areas affected by public health or 
humanitarian emergencies. 
Now reads: 
In the event of public health or humanitarian emergencies that result in site closure, travel 
restrictions, and/or clinical research activities being deprioritized at the site such that clinic 
visit(s) cannot occur, a protocol deviation would be incurred for any deviation from the 
protocol-specified visits and assessments, with additional notation that this protocol 
deviation is due to the public health or humanitarian emergency. If a protocol-specified 
clinical visit cannot occur due to a public health or humanitarian emergency, the following 
mitigating options should be pursued: 1) transfer to another active study site that is open 
and 2) local laboratory visit. These mitigating options only apply in the setting of a public 
health or humanitarian emergency in which a protocol-specified clinic visit cannot occur 
and should not be pursued solely due to the participant’s preference. If the participant does 
not participate in one of these options, a safety telephone call must be conducted within 
14 days of the last dosing visit. 
If any participants with later-onset SMA enrolled in Part B are unable to comply with 
study visits in areas affected by public health or humanitarian emergencies and are 
withdrawn early from the study (prior to the Day 183 dose and assessments), up to 
4 additional participants may be enrolled at the Sponsor’s discretion. 
Rationale: This section was added to provide guidance in the event of public health or 
humanitarian emergencies. In case any such emergency impacts the Sponsor’s ability to collect 
data from a significant portion of the later-onset participants enrolled in Part B, conditional 
language has been added to allow enrollment of additional later-onset participants for effective 
data analyses. 
This change also affects Section 1.1, Synopsis; footnote 16 of Table 2, Schedule of Activities for 
Part B; Section 10.2, Laboratory Safety Assessments; Section 12.11, Sample Size 
Considerations; Section 14.1.4, Central Laboratories for Laboratory Assessments; and footnote 1 
of 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 updated throughout the protocol. 
• Typographical errors and formatting were corrected throughout the protocol. 
• Some wording was revised throughout the protocol for clarity. 
• Abbreviations and wording were modified to align with the program-specific style 
guide. 
• Section numbers, eligibility criteria numbering, and footnote numbering were updated 
where applicable. 
• The business address of Biogen Australia was updated. 
• Details from Section 6.3.2 regarding the extension of the Screening period, which 
were inadvertently removed in version 5.0, were added back to footnote 1 of Tables 2 
(Schedule of Activities for Part B), 3 (Schedule of Activities for Part C Cohort 1), and 
4 (Schedule of Activities for Part C Cohort 2). 
• Figure 1 footnote 1 was revised to clarify that the visits that male participants can 
complete via telephone interview and the visits that female participants need to return 
to the site for completion, if they meet the criteria for contraception use, are the 
Day 389, 399, or 361 visit for Part A, B, or C, respectively. A change related to this 
was also applied to footnote 2 of Table 1. 
• Section 2, List of Abbreviations, was updated. 
• References to Schedule of Assessments were revised to Schedule of Activities 
throughout to match Tables 1 to 5 captions. 
• Section 11.2.2 header was updated to “Relationship of Events to Study Treatment or 
LP/Sham Procedure” to reflect the section contents more accurately. 
• Numbering of sections adjusted to reflect insertion of new Section 16. 
• Appendix B, Laboratory Analytes was updated as follows: 
− Urine total protein was specified as quantitative. A corresponding footnote was 
added to state that quantitative urine total protein should be prioritized if there is 
not enough urine sample for all tests and that repeat testing and further evaluation 
should be considered if urinary protein concentration is > 0.2 g/L. 


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− A footnote stating that for the Screening visit only, a local laboratory instead of 
the central laboratory may be used for the analysis of blood chemistry, 
hematology, and urinalysis samples, if needed, for the timely treatment of the 
participant at the discretion of the Investigator, for consistency with the footnotes 
in the Schedules of Activities. 


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LIST OF ABBREVIATIONS 
 
 
ASO 
antisense oligonucleotide 
CHOP-INTEND 
Children’s Hospital of Philadelphia-Infant Test of 
Neuromuscular Disorders 
Cmax 
maximum concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CSF 
cerebrospinal fluid 
Ctrough 
trough concentration 
HINE 
Hammersmith Infant Neurological Examination 
HRQOL 
health-related quality of life 
IDMC 
independent data monitoring committee 
LP 
lumbar puncture 
PedsQL 
Pediatric Quality of Life Inventory™ 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
SMA 
spinal muscular atrophy 
SMN2 
survival motor neuron-2 gene 
WHO 
World Health Organization 
 


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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 232SM203 
Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants 
With Spinal Muscular Atrophy 
Version 5 
Date: 01 October 2021 
EUDRA CT Number: 2019-002663-10 
Version 5 of the protocol has been prepared for this amendment, which supersedes Version 4. 


Amendment Summary for Protocol 232SM203, Version 5 
 
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PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 232SM203 is to increase the sample size for 
Part C by adding a second cohort consisting of up to approximately 20 adult participants. 
New text is shown in bold type; deleted text is shown with a strikethrough. 
 
Section 5.1, Study Overview 
Now reads:  
 
In Part C, up to approximately 2040 participants will be enrolled and will consist of patients of 
any age or SMA status who have already initiated treatment with nusinersen and have been 
receiving the approved dose of 12 mg for at least 1 year prior to entry in this study will be 
enrolled in Part C. The initial cohort in Part C (i.e., Cohort 1) consists of approximately 20 
participants of any age and of any SMA status. For Cohort 1, an. An attempt will be made to 
enroll at least 8 but no more than 12 participants ≥ 18 years of age (participants in Cohort 1 
≥ 18 years of age must be ambulatory). Up to 5 participants with severe scoliosis and/or severe 
contractures may be enrolled in Cohort 1 of Part C after consultation with the Medical Monitor. 
An additional cohort (i.e., Cohort 2) consisting of up to approximately 20 adult participants 
(≥ 18 years of age) was subsequently added to Part C in Protocol Version 5 in order to 
enable collection of data in adults transitioning from the currently approved nusinersen 
dosing regimen to a higher dose. Participants in Cohort 2 can be either ambulatory or 
nonambulatory. 
All Pparticipants in Part C will receive a single bolus dose of 50 mg (which should be 
administered 4 months ± 14 days after their most recent maintenance dose of 12 mg) followed by 
2 maintenance doses of 28 mg on Days 121 and 241. Participants in Part C will remain at the 
clinic for at least 24 hours after the first (bolus) dose for the purpose of completing study 
assessments.  
Rationale: Increasing the sample size by including an additional cohort of up to approximately 
20 adult participants in Part C will allow collection of clinical data in adults transitioning from 
the currently approved nusinersen dosing regimen to a higher dose. Since the previous design of 
Part C did not require enrollment of any adults, adding Cohort 2 will enable data collection in 
this SMA patient population. Results will be descriptive in nature, with no formal hypothesis 
testing performed. 
Relevant inclusion and exclusion criteria have been modified or added as appropriate for this 
cohort. The assessment includes safety, tolerability, 
 and efficacy assessments, consistent 
with Part C objectives.  


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3 
This change also affects Section 1.1, Synopsis; Section 1.2, Study Design Schematic; Section 
1.3, Schedule of Activities (Tables 3 and 4); Section 3.1.1, Rationale for Study Population; 
Section 4, Study Objectives and Endpoints; Section 6.1, Inclusion Criteria; Section 6.2, 
Exclusion Criteria; Section 7.1, Regimen; Section 9.1, Clinical Efficacy Assessments; Section 
12.11, Sample Size Considerations. 


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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. 
Section 1.1, Synopsis 
The synopsis was revised to reflect changes made throughout the protocol. 
 
Section 1.3, Table 2: Schedule of Activities for Part B; Table 3: Schedule of Activities for Part C 
Cohort 1 
Change: The timepoints for collection of vital signs, neurological examinations, and ECGs and 
the collection windows for 
 were updated for Parts B and C. The impacted 
footnotes for Tables 2 and 3 are presented below. 
Now reads: 
Table 2: 
Schedule of Activities for Part B910 On Days 1 and 15, postdose Vvital signs will 
be collected at 1, 2, 4, 6, and 8 hours (± 15 minutes) postdose and at 24 hours (± 2 hours) 
postdose. On Days 29, 64, 135, 183, and 279, postdose vital signs will be collected at 1 hour 
(± 30 minutes) and 6 hours (± 1 hour) postdose. 
… 
1314 HINE Sections 1 and 3 will be administered to participants with infantile-onset SMA, and a 
neurological examination will be performed in participants with later-onset SMA. On dosing 
visits, aA neurological examination will be performed at Screening; predose, at 3 and 6 hours 
(± 15 minutes) postdose, and at 24 hours (± 2 hours) postdose, or when anesthesia/sedation (if 
used) has worn off on Days 1 and 15; predose and at 1 and 3 hours (± 30 minutes) postdose 
on Days 29, 64, 135, 183, and 279; and at Day 302/ET. Predose neurological examinations 
should be repeated when the assessment falls outside the protocol-specified window because of a 
delay in dosing. 
1415 ECGs will be performed predose, at 5 hours (± 1 hour) postdose, and at 24 hours (± 2 hours) 
postdose on Days 1, and 15; predose and at 5 hours (± 1 hour) postdose on Days, 29, and 64; 
at 5 hours (± 1 hour) postdose on Days 135, 183, and 279; and at Day 302/ET. Predose ECGs 
should be repeated when the assessment falls outside the protocol-specified window because of a 
delay in dosing. If a postdose ECG result is abnormal and clinically significant, a repeat ECG 
should be performed within 2 hours later. 
… 


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Table 3: 
Schedule of Activities for Part C Cohort 1 
9 On Day 1, postdose Vvital signs will be collected at 1, 2, 4, 6, and 8 hours (± 15 minutes) 
postdose and at 24 hours (± 2 hours) postdose. On Days 121 and 241, postdose vital signs will 
be collected at 1 hour (± 30 minutes) and 6 hours (± 1 hour) postdose. 
… 
13 HINE Sections 1 and 3 will be administered to participants < 2 years of age at the time of 
informed consent, and a neurological examination will be performed in participants ≥ 2 years of 
age at the time of informed consent. On dosing visits, a A neurological examination will be 
performed at Screening; predose, at 3 and 6 hours (± 15 minutes) postdose, and at 24 hours 
(± 2 hours) postdose, or when anesthesia/sedation (if used) has worn off on Day 1; predose and 
at 1 and 3 hours (± 30 minutes) postdose on Days 121 and 241; and at Day 302/ET. Predose 
neurological examinations should be repeated when the assessment falls outside the protocol-
specified window because of a delay in dosing. 
… 
 
 
 
 
Rationale: Postdose timepoints for vital signs, neurological examinations, and ECGs were 
revised to align with the change in the requirements for the 24-hour inpatient stay in Part B. 
Since participants are only required to remain in the clinic for the first 2 dosing visits (i.e., Days 
1 and 15) with this protocol amendment, timepoints for these assessments at the subsequent 
study visits were reduced. Similarly, the footnotes in the Part C Schedule of Activities tables 
regarding timepoints for postdose vital signs and neurological examinations were corrected to 
align with the 24-hour inpatient stay occurring at the Day 1 study visit only. In addition, 
 
 
This change also affects Table 4, Schedule of Activities for Part C Cohort 2. 
 
 


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Section 1.3, Table 4: Schedule of Activities for Part C Cohort 2 
Change: A schedule of activities table specifically for Part C Cohort 2 (Table 4) was added, 
given that this is exclusively focused on a different population and therefore some assessments 
are different. Consequently, Table 3 was revised to correspond specifically to Cohort 1 of Part C. 
Table 4 is presented below. Major relevant changes affecting Tables 2, 3, and/or 4 include the 
following: 
• Assessments for vital signs, weight, growth parameters, and physical examination at 
Screening were added to Part C (Cohorts 1 and 2) to align with the baseline data 
collected for Parts A and B. 
• 
 
 
 
• Flexibility to perform assessments up to 7 days prior to dosing at the maintenance 
dose visits was added for the following assessments: 
 PASA (Part 
B only); ACEND and PedsQL (Part B and Part C Cohort 1 only); 
 
 


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7 
Now reads: 
Table 4: 
Schedule of Activities for Part C Cohort 2
 
Screening 
Visit1 
Treatment 
Follow-up2 
EOS 
Assessments 
D-21 to  
D-1 
D13 
D121 (±7 days),  
D241 (±7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(±7 days) 
D361 
(+14 days) 
 
 
Predose 
LP 
Postdose 
Predose 
LP 
Postdose 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Local Urine/Serum Pregnancy 
Test for Females of Childbearing 
Potential4 
X 
X 
 
 
X 
 
 
 
X 
X 
Medical (including SMA) History 
X 
 
 
 
 
 
 
 
 
 
SMA Genetic Testing5 
X 
 
 
 
 
 
 
 
 
 
X-ray Examination (with the 
participant in a sitting or 
supported sitting position)6 
X 
 
 
 
 
 
 
 
 
 
LP Opening Pressure 
 
 
X 
 
 
X 
 
 
 
 
Study Treatment Injection7 
 
 
X 
 
 
X 
 
 
 
 
Inpatient Stay 
 
 
 
X 
 
 
 
 
 
 
Vital Signs and Pulse Oximetry8  
X 
X 
 
X9 
X 
 
X9 
 
X 
 
Weight 
X 
X 
 
 
X 
 
 
 
X 
 
Growth Parameters (including 
height/body length/ulnar length, 
and head/chest/arm 
circumference)10 
X 
X 
 
 
X11 
 
 
 
X 
 


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8 
 
Screening 
Visit1 
Treatment 
Follow-up2 
EOS 
Assessments 
D-21 to  
D-1 
D13 
D121 (±7 days),  
D241 (±7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(±7 days) 
D361 
(+14 days) 
 
 
Predose 
LP 
Postdose 
Predose 
LP 
Postdose 
 
 
 
Physical Examination12 
X 
X 
 
 
X 
 
 
 
X 
 
Neurological Examination13 
X 
X 
 
X 
X 
 
X 
 
X 
 
ECG14 
 
X 
 
X 
 
 
X 
 
X 
 
Safety Laboratory Tests15 
X 
X 
 
 
X 
 
 
 
X 
 
Local Coagulation Laboratory 
Tests16 
X 
X 
 
 
X 
 
 
 
 
 
Safety Follow-Up Telephone 
Contact 
 
 
 
X17 
 
 
 
X 
 
 
CSF Local Lab Sample (cell 
count, protein, and glucose) 
 
X 
 
 
X 
 
 
 
 
 
CGIC20 
 
 
 
 
X 
 
 
 
X 
 
HFMSE21 
X22 
X22 
 
 
X11 
 
 
 
X 
 
RULM21 
X22 
X22 
 
 
X11 
 
 
 
X 
 
WHO Motor Milestones21 
X 
 
 
 
X11 
 
 
 
X 
 


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9 
 
Screening 
Visit1 
Treatment 
Follow-up2 
EOS 
Assessments 
D-21 to  
D-1 
D13 
D121 (±7 days),  
D241 (±7 days) 
2 to 14 Days 
After Each 
Maintenance 
Dose 
D302/ET 
(±7 days) 
D361 
(+14 days) 
 
 
Predose 
LP 
Postdose 
Predose 
LP 
Postdose 
 
 
 
ACEND23 
 
X 
 
 
 
 
 
 
X 
 
Ventilator Use26 
X 
X 
 
 
X 
 
 
X 
X 
 
AE Recording 
X-----------------------------------------------------------------------------------------------------------------------------------X 
SAE Recording 
X-----------------------------------------------------------------------------------------------------------------------------------X 
Concomitant Therapy and 
Procedures Recording 
X-----------------------------------------------------------------------------------------------------------------------------------X 
 ACEND = Assessment of Caregiver Experience with Neuromuscular Disease; 
AE = adverse event; CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; EOS = end of 
study; 
 ET = early termination; 
 
 HFMSE = Hammersmith Functional Motor Scale – Expanded; HINE = Hammersmith Infant Neurological Examination; ICF = informed 
consent form; LP = lumbar puncture; 
; RULM = Revised Upper Limb Module; SAE = serious adverse event; SMA = spinal 
muscular atrophy; 
SMN = survival motor neuron; 
 
WHO = World Health Organization 
1 If the Screening visit occurs within 7 days before Day 1, screening assessments can be used for Day 1 predose assessments. 
2 Participants who do not meet the criteria for contraception use will have their last visit on Day 302. Participants who meet the criteria for 
contraception use (see Section 11.5) will have a Day 302 and a Day 361 visit. Male participants who meet the criteria may complete the Day 361 visit 


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10 
via a telephone interview. Female participants who meet the criteria will return to the site for the Day 361 visit. Day 361 will take place at least 120 
days after the final dose. For participants who meet the criteria for contraception use and enroll into the long-term extension study (232SM302) at the 
Day 302 visit, that will be their final visit in Study 232SM203. 
3 Day 1 should be 4 months ± 14 days after the participant’s most recent nusinersen maintenance dose of 12 mg. 
4 A serum pregnancy test will be performed locally in female participants of childbearing potential in the event of a positive or equivocal urine 
pregnancy test result. 
5 For all participants, a blood sample will be collected to evaluate SMN1 gene status (copy number, deletion, and mutation where necessary to confirm 
5q SMA) and SMN2 copy number by the central laboratory. For participants without acceptable documentation of these genetic testing results before 
Screening, a blood sample must be collected during the Screening period to determine eligibility (preferably for analysis by the central laboratory, but 
may be determined by local lab genetic testing if needed). For participants with documentation of genetic testing results before Screening or whose 
sample was analyzed locally during the Screening period (with documentation of these genetic testing results), a blood sample will be collected 
(preferably at Screening, but must be collected by the Day 121 visit) for confirmatory testing through the central laboratory. 
6 Eligibility based on scoliosis severity at Screening will be determined by local analysis of the X-ray results. Results of the central X-ray read will be 
documented and used for subsequent data analyses. For sites with local regulation on use of X-ray (e.g., Germany), the Investigator may assess 
scoliosis based on physical examination without imaging. 
7 Spinal ultrasound, fluoroscopy, or similar techniques may be used for the LP procedure, if deemed necessary, but is not required. Local anesthesia 
and/or sedation may be used for the LP procedure in participants < 2 years of age, and anesthesia (local or general) and/or sedation may be used for 
the LP procedure in participants ≥ 2 years of age, at the discretion of the Investigator and/or study center. LP injections may not occur within 
72 hours after an immunization. 
8 Vital signs will include temperature, pulse rate, systolic and diastolic blood pressure, respiratory rate, and pulse oximetry. 
9 On Day 1, postdose vital signs will be collected at 1, 2, 4, 6, and 8 hours (± 15 minutes) postdose and at 24 hours (± 2 hours) postdose. On Days 121 and 
241, postdose vital signs will be collected at 1 hour (± 30 minutes) and 6 hours (± 1 hour) postdose. 
10 Length and head, chest, and arm circumference will be measured in participants with infantile-onset SMA, and height or body length (for 
participants who are not able to stand independently) and ulnar length will be measured in participants with later-onset SMA. The same 
measurement (height or body length) should be evaluated at all study visits whenever possible. 
11 These assessments may be performed up to 7 days prior to dosing. 
12 Videotaping of physical examinations is optional. 
13 A neurological examination will be performed at Screening; predose, at 3 and 6 hours (± 15 minutes) postdose, and at 24 hours (± 2 hours) postdose or 
when anesthesia/sedation (if used) has worn off on Day 1; predose and at 1 and 3 hours (± 30 minutes) postdose on Days 121 and 241; and at Day 
302/ET. Predose neurological examinations should be repeated when the assessment falls outside the protocol-specified window because of a delay in 
dosing. 
14 ECGs will be performed predose, at 5 hours (± 1 hour) postdose, and at 24 hours (± 2 hours) postdose on Day 1; at 5 hours (± 1 hour) postdose on 
Days 121 and 241; and at Day 302/ET. Predose ECGs should be repeated when the assessment falls outside the protocol-specified window because of a 
delay in dosing. If a postdose ECG result is abnormal and clinically significant, a repeat ECG should be performed within 2 hours. 
15 Blood chemistry, hematology, and urinalysis samples will be analyzed by a central laboratory. For the Screening visit only, a local laboratory may be 
used for analysis instead if needed for timely treatment of the participant at the discretion of the Investigator. If a local laboratory is used for the 
Screening visit, the samples should be collected on Day 1 for central laboratory evaluation (even if within 7 days of Screening). These assessments may 
be performed up to 7 days prior to dosing/study visit, if necessary. Urine total protein will be analyzed by local laboratory only (Appendix B). Predose 
clinical safety laboratory assessments should be repeated when the assessment falls outside the protocol-specified window because of a delay in dosing. 


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16 Coagulation testing will be conducted locally at Screening and predose (within 7 days prior to dosing) at each dosing visit; results should be reviewed 
prior to dosing. Predose coagulation parameters should be repeated when the assessment falls outside the protocol-specified window because of a 
delay in dosing. 
17 A safety follow-up telephone call will be made 2 weeks (± 3 days) after the Day 1 bolus dose. 
 
 
 
 
20 Adult participants who do not require a caregiver during the study visits will only have the CGIC assessed by the Investigator. 
21 Videotaping of all motor milestone and motor function assessments is optional; however, if the participant/caregiver consents to video recording, all 
assessments should be recorded. 
22 Two baseline assessments are required for HFMSE and RULM. At least 1 assessment must be conducted during the Screening period. The second 
assessment may be conducted either during the Screening period or at Day 1 predose. If both baseline assessments are conducted during the 
Screening period, they should be completed on different days and the assessments do not need to be repeated on Day 1. 
23 The ACEND questionnaire will not be collected for adult participants who do not require a caregiver during the study visits. 
24 Assessment will be performed on Day 121 only. 
 
 
 
 
26 Ventilator use will be collected at every study visit (see Section 9.1.14). 
 




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Now reads: 
Participants in Part B who discontinue treatment may remain in the study to continue the protocol-required tests and 
assessments described in Table 5 (unless the reason for discontinuation is to initiate treatment with a disallowed concomitant 
therapy per Section 7.6.1.2). 
… 
Table 5: 
Schedule of Activities for Participants in Part B Who Discontinue Study Treatment but Agree to Remain in the 
Study 
Assessment1 
Follow-Up Visits2 
Weight 
X 
Growth Parameters 
X 
Physical Examination 
X 
Vital Signs (Temperature, Pulse Rate, Systolic and Diastolic Blood Pressure, Respiratory Rate, and 
Pulse Oximetry) 
X 
Neurological Examination3 
X 
Urine/Serum Pregnancy Test for Females of Childbearing Potential4 
X 
Safety Laboratory Tests 
X 
WHO Motor Milestones 
X 
HINE Section 2 Motor Milestones (as appropriate) 
X 
Motor Function Assessments (as appropriate, including CHOP INTEND, HFMSE, RULM, 
 
)  
X 
Ventilator Use 
X 
Ventilator Use Diary (Participants with Infantile-Onset SMA) 
--------------------------X-------------------------- 
Concomitant Therapy and Procedure Recording 
--------------------------X-------------------------- 


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14 
Assessment1 
Follow-Up Visits2 
AE and SAE Recording 
--------------------------X-------------------------- 
 AE = adverse event; CHOP INTEND = Children’s Hospital of Philadelphia Infant 
Test of Neuromuscular Disorders; HFMSE = Hammersmith Functional Motor Scale – Expanded; RULM = Revised Upper Limb Module; SAE = 
serious adverse event; WHO = World Health Organization 
Note: See Section 9 for additional details regarding efficacy, 
 assessments. 
1 Participants who initiate treatment with a disallowed concomitant therapy (see Section 7.6.1.2) must be withdrawn from Study 232SM203; they are 
not eligible to remain in the study for follow-up visits per Table 5. 
2 Participants should return to the clinic according to the original visit schedule per Table 2 (i.e., Days 1, 15, 29, 64, 135, 183, 279, 302) for follow-up 
visits after discontinuing treatment, but will follow a reduced schedule of assessments at these visits. 
3 HINE Sections 1 and 3 will be administered to participants with infantile-onset SMA, and a neurological examination will be performed in 
participants with later-onset SMA. 
4 A serum pregnancy test will be performed locally in females of childbearing potential in the event of a positive or equivocal urine pregnancy test 
result. 


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Rationale: This new schedule of activities table provides Investigators and other site personnel 
with guidelines for which samples and assessments need to be collected and performed for any 
participants in Part B of the study who discontinue study treatment but agree to return to the 
clinic for regular follow-up visits. These guidelines are intended to streamline operation at the 
sites as well as ensure consistency in the data collected and reported.This change also affects 
Section 8.1, Discontinuation of Study Treatment. 
 
Section 3.1.2, Rationale for Dosing Regimen 
Change: Language on steady-state exposures for the 12 mg dose (~5 ng/mL) vs. the higher dose 
(~12 ng/mL) of nusinersen was updated based on the most recent PK modeling data available. 
Now reads:  
An exploratory exposure-response analysis performed in participants with infantile-onset SMA 
(Study CS3A, n = 20, age 38 days to 8 months) showed a statistically significant positive 
correlation between nusinersen cerebrospinal fluid (CSF) exposure and motor function 
(e.g., CHOP INTEND scores). Additional analyses in the same patient population from 
Studies CS3A and CS3B (n = 80, age 30 days to 8 months) showed that the near steady state 
CSF exposure (approximately 10 ng/mL) closely approximated the model predicted 
concentration at 50% of the maximum observed biological effect (EC50) using CHOP INTEND 
(change from baseline) as the primary efficacy endpoint. These results suggest that additional 
clinical efficacy may be possible with increased nusinersen central nervous system (CNS) 
exposure. Under the assumption of PK linearity, increasing the nusinersen dose to 24 mg, with a 
dosing frequency of 4 loading doses followed by maintenance doses administered every 
4 months, should effectively increase the CSF trough concentration (Ctrough) at steady state to 
approximately 20 ng/mL. This concentration is comparable to the predicted concentration at 90% 
of the maximum observed biological effect (EC90) from the infantile onset SMA population. 
Population PK modeling predicts that with increasing the nusinersen maintenance dose 
from 12 to 28 mg administered every 4 months, CSF Ctrough should increase from 5 to 
12 ng/mL at steady state. The exposure-response (PK/PD) relationship between steady-
state CSF trough concentrations and CHOP INTEND response continuously increases as a 
function of PK, and is on an upward trajectory at concentrations consistent with the 12 mg 
maintenance dose. It is therefore predicted that additional clinical benefit (i.e., a 5-point 
increase in CHOP INTEND score) could be achieved by increasing CSF exposures to 
12 ng/mL. This assumption is supported by nusinersen toxicokinetic results in nonhuman 
primates, which showed nearly dose-proportional PK in the plasma and CNS tissues (target site 
of action) up to 15 mg (human equivalent dose of 150 mg). It is important to highlight that the 
maximum response from the existing clinical data is limited because 12 mg was the highest dose 
administered in humans, and the majority of the dataset are within the CSF Ctrough range of 5 to 
15 ng/mL; therefore, extrapolation of the efficacy response above 20 ng/mL is not 
recommended. The PK/PD relationship has thus far been demonstrated primarily in the 
infantile-onset SMA population. However, the same positive PK/PD relationship is expected 


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16 
across SMA types and patient age groups because they share the same disease mechanism. This 
is supported by the preliminary correlation analysis from Study 232SM202, which showed a 
positive relationship between CSF Ctrough and total motor milestones scores in participants with 
infantile- and later-onset SMA who received 12 mg of nusinersen as 4 loading doses followed by 
maintenance doses every 4 months. 
Using 2012 ng/mL as the clinical CSF Ctrough target concentration and the predicted CSF PK 
profiles from 2428 mg of nusinersen (4 loading doses followed by maintenance doses every 
4 months) as the reference dosing regimen, simulations were performed to evaluate additional 
dosing scenarios with higher doses and reduced loading-dose frequency. Additional evaluation of 
the maintenance dosing frequency was not performed because previous modeling showed that a 
dosing frequency of every 4 months best maintained the CSF concentration achieved at steady 
state. 
Assuming PK linearity, PK simulations were performed in both infantile- and later-onset SMA 
populations after 2 years of treatment using a population PK model developed from patients 
across the age range of ≤ 6 months to 18 years old. Relative to the reference dosing regimen 
Based on the most recent PK modeling performed, relative to the approved 12-mg label 
regimen (CSF Ctrough of approximately 5 ng/mL), both 28 mg administered as 3 loading doses 
(biweekly) and or 50 mg administered as 2 loading doses (biweekly), each followed by 
maintenance doses of 28 mg every 4 months, were identified to achieve the desired CSF Ctrough 
(approximately 2012 ng/mL) more rapidly at the end of the loading dose period. Nusinersen 
28 mg administered as 3 loading doses (biweekly) had a comparable predicted CSF maximum 
concentration (Cmax) to the reference dosing regimen, whereas the 50-mg dosing regimen 
surpassed the predicted Cmax from the reference dosing regimen. Moreover, the 28-mg 
maintenance dosing regimen adequately maintained the higher CSF Ctrough target 
(approximately 12 ng/mL) during the maintenance dose period. Toxicology studies in 
nonhuman primates evaluating the nonhuman primate equivalent of the 28- and 50-mg doses 
have been conducted and support the safety of these doses in a clinical study (see Section 3.3). 
Therefore, the 28-mg dose (administered as 3 loading doses at biweekly intervals), 50-mg dose 
(administered as 2 loading doses at biweekly intervals), and 28-mg maintenance dose were 
recommended for additional clinical evaluation. 
The single bolus dose in Part C is supported by PK simulations showing that a titration dosing 
regimen of a single loading dose (50 mg) followed by maintenance doses of 28 mg every 
4 months thereafter achieved and maintained the higher CSF Ctrough target concentration 
(approximately 2012 ng/mL) in the representative populations for later-onset and infantile-onset 
SMA, respectively. The predicted exposures of the proposed titration dosing regimens are 
covered by the levels demonstrated to be safe in nonhuman primates. 
Rationale: Recent PK modeling data have revealed updated predicted steady-state exposures 
with the 12 mg dose as compared with the higher dose, in contrast to what was presented in 
Protocol Version 4. Consequently, this section has been updated to align with the new data, as 
presented in the latest version of the Investigator’s Brochure (Version 14). Importantly, the 


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PK/PD modeling continues to support that higher doses of nusinersen may lead to a clinically 
meaningful increase in efficacy. This change also affects Section 1.1, Synopsis. 
 
Section 3.3, Benefit-Risk Assessment 
Change: The summary of the toxicology studies of nusinersen in monkeys (Studies P058-17-03 
and 396443-AS06) was streamlined and updated to include recent findings and interpretations of 
the results. 
Now reads:  
Nusinersen (Spinraza) 12 mg has a positive benefit-risk profile, with more than 34 years of 
postmarketing experience and more than 10,00011,000 patients treated. The safety profile to date 
does not preclude study of higher doses in any population. 
Detailed information about the known and expected benefits and risks, reasonably 
expected AEs, and nonclinical toxicology studies supporting investigation of higher doses of 
nusinersen in the clinic are provided in the Investigator’s Brochure and informed consent 
form (ICF). A high-level summary of the benefits and risks known during study design is 
provided here. 
Anticipating a potential enhancement of benefit with the dosing regimens proposed for 
Study 232SM203, substantiated by PK/PD modeling described in Section 3.1.2, the safety of the 
loading period for Study 232SM203 is supported by a nonclinical study conducted in monkeys 
(Study P058-17-0503), with the dosing regimen matching with the most rigorous loading in 
Study 232SM203 (3 loading doses administered at 2 week intervals). In this study, Tthe 
no-observed-adverse-effect level (NOAEL) for Study P058 17 05 was determined to be 15 mg 
(human equivalent dose of 150 mg)., the high dose of the study, supported by the observation of 
non adverse findings limited to dose dependent/transient neurological clinical signs and 
histopathological findings in the brain and lymph nodes. This NOAEL provides As such, dosing 
for Study 232SM203 has a safety margin of at least 4.5-fold for the loading doses (based on 
cumulative doses during the loading period) and a 3-fold margin for a single loading dose of 
50 mg. 
The safety of long-term exposure during the Study 232SM203 maintenance period is supported 
by a 53-week monkey study (Study 396443-AS06). This study implemented a more frequent 
dosing regimen than what is planned for Study 232SM203, 13 total doses during the 53 week 
duration, with the first 5 doses given once every week during the first 29 days, followed by an 
additional 8 doses given once every 6 weeks. Based on the 3 dose levels (0.3, 1, and 4 mg per 
dose) used in the study, for a duration of 53 weeks, the monkeys received a cumulative 
nusinersen dose of 3.9, 13, and 52 mg, respectively, at each dose level. Monkeys received a 
cumulative dose of 3.9, 13, and 52 mg at each dose level (0.3, 1, and 4 mg per dose, 
respectively) during the 52-week treatment duration. Factoring in a CSF volume scale of 
10 between humans and monkeys, the annual cumulative doses in monkeys from this study 
ranged from 3.0  to 7.2 fold (loading doses) and 6.2  to 14.4 fold (maintenance doses) higher 


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than those planned for Study 232SM203. The major findings in monkeys were the 
histopathological changes in the hippocampus, which consisted of neuronal vacuolation and rare 
necrotic cells and cell debris at the 2 highest doses (1 and 4 mg). The overall no observed-effect 
level (NOEL) for the study was 0.3 mg, driven by findings limited to the hippocampus, while no 
effects in any other tissues were observed up to the high dose (4 mg) on a comprehensive 
histopathology evaluation. The overall NOAEL was determined to be 4 mg. PK scaling was 
used to estimate the nusinersen tissue concentration in patients with SMA during maintenance 
treatment at 28 mg from tissue concentrations measured in patients with SMA treated with 
12 mg of nusinersen (scaled from the tissue concentrations measured during autopsy of 
participants from Study CS3A). Tissue concentrations measured in monkeys from the 53-week 
toxicology study at the NOEL NOAEL (0.3 mg for the hippocampus and 4 mg for all other 
tissues evaluated) were compared to the estimated tissue concentrations in patients with SMA. 
Based on these data, t The exposure-based safety margin is at least 1.1 fold1.4-fold based on 
exposure in the spinal cord (safety margins are higher for other tissues). 
The potential risks related to participation in this study are justified by the anticipated benefit to 
participants. 
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of nusinersen is provided in the Investigator’s Brochure and informed consent form (ICF). 
A high level summary of the benefits and risks known during study design is provided here. 
Rationale: These changes were made to present the most recent data available on benefit-risk 
assessment relevant for this study and to align with the current version of the Investigator’s 
Brochure (Version 14).This change also affects Sections 1.1, Synopsis. 
 
Section 5.1, Study Overview 
Change: The requirement for inpatient stays for participants enrolled in Part B was limited to 
Day 1 and Day 15 only, with the option for inpatient stays at other visits based on the 
Investigator’s discretion. 
Now reads:  
Participants will remain at the clinic for at least 24 hours after each study treatment 
administration or sham procedure on Days 1 and 15; inpatient stays at other visits may occur 
based on the Investigator’s discretion. If the primary reason for the inpatient stay is due to 
an AE or SAE, reporting requirements per Section 11.3 must be followed. 
Rationale: Inpatient stays may be burdensome to study participants and their families. The 
current safety data available support removal of the required inpatient stays after the loading 
period for the higher dose (i.e., 50 mg administered on Days 1 and 15). Investigators are still able 
to use their clinical judgment on a case-by-case basis to determine whether an inpatient stay may 
be beneficial for participants following the Day 15 study visit. If an Investigator decides to keep 
a participant at the clinic for follow-up beyond what is required per protocol, it is important that 


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19 
the site personnel continue to report AEs or SAEs that occur during that time period as required 
by the study protocol.This change also affects Section 1.1, Synopsis; Section 1.3, Schedule of 
Activities (Table 2). 
 
Section 6.1, Inclusion Criteria 
Change: The inclusion criterion for Part B regarding gestational age was revised to allow for 
additional flexibility if there are no complications due to prematurity and with approval by the 
Medical Monitor. The inclusion criteria for Part C were updated to specify the age and functional 
status requirements for enrollment into Cohort 2 of Part C. 
Now reads: 
Part B 
Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) 
… 
13. Gestational age of 37 to 42 weeks for singleton births and 34 to 42 weeks for twins. Infants 
with a lower gestational age may be considered for enrollment if there are no complications 
due to prematurity and approval by the Medical Monitor has been granted. 
… 
Part C 
All Participants 
1. Signed informed consent of parent or guardian and signed informed assent of the participant, 
if indicated per participant’s age and institutional guidelines 
2. Males and females of any age (individuals ≥ 18 years of age at Screening must be ambulatory) 
3.2. Currently on nusinersen treatment at the time of Screening, with the first dose being at least 
1 year prior to Screening 
… 
Participants in Cohort 1  
10. Males and females of any age (individuals ≥ 18 years of age at Screening must be 
ambulatory) 
Participants in Cohort 2 


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11. Males and females ≥ 18 years of age at Screening (can be ambulatory or 
nonambulatory) 
12. HFMSE total score ≥ 4 points at Screening 
13. RULM entry item A score ≥ 3 points at Screening 
Rationale: The gestational age requirements for participants in Part B were revised to enroll 
children without complications due to prematurity because some children with lower gestational 
age may still be eligible for the study. This is consistent with participants who were enrolled in 
Study CS3B, which may be used in some of the prespecified analyses to evaluate the higher 
dose.  
The age and functional status requirements at Screening for Cohort 2 of Part C were added to 
inform Investigators of the eligibility criteria for Cohort 2 and ensure appropriate Screening of 
potential adult candidates. Participants may be ambulatory or nonambulatory to be representative 
of the real-world SMA patient population. An HFMSE total score of at least 4 and RULM entry 
item A score of at least 3 will enrich Cohort 2 with participants whose motor function abilities 
may enable greater potential to measure changes in efficacy with the higher dose. 
Section 6.2, Exclusion Criteria 
Change: The exclusion criteria for Part B were revised as follows: 1) to add a criterion related to 
history of systemic hypersensitivity reaction to the excipients contained in the study treatment 
formulation or to any diagnostic agents to be administered during the study; 2) to clarify that 
treatment with an investigational drug not specific for SMA is also exclusionary; and 3) to 
change the definition of “hypoxemia” for high-altitude study sites. 
The exclusion criteria for Part C were revised as follows: 1) to add a criterion related to history 
of systemic hypersensitivity reaction to nusinersen, the excipients contained in the formulation, 
or to any diagnostic agents to be administered during the study; and 2) to exclude participants 
with severe scoliosis from Cohort 2. 
Now reads:Part B 
All pParticipants 
… 
6. Clinically significant abnormalities in hematology of clinical chemistry parameters, as 
assessed by the Investigator, at Screening that would render the participant unsuitable for 
inclusion 
7. History of systemic hypersensitivity reaction to the excipients contained in the 
formulation, and if appropriate, any diagnostic agents to be administered during the study 
7. 8. Prior scoliosis surgery that would interfere with the LP injection procedure 


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21 
… 
10. 11. Treatment with an investigational drug given for including but not limited to the 
treatment of SMA (e.g., oral albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, 
valproate, and hydroxyurea), biological agent, or device within 30 days or 5 half-lives of the 
agent, whichever is longer, prior to Screening or anytime during the study; any prior or current 
treatment with any SMN2-splicing modifier or gene therapy; or prior antisense oligonucleotide 
treatment (e.g., nusinersen) or cell transplantation  
… 
Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) 
15. 16. Hypoxemia (O2 saturation [awake or asleep] <96%, without ventilation support] ˂ 96% 
at an altitude of < 1500 meters, < 92% at an altitude of 1500 to 2000 meters, or < 90% at an 
altitude > 2000 meters) at Screening 
… 
Part C 
All Participants 
… 
6. Clinically significant abnormalities in hematology of clinical chemistry parameters, as 
assessed by the Investigator, at Screening that would render the participant unsuitable for 
inclusion 
7. History of systemic hypersensitivity reaction to nusinersen, the excipients contained in 
the formulation, and if appropriate, any diagnostic agents to be administered during the 
study 
7. 8. Prior scoliosis surgery that would interfere with the LP injection procedure 
… 
Participants in Cohort 2 
19. Severe scoliosis evident on X-ray examination at Screening (with the participant in a 
sitting or supported sitting position). For sites with local regulation on use of X-ray 
(e.g., Germany), the Investigator may assess scoliosis based on physical examination 
without imaging. 
• Cobb’s angle > 40.0°: exclusionary for severe scoliosis 
• Cobb’s angle < 33.0°: not exclusionary for severe scoliosis 


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• For participants with a Cobb’s angle between 33.0° and 40.0°, inclusive, 
discussion with the Medical Monitor must occur before determining eligibility. 
Rationale: Exclusion criteria were added to Parts B and C to exclude participants who may have 
a history of systemic hypersensitivity to nusinersen (Part C only), to the excipients in the 
nusinersen injection formulation, or to any diagnostic agents that may be used as part of the 
study treatment administration procedure. Since Part B explicitly excludes prior exposure to 
nusinersen, it is impossible to identify a history of systemic hypersensitivity in those candidates. 
The criterion in Part B that excludes participants who received treatment with an investigational 
drug for the treatment of SMA within 30 days or 5 half-lives of the agent was broadened to 
include other investigational drugs not given for the treatment of SMA as well. This aligns with 
changes made to Section 7.6.1.2, Disallowed Concomitant Therapy. 
Lower oxygen levels at high-altitude study sites will drive down basal oxygen levels, so the 
original definition of hypoxemia in the protocol was not appropriate for high-altitude sites. The 
protocol was therefore updated to specify different definitions of hypoxemia based on altitude 
for participants with infantile onset SMA being screened for Part B of the study. 
The exclusion criterion for severe scoliosis for participants in Cohort 2 of Part C was added to 
align with Parts A and B of the study. 
This change also affects Section 1.3, Schedule of Activities (Table 4). 
 
Section 6.3.2, Retesting and Rescreening 
Change: The protocol was revised to allow a full rescreening of participants who originally 
failed Screening, at the discretion of the Investigator. 
Now reads:  
During the Screening period, participants who have an out-of-range result that is not clinically 
significant can may be retested 1 time only at the discretion of the Investigator within the 
Screening process, without the need for a repeat full Screening. The Screening period may be 
extended for up to 10 days for individuals who cannot complete the Day 1 Visit within 21 days 
of signing the ICF, as long as they continue to meet other eligibility criteria. 
Participants who fail Screening (see Section 6.3.3) may be rescreened once at the discretion 
of the Investigator. Participants who are rescreened will be assigned a new identification 
number. 
Rationale: Potentially eligible study participants may have an acute ongoing medical condition 
that could lead to screen failure in the short-term, but after resolution could allow that participant 
to pass all Screening criteria. Protocol Version 4 does not specifically address rescreening; it 
only addresses retesting. The protocol has been updated to allow retesting of an out-of-range 


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23 
result without repeating the full screening and has been revised to clarify that each candidate 
may be rescreened once at the discretion of the Investigator. It was also clarified that any 
participant who is rescreened will need to be assigned a new identification number. 
Section 7.3.1, Nusinersen 
Change: The study drug formulation language was revised to align with upcoming formulations 
that will be available for Study 232SM203. 
Now reads:  
Nusinersen will be supplied as specified in the DHA. The proposed new study treatment is 
supplied as a formulation that contains 12 mg/mL nusinersen, 0.034 mg/mL sodium dihydrogen 
phosphate dihydrate, 0.111 mg/mL sodium phosphate dibasic anhydrous, 7.96 mg/mL sodium 
chloride, 0.224 mg/mL potassium chloride, 0.206 mg/mL calcium chloride dihydrate, and 
0.163 mg/mL magnesium chloride hexahydrate in water for injection, adjusted, if necessary, to a 
target pH of 7.2 with hydrochloric acid or sodium hydroxide during compounding. The drug 
product will be diluted at the clinical site with supplied artificial CSF diluent to enable ascending 
doses in the proposed clinical study, as described in the DHA. Further details on drug 
preparation and administration may be found in the DHA. 
Rationale: New formulations (i.e., ready-to-use kits) will be available and may be used at 
clinical sites for Study 232SM203. The language in Protocol Version 4 was not consistent with 
use of the planned ready-to-use kits. Therefore, the protocol was revised to remove reference to 
dilution of the drug product and instead refers to the DHA for all information on drug supply, 
preparation, and administration. In addition, the concentrations of excipients were removed to 
align with the latest Investigator’s Brochure template update by the Sponsor.  
Section 7.6.1.2, Disallowed Concomitant Therapy 
Change: The protocol was revised to prohibit participation in any other interventional clinical 
studies (including those for non-SMA treatments) while enrolled in Study 232SM203. 
Now reads:Participants are prohibited from receiving other experimental or approved agents for 
the treatment of SMA, including gene therapy, SMN2-splicing modifier, biological agent, or 
device, during the study. This includes marketed agents at experimental doses that are being 
tested for the treatment of SMA (oral albuterol/salbutamol, riluzole, carnitine, sodium 
phenylbutyrate, valproate, hydroxyurea, etc.). In addition, participants will not be allowed to 
enroll in other interventional studies during Study 232SM203. 
Rationale: Protocol Version 4 does not prohibit participants from enrolling in other 
interventional clinical studies for non-SMA treatments. Receiving treatment with other 
investigational therapies could interfere with the interpretation of the safety and efficacy findings 
for Study 232SM203. Therefore, the protocol was revised so that any participant who initiates 
treatment with an experimental or approved SMA therapy or enrolls in another interventional 
clinical study for any indication would need to be withdrawn from Study 232SM203. In addition, 
SMN2-splicing modifiers were added to the list of examples of treatments for SMA to align with 
the language in the exclusion criteria.This change also affects Section 1.3, Schedule of 


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24 
Activities; Table 5, Schedule of Activities for Participants in Part B Who Discontinue Study 
Treatment but Agree to Remain in the Study; Section 8.1, Discontinuation of Study Treatment; 
Section 8.3, Withdrawal of Participants From the Study. 
 
Section 9.1, Clinical Efficacy Assessments 
Change: The protocol was revised 
 to update the 
information on PedsQL, and to add measures of 
 for the adult 
participants who will enroll in Cohort 2 of Part C. 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
9.1.10.1. 
Pediatric Quality of Life Inventory (Generic Core Scales and Neuromuscular 
Module) 
Participants with later-onset SMA will be evaluated using the 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 
Patient self-report is measured in children and adolescents 5 to 18 25 years of age, and parent 
proxy-report of child HRQOL is measured for children and adolescents 2 to 18 25 years of age. 
Patient self-report and parent proxy-report are available for participants who are ≥ 26 
years of age for the Generic Core Scale. The PedsQL 4.0 Generic Core Scales include an 
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 2 to 18 years of age with neuromuscular disorders, including 
SMA. 


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25 
In Parts A and B, all participants with later-onset SMA will be evaluated using the PedsQL. In 
Part C Cohort 1, the PedsQL (in addition to ACEND) will be evaluated in participants who are 
≥ 2 years of age at Screening. The PedsQL will not be evaluated for participants in Part C 
Cohort 2. 
If a participant is assessed on PedsQL at baseline, then the age range of the scale used at 
Screening for that participant will continue to be used up to Day 302, regardless of changes in 
the participant’s age. 
… 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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26 
 
  
Rationale: 
 
 
 
 
The description of the PedsQL was updated to clarify that the adults in Cohort 1 of Part C will be 
assessed with this scale and to provide more details regarding the scales available for participants 
up to age 25 and aged 26 years or older. The text clarifies that participants in Cohort 2 of Part C 
will not be evaluated with the PedsQL. 
With the increase in the number of adult participants as part of this protocol amendment, the 
following measures were added for Cohort 2 of Part C: 
. These will enable collection of additional data that are important for adults with SMA, 
including 
.This change also affects Section 1.3, 
Schedule of Activities (Tables 2, 3, and 4); Section 4, Study Objectives and Endpoints; Section 
16, References. 
 
 
Change: 
 
 
Now reads:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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27 
 
 
Rationale: 
 
 
 
 
 
  
This change also affects Section 4, Study Objectives and Endpoints; 
 
 
 
 
Section 10.1, Clinical Safety Assessments 
Change: Growth parameters were updated to allow for measurement of length for participants 
with later-onset SMA who are not able to have height measured. In addition, the requirements 
for measuring LP opening pressure were revised. 
Now reads:The following clinical assessments will be performed to evaluate the safety profile of 
nusinersen: 
• AE and SAE recording 
• Medical (including SMA) history. 
 
• Vital sign measurements: temperature, pulse rate, systolic and diastolic blood 
pressure, respiratory rate, and pulse oximetry 
• Growth parameters: body length/height (for all participants; body length will be 
measured for participants who are not able to stand independently), head, chest, 
and arm circumference (for participants with infantile-onset SMA), and ulnar length 
(for participants with later-onset SMA) will be measured. Additional parameters of 
weight-for-age, weight-for-length, and head-to-chest circumference ratio will be 
calculated. 
• Neurological examinations: HINE Sections 1 and 3 will be administered to 
participants in Part B with infantile-onset SMA, and participants in Part C < 2 years 
of age at the time of informed consent. A neurological examination will be performed 
in participants in Parts A and B with later-onset SMA and participants in Part C 
≥ 2 years of age at the time of informed consent.  
• Physical examinations (videotaping of physical examinations is optional) 


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• Electrocardiograms (ECGs) 
• LP opening pressure: dDetails available in the DHA. LP opening pressure will be 
evaluated for all participants in Parts A and C, but only for participants with 
later-onset SMA in Part B. 
• Concomitant therapy and procedure recording 
Rationale: Protocol Version 4 required height and ulnar length to be measured for participants 
with later-onset SMA, but there are participants with later-onset SMA in Study 232SM203 who 
are unable to stand and cannot have height measured. Therefore, measurement of length is being 
offered as an alternative to height for these participants. 
The requirement to evaluate LP opening pressure for the infantile-onset SMA population in Part 
B was removed. Measuring an accurate value for LP opening pressure is difficult in infants 
because the pressure can be elevated due to crying (increased intra-thoracic pressure increase) 
and posturing (intra-abdominal pressure increase) during the assessment. LP opening pressure 
values in this patient population would be varied and inconsistent. Furthermore, although 
sedation of infants could enable a more accurate reading of LP opening pressure, infants are not 
typically sedated for this procedure (either in clinical practice or the clinical study). Requiring 
sedation purely for this purpose does not justify the risks introduced. Therefore, the protocol has 
been revised to remove this assessment for the infantile-onset SMA participants in Part B, while 
retaining this assessment for all other participants in the study. This is aligned with the PSUR 05 
PRAC recommendation and commitment to measure LP opening pressure in a clinical study 
with nusinersen to help further assess the important identified risk of hydrocephalus. 
This change also affects Section 1.3, Schedule of Activities (Tables 2, 3, and 4). 
 
Section 14.1.4, Central Laboratories for Laboratory Assessments 
Change: The requirements for SMA genetic testing were clarified, noting that all laboratory 
samples collected from participants in China will be analyzed within China. 
Now reads:  
A central laboratory will be selected by the Sponsor to analyze all hematology, blood chemistry, 
urinalysis, and CSF samples (except for local analysis of CSF protein, cell count, and glucose) 
collected for this study. Analysis of urine total protein, coagulation, pregnancy tests, and 
CSF protein/cell count/glucose will be conducted by local laboratories. 
 
 will be analyzed at a laboratory selected by the Sponsor 
(Appendix B). 
A blood sample will be collected at Screening for SMN2 copy number for those participants 
without acceptable historical genetic documentation of SMN2 copy number. For all other 
participants, a blood sample will be collected during the study (preferably before or on the first 


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29 
maintenance dosing visit) for the analysis of both to evaluate SMN1 gene status (copy number, 
and deletion/, and mutation where necessary to confirm 5q SMA) and SMN2 copy number by 
the central laboratory. For participants without acceptable documentation of these genetic 
testing results before Screening, a blood sample must be collected during the Screening 
period to determine eligibility (preferably for analysis by the central laboratory, but may 
be determined by local lab genetic testing if needed). For participants with documentation 
of these genetic testing results before Screening or whose sample was analyzed locally 
during the Screening period (with documentation of these genetic testing results), a blood 
sample will be collected (preferably at Screening, but must be collected by the first 
maintenance dosing visit) for confirmatory testing through the central laboratory. 
Sample analysis for participants from China will be performed within China. 
Rationale: The SMA genetic testing language was revised to further clarify for site personnel 
which samples need to be collected at specific times, as well as to further describe the different 
methods of determining study eligibility (i.e., through acceptable historical genetic 
documentation prior to Screening for Study 232SM203 or through collection and analysis of a 
blood sample at Screening). In addition, in order to simplify analysis of the samples collected in 
China, the protocol was updated so that those samples could be analyzed within China, removing 
the need to export genetic material out of the country. 
This change also affects Section 1.3, Schedule of Activities (Tables 2, 3, and 4); 
 
 


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30 
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. 
• Typographical errors and formatting were corrected throughout the protocol. 
• Section numbers, eligibility criteria numbering, and footnote numbering were updated 
where applicable. 
• The sample size was updated to “up to approximately 172 participants” throughout 
the protocol. 
• The long-term extension study number (232SM302) was added throughout the 
protocol. 
• Reference to the “high dosing regimen” was updated to “higher dosing regimen” 
throughout the protocol. 
• The overall exposure of nusinersen worldwide was updated throughout the protocol 
with data available as of December 2020. 
• In Section 1.3, Schedule of Activities for Parts B and C, several minor changes were 
made either to align with other changes made throughout the protocol or to clarify 
existing content: 
− Details on Screening were removed from the footnotes but are available in 
Section 6.3.1, Screening. 
− It was noted that if participants who meet the criteria for contraception use in 
Parts B and C enroll into the long-term extension study (232SM302) at the Day 
302 visit, they do not need to return for the additional follow-up visit for Study 
232SM203 at Day 399 (Part B) or Day 361 (Part C). 
− It was clarified that a local laboratory may be used for analysis of blood 
chemistry, hematology, and urinalysis samples for the Screening visit if needed 
for timely treatment at the Investigator’s discretion. 
− It was clarified that coagulation testing results should be reviewed prior to dosing. 
− Removed the requirement for evaluating HFMSE and RULM prior to other motor 
function and motor milestone assessments because details on the order of 
assessments is provided in the scale manuals. 


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− It was clarified that the 2 baseline assessments for CHOP INTEND, HFMSE, and 
RULM must occur on different days. 
− In the Part C Schedule of Activities tables, it was clarified that adult participants 
who do not require a caregiver during the study visits will only have the CGIC 
assessed by the Investigator. 
− In the Part C Schedule of Activities tables, it was clarified that the ACEND will 
not be collected for adult participants who do not require a caregiver. 
− In the Part C Cohort 2 Schedule of Activities table, the Day 241 timepoint for the 
ACEND assessment was removed. 
• Section 2, List of Abbreviations, was updated. 
• In Section 3.2.2, Current Therapies for SMA, language regarding the current 
therapies available for SMA was updated based on recent regulatory approvals. 
• In Section 3.2.3, Profile of Previous Experience With Nusinersen, the information on 
regulatory approvals of nusinersen was simplified. 
• In Section 6.2, Exclusion Criteria, it was clarified that nusinersen is an example of an 
antisense oligonucleotide treatment. 
• In Section 7.1, Regimen, it was clarified that a protocol deviation should be recorded 
if a loading dose is delayed or missed (as per the schedule of activities) and that 
dosing should be continued according to the schedule of activities (rather than “the 
prescribed dosing frequency”). 
• In Section 7.3, Study Treatment Management, a statement was added clarifying that 
the DHA aligns with all other references, including the protocol. 
• In Section 8.3, Withdrawal of Participants From the Study, it was clarified that 
participants who initiate treatment with a disallowed concomitant therapy as 
described in Section 7.6.1.2 must be withdrawn from the study. Similarly, in Table 5, 
it was clarified that these participants are not eligible to remain in the study for 
follow-up visits after discontinuing study treatment. 
• In Section 9.1, Clinical Efficacy Assessments, several minor changes were made: 
− Information regarding the definitions of sitting without support and ambulatory 
were moved to the top of the section. 
− It was clarified that while videotaping of motor milestone and motor function 
assessments is optional, if the participant/caregiver provides consent to video 
recording, all assessments should be recorded. 


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− The QoL questionnaires that apply for each part of the study were specified. 
− The appropriate patient populations for each assessment were clarified for Cohort 
1 of Part C and added for Cohort 2 of Part C. 
− Assessment of the different efficacy measures was changed from “by the 
Investigator” to “by the clinical site evaluator.” 
− Statements were added to clarify that, whenever possible, for each participant, the 
same clinical evaluator should conduct all motor milestone and motor function 
assessments across all study visits since the use of different raters can lead to 
variability in the data. 
− It was clarified that adult participants who do not require a caregiver may self-
report WHO motor milestone achievement. 
− 
 
 
 
 
− 
 
 
 
− It was clarified that all participants with infantile-onset SMA in Part B need to 
record daily ventilator use in the ventilator use diary for the duration of the study, 
regardless of whether or not a ventilator is being used. 
− Some of the subsections were reordered to improve flow in the section. 
• In Section 11.3, Monitoring and Recording Events, and Section 11.6, Safety 
Responsibilities, language regarding reporting requirements for SAEs was updated to 
include “or according to national law,” in line with the latest protocol template update 
by the Sponsor to accommodate countries that may have different reporting 
requirements. 
• In Section 12, Statistical Methods and Determination of Sample Size, subheading 
12.1 was moved. 
• Section 16, References, was updated. 


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33 
LIST OF ABBREVIATIONS 
 
 
 
 
ACEND 
Assessment of Caregiver Experience with Neuromuscular Disease 
AE 
adverse event 
CHOP INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders 
CSF 
cerebrospinal fluid 
Cmax 
maximum concentration 
CNS 
central nervous system 
Ctrough 
trough concentration 
DHA 
Directions for Handling and Administration 
EC50 
concentration at 50% of the maximum observed biological effect 
ECG 
electrocardiogram 
 
 
EU 
European Union 
HFMSE 
Hammersmith Functional Motor Scale – Expanded 
HINE 
Hammersmith Infant Neurological Examination 
HRQOL 
health-related quality of life 
ICF 
informed consent form 
IDMC 
independent data monitoring committee 
 
 
LP 
lumbar puncture 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PedsQL 
Pediatric Quality of Life Inventory™ 
PK 
pharmacokinetic(s) 
 
 
PRAC 
Pharmacovigilance Risk Assessment Committee 
PSUR 
Periodic Safety Update Report 
QoL 
quality of life 
RULM 
Revised Upper Limb Module 
SAE 
serious adverse event 
SMA 
spinal muscular atrophy 
 
 
SMN 
survival motor neuron 
SMN1 
survival motor neuron-1 (gene) 
SMN2 
survival motor neuron-2 (gene) 
US 
United States 
 
 
WHO 
World Health Organization 
 


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1
Biogen MA Inc.
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United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 232SM203
Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants 
With Spinal Muscular Atrophy
Version 4
Date: 05 August 2020
EUDRA CT Number: 2019-002663-10
Version 4 of the protocol has been prepared for this amendment, which supersedes Version 3.




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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.
Section 15.3, Monitoring of the Study
Change:  Language was added to the protocol regarding remote monitoring of study sites during 
the global COVID-19 pandemic.
Now reads:  
The Site Monitor will visit the study site at regular intervals during the study and after the study 
has completed, as appropriate, or may perform monitoring activities remotely (where permitted 
by local regulations) only during the COVID-19 pandemic where on-site monitoring is not  
allowed per local/regional restrictions. A clinical site monitoring plan will detail who performs 
the monitoring, how often, and the extent of the review. It also will provide the monitoring 
strategy, with emphasis on participant safety, data integrity, and critical data and processes.
Rationale: This change was made to clarify that remote monitoring may be implemented only 
in the event that the COVID-19 pandemic precludes on-site monitoring. 


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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.

Section 2, List of Abbreviations, was updated.


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LIST OF ABBREVIATIONS
AE
adverse event
COVID-19
coronavirus disease 2019
IDMC
independent data monitoring committee
SAE
serious adverse event


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______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 232SM203
Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants 
With Spinal Muscular Atrophy
Version 3
Date: 05 June 2020
EUDRA CT Number: 2019-002663-10
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2.2.






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Section 1.3, Table 2: Schedule of Activities for Part B
Change: A footnote was added to Table 2 to specify that the LP opening pressure and CSF local 
lab sample can only be measured and collected on Days 1, 15, and 279 in Part B of 
Study 232SM203.
Now reads:
Table 2:       Schedule of Activities for Part B
Footnote 6: Only measure LP opening pressure and assess CSF local lab sample on Days 1, 
15, and 279 to avoid potential unblinding.
Rationale: In Part B, the Control Group (12/12 mg) will receive 4 loading doses of nusinersen 
on Days 1, 15, 29, and 64 followed by 2 maintenance doses of nusinersen on Days 183 and 279. 
The 50/28-mg Group will receive 2 loading doses of nusinersen on Days 1 and 15 followed by 
2 maintenance doses of nusinersen on Days 135 and 279. In order to maintain the blinding in 
Part B of the study, both the LP opening pressure and the local CSF analysis will only be 
assessed at those visits where both groups are administered a dose of study treatment.
Section 1.3, Schedule of Activities
Change: The footnotes regarding study treatment injection in Tables 1, 2, and 3 were revised to 
clarify the potential anesthesia and/or sedation options that may be used for the LP procedure 
and to ensure that all participants in Part B would receive equivalent levels of anesthesia and/or 
sedation to maintain the blind.
Now reads:
Table 1:       Schedule of Activities for Part A
Footnote 46: Spinal ultrasound, fluoroscopy, or similar techniques may be used for the LP 
procedure, if deemed necessary, but are not required. Anesthesia (local or general) and/or 
sedation may be used for the LP procedure, at the discretion of the Investigator and/or study 
center.
Table 2:       Schedule of Activities for Part B
Footnote 47: Spinal ultrasound, fluoroscopy, or similar techniques may be used for the LP 
procedure, if deemed necessary, but are not required. Local anesthesia and/or sedation may be 
used for the LP procedure in participants with infantile-onset SMA, and Aanesthesia (local 
or general) and/or sedation may be used for the LP procedure in participants with later-onset 
SMA, at the discretion of the Investigator and/or study center. If anesthesia and/or sedation is 
used for the LP procedure for an individual participant with later onset SMA, in order to 
maintain the blind, that participant will receive equivalent anesthesia and/or sedation (according 


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to institutional procedures) for all of the sham procedures and LP injections. Participants with 
infantile onset SMA will receive minimal sedation (i.e., a low dose of an anxiolytic) for the sham 
procedure, according to institutional procedures. For participants with infantile-onset SMA, LP 
injections/sham procedures may not occur within 72 hours after an immunization.
Table 3:       Schedule of Activities for Part C
Footnote 47: Spinal ultrasound, fluoroscopy, or similar techniques may be used for the LP 
procedure, if deemed necessary, but is not required. Local anesthesia and/or sedation may be 
used for the LP procedure in participants < 2 years of age, and Aanesthesia (local or general) 
and/or sedation may be used for the LP procedure in participants ≥ 2 years of age, at the 
discretion of the Investigator and/or study center. For participants with infantile onset SMA, LP 
injections may not occur within 72 hours after an immunization.
Rationale: Although the benefit/risk ratio of general anesthesia in young participants does not 
justify use in this study, some forms of sedation to reduce anxiety may be indicated and the 
protocol was clarified to allow sites to use these methods at their discretion throughout the study 
as long as it is consistently used in an individual participant for all visits in Part B to maintain 
blinding to dosing regimen.
This change also affects Section 7.4, Blinding Procedures.
Section 1.3, Schedule of Activities
Change: The footnotes regarding ECG monitoring in Tables 1, 2, and 3 were revised to adjust 
the postdose ECG timing and address abnormal ECG results.
Now reads:
Table 1:       Schedule of Activities for Part A
Footnote 1012: ECGs will be performed predose, at 25 hours (±15 minutes1 hour) postdose, and 
at 24 hours (±2 hours) postdose on Days 1, 15, and 29; at the Day 64 visit;, at 45 hours (±30 
minutes1 hour) postdose on Days 15 and 29149 and 269;, at 24 hours (±2 hours) postdose at all 
dosing visits, and at EOSDay 302/ET. Predose ECGs should be repeated when the assessment 
falls outside the protocol-specified window because of a delay in dosing. If a postdose ECG 
result is abnormal and clinically significant, a repeat ECG should be performed within 
2 hours.
Table 2:       Schedule of Activities for Part B
Footnote 1114: ECGs will be performed predose, at 25 hours (±15 minutes1 hour) postdose, and 
at 24 hours (±2 hours) postdose on Days 1, 15, 29, and 64; at 45 hours (±30 minutes1 hour) 


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postdose on Days 15 and 29135, 183, and 279;, at 24 hours (±2 hours) postdose at all dosing 
visits, and at EOSDay 302/ET. Predose ECGs should be repeated when the assessment falls 
outside the protocol-specified window because of a delay in dosing. If a postdose ECG result is 
abnormal and clinically significant, a repeat ECG should be performed within 2 hours.
Table 3:       Schedule of Activities for Part C
Footnote 1114: ECGs will be performed predose, at 25 hours (±15 minutes1 hour) postdose, and 
at 24 hours (±2 hours) postdose on Day 1,; at 5 hours (±1 hour) postdose on Days 121 and 
241; and at Day 302/ET and at 24 hours (±2 hours) after the Day 121 and 241 doses. Predose 
ECGs should be repeated when the assessment falls outside the protocol-specified window 
because of a delay in dosing. If a postdose ECG result is abnormal and clinically significant, 
a repeat ECG should be performed within 2 hours.
Rationale: The ECG monitoring schedule in the footnote was clarified to align with the content 
presented in the Schedule of Activities table. The postdose ECG assessments after each dosing 
visit were modified to align with the expected
 (i.e., 4 to 6 hours postdose). 
Additional details were added to clarify that a clinically significant finding on a postdose ECG 
should prompt a repeat assessment within 2 hours of the initial abnormal finding.
Section 1.3, Schedule of Activities
Change: Additional text was added to allow the participants to complete the Safety Laboratory 
Tests prior to the dosing visit for Parts A, B, and C.
Now reads:
Table 1:       Schedule of Activities for Part A
Footnote 1113: …These assessments may be performed up to 7 days prior to dosing/study 
visit, if necessary…
Table 2:       Schedule of Activities for Part B
Footnote 1215: …These assessments may be performed up to 7 days prior to dosing/study 
visit, if necessary…
Table 3:       Schedule of Activities for Part C
Footnote 1215: …These assessments may be performed up to 7 days prior to dosing/study 
visit, if necessary…
Rationale: Allowing efficacy assessments to be conducted prior to the dosing visit days will 
reduce participant burden at those visits and increase flexibility for sites and study participants.






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Assessments
D-21 to 
D-1
D1, D15 (±1 day), D29 
(±1 day), D64
(±17 days)
D135 (±7 days), 
D183 (±7 days), 
D279 (±7 days)
2 to 14 Days 
After Each 
Maintenance 
Dose
D302/ET
(±7 days)
D399
(+14 days)
Rationale: The 1-day visit windows for the Days 15 and 29 loading dose visits were clarified. 
For Part A, a 7-day window was added for the Day 64 visit, and in Part B, the Day 64 visit 
window was increased from 1 day to 7 days to offer greater visit scheduling flexibility for the 
sites and study participants with no anticipated impact on patient safety or quality of efficacy 
data collected.
This change also affects Section 1.1, Synopsis; and Section 5.2, Study Duration for Participants.
Section 1.3, Schedule of Activities
Change: A footnote was added to Tables 1, 2, and 3 in order to ensure that efficacy assessments 
(CHOP INTEND, HFMSE, and RULM) are conducted twice prior to the first dose of study 
treatment.
Now reads:
Table 1:       Schedule of Activities for Part A
Footnote 20: Two baseline assessments are required for HFMSE and RULM. At least 
1 assessment must be conducted during the Screening period. The second assessment may 
be conducted either during the Screening period or at Day 1 predose. If both baseline 
assessments are conducted during the Screening period, the assessments do not need to be 
repeated on Day 1.
Table 2:       Schedule of Activities for Part B
Footnote 21: Two baseline assessments are required for CHOP INTEND, HFMSE, and 
RULM. At least 1 assessment must be conducted during the Screening period. The second 
assessment may be conducted either during the Screening period or at Day 1 predose. If 
both baseline assessments are conducted during the Screening period, the assessments do 
not need to be repeated on Day 1.
Table 3:       Schedule of Activities for Part C
Footnote 22: Two baseline assessments are required for CHOP INTEND, HFMSE, and 
RULM. At least 1 assessment must be conducted during the Screening period. The second 
assessment may be conducted either during the Screening period or at Day 1 predose. If 
both baseline assessments are conducted during the Screening period, the assessments do 
not need to be repeated on Day 1.


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Rationale: The requirement to assess efficacy twice prior to the first dose of study treatment was 
added to establish a more stable baseline and to be consistent with historical studies for 
nusinersen.
Section 1.3, Table 1: Schedule of Activities for Part A
Change: A footnote was added to Table 1 in order to specify that efficacy assessments are not 
required to be performed on Days 1 and 15 for Part A, except in cases when the Day 1 efficacy 
assessment is required for the second baseline measurement for HFSME and RULM.
Now reads:
Table 1:       Schedule of Activities for Part A
Footnote 21: During the loading period, the efficacy assessments will be performed on 
Day 29 predose only…
Rationale: A Day 1 predose motor assessment is unnecessary in cases where the baseline has 
been established during Screening. The schedule for capturing efficacy data during Part A of the 
study was modified to reduce participant burden by removing the need for assessments on 
Day 15.
Section 1.3, Schedule of Activities
Change: A footnote was added to Table 1 and an existing footnote was modified in Table 2 in 
order to add windows for the predose efficacy assessments required at the loading dose visits 
(i.e., Days 29 and 64, respectively) in Parts A and B of Study 232SM203.
Now reads:
Table 1:       Schedule of Activities for Part A
Footnote 21: …The Day 29 efficacy assessments may be performed up to 3 days prior to 
dosing, if necessary.
Table 2:       Schedule of Activities for Part B 
Footnote 2022: During the loading period, the efficacy assessments will be performed on 
Days 29 and 64 predose only. The Day 29 efficacy assessments may be performed up to 
3 days prior to dosing, if necessary. The Day 64 efficacy assessments may be performed up 
to 7 days prior to dosing, if necessary.






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This change also affects Section 1.1, Synopsis; Section 3.1, Study Rationale; Section 12.11, 
Sample Size Considerations; and Section 14.2.2, Independent Data Monitoring Committee.
Section 5.1, Study Overview
Change: Guidance was added on the number patients with scoliosis and/or severe contractures 
to be included in Part C of the study.
Now reads:
…Up to 5 participants with severe scoliosis and/or severe contractures may be enrolled in 
Part C after consultation with the Medical Monitor....
Rationale: Guidance describing the inclusion of participants with severe scoliosis and/or severe 
contractures was added to allow a representative population of participants currently taking 
Spinraza to qualify for Part C of this study.
This change also affects Section 1.1, Synopsis; and Section 1.3, Schedule of Activities. 
Section 5.1, Study Overview
Change: Guidance was added to the date of first dose given to participants on study to assist 
investigators in scheduling participant enrollment in Part C.
Now reads:
…Participants will receive a single bolus dose of 50 mg (which should be administered 4 months 
± 14 days after their most recent maintenance dose of 12 mg) followed by 2 maintenance doses 
of 28 mg on Days 121 and 241...
Rationale: To clarify for sites that the schedule of the Day 1/first dose for participants in Part C 
of Study 232SM203 should be within 4 months ± 14 days from a participant’s previous dose of 
nusinersen. Dose administration within this time frame is expected to produce nusinersen 
 
 consistent with those found in Parts A and B.
This change also affects Section 1.1, Synopsis; Section 1.3, Schedule of Activities; Section 3.1, 
Study Rationale; and Section 7.1, Regimen.


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Section 5.2, Study Duration for Participants
Change: The study duration has been extended and an assessment has been added on Day 410, 
Day 420, and Day 382 for Part A, Part B, and Part C, respectively. 
Now reads:
The total study duration for each participant will be up to 323420 days, divided as follows:

Part A: approximately 323 to 410 days

Screening: 21 days

Loading period: 64 days

Maintenance period: 205 days

Follow-up: 33 to 120 days

Part B: approximately 323 to 420 days

Screening: 21 days

Loading period: 64 days

Maintenance period: 215 days

Follow-up: 23 to 120 days

Part C: approximately 323 to 382 days

Screening: 21 days

Loading period: 1 day

Maintenance period: 240 days

Follow-up: 61 to 120 days
Participants will have the following number of visits during the study: 

Part A: 8 to 9 visits

Part B: 9 to 10 visits

Part C: 5 to 6 visits


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Rationale: In order to align the requirements of contraception use and reporting, the follow-up 
period of the study was extended for those participants who require contraception use (as 
described in Section 11.5, Contraception Requirements). All participants requiring use of 
contraception will have last visit 120 days after the last dose. The 120-day follow-up interval 
after the last dose for subjects who are required to use contraception in the study is equivalent to 
approximately 5 half-lives of nusinersen in the target tissue. The Day 302 visit will remain the 
last visit for participants who do not meet the criteria for contraception use. 
This change also affects Section 1.1, Synopsis; Section 1.2, Figure 1: Study Schematic; 
Section 1.3, Schedule of Activities; Section 5.1, Study Overview; Section 11.4.1, Pregnancy; and 
Section 11.5, Contraception Requirements.
Section 6, Study Population
Change: Inclusion criteria were added for Parts A, B, and C, and exclusion criteria were added 
for Parts A, B, and C relating to fertility status.
Now reads:
6.1.       Inclusion Criteria
Part A
10. All female participants of childbearing potential (defined as any female physiologically 
capable of becoming pregnant) and all male participants of reproductive age must practice 
contraception as described in Section 11.5
…
Part B
7. All female participants of childbearing potential (defined as any female physiologically 
capable of becoming pregnant) and all male participants of reproductive age must practice 
contraception as described in Section 11.5
…
Part C
10. Post-menopausal female participants must be amenorrheic without an alternative 
medical cause and have a serum follicle-stimulating hormone level > 40 mIU/mL for 
≥12 months prior to Screening or ≥6 weeks postsurgical bilateral oophorectomy (with or 
without hysterectomy) prior to Screening


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…
6.2.       Exclusion Criteria
Participants who are pregnant or currently breastfeeding and those intending to become 
pregnant during the study
Rationale: The risk of nusinersen to women who are pregnant or currently breastfeeding is 
unknown; therefore, the inclusion and exclusion criteria were updated to only allow female 
participants in Part C who meet this inclusion criterion and participants in Parts A, B, and C who 
do not meet these exclusion criteria to enroll in this study.
Section 6.1, Inclusion Criteria
Change: Compliance with the study travel policy was added to the inclusion criteria in Parts A, 
B, and C. 
Now Reads:
Part A
6.
Must be compliant with the study travel policy (see Section 15.4)
…
Part B
5.
Must be compliant with the study travel policy (see Section 15.4)
…
Part C
7.
Must be compliant with the study travel policy (see Section 15.4)
…
Rationale: As detailed in Section 15.4 in previously approved versions of the protocol, 
participants are required to adhere to the study travel policy in order to participate in the study. 
The ability to adhere to the travel policy was added to the inclusion criteria in order to fully 
evaluate participant eligibility during Screening.
Section 6.2, Exclusion Criteria


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Change: Exclusion criteria in Part B were revised so that respiratory insufficiency and the 
medical necessity for a gastric feeding tube only apply to participants with later-onset SMA. 
Participants with infantile-onset SMA with those conditions may be enrolled.
Now reads:
All participants
1. Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive 
ventilation for > 6 hours during a 24 hour period, at Screening 
2. Medical necessity for a gastric feeding tube, where the majority of feeds are given by this 
route, as assessed by the Investigator 
…
Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset)
17. Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive 
ventilation for > 6 hours during a 24-hour period, at Screening 
18. Medical necessity for a gastric feeding tube, where the majority of feeds are given by 
this route, as assessed by the Investigator
Rationale: The exclusion criteria related to the need for respiratory support and gastric feeding 
tubes was clarified to specify that it only applies to participants with later-onset SMA. Previous 
data from nusinersen treatment in patients with early-onset SMA suggest that participants who 
need these supportive measures may still benefit from nusinersen treatment and are appropriate 
for inclusion in this trial. These criteria are consistent with the previous pivotal study of 
nusinersen in infantile-onset participants (CS3B, ENDEAR).
Section 6.2, Exclusion Criteria
Change: The participant’s position for the Screening X-ray in Part B was changed from supine 
to sitting/supported sitting for participants with later-onset SMA. Physical assessment of 
scoliosis was added for regions where X-ray use is regulated.
Now reads:
Part A
3. Severe scoliosis evident on X-ray examination at Screening (with the participant supine, not in 
a supported sitting position). For sites with local regulation on use of X-ray (e.g., Germany), 
the Investigator may assess scoliosis based on physical examination without imaging.


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…
Part B
Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset)
18.19. Severe scoliosis evident on X-ray examination at Screening (with the participant supine, 
not in a sitting or supported sitting position). For sites with local regulation on use of X-ray 
(e.g., Germany), the Investigator may assess scoliosis based on physical examination 
without imaging.
…
Rationale: The position of the Screening X-ray was modified in Part B for consistency with the 
historical study of nusinersen in later-onset participants (CS4, CHERISH). Parts A and B were 
updated to allow Investigators to perform a physical examination of scoliosis, in lieu of an X-ray 
examination, in regions with local regulations on use of X-ray.
This change also affects Section 1.3, Schedule of Activities.
Section 6.2, Exclusion Criteria
Change: An exclusion criterion to exclude participants who have had prior scoliosis surgery that 
may interfere with the LP injection procedure was added for Parts B and C.
Part B
All participants
7. Prior scoliosis surgery that would interfere with the LP injection procedure
…
Part C
7. Prior scoliosis surgery that would interfere with the LP injection procedure
…
Rationale: Investigators may be unable to administer nusinersen via the LP injection procedure 
to participants who have undergone scoliosis surgery.
Section 6.2, Exclusion Criteria


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Change: The exclusion criteria regarding use of other investigational medications or 
participation in other clinical trials were revised.
Now reads:
Part A
12.13. Treatment with an investigational drug given for the treatment of SMA (e.g., oral 
albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, and hydroxyurea), 
biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer,
prior to Screening or anytime during the study; any prior or current treatment with risdiplam or 
branaplam;any SMN2-splicing modifier or any history of gene therapy,; or prior antisense 
oligonucleotide treatment, or cell transplantation
…
Part B
11.10. Treatment with an investigational drug given for the treatment of SMA (e.g., oral 
albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, and hydroxyurea), 
biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer,
prior to Screening or anytime during the study; any prior or current treatment with risdiplam or 
branaplam;any SMN2-splicing modifier or any history of gene therapy,; or prior antisense 
oligonucleotide treatment, or cell transplantation
…
Part C
911. Concurrent or previous participation and/or administration of nusinersen in another clinical 
study. Previous participation in a clinical trial of nusinersen is permitted, provided that the 
participant completed all study visits that have been scheduled prior to Screening in this study.
12. Concomitant or previous administration of any SMN2-splicing modifier (excluding 
nusinersen) or gene therapy, either in a clinical study or as part of medical care.
13. Concurrent or previous participation in any interventional investigational study for any 
other drug or device within 30 days or 5 half-lives of the agent, whichever is longer, prior 
to Screening.
10. Dosing with onasemnogene abeparvovec xioi (Zolgensma) within 6 months prior to 
Screening. Prior use of onasemnogene abeparvovec xioi is permitted in participants, as long as it 
has been at least 6 months since treatment; the corticosteroids administered concomitantly with 
this treatment must also have been stopped prior to Screening in this study.
Rationale: The exclusion criteria have been modified to minimize potentially confounding 
factors when interpreting safety.










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age and is currently being used to measure therapeutic response in clinical trials. The SMA HI 
measures a patient’s perception of total disease burden and 15 additional areas of SMA specific 
symptomatic health. Fifteen scores are generated (one for each of the subscales) in addition to a 
total SMA HI score (measuring overall disease burden).
Rationale: This scale is not anticipated to provide data essential to the evaluation of the 
benefit/risk of patients transitioning from the 12/12-mg dosing regimen of nusinersen to the 
28 mg maintenance dosing regimen in this study beyond what is provided by the PedsQL which
will now be administered to all participants with later-onset SMA who are ≥2 years of age.
This change also affects Section 1.1, Synopsis; Section 1.3, Schedule of Activities; Section 2, 
List of Abbreviations; Section 4, Study Objectives and Endpoints; and Section 12.4.3, Analysis 
of the Remaining Endpoints.
Section 9.1.10, Ventilator Use
Change: A new section was added to the protocol to provide additional details on ventilation 
use.
Now reads:
9.1.10.       Ventilator Use
9.1.10.1.    All Participants
The participant’s ventilator use will be collected at every study visit. If ventilation is used 
daily, the average number of hours per day for the past 7 days will be recorded (except for 
participants with infantile-onset SMA enrolled in Part B; see Section 9.1.10.2).
9.1.10.2.    Participants With Infantile-Onset SMA in Part B
The participant’s ventilator use (number of hours/day) will be recorded daily by the 
caregiver using a daily ventilator use diary for the duration of the study. This information 
will be obtained by the site during study visits and telephone contacts and entered into the 
CRF.
Rationale: To clarify that ventilator use will be assessed for all study participants and to provide 
additional details on the daily ventilation diary that is required for participants with infantile-
onset SMA who are enrolled in Part B of the study.
This change also affects Section 1.1, Synopsis; Section 1.3, Schedule of Activities; and 
Section 4, Study Objectives and Endpoints.




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…
11.5.       Contraception Requirements
All female participants of childbearing potential and all male participants of reproductive age 
must ensure that highly effective contraception is used for the duration of the study. In addition, 
participants should not donate sperm or eggs for the duration of the study and for at least 90 days 
after their last dose of study treatment.
…

Female surgical sterilization (e.g., bilateral tubal ligation), where applicable, 
according to local guidelines.
For the purposes of the study, highly effective contraception is defined as the use of one of the 
following:
For females:

Female surgical sterilization (e.g., bilateral tubal ligation), where applicable, 
according to local guidelines.
…

Established use of oral, injected, or implanted progestogen only hormonal methods of 
contraception associated with the inhibition of ovulation
…
Rationale: Current safety data on nusinersen do not suggest a risk to the fetus; however, there 
are no data in humans. Because of the long half-life of nusinersen, a longer requirement for 
contraception, equivalent to 5 half-lives of nusinersen, was included in the study by increasing 
the study duration for those participants who meet these criteria.
Section 12.10, Interim Analyses
Change: The interim analyses section was modified to add text describing the potential for 
interim analyses of Parts A and C data.
Now reads:
Interim and final analyses for Parts A and C may occur prior to completion of Part B of 
the study.




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28
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities.
Rationale:  In response to the global COVID-19 pandemic, the protocol was modified to allow 
for remote monitoring of the sites in order to reduce the amount of direct human contact required 
per protocol, thereby improving safety for both study participants and staff.


Amendment Summary for Protocol 232SM203, Version 3
CONFIDENTIAL
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Biogen MA Inc.
29
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.

Typographical errors and formatting were corrected.

Minor editorial changes were made throughout the protocol.

On the Sponsor Signature Page, the signatory’s name and role were updated.

Text was revised throughout the protocol to clarify that Part A will enroll participants 
aged 2 to ≤ 15 years, inclusive.

In Section 1.3, Schedule of Activities (Tables 1, 2, and 3), the placement of several 
footnotes was changed. In addition, the footnotes regarding predose 
 
were deleted because that information was already presented within the Schedule of 
Activities tables. 

In Section 1.3, Schedule of Activities (Tables 1, 2 and 3), an additional pregnancy test 
was added to the Day 302 follow-up visit for Parts A, B and C to align with changes 
in Section 5.2, Study Duration for Participants, and a footnote was added to the 
assessment to provide clarity. 

In Section 1.3, Schedule of Activities, Tables 1, 2, and 3 were updated to clarify that 
pregnancy tests, X-ray examinations to confirm eligibility at Screening, and CSF cell 
count/protein/glucose are to be analyzed locally. This change also affects Section 
10.2, Laboratory Safety Assessments; Section 14.1.4, Central Laboratories for 
Laboratory Assessments; and Appendix B, Laboratory Analytes.

In Section 3.1, Study Rationale, the phrase “with less frequent dosing during the 
loading period” was removed. This change also affects Section 1.1, Synopsis.

In Section 3.1.2, Rationale for Dosing Regimen, the number of subjects in 
Study CS3A was corrected and the age range of participants was included. 
Study CS3B was also updated to include the number of subjects and age range of 
participants. This change also affects Section 1.1, Synopsis.

In Section 3.1.2, Overview of SMA, the phrase “at the end of the loading dose 
period” was removed. This change also affects Section 1.1, Synopsis.

In Section 3.2.2, Current Therapies for SMA, the countries where Zolgensma® has 
been approved were updated.






Amendment Summary for Protocol 232SM203, Version 3
CONFIDENTIAL
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Biogen MA Inc.
32

In Section 12.4, Methods of Analysis for Efficacy Endpoints, the text was modified to 
correct the details regarding the feasibility of borrowing data from Study CS3B for 
the analysis of Part B in Study 232SM203.

In Section 12.4.2, Analysis of the Secondary 
Endpoints in Part B, 
“total” was added to the HINE Section 2 motor milestone score at Day 302 in Table 7 
as was originally intended and to align with Section 4, Study Objectives and 
Endpoints.

In Section 12.11, Sample Size Considerations, the text was revised to correct the 
loading dose of nusinersen that will be administered to participants in Part A and the 
loading and maintenance dose that will be administered to participants in Part B. This 
change also affects Section 1.1, Synopsis.

In Appendix A, Permanent Ventilation Definition Criteria: Acute Reversible Event, 
the requirement to document the reason for determination of an acute reversible event 
in the CRF was removed because other sources besides the CRF (e.g., patient notes) 
may contain this information as well.


Amendment Summary for Protocol 232SM203, Version 3
CONFIDENTIAL
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Biogen MA Inc.
33
LIST OF ABBREVIATIONS
AE
adverse event
BiPAP
bilevel positive airway pressure
CGIC
Clinical Global Impression of Change
CHOP INTEND
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders
CK
creatine kinase
Cmax
maximum concentration
COVID-19
coronavirus disease
CRF
case report form
CSF
cerebrospinal fluid
DHA
Directions for Handling and Administration
ECG
electrocardiogram
EOS
end of study
ET
early termination
GCP
Good Clinical Practice
HFMSE
Hammersmith Functional Motor Scale – Expanded
HINE
Hammersmith Infant Neurological Examination
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
LP
lumbar puncture
PASA
Parent Assessment of Swallowing Ability
PedsQL 
Pediatric Quality of Life Inventory™
QoL
quality-of-life
RULM
Revised Upper Limb Module
SAE
serious adverse event
SMA
spinal muscular atrophy
SMA-HI
Spinal Muscular Atrophy – Health Index
SMN2
survival motor neuron-2
WHO
World Health Organization


CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
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Maidenhead, Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 232SM203
Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants 
With Spinal Muscular Atrophy
Version 2
Date: 04 December 2019
EUDRA CT Number: 2019-002663-10
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1.






Amendment Summary for Protocol 232SM203, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
4

Shifts from baseline in clinical 
laboratory parameters, ECGs, and 
vital signs

Change in growth parameters

Shifts from baseline in coagulation 
parameters (aPTT, PT, and INR)

Change in urine total protein

Change from baseline in 
neurological examination 
outcomes

The proportion of participants with 
a postbaseline platelet count below 
the lower limit of normal on at 
least 2 consecutive measurements

The proportion of participants with 
a postbaseline QTcF of 
> 500 msec and an increase from 
baseline to any postbaseline 
timepoint in QTcF of > 60 msec
To examine the effect of nusinersen 
administered intrathecally at higher and less 
frequent doses compared to the currently 
approved dose in participants with SMA
Parts A, B, and C:
Quality of Life

Number and duration of 
hospitalizations

Change in PedsQL from baseline 
to Day 302 (later onset SMA 
population)

Change in ACEND from baseline 
to Day 302 (later onset SMA 
population)

CGIC (physician, caregiver) at 
Day 302

Number of serious respiratory 








Amendment Summary for Protocol 232SM203, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
8
 ACEND = Assessment of Caregiver 
Experience with Neuromuscular Disease; AE = adverse event; aPTT = activated partial thromboplastin time; 
CGIC = Clinical Global Impression of Change; CHOP INTEND = Children’s Hospital of Philadelphia Infant 
Test of Neuromuscular Disorders; CSF = cerebrospinal fluid; ECG = electrocardiogram; 
HFMSE = Hammersmith Functional Motor Scale – Expanded; HINE = Hammersmith Infant Neurological 
Examination; INR = international normalized ratio; PASA = Parent Assessment of Swallowing Ability; 
PedsQL = Pediatric Quality of Life Inventory™; 
 
 
; PT = prothrombin time; QTcF = corrected QT interval using Fridericia’s 
formula; RULM = Revised Upper Limb Module; SAE = serious adverse event; SMA = spinal muscular 
atrophy; SMA-HI = Spinal Muscular Atrophy Health Index; WHO = World Health Organization
Rationale:  These changes were made to clarify that the primary objective for Part B is to 
examine efficacy, as measured by the change from baseline in CHOP INTEND total score. The 
remaining assessments that will be used to evaluate the clinical efficacy of nusinersen for
participants in Part B are secondary endpoints related to a secondary objective, which also has 
been clarified. A separate table containing the objectives and endpoints for Parts A and C of the 
study is added to emphasize the differences between Part B and Parts A and C, and to clarify that 
safety is the primary objective for Parts A and C.
This change also affects Section 12, Statistical Methods and Determination of Sample Size; and 
Appendix A, Permanent Ventilation Definition Criteria: Acute Reversible Event.


Amendment Summary for Protocol 232SM203, Version 2
CONFIDENTIAL
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Biogen MA Inc.
9
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.
Section 1.1, Synopsis
The synopsis was revised to reflect changes made throughout the protocol.
Section 5, Study Design
Change:  Text regarding the Independent Data Monitoring Committee (IDMC) review of Part B 
safety data was revised.
Now reads:  
Continued enrollment into Part B and Eenrollment into Part C will beginoccur after a safety
review by the IDMC of 15 participants in Part B who have available safety and 
 data through 
Day 29 (in order to achieve 6 participants who have received 50 mg in the 50/28-mg Group, 
while maintaining the blind), provided that no safety concerns are identified.
Rationale:  While it was originally intended that the IDMC review of the first 15 participants in 
Part B with Day 29 safety and 
 data would determine whether enrollment in this part of the 
study could continue, this has now been clarified in the protocol.
This change also affects Section 14.2.2, Independent Data Monitoring Committee.


Amendment Summary for Protocol 232SM203, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
10
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.

On the Sponsor Signature Page, the signatory’s role was updated.

In Section 7.3.1, Nusinersen, a reference to the Directions for Handling and 
Administration (DHA) was added with respect to details on diluting the drug product 
to the appropriate dosage.

Typographical errors and formatting were corrected.

SAP_001.pdf: 
COVER PAGE 
Official Title: 
Escalating Dose and Randomized, Controlled Study of Nusinersen 
(BIIB058) in Participants With Spinal Muscular Atrophy 
NCT Number: 
NCT04089566 
Document Date: 
Part A: 22 February 2021 
Part B Infantile Onset: 19 July 2024 
Part B Later Onset: 10 April 2024
Part C: 06 October 2023 


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Statistical Analysis Plan 
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PART A  
STATISTICAL ANALYSIS PLAN 
Version No.: V1.0
Date: 22 February 2021
Author: 
 
Study Title: Escalating Dose and Randomized, Controlled Study of Nusinersen 
(BIIB058) in Participants With Spinal Muscular Atrophy 
Name of Study Treatment: Nusinersen 
Protocol No.: 232SM203 
Study Phase 2/3 
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) is confidential and may not be 
reproduced or otherwise disseminated without the approval of Biogen, Inc.   


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Statistical Analysis Plan 
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Page 2
 
 
 
APPROVAL 
 
This document has been reviewed and approved by: 
 
 
  
 
  
SMT Statistician 
 
Si
Date 
 
   
  
Program Statistician 
 
Si
Date 
 
   
  
 
 
 
Si
Date 
 
 
 


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VERSION HISTORY 
 
SAP Version
Date 
Primary Reasons for 
Amendment 
 
 
 
 
 
 


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TABLE OF CONTENTS
 
PART A ............................................................................................................................................... 1 
STATISTICAL ANALYSIS PLAN .................................................................................................... 1 
APPROVAL ........................................................................................................................................ 2 
VERSION HISTORY ......................................................................................................................... 3 
TABLE OF CONTENTS .................................................................................................................... 4 
LIST OF ABBREVIATIONS ............................................................................................................. 6 
1. 
Introduction ................................................................................................................................. 8 
2. 
Study Overview............................................................................................................................ 8 
2.1. 
Study Objectives and Endpoints ...................................................................................... 8 
2.2. 
Study Design..................................................................................................................... 9 
2.3. 
Sample Size Considerations ............................................................................................. 9 
3. 
Definitions .................................................................................................................................... 9 
3.1. 
Dates and Points of Reference.......................................................................................... 9 
3.2. 
Study Treatment ............................................................................................................ 10 
3.3. 
Study Periods.................................................................................................................. 10 
3.4. 
Key Derived Variables ................................................................................................... 10 
3.5. 
Stratification Factors and Subgroup Variables............................................................. 10 
3.5.1. 
Stratification Factors .................................................................................................. 10 
3.5.2. 
Subgroup Variables .................................................................................................... 10 
3.6. 
Analysis Sets................................................................................................................... 10 
4. 
List of Planned Study Analyses ................................................................................................. 11 
4.1. 
Interim Analysis ............................................................................................................. 11 
4.2. 
Primary Analysis ............................................................................................................ 11 
4.3. 
Final Analysis ................................................................................................................. 11 
5. 
Statistical Methods for Planned Analyses ................................................................................. 11 
5.1. 
General Principles.......................................................................................................... 11 
5.2. 
Participant Accountability ............................................................................................. 13 
5.3. 
Demographic and Baseline Characteristics ................................................................... 13 


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5.4. 
Protocol Deviations ........................................................................................................ 13 
5.5. 
Study Treatment Exposure and Concomitant Medications.......................................... 14 
5.6. 
Efficacy Endpoints ......................................................................................................... 15 
5.6.1. 
Primary Efficacy Endpoint ........................................................................................ 15 
5.6.2. 
Secondary Efficacy Endpoints ................................................................................... 15 
21 
5.7. 
Primary Safety Endpoints .............................................................................................. 22 
25 
6. 
Changes from Protocol-Specified Analyses............................................................................... 27 
7. 
Summary of Changes from the Previous Version of the SAP .................................................. 27 
8.
References..................................................................................................................................27
APPENDICES ................................................................................................................................... 29 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACEND 
Assessment of Caregiver Experience with Neuromuscular Disease 
AE 
adverse event 
AESTDT 
Start date of AE 
CDC 
Centers for disease control and prevention 
CGIC
Clinical Global Impression of Change
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
DHA 
Directions for Handling and Administration
EAC 
endpoint adjudication committee 
ECG 
electrocardiogram 
GCP 
Good Clinical Practice 
HFMSE 
Hammersmith Functional Motor Scale Expanded 
HINE 
Hammersmith Infant Neurological Examination 
HRQOL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee
IRT 
interactive response technology 
ITT 
Intent-to-Treat 
LP 
lumbar puncture 


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NOAEL 
no-observed-adverse-effect level 
NOEL 
no-observed-effect level 
PASA 
Parent Assessment of Swallowing Ability
 
 
PedsQL 
 
 
 
 
QoL 
quality-of-life 
QTcF 
 
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 
SUSAR 
suspected unexpected serious adverse reaction
 
 
TRTSDT 
study treatment start date 
US  
United States 
WHO   
WHO World Health Organization 
 
 
 


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1. 
Introduction 
Nusinersen is an antisense oligonucleotide administered intrathecally via lumbar puncture 
(LP); it increases survival motor neuron (SMN) protein expression and significantly improves 
motor function in patients with spinal muscular atrophy (SMA). Nusinersen was approved for 
the 
Union, and 15 other countries. The population for this study includes participants with 
infantile-onset and later-onset SMA.  
2. Study Overview 
2.1. Study Objectives and Endpoints 
Study Primary Objective (Part A) 
To examine the safety and tolerability of nusinersen administered intrathecally at higher 
doses to participants with SMA.  
Study Primary Endpoint (Part A) 
 
Incidence of AEs, including SAEs 
 
Shifts from baseline in clinical laboratory parameters, ECGs, and vital signs 
 
Change in growth parameters 
 
Shifts from baseline in coagulation parameters (aPTT, PT, and INR) 
 
Change in urine total protein 
 
Change from baseline in neurological examination outcomes 
 
The proportion of participants with a post-baseline platelet count below the lower 
limit of normal on at least 2 consecutive measurements 
 
The proportion of participants with a post-baseline QTcF of> 500 msec and an 
increase from baseline to any post-baseline timepoint in QTcF of > 60 msec 
Study Secondary Endpoint (Part A) 
 
Change from baseline in HFMSE score 
 
Change from baseline in RULM score 
 
Total number of new WHO motor milestones 
 
Change from baseline in ACEND 
 
 Change from baseline in PedsQL 
 
Number and duration of hospitalizations 
 
CGIC (physician, caregiver) at Day 302 
 
Number of serious respiratory events 
 
Ventilator use
 
Change in the PASA scale  


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2.2. Study Design
This 3-part study will evaluate the efficacy and safety of a high dosing regimen of 
nusinersen in approximately 152 participants. The study will be conducted at approximately 
65 sites globally. Following the completion of this study, all eligible participants may elect 
to enrol in a separate long-term extension study, pending study approval by ethics 
committees and the appropriate regulatory authorities.  
This SAP is focusing only on Part A that is an open-label safety evaluation. Six participants 
with later-onset SMA who are 2 
consent will receive 3 loading doses of 28mg of nusinersen on Days 1, 15, and 29, followed 
by 2 maintenance doses of 28 mg on Days 149 and 269.  
2.3. Sample Size Considerations   
A minimum of 6 participants with later-onset SMA will be enrolled in Part A to 
characterize the safety, tolerability, and 
 of a 28/28 mg dose of nusinersen (28-
mg loading dose; 28-mg maintenance dose) 
3. Definitions 
3.1. Dates and Points of Reference 
In order to distinguish nominal visit names from duration defined in days, visit names will 
 etc. will be used to 
define time intervals.
Summary statistics will be presented throughout.  For continuous endpoints, summary 
statistics will generally include number of subjects with data, mean, standard deviation, 
median, minimum, and maximum.  For categorical endpoints, summary statistics will 
generally include number of subjects dosed, number of subjects with data, and the 
percentage of those with data in each category.  Frequency distributions will be presented as 
appropriate.  
 
The statistical software, SAS® version 9.4 or above, will be used for all summaries and 
statistical analyses.   


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Overall time on study will be defined as the total number of days a subject is known to be 
followed on study calculated as follows: 
 
Overall time on Study = (Last date on study)  (Date of first dose) +1 
 
The last date on study is defined as the date of the latest visit or evaluation or telephone 
contact, or time of death from all available data for a subject. 
3.2. Study Treatment
Part A all participants will receive 3 loading doses of 28 mg (Days 1, 15, and 29) followed 
by 2 maintenance doses of 28 mg (Days 149 and 269). 
3.3. Study Periods 
N/A 
3.4. Key Derived Variables 
N/A. 
3.5. Stratification Factors and Subgroup Variables 
3.5.1. Stratification Factors 
N/A. 
3.5.2. Subgroup Variables 
N/A 
3.6. Analysis Sets
The Intent-to-Treat (ITT) Set is defined as all participants who receive at least a dose of 
nusinersen.  
The Safety Analysis will be performed on the ITT Set. 
 
  
 
  
 


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4. List of Planned Study Analyses 
4.1. Interim Analysis
An Interim analysis may be performed to support publications or clinical decisions. 
4.2. Primary Analysis 
N/A 
4.3. Final Analysis 
The final analysis will be conducted after all Part A subjects have completed the study. 
5. 
Statistical Methods for Planned Analyses 
5.1.  General Principles  
Adverse Events 
The first AE record occurs prior to the first dose, the second AE record occurs on or after the 
first dose, and the severity increases: Only the second record will be counted as treatment 
emergent. 
The first AE record occurs prior to the first dose, the second AE record occurs on or after the 
first dose, and the severity decreases: Neither record will be counted as treatment emergent. 
Both records occur on or after the first dose: If the AE severity on the second record is worse 
than the severity on the first record, then count both records as treatment emergent.  But, if 
the severity improves, then only count the first record as treatment emergent. 
Of note, when counting the total number of treatment-emergent events, events linked 
through change in severity will still be counted as separate events. 
For events with missing start or stop dates, the following criteria will be used for the purpose 
of identifying treatment-emergent adverse events:  
Denote the start date of Adverse Event as AESTDT and the study treatment start date as 
TRTSDT 
 
If both the start and stop dates for a particular event are missing, then the event is 
considered to have occurred on or after the first dose of study treatment; 
 
If the start date for a particular event is missing and the stop date/time falls after the 
first dose date/time, then the event is considered to have occurred on or after the first 
dose of study treatment; 
 
If the start time is missing and the start date is the same as the first dosing date, then 
the event is considered to have occurred on or after the first dose of study treatment; 


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If it cannot be determined whether or not an event has occurred on or after dosing 
due to a missing or partial date, then the event will be assumed to have occurred on 
or after the first dose for the purpose of identifying treatment-emergent adverse 
events. 
 
If AESTDT is completely missing or the year is missing, then impute AESTDT to 
TRTSTDT.
 
If, in AESTDT, year is present and month/day are missing and year is equal to the 
year portion of TRTSTDT, then impute the month/day portion of AESTDT to the 
month/day portion of TRTSTDT.  
 
If, in AESTDT, year is present and month/day are missing and year is not equal to 
the year portion of TRTSTDT, then impute the month/day portion of AESTDT to 
January 01. 
 
Consider the situation in AESTDT where year and month are present with only day 
missing. If the year and month are the same as those for TRTSTDT, then impute day 
in AESTDT with day in TRTSTDT. Otherwise, impute the day in AESTDT with the 
first day of the month.  
It is important to emphasize that the imputed date will not be used for calculations such as 
onset and duration of an adverse event. Due to the long half-life of nusinersen, analyses of 
treatment-emergent adverse events will include all events reported during the study. 
Concomitant Medications and Procedure 
In order to define concomitant therapies with missing start or stop dates, the following 
additional criteria will be used: 
 
 
If both the start and stop dates of a particular therapy were missing, that therapy is 
considered concomitant. 
 
If the start date of a therapy was missing and the stop date of that therapy fell on or 
after the date of dosing, that therapy is considered concomitant. 
 
If the start date of a therapy was prior to the date of dosing and the stop date of that 
therapy was missing and the therapy was listed as continuing, that therapy is 
considered concomitant.  
 
If the start date of a therapy was prior to the date of dosing and the stop date of that 
therapy was missing and the therapy was listed as not continuing, that therapy is 
considered concomitant, or 
 
If the start/stop date of a therapy is partial then where it is not possible to rule out 
that it was not taken concomitantly it will be considered concomitant 
 
Denote the end date of medication as CMENDT.  The medication is classified concomitant 
provided any of the following is NOT true: 


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CMENDT is complete and CMENDT is less than TRTSDT 
 Day of CMENDT missing and year/month of CMENDT is strictly before year-month 
of TRTSDT
 Month of CMENDT is missing and year of CMENDT is strictly before year of 
TRTSDT 
5.2.  Participant Accountability  
The number of subjects who were screened, enrolled, dosed, and completed treatment and  
study, along with the reasons for discontinuing treatment and withdrawing from the study, 
will be presented.  
Listings of those subjects who discontinued treatment and/or withdrew from the study and 
the reasons for discontinuation/withdrawal will be presented.  Subjects who died during the 
study will be listed separately. 
5.3.  Demographic and Baseline Characteristics 
Demography includes age categories, age at first dose, sex, ethnicity, and race.  Medical 
history will be coded in MedDRA and the number and percentage of subjects with each 
history presented.  SMA history includes age of symptom onset, age at SMA diagnosis, time 
from diagnosis to enrollment, number of copies of the SMN 1 and SMN2 genes, current 
motor function,  
The 2000 CDC Growth Charts (ages 2 to <20 years) will be used to assess the weight change 
for older subjects. The National Center for Health Statistics provides a SAS macro which 
can be downloaded from their website [https://www.cdc.gov/growthcharts/clinical_ 
charts.htm] and this will be utilized to calculate the weight for age percentiles for each 
participant in the later onset population.  
Subjects will be cross referenced with these files, given the age and sex of the subject to 
determine below which percentile they lie for each parameter.  
Baseline quality of life and caregiver burden of SMA will be assessed by PedsQL and 
ACEND, respectively. Demographic, baseline disease characteristics, and baseline quality of 
life will be presented for the Safety Set. 
5.4.  Protocol Deviations
Protocol deviations identified during site monitoring will be captured in a protocol deviation 
log and categorized as major or minor deviations.  These deviations will be listed.  Major 
protocol deviations will be summarized. 
 


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5.5. Study Treatment Exposure and Concomitant Medications 
Exposure  
The number of doses received will be summarized using frequency distributions.  The 
amount of nusinersen received will be summarized using summary statistics. 
Overall time on study definition see section 3.1. 
Given the long half-life of nusinersen, participants are considered to be exposed from the 
time the first dose of nusinersen was administered (in or before the start of study) to the date 
of last visit or contact. 
Concomitant Medications and Procedure 
A concomitant therapy is any drug or substance administered between screening and the 
final study visit/telephone call. Participants should be instructed to contact their Investigators 
before taking any new medications, including nonprescription drugs and herbal preparations. 
Throughout the study, Investigators or designated licensed physicians involved in the study 
may prescribe concomitant therapies (procedures) or treatments deemed necessary for AEs 
or to provide adequate supportive care. 
Participants are prohibited from receiving other experimental or approved agents for the 
treatment of SMA, including gene therapy, biological agent, or device, during the study. 
This includes marketed agents at experimental doses that are being tested for the treatment 
of SMA (oral albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, 
hydroxyurea, etc.). 
All concomitant medications will be coded using the World Health Organization drug 
dictionary (WHO Drug). 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical 
therapy) or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) 
performed between Screening and the final study visit/telephone call. Concomitant 
procedures will be coded using MedDRA. 
For the purposes of analysis, a concomitant therapy (including medication or procedure) is 
defined as any therapy that was taken or administered on or after the first injection of 
nusinersen.  This includes therapies that were started prior to the initiation of injection of 
nusinersen if their use continued on or after the first injection of nusinersen. The number and 
percentage of subjects who were taking each type of concomitant medication at baseline and 
during the study will be presented. The number and percentage of subjects taking each type 
of ancillary procedure will be presented by preferred term.   
  


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5.6. Efficacy Endpoints 
No primary efficacy endpoints will be investigated. 
 
The following secondary 
 efficacy assessments will be evaluated: 
  
 
HFMSE 
 
WHO Motor Milestones 
 
RULM 
 ACEND 
 PedsQL 
 Hospitalizations  
 CGIC 
 Serious respiratory events 
 Ventilator use
 
PASA  
 
 
5.6.1. Primary Efficacy Endpoint   
N/A 
5.6.2. Secondary Efficacy Endpoints  
Number of serious respiratory events  
Respiratory events encompass a range of reported events and interventions. Adverse events 
coded into the SOC of respiratory, thoracic and mediastinal disorders will be defined as 
respiratory events and the subset of these which led to hospitalization will be identified using 
AE and hospitalization information together.  Number of serious respiratory events will be 
listed for each subject. 
Number and duration of hospitalizations  
The number and duration of hospitalization will be listed for each subject. 
Clinical Global Impression of Change  
al functioning after initiating a study medication [Guy 1976]. The 
CGIC provides an overall clinician-determined summary measure that takes into account all 
circumstances, sy


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to function. The CGIC 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 
level of distress and other aspects of impairment, and the impact of the illness on 
at any clinical 
changes are or are not due to medication and without consideration of the etiology of the 
symptoms. 
The CGIC is a 7-
illness has changed 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. CGIC should be 
assessed consistently by the same rater for each study participant. A separate CGIC 
assessment will be performed by the Investigator (Principal Investigator or Sub investigator) 
and caregiver. Adult participants who do not require a caregiver during the study visits will 
only have the CGIC assessment assessed by the Investigator. 
The CGI score will be plotted over time for each subject and listed. 
Hammersmith Functional Motor Scale  Expanded (HFMSE) 
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 II and Type III 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 the evaluation of 
ambulatory patients with SMA [O' Hagen 2007] 
Each item is scored 0 (unable), 1 (performs with modification or adaptation) or 2 (able) and 
the total score is calculated by summing the 33 items and ranges from 0 to 66 with higher 
scores indicating greater motor function. 
Baseline 
The baseline for HFMSE is defined as the last non missing assessment prior to the first dose 
of study treatment. 
Missing values 
If 6 or fewer items are missing, then these items will be imputed to be 0 when summing all 
33 items. 
If greater than 6 items are missing, then the total score will be set to be missing; missing data 
will not be imputed. 


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Total score and total score change from baseline will be plotted over time for each subject 
and listed. 
Revised Upper Limb Module (RULM) 
Participants with later-onset SMA will be evaluated using the Revised Upper Limb Module 
(RULM) [Mazzone 2016]. The RULM will continue to be performed should participants 
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 of detecting 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 the 
mouth as if drinking, take a coin and place it in a box, and 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 the change that occurs in the 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 the performance of the shoulder, 
elbow, wrist, and hand.
A derived total score will be calculated by summing the scores from these individual items.  
For each item, a score will be collected on the left and right side. A derived total score will 
be calculated by summing the scores from these 19 individual items and ranges from 0 if the 
subject fails all activities to 37 if the subject achieves all activities. If, for an individual item, 
a response is recorded for both the left and right side the highest score will be used in 
calculating the total. 
Baseline 
The baseline for RULM is defined as the last non missing assessment prior to the first dose 
of study treatment. 
Missing values 
If 3 or fewer items are missing, then these items will be imputed to be 0 when summing all 
items. If greater than 3 items are missing, then the total score will be set to be missing. 
Missing data will not be imputed.  
Total score and total score change from baseline will be plotted over time for each subject 
and listed. 
 


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WHO motor milestones 
The WHO motor milestones are a set of six milestones in motor development, all of which 
would be expected to be attained by 24 months of age in healthy children.  The individual 
milestones are: sitting without support, standing with assistance, hands and knees crawling, 
walking with assistance, standing alone and walking alone.  The WHO reported [WHO 
Motor Development Study] that in about 90% of cases the order of attainment followed a 
fixed sequence for five of the milestones (namely, sitting without support, standing with 
assistance, walking with assistance, standing alone and walking alone) with only hands and 
knees crawling shifting between the earlier milestones.   
The motor milestones will be assessed using the WHO motor milestone criteria [WHO 
Multicentre Growth Reference Study Group 2006].  As part of the assessment, the examiner 
the following four classifications: 
 No (inability)  Child tried but failed to perform the milestone. 
 No (refusal)  Child refused to perform despite being calm and alert. 
 Yes  Child was able to perform the milestone. 
 Unable to test  Could not be tested because of irritability, drowsiness or sickness. 
Missing values 
result will be first set to missing.  Missing data will not be imputed. 
Each milestone will be plotted in a binary way (0=not present/not achieved and 1=present 
/achieved) over time for each subject and a listing will be provided. 
Quality-of-Life Questionnaires  
Assessment of Caregiver Experience with Neuromuscular Disease (ACEND). QoL 
questionnaires will be collected on the days specified. 
Pediatric Quality of Life Inventory (Generic Core Scales and Neuromuscular Module)  
Participants in Part A will be evaluated using the 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, 


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generic core scales, as well as condition-specific modules for use in designated clinical 
populations. Pediatric self-report is measured in children and adolescents 5 to 18years of 
age, and parent proxy-report of child HRQOL is measured for children and adolescents 2 to 
18 years of age. The PedsQL4.0 Generic Core Scales include an 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 2 to 18years of age with neuromuscular disorders, including SMA.  
Subjects in Part A can be between 2 and 15-year-old at screening. 
The PedsQL parent questionnaire is collected for children in the following age categories: 2-
4, 5-7, 8-12 and 13-18. Four dimensions are collected: Physical, Emotional, Social and 
School functioning and each item is scored on a 5-point ordinal scale (0= Never, 1 = Almost 
Never, 2= Sometimes, 3 = Often, 4 = Almost Always). 
The PedsQL patient questionnaire is collected for children in the following categories: 5-7, 
8-12 and 13-18. Similar dimensions and 5-point ordinal scale are used as for the parents but 
for subjects aged 5 to 18 years a 3-point ordinal scale is collected, omitting the response 
levels of 1 and 3.  
In the neuromuscular module, one parent questionnaire is collected for all subjects 
-point ordinal scale is collected for 
each question.  
The patient neuromuscular disease questionnaire is collected for subjects in the following 
age categories: 5-7,8-12 and 13-18. The questionnaire for subjects aged 5-18 years uses the 
3-point ordinal scale as above and has only one dimension - 
  
In scoring a dimension the first step is to reverse and linearly transform to a 0-100 scale (0 = 
100, 1 =75, 2=50, 3= 25, 4= 0), so a higher score is indicative of a better health related 
quality of life.  
A psychosocial health summary score, constructed from three dimensions, will be calculated 
as the sum of items over the number of items answered in the emotional, social and school 
functioning scales. 
A total score will be calculated as the sum of all the items over the number of items 
answered on all the scales.  
For the neuromuscular module, a score for each dimension and then total score will be 
calculated in the same manner, no health summary scores are evaluated.  
Due to the age specific nature of these questionnaires, subjects aged 2-4 years would not be 
expected to complete the self-evaluation. 


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Items scores, total scores and the change from baseline will be plotted over time for each 
subject and listed. 
Baseline 
The baseline for PedsQL is defined as the last non missing assessment prior to the first dose 
of study treatment. 
Missing values 
If greater than 50 percent of the items within a dimension are missing then the dimension 
score will not be computed, otherwise the mean score for the dimension will be calculated as 
the sum of items over the number of items answered.  
Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) 
 Parents/caregivers of participants will complete the ACEND questionnaire. The ACEND 
questionnaire will not be collected for adult participants who do not require a caregiver 
during the study visits. This assessment instrument has been designed to quantify the 
caregiver impact experienced by parents/caregivers of children affected with severe 
neuromuscular diseases, including children with SMA [Matsumoto 2011]. ACEND includes 
domains assessing physical impact (including feeding/grooming/dressing, sitting/play, 
transfers, and mobility) and general caregiver impact (including time, emotion, and finance). 
and each domain comprises several items.   
The total score for a domain with n items, each item assessed on ordinal scale from 1 to z, is 
derived as follows: 100 multiplied by (Mean of the n items in the domain -1) divided by (z-
1).   
This total score will be on a scale of 0 to 100 with a higher score indicating a greater impact 
on the caregiver. 
All items score, total score and the change from baseline will be plotted over time for each 
subject and listed. 
Baseline 
The baseline for ACEND is defined as the last non missing assessment prior to the first dose 
of study treatment. 
Missing values 
At least two items for the time domain and one item for the remaining domains need to be 
non-missing for a total to be calculated; else the total score will be set to be missing. 
 


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Parent Assessment of Swallowing Ability  
Will be assessed in Part A at the timepoints specified in the Schedule of Activities using the 
PASA questionnaire. Caregivers will be asked a series of questions regarding the mealtime 
behavior of the participant. The PASA questionnaire was developed by a Biogen team in 
order to assess the signs and symptoms of dysphagia. This questionnaire consists of 33 items 
across 4 domains that cover general feeding, drinking liquids, eating solid foods, and 
assessment of swallowing concerns. The first 3 of these domains are generally assessed with 
5 levels of response (Never, Rarely, Sometimes, Often, and Always), although 2 items are 
swallowing concerns has 4 levels of response: Strongly Agree, Agree, Disagree, and 
Strongly Disagree. In answering each item, the caregiver is directed to consider the previous 
7 days. 
All of the item results will be plotted over time for each subject and listed. 
Ventilator Use  
daily, the average number of hours per day for the past 7 days will be recorded. 
The ventilation use and number of hours collected and will be listed.
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.7. Primary Safety Endpoints 
Analyses of safety data will include adverse events and serious adverse events, laboratory 
data, ECGs, growth parameters, vital signs, and neurological examinations. Worsening or 
new findings noted from the physical or neurological examinations will be reported as AEs 
as appropriate. 
Adverse events 
All adverse events (AEs) will be analyzed based on the principle of treatment emergence. An 
adverse event will be regarded as treatment-emergent if it was present prior to receiving the 


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first dose of nusinersen and subsequently worsened in severity, or was not present prior to 
receiving the first dose of nusinersen and subsequently appeared.
Adverse events will be coded using the MedDRA dictionary.  This coding system provides 
more than five levels to classify adverse events.  In general, adverse events will be presented 
by system organ class and preferred terms but other classifications may be used if warranted.   
The incidence and frequency (event count) of treatment-emergent adverse events will be 
summarized.  A subject having the same adverse event more than once will be counted only 
once in the incidence for that adverse event; multiple occurrences of the same adverse event 
for the same subject will all be counted in the frequency for that adverse event. The 
summary tables will include incidence estimates for overall system organ class as well as for 
preferred terms within each system organ class.  Incidence will be presented by decreasing 
order by system organ class and by decreasing order by preferred term within each system 
organ class.  The most common adverse events, i.e., those that occurred in at least 3 subjects, 
will be presented.  Upon examination of the actual data, different cut-offs may be used if it is 
deemed more appropriate. 
Clinical laboratory data  
The following clinical laboratory parameters are to be assessed:  
 Hematology: red blood cells, hemoglobin, hematocrit, platelets, white blood cells, 
white blood cell differential, neutrophils, eosinophils, basophils, lymphocytes and 
monocytes. 
 Blood chemistry: sodium, potassium chloride, total protein, albumin, calcium, 
phosphorus bicarbonate, glucose, blood urea nitrogen, creatinine, cystatin C, total 
serum bilirubin (direct and indirect), alkaline phosphatase, aspartate 
aminotransferase; alanine aminotransferase, creatine phosphokinase, creatine kinase 
and gamma glutamyl transferase. 
 Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, red blood cells, 
white blood cells, epithelial cells, bacteria, casts, crystals, Cystatin C (for subjects 
 and urine total protein assessed by local 
laboratories 
 Coagulation: aPTT, PT, INR  
For a parameter if the local and central result are available with the same date and time then 
only the central analysis result will be considered for presentations by visit. In a situation 
where two or more results have the same date and time and are both central (or both local) 
then we will check with the Safety physician if it would be more appropriate or take the 
highest or lowest value. 
available data will be considered for these irrespective if collected centrally or locally. Each 
(i.e., above the upper limit of normal [ULN]). If a subject is missing a baseline value but had 


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a post-
subject had a baseline value but had no post-baseline values, then the minimum and 
maximum 
 
All the parameter above will be listed (including change and shift from baseline) and plotted 
for each subject. Also, the participants with a post-baseline platelet count below the lower 
limit of normal on at least 2 consecutive measurements will be listed. 
Baseline 
The baseline for all the laboratory parameters is defined as the last non missing assessment 
prior to the first dose of study treatment. 
CSF local laboratory samples. 
Cell count, protein, and glucose from the CSF local laboratory sample will be listed and 
plotted for each subject. 
ECG 
ECGs are to be recorded at Days 1, 15, 29, 149, 269 and 302/ET, pre-dosing and post-dosing 
at various time points on dosing days and end pre-dosing at 302/ET. The ECGs are assessed 
at a central reading laboratory and the results provided as external vendor data. On the eCRF 
the investigator interpretation is also collected  
ECG listings will be presented for all subjects and for subjects with post-baseline QTcF of > 
500 msec and increase from baseline >60 msec. 
Baseline 
The baseline for ECG is defined as the assessment prior to the first dose of study treatment. 
Growth parameters
Growth parameters comprise height/length, ulnar length, weight for age percentile and 
length for age percentile will be listed.  
LP opening pressure. 
LP opening pressure results will be plotted over time for each subject and a listed. 
Vital signs 
Vital signs are to be measured at Screening, pre-dosing and at various time points post- 
dosing on dosing days.  At each of these times, temperature, heart rate, respiratory rate, 
systolic and diastolic blood pressure, and pulse oximetry awake will be measured. 
Vital sign will be listed.  


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Baseline 
The baseline for vital sign is defined as the last non missing assessment prior to the first dose 
of study treatment. 
Neurological exams
Standard neurological examinations, which include assessments of mental status, level of 
consciousness, sensory function, motor function, cranial nerve function, and reflexes, will be 
conducted. 
 
The neurological items comprise of mental status, level of consciousness, sensory function, 
motor function, cranial nerve function, and reflexes will be assessed.  These assessments will 
be done at screening, pre-dosing and post-dosing.   
of reflexes which is captured on an ordinal scale. For each abnormal test result, it is recorded 
whether or not it is secondary to SMA.  
All the neurological items result will be plotted over time for each subject and listed.  
 
 
 
 
 
 
  
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 


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6. Changes from Protocol-Specified Analyses 
N/A 
7. Summary of Changes from the Previous Version of the SAP
N/A 
8. References 
CDC growth scale https://www.cdc.gov/growthcharts/clinical_charts.htm 
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.
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. 
Department of Health, Education, and Welfare; 1976. 
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. 


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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.  
 
 
 
 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of 
life inventory. Med Care. 1999;37(2):126-39. 
 
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. 2006a; 450:66-75. 
 
WHO Motor Development Study: Windows of achievement for six gross motor 
development milestones, Acta Pædiatrica, 2006; Suppl 450: 86/95.
 
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.  
 
 


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APPENDICES 
N/A 
 


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Statistical Analysis Plan 
Version: 3.0 Final
Page 1
PART B INFANTILE-ONSET SMA 
STATISTICAL ANALYSIS PLAN 
Version No.: 3.0 
Date: 19Jul2024 
 Author: 
 
Study Title:  
Escalating Dose and Randomized, Controlled Study of Nusinersen 
(BIIB058) in Participants With Spinal Muscular Atrophy 
Name of Study Treatment: Nusinersen 
Protocol No.: 232SM203 
Study Phase: 2/3 
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The information contained in this Statistical Analysis Plan (SAP) is confidential and may not be reproduced or 
otherwise disseminated without the approval of Biogen, Inc.   
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APPROVAL 
This document has been reviewed and approved by: 
 
SMT Statistician 
Signature 
Date 
 
Program Statistician 
Signature 
Date 
 
SMT Medical Director 
Signature 
Date 
VERSION HISTORY 
SAP Version 
Date 
Primary Reasons for 
Amendment 
Version 2 
18July2024 
Updated based on FDA 
comments 
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G-., ....... 
19-Jul-2024 
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C
19-Jul-2024 


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Statistical Analysis Plan 
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Version 3 
19July2024 (prior to 
release of treatment 
codes) 
Updated based on FDA 
comment 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
PART B INFANTILE-ONSET SMA ................................................................................ 1 
STATISTICAL ANALYSIS PLAN .................................................................................. 1 
APPROVAL ...................................................................................................................... 2 
VERSION HISTORY ........................................................................................................ 2 
LIST OF ABBREVIATIONS ............................................................................................ 6 
1. 
Introduction ................................................................................................... 12 
2. 
Study Overview ............................................................................................. 13 
2.1. 
Study Objectives and Endpoints ................................................................................. 13 
2.2. 
Study Design............................................................................................................... 15 
2.3. 
Sample Size Considerations ....................................................................................... 17 
2.4. 
Historical Data ............................................................................................................ 17 
CS3B Study ........................................................................................................................... 17 
3. 
Definitions ..................................................................................................... 18 
3.1. 
Dates and Points of Reference .................................................................................... 18 
3.2. 
Study Treatments ........................................................................................................ 19 
3.3. 
Study Periods .............................................................................................................. 20 
3.4. 
Key Derived Variables ............................................................................................... 21 
3.5. 
Stratification Factors and Subgroup Variables ........................................................... 21 
Stratification Factors.............................................................................................................. 21 
Subgroup Variables ............................................................................................................... 21 
3.6. 
Analysis Sets............................................................................................................... 22 
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Statistical Analysis Plan 
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3.6.1. 
Within 232SM203 ................................................................................................... 22 
3.6.2. 
External data ........................................................................................................... 23 
4. 
List of Planned Study Analyses ..................................................................... 24 
4.1. 
Interim Analysis ......................................................................................................... 24 
4.2. 
Primary Analysis ........................................................................................................ 24 
4.3. 
Final Analysis ............................................................................................................. 24 
5. 
Statistical Methods for Planned Analyses ..................................................... 24 
5.1. 
General Principles ....................................................................................................... 25 
5.2. 
Participant Accountability .......................................................................................... 27 
5.3. 
Demographic and Baseline Characteristics ................................................................ 27 
5.4. 
Protocol Deviations .................................................................................................... 28 
5.5. 
Study Treatment Exposure ......................................................................................... 28 
6. 
Efficacy Endpoints ........................................................................................ 28 
6.1. 
General Analysis Methods for Efficacy Endpoints .................................................... 28 
6.2. 
Use of Historical Data ................................................................................................ 35 
6.2.1. 
For the primary endpoint the following sensitivity analyses will be implemented. 36 
6.3. 
Primary Efficacy Endpoint ......................................................................................... 38 
6.3.1. 
CHOP INTEND ...................................................................................................... 38 
6.4. 
Secondary Efficacy Endpoints .................................................................................... 43 
6.4.1. 
Proportion of motor milestone responders at Day 183: comparison: 50/28mg versus 
CS3B sham control ................................................................................................................ 43 
6.4.2. 
Change in Motor Milestones total score from baseline to Day 183: comparison: 
50/28mg versus CS3B sham control. .................................................................................... 47 
6.4.3. 
Change in Plasma NF-L from (ratio to) baseline to Day 183: comparison: 50/28mg 
versus CS3B sham control. .................................................................................................... 49 
6.4.4. 
Change from baseline to Day 302 in CHOP INTEND total score: comparison: 
50/28mg versus 12 mg Group from 232SM203. ................................................................... 51 
6.4.5. 
Change from baseline to Day 302 in HINE Section 2 motor milestones total score: 
comparison: 50/28mg versus 12 mg Group from 232SM203. .............................................. 53 
6.4.6. 
Change in Plasma NF-L from (ratio to) baseline to Day 64: comparison: 50/28mg 
versus 12 mg Group from 232SM203. .................................................................................. 54 
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6.4.7. 
for > 21 days in the absence of an acute reversible event, or tracheostomy): comparison: 
50/28mg versus CS3B sham control ..................................................................................... 55 
6.4.8. 
Time to death (overall survival): comparison: 50/28mg versus CS3B sham control
 
57 
6.4.9. 
ventilation/day continuously for > 21 days in the absence of an acute reversible event): 
comparison: 50/28mg versus 12 mg Group from 232SM203 ............................................... 58 
6.4.10. Time to death (overall survival) - comparison: 50/28mg versus 12 mg Group from 
232SM203 ............................................................................................................................. 58 
6.5. 
Supplemental analyses supporting primary and secondary endpoints. ...................... 59 
6.5.1. 
Comparison: 50/28 mg Group versus CS3B sham control ..................................... 59 
6.5.2. 
Comparison: 50/28mg versus 12 mg Group from 232SM203 ............................... 60 
 
 61 
6.6. 
Analysis of the Remaining Secondary Endpoints - comparison: 50/28mg versus 12 
mg Group from 232SM203 ....................................................................................................... 62 
6.6.1. 
Change in CSF NF-L from (ratio to) baseline to Day 279 ..................................... 62 
6.6.2. 
Number and Length of Hospitalizations ................................................................. 62 
6.6.3. 
Clinical Global Impression of Change (CGIC) [Physician, Caregiver] at Day 302 63 
6.6.4. 
Number of Serious Respiratory Events................................................................... 63 
6.6.5. 
Proportion of Time on Ventilation .......................................................................... 64 
6.6.6. 
Ventilator Use ......................................................................................................... 65 
6.6.7. 
Change in the Parent Assessment of Swallowing Ability Scale (PASA) ............... 65 
7. 
Safety Endpoints ............................................................................................ 65 
7.1.1. 
Adverse events ........................................................................................................ 65 
7.1.2. 
Concomitant therapy and Procedure ....................................................................... 68 
7.1.3. 
Clinical laboratory data ........................................................................................... 69 
7.1.4. 
Neurological Examinations ..................................................................................... 70 
7.1.5. 
ECG......................................................................................................................... 72 
7.1.6. 
Vital Signs ............................................................................................................... 73 
7.1.7. 
Growth parameters .................................................................................................. 74 
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Time to death or permanent ventilation(~ 16 hours ventilation/day continuously 
Time to death or permanent ventilation (tracheostomy or~ 16 hours of 


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7.1.8. 
LP opening pressure ................................................................................................ 75 
7.1.9. 
X-ray Examination of Spine ................................................................................... 75 
 
 75 
 
 75 
 
 77 
10. 
Pharmacodynamic Endpoints ........................................................................ 79 
Other Analyses ................................................................................................................. 79 
Statistical Considerations for Interim Analysis ............................................................... 79 
Changes from Protocol-Specified Analyses .................................................................... 80 
Summary of Changes from the Previous Version 1.0 of the SAP ................................... 80 
Summary of Changes from the Previous Version 2.0 of the SAP ................................... 80 
References 80 
APPENDICES ................................................................................................................. 84 
APPENDIX A. ................................................................................................................. 84 
APPENDIX B. ................................................................................................................. 86 
 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
   
 
 
  
 
aPTT 
Activated Partial Thromboplastin Time 
ACEND Assessment of 
Caregiver Experience with 
Neuromuscular Disease 
Assessment of Caregiver Experience with Neuromuscular 
Disease 
 
 
AE   
Adverse event 
ALT 
Alanine Aminotransferase (SGPT) 
AST 
Aspartate Aminotransferase (SGOT) 
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BLQ 
Below limit of quantification 
BUN 
Blood Urea Nitrogen 
CGIC  
Clinical Global Impression of Change 
CGIC  
Clinical Global Impression of Change 
CHOP INTEND   
Neuromuscular Disorders 
   
 
CO2 
Carbon dioxide 
COVID-19   
Coronavirus disease 2019 
CRF  
Case report form 
CSF   
Cerebrospinal fluid 
CV 
Coefficient of variance 
 
 
EAC  
Endpoint adjudication committee 
ECG   
Electrocardiogram 
GGT 
Gamma-Glutamyl Transferase 
HFMSE   
Hammersmith Functional Motor Scale  Expanded 
HINE   
Hammersmith Infant Neurological Examination 
HRQOL   
Health-related quality of life 
ICF   
Informed consent form 
ICH   
International Council for Harmonization 
INR 
International Normalized Ratio 
IDMC   
Independent data monitoring committee 
IRT  
Interactive response technology 
ITT   
Intent-to-Treat 
JRT 
Joint Rank Test 
LLOQ 
Lower Limit of Quantification 
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Statistical Analysis Plan 
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LP 
Lumbar puncture 
MI 
Multiple imputation  
NF-L 
Neurofilament Light chain 
PASA   
Parent Assessment of Swallowing Ability 
PD   
Pharmacodynamic(s) 
PT 
Prothrombin Time 
PedsQL  
 
PK   
Pharmacokinetic(s) 
PPS 
Per protocol Set 
QoL 
Quality-of-life 
QTcF 
Corrected QT 
 
RULM  
Revised Upper Limb Module 
SAE 
Serious adverse event 
SD 
Standard deviation 
SE 
Standard error 
SMA 
Spinal muscular atrophy 
SMN 
Survival motor neuron 
SMN1  
Survival motor neuron 1 
SMN2  
Survival motor neuron 2 
SOC 
System Organ Class 
 
 
ULN 
Upper Limit of Normal 
US  
United States 
WHO 
World Health Organization 
1.
Introduction
This Statistical Analysis Plan is based on Version 7 of the protocol, dated 14Jun2024. All 
references to the protocol refer to Version 7. 
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Nusinersen is an antisense oligonucleotide administered intrathecally via lumbar puncture (LP); it 
increases survival motor neuron (SMN) protein expression and significantly improves motor 
function in patients with spinal muscular atrophy (SMA). Nusinersen was approved for the 
and other countries. The population for this study includes participants with infantile-onset and 
later-onset SMA.  
Efficacy and safety results across the nusinersen clinical development program have demonstrated 
an overall positive benefit-risk profile of nusinersen across a broad range of SMA phenotypes and 
patient populations. Nusinersen is approved in the US, Europe, and other countries and regions for 
the treatment of SMA in paediatric and adult patients at a recommended dosage of 12 mg 
administered in 3 loading doses at 14-day intervals, a fourth loading dose 30 days after the third 
dose, and maintenance doses every 4 months thereafter in most countries and regions. 
Pharmacokinetic (PK) and pharmacodynamic (PD) analyses indicate that nusinersen drug 
exposure higher than that achieved with 12 mg in patients with SMA may produce an even greater 
benefit in motor function. Additionally, PK modelling and simulations identified dosing regimens 
that achieve higher drug exposure more rapidly. Therefore, this study is being conducted to 
investigate the efficacy, safety, tolerability, and PK of a 50/28-mg dose of nusinersen (50 mg 
loading dose/28 mg maintenance dose) and a dosing regimen targeted to achieve higher drug 
exposure more rapidly. This study will be conducted in participants with genetically confirmed 
SMA. 
This is a 3-part study Part A, Part B (infantile-onset and later-onset), and Part C. 
Part A was an open label safety evaluation in which later-onset SMA subjects received 3 loading 
doses of 28 mg of nusinersen and 2 maintenance doses of 28 mg. All 6 participants enrolled in Part 
A completed the study. 
Part B was double-blind, active-controlled controlled study designed to evaluate the proposed 
higher dosing regimen and included infantile and   later-onset SMA participants. 
Part C was an open label safety evaluation in which infantile and later-onset SMA of the 
participants, who were on the currently approved dose of nusinersen (12-mg maintenance for at 
least 1 year after the initiation of treatment) received  higher dosing regimen via the administration 
of a single bolus dose of 50 mg of nusinersen (which should be administered 4 months ± 14 days 
after their most recent maintenance dose of 12 mg), with maintenance dosing at 28 mg thereafter. 
All 40 participants enrolled in Part C completed. 
maintenance dose of 12 mg), with maintenance dosing at 28 mg thereafter.
This SAP will cover the planned analysis of Part B infantile-onset population, a separate SAP 
will cover the later-onset population.  
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Statistical Analysis Plan 
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2. 
 Study Overview 
2.1. Study Objectives and Endpoints 
This analysis plan is for Part B infantile-onset. Separate SAPs will cover the planned analyses for 
other parts of 232SM203. 
 
Primary Objective 
To examine the clinical efficacy of nusinersen administered intrathecally at higher doses to 
participants with SMA in the 232SM203 50/28 mg Group compared to the CS3B Matched Sham 
Control Group, as measured by change in CHOP INTEND total score. 
Primary Endpoint 
 Change from baseline to Day 183 in CHOP INTEND total score, accounting for 
mortality/dropout using the joint-rank test (comparison of higher dose to matched sham 
control) 
Secondary Objectives  
To examine the clinical efficacy of nusinersen administered intrathecally at higher doses to 
participants with SMA in the 232SM203 50/28 mg group compared to:  
 CS3B Matched Sham Control Group 
  AND 232SM203 nusinersen 12 mg Group 
Secondary Endpoints 
In a change from protocol V7.0, at the time of finalizing this Statistical Analysis Plan it was 
decided to change the timepoint for the testing of plasma NF-L for the 50/28mg versus 12mg 
comparison from Day 29 to Day 64. 
Endpoint 
 
Comparison: 50/28-mg 
Group versus 
 
Proportion of Hammersmith Infant Neurological Examination 
(HINE) Section 2 motor milestone responders at Day 183 
Matched Sham Set 
Change from baseline to Day 183 in HINE Section 2 motor 
milestones total score accounting for mortality/dropout using the 
joint-rank test  
Matched Sham Set 
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Change from baseline to Day 183 in plasma concentration           
of NF-L. 
Matched Sham Set 
Change from baseline to Day 302 in CHOP INTEND total score 
12 mg nusinersen  
Change from baseline to Day 302 in HINE Section 2 motor 
milestones total score 
12 mg nusinersen  
Change from baseline to Day 64 in plasma concentration of NF-L 
12 mg nusinersen  
Time 
hours of ventilation/day continuously for > 21 days in the absence 
of an acute reversible event)   
Matched Sham Set 
Time to death (overall survival)  
Matched Sham Set 
Time to death or permanent ven
hours of ventilation/day continuously for > 21 days in the absence 
of an acute reversible event)   
12 mg nusinersen  
Time to death (overall survival)  
12 mg nusinersen  
 
Secondary Safety Objectives 
To examine the safety and tolerability of nusinersen administered intrathecally at higher doses to 
participants with SMA. 
 Secondary Safety Endpoints 
 Incidence of AEs, including SAEs 
 Shifts from baseline in clinical laboratory parameters, ECGs, and vital signs  
 Change in growth parameters  
 Shifts from baseline in coagulation parameters (aPTT, PT, and INR)  
 Change in urine total protein  
 Change from baseline in neurological examination outcomes  
 The proportion of participants with a post baseline platelet count below the lower limit of 
normal on at least 2 consecutive measurements  
 The proportion of participants with a post baseline QTcF of > 500 msec and an increase 
from baseline to any post baseline timepoint in QTcF of > 60 msec 
Additional Secondary Objectives  
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to death or permanent ventilation (tracheostomy or~ 16 
tilation (tracheostomy or~ 16 


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To examine the effect of nusinersen administered intrathecally at higher doses compared to the 
currently approved dose in participants with SMA  
Secondary Endpoints 
 Number and duration of hospitalizations 
 Clinical Global Impression of Change (CGIC) [physician, caregiver] at Day 302 
 Number of serious respiratory events  
 Proportion of time on ventilation  
 Ventilator use 
 Change in the Parent Assessment of Swallowing Ability (PASA) scale 
 Change from baseline in CSF concentration of NF-L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2. Study Design 
This 3-part study will evaluate the efficacy and safety of a high dosing regimen of nusinersen in 
approximately 145 participants. The study will be conducted at approximately 65 sites globally. 
Following the completion of this study, all eligible participants may elect to enrol in a separate 
long-term extension study (232SM302), pending study approval by ethics committees and the 
appropriate regulatory authorities. In regard to participants rolling over from Part B, this will be 
done without unblinding the 
 
Part B will consist of a pivotal, double-blind, active-controlled treatment period with either 2 or 
4 loading doses of nusinersen (for the 50/28 mg Group and Control Group, respectively) 
administered intrathecally followed by maintenance doses approximately every 4 months 
thereafter. Approximately 75 participants with infantile-onset SMA will be randomized in a 1:2 
ratio to receive either the currently approved dosing regimen or a 50/28 mg dosing regimen.  
In the Control Group, up to a total of 25 participants will receive 4 loading doses of 12 mg of 
nusinersen administered intrathecally (Days 1, 15, 29, and 64), followed by maintenance doses 
of 12 mg on Days 183 and 279 (and a sham procedure on Day 135). 
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participant's treatment group. 


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In the 50/28 mg Group, up to a total of 50 participants will receive 2 loading doses of 50 mg of 
nusinersen administered intrathecally (Days 1 and 15) and 2 sham procedures on Days 29 and 
64, followed by maintenance doses of 28 mg on Days 135 and 279 (and a sham procedure on 
Day 183). In order to maintain blinding sham procedures will be used as shown in the table 
below.  
 
Arm  
Dose 1  
Dose 2  
Dose 3  
Dose 4  
Dose 5  
Dose 6  
Dose 7  
50/28 mg 
Group 
D1 
(50 mg) 
D15 
(50 mg) 
D29 
(sham) 
D64 
(sham) 
D135 
(28 mg) 
D183 
(sham) 
D279 
(28 mg)  
Control (12/12 
mg) Group 
D1 
(12 mg) 
D15 
(12 mg) 
D29 
(12 mg) 
D64 
(12 mg) 
D135 
(sham) 
D183 
(12 mg) 
D279 
(12 mg) 
 
Participants will remain at the clinic for at least 24 hours after each study treatment 
administration or sham procedure.  
 
Randomization in Part B will be performed using interactive response technology (IRT) and the 
randomization will be stratified by disease duration as follows:  
 
> 12 weeks (time from age at symptom onset to age at informed consent)  
Blinded safety data will be reviewed on an ongoing basis by the Sponsor and the Medical 
Monitor. Unblinded safety data will be reviewed on an ongoing basis by an Independent Data 
Monitoring Committee (IDMC).  
Time to death or permanent ventilation will be determined in a blinded fashion by a central, 
independent Endpoint Adjudication Committee (EAC). Procedures for reviewing and 
adjudicating events are described in the charter that governs the operation of the EAC. 
2.3. Sample Size Considerations   
The justification for the sample size for the infantile-onset SMA population in Part B is detailed 
as follows.  
For the purposes of sample size determination, it is assumed that the higher dose will achieve an 
additional 4.5 improvement in CHOP INTEND and additional 3% in survival over the 12 mg 
dose.  For the infantile-onset SMA population in Part B, a sample size of approximately 
50 participants in the 50/28 mg Group and 20 sham subjects from study CS3B will provide at 
least approximately 99% power for the primary endpoint to detect an improvement of 24 points 
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on CHOP INTEND and 23% survival rate benefit (compared to that observed in Study CS3B 
participants receiving sham control) at Day 183 based on the joint rank test at a 2 sided 
significance level of 0.05.  This power calculation is based on simulations using data generated 
from a joint model of survival and functional change. The model used a difference of 24 points 
for the Day 183 change from baseline in CHOP INTEND total score (50/28 mg Group  
Study CS3B Sham Control Group) and a population standard deviation of 8.8 for change from 
baseline. 
2.4. Historical Data 
CS3B Study  
CS3B was a phase 3, randomized, double-blind, sham-procedure controlled study to assess the 
clinical efficacy and safety of 12 mg nusinersen administered intrathecally in participants with 
infantile-onset SMA.  122 participants were randomized 2:1 to receive a scaled equivalent 12 mg 
dose of nusinersen or underwent a sham procedure as control, respectively.  
Key eligibility criteria were SMN2 copy number = 2, onset of SMA symptoms <= 180 days of 
age and age at screening <=210 days.  The study had two primary endpoints: 
1) Proportion of HINE Section 2 motor milestone responders and  
2) Time to death or permanent ventilation.   
A key secondary endpoint was change in CHOP INTEND. 
 
The first participant in CS3B was dosed in August 2014 and the last participant last visit was 
November 2016. The study was stopped early for efficacy based on the results of an interim 
analysis and the final study results were published (Finkel et al. 2017).   
 
Figure Showing Key Analysis Sets From CS3B  
The figure below shows the number of participants in the ITT/Safety set and efficacy sets for the 
CS3B. 
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Summary of How Historical Data Will be Used in the Analysis 
The enrollment criteria of the Part B infantile-onset in 232SM203 has been designed to be 
similar to CS3B study (external data).  In general, consistent inclusion/exclusion criteria have 
been utilized and efficacy assessments at the same timepoints have been included. 
As part of the analysis of the 232SM203 study the external data will be utilized for the following 
purposes: 
 For the primary and secondary endpoints comparing to sham, the higher dose participants 
from 232SM203 will be compared to matched sham control participants from CS3B.   
Comparability will be assessed for 232SM203 compared to CS3B sham based on key 
covariates and a matching algorithm will be utilized to select at least 20 CS3B sham 
control subjects.  For the remaining secondary endpoints, the high dose participants will 
be compared to 12 mg dose using the 232SM203 ITT population.   
 
 
 
 
  
 Use of the group of matched control subjects described in the first bullet for summaries 
of safety endpoints.  This is in order to provide a reference group of participants with 
similar disease who have not undergone lumbar puncture SMA.   
3. 
Definitions 
3.1. Dates and Points of Reference 
 Study Day 1: the date of the first dose of study treatment in 232SM203 
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Summary of analysis sets from CS3B 
ITT Set/Safety Set 
Day 183 efficacy set 
Day 302 efficacy set 
Nusinersen 
N=80 
N=73 
CS3B 
Sham 
N=41 
N=37 
N=28 
Note: Efficacy sets defined as subjects with the opportuoity to attend the visit if the study had not stopped due to effirncy . 
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 Study Day  
o For a date on or after Study Day 1  
Study Day = (Date of Interest)  (Study Day 1) + 1  
o For a date before Study Day 1  
Study Day = (Date of Interest)  (Study Day 1) 
In order to distinguish nominal visit names from duration defined in days, visit names will be 
time intervals. 
Overall time on study will be defined as the total number of days a participant is known to be 
followed on study calculated as follows: 
 
Overall time on Study = (Last date on study)  (Date of first dose) +1 
Last date on study is defined as the date of the latest visit or evaluation or telephone contact, or 
time of death from all available data for a given participant. 
Disease duration is defined as time from age at symptom onset to age at informed consent. 
3.2. Study Treatments 
The main presentations of data will use the following groups: 
Baseline characteristics displays for assessing sham and 232SM203 similarity. 
 
 
 
 
 
232SM203 
 CS3B 
CS3B 
Sham control 
Matched Sham 
control 
12/12 mg 
nusinersen
50/28 mg 
nusinersen Total
Baseline characteristics, disposition, exposure, time on study   
232SM203 
 
Matched CS3B 
 
Sham control 
12/12 mg  
nusinersen 
50/28 mg 
nusinersen 
Total 
 
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• 
referred to as "Day 15", "Day 29", etc., and "15 days" or "29 days", etc. will be used to define 


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For summaries of post-baseline efficacy by visit/time  
232SM203 
Matched CS3B 
Sham control 
12/12 mg  
nusinersen 
50/28 mg 
nusinersen 
 
Primary and secondary endpoints analyses comparing sham and key adverse event displays 
 
232SM203 
Matched CS3B 
Sham control 
50/28 mg 
nusinersen 
 
For secondary endpoints comparing higher dose to 12/12 mg in 232SM203, safety and post 
baseline safety parameters: 
 
232SM203 
12/12 mg  
nusinersen 
50/28 mg 
nusinersen 
 
 
 
 
 
 
 
3.3. Study Periods 
  The total study duration for each participant will be approximately 323 to 420 days   
 
Screening: 21 days  
 
Loading period: 64 days  
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Maintenance period: 215 days 
 
Follow-up: 23 to 120 days 
3.4. Key Derived Variables 
Not applicable. 
3.5. Stratification Factors and Subgroup Variables 
Stratification Factors 
Randomization was stratified as follows: 
 For participants with infantile-onset SMA by disease duration:  
 
 
 
> 12 weeks   
Subgroup Variables 
The following are defined as subgroups: 
 
Baseline CHOP INTEND (<= median, > median, median calculated 232SM203 ITT 
Set) 
 
Geographic region: 
o Asia-Pacific (Australia, China, Hong Kong, Japan, Lebanon, Saudi Arabia, 
South Korea, Taiwan, Turkey) 
o Europe (Belgium, France, Germany, Great Britain, Hungary, Italy, Poland, 
Russia, Spain, Sweden) 
o North America (Canada, United States) 
o South/Central America (Brazil, Chile, Colombia, Mexico) 
 
The main analyses for the primary endpoint and time to death and time to death or permanent 
ventilation for higher dose versus sham will be repeated for the subgroups: disease duration and 
baseline CHOP INTEND total score. Summaries of change from baseline in CHOP INTEND 
will be repeated for each of the three subgroups up to Day 183.   
The main analyses for the change in CHOP INTEND to Day 302 and time to death and time to 
death or permanent ventilation will be repeated for subgroups: disease duration, baseline CHOP 
INTEND for the higher dose versus 12 mg comparison within 232SM203. 
Summaries of change from baseline in CHOP INTEND by visit will be presented for each of the 
three subgroups for the higher dose versus 12 mg comparison within 232SM203. 
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3.6. Analysis Sets 
3.6.1. Within 232SM203 
The Safety Set 
The Safety Set is defined as all participants who receive at least one dose of nusinersen; 
participants will be analyzed in the treatment group based on what they actually received.  
The Intent-to-Treat (ITT) Set  
The Intent-to-Treat (ITT) Set is defined as all participants who are randomized and receive at 
least one dose of nusinersen; participants will be analyzed in the treatment group to which they 
are randomized. This will be the primary population for the analysis of efficacy endpoints. 
 
 
  
  
 
 
Per Protocol Set 
A Per Protocol Set will include the subset of the ITT Set who have no significant protocol 
deviations that would be expected to affect efficacy assessments. 
Significant protocol deviations will be determined prior to database lock and will include: 
Participants who have an SMN copy number other than 2, participants who were greater than 7 
months of age at Screening, age of onset of clinical sign >180 days, participants who had 
hypoxemia at baseline (  96% at an altitude of < 1500 meters, < 92% at an altitude of 1500 to 
2000 meters, or < 90% at an altitude > 2000 meters at Screening). 
 
Participants who are on permanent ventilation or tracheostomy at Screening. 
Participants who took experimental or approved agents for the treatment of SMA, including gene 
therapy, biological agent, or device, during the study. This includes marketed agents at 
experimental doses that are being tested for the treatment of SMA (oral albuterol/salbutamol, 
riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea, etc.). 
Participants who had a previous diagnosis that would confound the data/conflict with SMA. 
If participants have missed planned doses/sham but still completed study. 
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3.6.2. External data  
For CS3B, the efficacy set at Day 183 and Day 302 as defined for the final analysis of CS3B will 
be utilized. 
The following table describes analysis sets for the historical data and how they will be referenced 
in the remainder of the document. 
Table 1: Analysis set  
Analysis Set Label 
Description 
 
CS3B Day 183 efficacy set 
referenced in the Final CS3B CSR. It consists 
of N=37 sham control and N=73 12 mg 
nusinersen participants. 
CS3B Day 302 efficacy set 
referenced in the Final CS3B CSR. It consists 
of N=28 sham control and N=49, 12 mg 
nusinersen participants. 
Matched Sham Set 
Analysis set for main comparisons of higher 
dose versus sham control.  
Subset of the 37 sham control participants in 
the CS3B Day 183 efficacy set similar to 
higher dose 232SM203 participants and all 
higher dose participants in the ITT set. 
Matched Sham Set (sensitivity) 
Subset of the 37 sham control participants in 
the CS3B Day 183 efficacy set similar to all 
N=75 232SM203 participants in the ITT set. 
Greedy matched set (sensitivity) 
Set of CS3B sham and 232SM203 higher dose 
participants matched by greedy matching.  
Note that not all higher dose participants will 
have a match. 
 
 
 
 
 
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4. 
List of Planned Study Analyses 
4.1. Interim Analysis 
No interim analysis is planned.  The unblinding plan details the steps to ensure that the blind is 
maintained throughout the entire study. 
4.2. Primary Analysis 
The primary analysis is to test the mean change in CHOP INTEND total score from baseline to 
Day 183 for the 50/28-mg in 232SM203 compared to the CS3B matched sham control Group, 
using the joint-rank test and handling drop out not due to death with multiple imputation.  
4.3. Final Analysis 
The final analysis will be performed when all infantile onset participants in Part B have 
completed the follow-up period.  
5. 
Statistical Methods for Planned Analyses 
Within the infantile-onset population to control the overall type 1 error at a 2-sided alpha level of 
0.05, a sequential testing procedure ranked in the order of the primary and secondary endpoints 
will be utilized. Table 2 summarizes the planned statistical testing. Inferential conclusions about 
each successive analysis require statistical significance of the prior one.   
Table 2: 
Sequential Testing Procedure for Primary and Secondary endpoints  
Rank 
Endpoint  
Comparison Higher 
dose to: 
Population 
Description 
1 
Change from baseline to Day 183 in 
CHOP-INTEND total score 
CS3B Sham 
control 
Matched Sham 
Set 
Primary 
2 
Proportion of HINE Section 2 motor 
milestone responders at Day 183 
CS3B Sham 
control 
Matched Sham 
Set 
Secondary 
3 
Change from baseline to Day 183 in 
HINE Section 2 total score 
CS3B Sham 
control 
Matched Sham 
Set 
Secondary 
4 
Change from baseline to Day 183 in 
plasma NF-L   
CS3B Sham 
control 
Matched Sham 
Set 
Secondary 
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Rank 
Endpoint  
Comparison Higher 
dose to: 
Population 
Description 
5 
Change from baseline to Day 302 in 
CHOP-INTEND total score 
232SM203 12 mg 
ITT set 
Secondary 
6 
Change from baseline to Day 302 in 
HINE Section 2 total score 
232SM203 12 mg 
ITT set 
Secondary 
7 
Change from baseline to Day 64 in 
plasma NF-L 
232SM203 12 mg 
ITT set 
Secondary 
8 
Time to death or permanent ventilation 
CS3B Sham 
control 
Matched Sham 
Set 
Secondary 
9 
Time to death 
CS3B Sham 
control 
Matched Sham 
Set 
Secondary 
10 
Time to death or permanent ventilation 
232SM203 12 mg 
ITT set   
Secondary 
11 
Time to death 
232SM203 12 mg 
ITT set   
Secondary 
 
 
 
 
                   
 
5.1. General Principles  
Descriptive summary statistics will be presented for all primary, secondary 
 
endpoints collected. Unless otherwise specified, for continuous endpoints, the summary statistics 
will generally include number of participants with data, mean, standard deviation, median, 25th 
percentile, 75th percentile, minimum and maximum. For categorical endpoints, the summary 
statistics will generally include number of participants with data, and the percentage of those 
with data in each category. 
 
All summaries and listings will be presented by study groups unless otherwise specified. Visits 
in listings will be displayed as per CRF data collection rather than analysis visits. 
 
The statistical software, SAS®(Version 9.4) will be used for all summaries and statistical 
analyses.  
 
Visit Windows for Early Withdrawal, Unscheduled Visits 
Data from early withdrawal visits, post baseline unscheduled assessments will be assigned to an 
appropriate scheduled post baseline visit using a windowing scheme for assessments that are 
tabulated or summarized by visit. Scheduled visits will not be windowed. 
The visit windowing will be performed for efficacy and safety endpoints.  
For safety endpoints the following windows will be utilized. 
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Table 3: Visit windows for safety Endpoints in 232SM203. 
Visit 
Lower Bound  
Upper Bound  
Target Day 
Baseline 
 
 
<=2 
Day 15 
2 
21 
15 
Day 29 
22 
47 
29 
Day 64 
48 
99 
64 
Day 135 
100 
159 
135 
Day 183 
160 
232 
183 
Day 279 
233 
290 
279 
Day 302 
291 
348 
302 
 
For efficacy endpoints, if the actual study day falls within: +/- 7 days of scheduled post baseline 
loading dose visits and +/-14 days of a maintenance dose then it will be considered for 
windowing.   
The following rules will be implemented for windowing of these visits for both safety and 
efficacy. 
 If more than one observation is within the same window, data from the regular scheduled 
visit will be used for that visit.  
 If neither of the observations are from a regular scheduled visit the observation closest to 
the planned target date will be used. However, if both the observations are equidistant 
from the target date, the latest one will be used; if repeated measurements are on the same 
day, then the last measurement will be used. 
 If windowing safety data and there is more than one observation in a window for a dosing 
visit the observation on the day of dosing will be chosen over the observation where 
dosing did not occur on the same day. 
 In windowing laboratory data, if a central and local result is available within the window 
then the central laboratory result will be chosen.  
 
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5.2.  Participant Accountability  
The number (and percentage) of subjects screened, screening failure, randomized, withdrew prior 
to dosing, dosed, completed treatment, discontinued treatment and the reasons for 
discontinuation from treatment, completed the study, withdrew the study and reason for 
withdrawal will be summarized in a table.  
If there are any subjects who discontinued from treatment or withdrew from study due to reasons 
associated with the COVID-19 pandemic or reasons associated with humanitarian emergencies, a 
separate summary will be presented to summarize these reasons.  
A listing of subjects who discontinued treatment/withdrew from study and the associated reasons 
for discontinuation/withdrawal will be presented. Two separate listings will also be presented for 
subjects who discontinued treatment/withdrew from study due to the COVID-19 pandemic or to 
humanitarian emergencies if applicable. 
5.3. Demographic and Baseline Characteristics 
Baseline data (demography, medical history, SMA history, and baseline disease characteristics) 
will be summarized.  
Formal statistical analyses will not be done to test for homogeneity between treatment groups. If 
there are apparent heterogeneities between the groups in any of the participant characteristics 
that are of clinical importance or could affect the treatment outcome, the impact of the 
imbalances will be investigated and, if appropriate, adjustments made in the efficacy and safety 
analyses. 
Demography includes age at screening, age at first dose, sex, ethnicity, race and country,  
Medical history will be coded in MedDRA and the number and percentage of subjects with each 
medical history presented by preferred term.  
SMA history will include gestational age, birth weight, age at symptom onset, time from disease 
onset to enrollment, age at SMA diagnosis, history of SMA symptoms (hypotonia, 
developmental motor delay, paradoxical breathing, pneumonia or respiratory symptoms, limb 
weakness, swallowing or feeding difficulties, and other symptoms), and the number of copies of 
the SMN1 and SMN2 gene.  
Baseline disease characteristics will be assessed by CHOP INTEND total score, total HINE 
Section 2 motor milestones, and growth parameters - these assessments are further described in 
Section 6. If a participant was receiving ventilation at Day 1, then the number of hours of 
ventilation use on Day 1 will also be summarized as baseline.  In addition, use of a 
gastrointestinal tube will be presented.  Use of gastrointestinal tube will be determined from 
either medi
 
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Demographic and baseline disease characteristics will be presented for the ITT Set, the PPS, the 
Safety Set as appropriate.  Additional presentations will be presented to facilitate comparisons at 
baseline for the planned efficacy comparisons.  For example, for the primary endpoint to 
compare the higher dose to CS3B sham control. 
5.4. Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a protocol deviation log 
and categorized as major or minor deviations. These deviations will be listed. Major protocol 
deviations will be summarized including those that lead to exclusion from the Per protocol Set. 
Participants with incorrect stratification i.e. any mismatch between the stratification used for 
randomization on the IRT system and the actual stratification according to the eCRF will also be 
listed. A separate summary of major protocol deviations related to the COVID-19 pandemic will 
be presented.  
5.5. Study Treatment Exposure  
The number of doses received, and the number of sham procedures performed will be displayed 
using frequency distributions. The cumulative amount of nusinersen received will be 
summarized using summary statistics. 
The overall time on study will be summarized descriptively by treatment. Overall time on study 
will be calculated (section 3.1). The duration will also be categorized and summarized using the 
following categories: <29 days, >=29 to 64 days, >=64 to 99 days, >=99 to 135 days, >=135 to 
183 days, >=183 to 218 days, >=218 to <260, >=260 to 302 and >=302 days 
Given the long half-life of nusinersen, participants are considered to be exposed from the time 
the first dose of nusinersen was administered (in or before the start of study) to the date of last 
visit or contact. 
Separate listings will be provided showing what subjects were randomized to as well as study 
drug administration data which will include lot numbers, actual treatment received, cumulative 
number of doses and cumulative doses. A listing of dosing errors will also be provided i.e. where 
either the incorrect dose was administered as specified in protocol deviation log and kit 
description from IRT system. A listing will also be presented to show whether any of the missed 
doses are related to COVID-19. If any of the doses are due to COVID-19, then the number of 
impacted doses will be presented. 
6. 
Efficacy Endpoints 
6.1. General Analysis Methods for Efficacy Endpoints 
Multiple imputation (MI)  
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The multiple imputation method [Schafer 1997, Schafer 1999] will be used for participants who 
discontinue for a reason other than death or have a missing efficacy result at the timepoint of 
interest.  This will be performed for CHOP INTEND, HINE Section 2 total score and NF-L. Any 
imputation on an item level within a scale for CHOP INTEND and HINE section 2 will be 
performed prior to performing MI.  
The imputations will be performed on total scores. All available data will be used i.e., where 
subjects have missed doses but continued to perform assessments; otherwise, any missing values 
will be imputed using MI. In a situation where historical data is used as the control group only 
the visits which are common between the two groups will be utilized. For example, for the CS3B 
sham control versus higher dose comparison only the Day 64, Day 183 and Day 302 visits will 
be included in the list of post baseline visits. 
In this situation if convergence issues occur then only the Day 64 and Day 183 post baseline 
visits will be included. 
The Markov Chain Monte Carlo (MCMC) method will be used to impute the missing score.   
The treatment variable will be coded so that the Higher dose group is the first in the sort order. Prior 
to the Proc MI step the dataset will be sorted by treatment and then ascending unique subject 
identifier (USUBJID). The variable list in the model for imputations will include: 
 treatment group, disease duration, baseline value for the endpoint, and all available post 
baseline values 
 For NF-L, the log of baseline and post-baseline values will be used in the PROC MI step.  
A set of 100 complete imputed datasets will be generated and the relative efficiency parameter 
will also be checked to determine the acceptability of the imputed results i.e. it should be close to 
98% or higher.  The seed used for the multiple imputation for CHOP INTEND will be 5846892, 
for HINE section 2 Motor Milestones will be 8746890 and for NF-L will be 7635789. 
If the MI procedure imputes any values outside the expected range for the scale, e.g. from 0 to 64 
for CHOP INTEND, then values below 0 will be set to 0 and values above 64 will be set to be 
64. For NF-L if any imputed values are < log(LLOQ) then set as log(LLOQ/2). 
For each of the 100 imputed datasets, the endpoint will be compared between treatment groups 
using an ANCOVA model for continuous endpoints and logistic regression for binary endpoints 
as described in the main analysis for each endpoint.  Additional detail such as how the joint rank 
test will be implemented and the adjustment for baseline covariates is described below and for 
each endpoint in Section 6.3 and 6.4  
The estimates from the 100 fitted models will be combined to provide an overall estimate with 
corresponding confidence intervals and p-value using PROC MIANALYZE [Little et al, 2002]. 
For the continuous endpoints, the difference between treatments and the corresponding CI will 
be presented. For the analyses using logistic regression the odds ratio and corresponding CI will 
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be presented. In addition, the estimates of the binomial proportions in each treatment arm and the 
differences between treatments will be presented (Ratitch, 2013). 
In the presentation of results from multiple imputed data, the number of subjects with missing 
data will be summarized. 
Joint rank methodology  
Death is a potential outcome in the infantile-onset population and the joint rank methodology 
will be utilized to incorporate both the functional endpoint and mortality. 
The joint rank methodology [Berry 2013] allows for a statistical test of the treatment effect on 
joint rank score will be calculated by comparing each subject to every other subject in the study, 
resulting in a score of +1 if the outcome was better than the subject being compared, -1 if worse, 
by summing their comparison to all 
the other subjects in the study.  
For the purpose of this calculation, considering an endpoint for change to Day 183, subjects will 
be grouped into the following 2 categories: 
 Group 1: Participants who complete Day 183 and have data available AND subjects 
data available 
 Group 2: Participants who die will be ranked based on the time of death 
The criteria for withdrawals are based on withdrawal from study. A subject may discontinue 
treatment but still continue in the study and in this case data from assessments conducted after 
treatment will be included for analysis. 
Joint rank methodology + MI  
MI will be used to impute all missing data including data after withdrawal from the study or 
where a participant 
interest. No efficacy data would be available after death. MI will be performed as described 
earlier and subjects who died will be included in the MI model, but any values imputed after 
death will not be used for determining the rank score. Therefore, all subjects except withdrawals 
due to death will have a value at Day 183 (either observed or imputed). In each of the 100 
imputed datasets, subjects will be ranked as follows:  
 Subjects in Group 2 will be given lower ranks than subjects in Group 1, with the 
lowest ranks being given to the subjects who die in the shortest time after first dose. 
Progressively higher ranks will be given to subjects who die at longer times after first 
dose.  
 Subjects in Group 1 will rank higher than subjects in Group 2. Progressively higher 
ranks will be given to subjects with a higher change in CHOP INTEND at Day 183. 
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the endpoint while accounting for truncation of data due to deaths. In this analysis, a subject's 
and O if the same. The subject's score will then be calculated 
• 
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• 
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For example, for 2 subjects in Group 1 their comparison score will be based on the 
endpoint of Day 183 CHOP INTEND. The subject being ranked will be given a 
comparison score of -1 if their CHOP INTEND is worse than that of the comparison 
subject. If the score is the same in both subjects their comparison will be considered a 
tie and so a comparison score of 0 will be assigned.  For subjects who do not survive, 
a subject who dies earlier than the comparator subject will be given a comparison 
score of -1. If two subjects die the same number of days from their first dose of study 
medication their comparison will be considered a tie i.e. comparison score of 0 will 
be assigned. 
The subjects will be ranked according to their subject rank scores in each of the 100 MI datasets. 
In the instance of ties, the mean of the corresponding ranks will be assigned to the tied subjects. 
Hence, in general, these comparisons will result in subjects who die being assigned the worst 
scores and ranked according to time of death. Subjects who survive and complete the study and 
subjects who withdraw from the study will be ranked more favorably than subjects who die.  
For each of the 100 imputed datasets, the ranked scores will be compared between treatment 
groups using an ANCOVA model. The ANCOVA model will include treatment as a fixed effect 
and adjusted for each of the corresponding baseline value for the endpoint and disease duration 
 
The model will be used to obtain the p-value from PROC MIANALYZE for the joint rank.  
 
 
Adjustment of ranking criteria for JRT for withdrawals not due to death 
In order to test the sensitivity of handling withdrawals not due to death, ranking criteria will be 
adjusted as a sensitivity analysis for JRT. Instead of 2 categories, subjects will be grouped into 3 
categories: 
 Group 1: Participants who complete Day 183 and have data available or complete the 
 
 Group 2: Participants who withdraw from the study due to reasons other than death 
 
 Group 3: Participants who die will be ranked based on the time of death 
 Subjects will be ranked as follows:  
 Participants in Group 3 will be given lower ranks than subjects in Groups 1 and 2, with 
the lowest ranks being given to the subjects who die in the shortest time after first dose. 
Progressively higher ranks will be given to subjects who die at longer times after first 
dose.  
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 Participants in Group 2 will rank lower than subjects in Group 1, with the lowest ranks 
being given to the subjects who withdraw from the study in the shortest time after first 
dose. Progressively higher ranks will be given to subjects who withdraw from the study 
at longer times after first dose. 
 Subjects in Group 1 will rank higher than subjects in Groups 2 and 3. Progressively 
higher ranks will be given to subjects with a higher change from baseline at Day 183 i.e. 
smaller decline at Day 183. 
The same approach using the joint rank test with MI will be implemented for the analysis.  The 
main difference is that the imputed values will only be utilized for ranking if the participant is in 
group 1.  Otherwise, the ranking will be performed based on time in study. 
 
 
Adjustment of ranking criteria for JRT for permanent ventilation 
In order to examine the impact of considering permanent ventilation in evaluation of this endpoint 
the ranking criteria will be adjusted as sensitivity analysis for JRT. Subjects will be grouped into 
2 categories: 
 Group 1: Participants who complete Day 183 and have data available or reach beyond 
Day 183 and 
183 
 Group 2: Participants who die or are confirmed to have met permanent ventilation, 
i.e. tracheostomy or 22nd day of ventilation is on or prior to Day 183. Participants will 
be ranked based on the earlier of time of death or time of meeting permanent 
ventilation definition. 
The same approach using the joint rank test with MI will be implemented for the analysis.  The 
main difference is that the imputed values will only be utilized for ranking if the participant is in 
group 1.  Otherwise, the ranking will be performed based on time in study. 
 
 
Rank based implementation of Joint rank method + MI 
As a Sensitivity analysis, a new version of the joint rank test will be implemented, using the 
change in ranks rather than directly the survival time and change in CHOP INTEND.   
Initially, all participants will be ranked based on the baseline CHOP INTEND score, so for the 
12 mg versus 50/28mg comparison within 232SM203, with a total of N=75, the lowest score will 
be ranked as 1 and the highest as 75. 
Group 1 will be defined as participants who died prior to Day 183. For this group, ranking will 
be performed based on Study Day of Death. 
Group 2 will be defined as participants who did not die and have either an imputed or observed 
Day 183 result for total CHOP INTEND.  
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Subjects will be ranked in each of the 100 MI datasets as follows. The subjects will be ranked for 
Day 183 with subjects who died in group 1 given a lower rank than subjects in group 2.  The 
subject who died first will be given a rank of 1.  For group 2 the lowest Day 183 CHOP 
INTEND score will be given the lowest rank and the highest CHOP INTEND score will be 
assigned the highest rank. In the case of ties the mean of the ranks will be assigned to tied 
subjects 
For each of the 100 imputed datasets the change in ranks will be compared between treatment 
groups using an ANCOVA model.  The response variable will be determined as the difference: 
Rank at Day 183  
.  The model will include treatment as a fixed effect and 
adjusted for each of the corresponding baseline value for the endpoint and, disease duration. 
 
   
ANCOVA model 
For each of the 100 imputed datasets, the endpoint will be compared between treatment groups using 
an ANCOVA model for continuous endpoints (primary, secondary and NF-L endpoints). The 
ANCOVA model will include covariates for each of the corresponding baseline value for the 
endpoint, baseline CHOP INTEND total score (if not the endpoint under consideration) and disease 
duration at informed consent. The model will be used to present overall LS means and standard 
errors for each treatment group, and LS mean differences for treatment with corresponding 95% CI. 
ANCOVA model without equality of variances assumption 
As a sensitivity analysis the main analysis will be repeated using the repeated statement in PROC 
Mixed to estimate the variance for each treatment group separately.  For this analysis the degrees 
of freedom will be adjusted using the Satterthwaite option. 
Jump to reference analysis for MI with the Joint Rank test 
Jump to reference (J2R) is a sensitivity analysis such that imputed values for patients in the 
higher dose arm take on attributes of the reference arm (matched sham subjects) after 
discontinuation.  This is a conservative assumption for the higher dose versus sham comparisons 
as due to the long half-life it is not likely that following withdrawal the benefit of treatment will 
completely disappear. J2R analysis will be implemented using the SAS macro RMCONJPLUS 
(https://www.lshtm.ac.uk/research/centres-projects-groups/missing-data#dia-missing-data).    
In the joint rank step as for the main analysis, for patients who died the ranking will be 
performed based on day of death and then for patients who have not died the ranking will be 
based on the change from baseline in efficacy score (imputed or observed) at the time point 
under consideration.  
Trimmed mean 
As a supplemental analysis, the change from baseline in CHOP INTEND total score between 
treatment groups will be compared using the trimmed mean method to account for informative 
censoring due to death or withdrawal [Permutt and Li 2015].  
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The trimmed mean is an averaging method which eliminates a partial percentage of the smallest 
values before evaluating the standard mean of the given data. The trimmed mean difference can 
be interpreted as the mean difference of the top fraction of responses between the two groups. To 
do this, responses are ranked and subjects who have died or withdrew are considered as having 
worse outcomes than those who survived and completed the trial. To ensure that subjects who 
died or withdrew receive the lowest rank in response an arbitrary value of -999 will be assigned. 
The choice of this value does not impact the analysis results because these subjects are 
eventually excluded from the calculation of the trimmed mean statistics. Subject response scores 
in the two groups will then be ranked from the largest to the smallest separately. The top 100*p% 
response scores from the two groups will be retained and the mean response difference is 
calculated as the trimmed mean statistics. Here, p is the minimum of the proportions of subjects 
who survived and completed the assessment in the two groups.  
As a hypothetical example, using the 12 mg versus 50/28 mg with 232SM203 comparison, 
assume at the end of the study in which 75 subjects were randomized and dosed, the number of 
subjects who died or withdrew is 4 out of 50 (8.0%) in the nusinersen 50/28 mg group and 5 
subjects out of 25 (20%) in the control group. The 9 subjects who died or withdrew in the two 
groups are assigned a response score of -999. The CHOP INTEND scores at Day 183 in the two 
groups are then ranked from largest to smallest separately. The top 80% of scores from each 
group will be retained and the mean difference is then calculated as the trimmed mean statistic.  
data available (who do not withdraw from study or die), they will also be trimmed from analysis, 
i.e. they will also be assigned the arbitrary value of -999.  
The p-value associated with the observed test statistic is then calculated using a reference 
distribution generated by the re-randomization procedure described below: 
1. For all 75 subjects randomized in the ITT population, randomly assign subjects in a 
50/25 ratio to treatment (nusinersen 58/28 mg or control) such that there are 50 subjects 
in the nusinersen 58/28 mg group and 25 in the control group. This can be done using 
simple random sampling without replacement. The seed used will be 5846894.  
2. Calculate the trimmed-mean test statistic as described above using the random treatment 
assignment in Step 1  
3. Repeat Steps 1 and 2 N times (N=10,000). As a result, N trimmed-mean statistics will 
be generated. The empirical distribution of the N trimmed-mean statistics will then 
serve as the reference distribution for p-value calculations. 
Denote the observed trimmed mean statistic as T0. Once the reference distribution has been 
established, the p-value associated with the observed test statistic is calculated as proportion of 
simulated test statistics that are either greater than |T0| or less than - |T0|.  
 
Responder Analyses of CHOP INTEND and HINE Section 2 
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For CHOP INTEND it is planned to use multiple imputation to deal with missing data and the 
analysis will be performed using logistic regression. Should the number of responders be less 
io, it will not be 
possible to use multiple imputation and the following approach will be implemented to impute a 
missing response:  
For a given timepoint such as Day 183, subjects who die or withdraw from the study prior to Day 
183 will be counted as non-responders and will be included in the denominator for the 
calculation of the proportion of responders.  In determining the response at Day 183 where a 
subject has missing response but the two immediate flanking visits both have an evaluable 
response an imputation will be performed.  For example, the visit of interest is Day 183 and the 
immediate flanking visits are Day 135 and Day 279.  If at both Day 135 and Day 279 the subject 
is a responder, then an imputation will be performed to count the missing Day 183 as a 
responder.  For any other combination of missing/non response observed in flanking visits the 
subject will be considered a non-responder.   
For HINE Section 2 motor milestone responders it is not planned to use multiple imputation.  
Therefore, if the endpoint is at Day 302 and the participants has a missing HINE Section 2 
response, they will be considered to be a non-responder.  In a situation where the endpoint is at 
Day 183 and flanking visits may be available the imputation approach described above for 
CHOP INTEND response will be implemented. 
6.2. Use of Historical Data 
The primary and some secondary endpoints will compare high dose to sham control. A total of 
N=37 are available from CS3B at Day 183. The following algorithm will be used to select the 
maximum number of Sham control subjects who are comparable at baseline to 232SM203 
(N=75) based on two covariates: disease duration at informed consent, baseline CHOP INTEND 
total score.  The algorithm will stop at a minimum of 20 participants. 
 
 
 
 
 
 
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than 5 in either group, Fisher's exact test will be used instead. In this scenar 


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• 
• 
• 
• 
• 
• 


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6.3. Primary Efficacy Endpoint  
6.3.1. CHOP INTEND 
 The CHOP INTEND infant motor function scale is comprised of 16 test items, nine of which are 
scored 0, 1, 2, 3, or 4 with greater scores indicating greater muscle strength, five are scored as 0, 
2, or 4, one is scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4. This can result in a worst possible 
total score of 0 to a best possible total score of 64. CHOP INTEND is used to assess spontaneous 
movement in the upper extremities, spontaneous movement in the lower extremities, hand grip, 
head in midline with visual stimulation, hip adductors, rolling elicited from the legs, rolling 
elicited from the arms, shoulder and elbow flexion and horizontal abduction, shoulder flexion 
and elbow flexion, knee extension, hip flexion and foot dorsiflexion, head control, elbow flexion, 
neck flexion, head/neck extension, and spinal incurvation. 
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The baseline for CHOP INTEND is defined as the mean of the total score assessments taken 
during the screening/baseline period prior to the first dose.   
Missing Values 
 
Missing data will be imputed on an individual CHOP INTEND test item level to provide a total 
score only if at least one item is assessed.  
 
If a test item is missing at screening, then the missing value will be imputed as the median of the 
non-missing 
weeks, > 12 
 
 
 
 
 
 
 
 
 Age at symptom onset >12 weeks and disease duration >12 weeks 
If, for the subject with missing CHOP INTEND test items at a particular visit, the corresponding 
visit is flanked by visits with non-missing test items, then the missing value for those test items 
will be imputed using linear interpolation with the result rounded to the nearest integer score. 
Otherwise, if the missing visit is the last visit, missing test items will be imputed as the lowest 
value in the stratum (age at symptom onset by disease duration) to which the subject belongs 
within the same treatment group at the same visit. 
 
In the event of no observed data for imputation, disease duration by treatment will be used as the 
classification factor for the purpose of identifying non-missing data for imputation. 
 
Of note, only observed data will be utilized for imputation purposes. Missing CHOP INTEND 
items will be imputed first prior to any analysis. 
Main Analysis 
The primary efficacy endpoint of change from baseline to Day 183 in CHOP INTEND total 
score will be analyzed using the joint-rank methodology to account for mortality [Berry 2013]. 
This joint-ranking procedure allows for a statistical test of the treatment effect on the CHOP 
INTEND total score while accounting for loss of data due to deaths. Multiple imputation (MI) 
will be used to handle withdrawals, when implementing the JRT methodology. Any imputation 
on an item level within a scale will be performed prior to performing MI.  The estimates will be 
obtained from an ANCOVA model for change from baseline in CHOP INTEND total at Day 183 
with missing data imputed using multiple imputation. Note that all available data up to Day 302 
will be included in MI procedure.   
The main analysis of the primary endpoint of Day 183 change from baseline in CHOP INTEND 
is the composite estimand [ICH E9 (R1) Addendum 2017].  
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values of the stratum to which the subject belongs to: age at symptom onset (:512 
weeks) by disease duration (::Sl 2 weeks, > 12 weeks). Specifically, the four strata are: 
• 
Age at symptom onset :512 weeks and disease duration :512 weeks 
• 
Age at symptom onset :512 weeks and disease duration> 12 weeks 
• 
Age at symptom onset> 12 weeks and disease duration :512 weeks 
• 


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The estimand of the primary analysis is defined as:  
o Population: all Higher Dose subjects in the ITT population and CS3B sham Day 
183 matched efficacy set  
o Variable: change from baseline to Day 183 in CHOP INTEND total score OR  
Study day of death 
o Intercurrent events: handled using a composite strategy in which subjects who have 
intercurrent events are ranked against each other and against subjects without any 
intercurrent event using the joint rank methodology based on MI datasets as 
detailed in Section 6.1.  The relevant intercurrent events are death and withdrawals.  
For deaths, ranking will be based on time on study and for withdrawals not due to 
death ranking will be based on the imputed Day 183 value from the MI datasets.  
The ANCOVA model will include covariates for baseline CHOP INTEND total score and 
disease duration at screening. 
 
The P-value for the difference between treatment groups based on the rank 
scores at Day 183 will be calculated from PROC MIANALYZE. 
Sensitivity analyses   
o Repeated using CS3B sham Day 183 matched to 232SM203 efficacy set (sensitivity) 
o Repeated using Greedy matched set (sensitivity) 
o Adjustment of ranking criteria for JRT for withdrawals not due to death 
In order to test the sensitivity of handling withdrawals not due to death, ranking criteria 
will be adjusted as a sensitivity analysis for JRT 
These analyses will be performed as described in Section 6.1 
o Adjustment of ranking criteria for JRT for permanent ventilation  
o Main analysis will be repeated using an ANCOVA model where the variance in each 
treatment group is estimated separately 
In order to examine the impact of considering permanent ventilation in evaluation of this 
endpoint the ranking criteria will be adjusted as sensitivity analysis for JRT. These analyses will 
be performed as described in Section 6.1. 
o Exclusion of deaths from MI model 
The MI model will be run for CHOP INTEND total score for the ITT population 
excluding data from any subjects who died prior to Day 183, so that missing data for 
survivors are not influenced by any systematic difference there may be in data from 
subjects who died. The joint rank analysis will then be conducted using these imputed 
datasets for survivors and deaths will be ranked the lowest based on time of death. The p-
value from the joint rank analysis with MI will be presented as per the main analysis. 
o Data truncated to include only up to and including Day 183 
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In the event that a participant has CHOP INTEND missing items at Day 183 then data from 
later visits is utilized as part of interpolation.  Some of the subjects in the CS3B study only 
have data up to Day 183 before the study was stopped in contrast to 232SM203 where all 
subjects potentially could be followed to Day 302.  In order to investigate the sensitivity 
of the analysis to this truncation an additional analysis will be performed where only the 
data up to and including Day 183 is utilized from both CS3B and 232SM203 and the item 
level imputation approach described in Section 6.1 is applied. 
o The main analysis will be repeated incorporating Jump to reference in the MI step. 
o The main analysis will be repeated for the following subgroups:  
o disease duration  
o baseline CHOP INTEND 
 
Supplementary Analyses   
In order to provide additional understanding of the treatment effect, two supplementary analyses 
will be performed on the primary endpoint. The first, in order to provide an estimate of the 
difference in CHOP INTEND using an ANCOVA model at each timepoint the MI dataset 
generated for the primary endpoint will be utilized. As a sensitivity analysis, this will be repeated 
using an ANCOVA model where the variance in each treatment group is estimated separately. 
The second will utilize the following estimand which is described as the trimmed mean: 
o Population: The ITT Set is considered and the treatment arm with the highest % of 
participants withdrawn by Day 183 is determined (labelled X).  The same fraction 
is applied to the other treatment arm and the analysis is performed on (100-X) % of 
the ITT Set   
o Variable: difference between treatments in the endpoint means in the (100-X) % 
subset of participants with the most favorable outcomes,  
o Handling of intercurrent events: Due to the population definition, the intercurrent 
events of death or withdrawal from study are dynamically trimmed from the ITT 
Set. The assumption here is that any ICE is an equally bad outcome. 
o Population level summary  ANCOVA 
These analyses are further described in Section in Section 6.1. 
 
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Table 4: CHOP INTEND: Change from baseline to Day 183, accounting for 
mortality/dropout. Comparing the 50/28-mg Group to Study CS3B Sham Control  
 
Type 
Analysis Method  
Analysis Population: 
Further Notes 
Primary Analysis 
Joint rank using multiple imputation (MI) 
Matched Sham Set 
Sensitivity 
Analysis
Joint rank using multiple imputation (MI) 
Matched Sham Set 
(sensitivity) 
 
Joint rank using multiple imputation (MI) 
Greedy matched set 
(sensitivity) 
 
Adjustment of ranking criteria for JRT for 
withdrawals not due to death 
Matched Sham Set 
 
Adjustment of ranking criteria for JRT for 
permanent ventilation 
Matched Sham Set 
 
Subjects who died will be excluded from the 
MI model 
Matched Sham Set 
 
Joint rank using multiple imputation (MI) 
Matched Sham Set. 
Data truncated to only 
include data up to Day 
183 (inclusive). 
 
Joint rank using Jump to Control MI 
Matched Sham Set 
 
Rank based implementation of joint rank 
method + MI 
Matched Sham Set  
 
Joint rank test using multiple imputation (MI), 
ANCOVA model not assuming equality of 
variance 
Matched Sham Set 
 
Joint rank using multiple imputation (MI) 
by disease duration 
Matched Sham Set 
 
 
Joint rank using multiple imputation (MI) 
by baseline CHOP INTEND 
Matched Sham Set 
 
 
 
 
Supplementary 
Analysis 
Trimmed mean 
Matched Sham Set  
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Endpoint and 
Comparison  
Analysis Method 
Analysis 
Population: further 
notes 
Supplemental 
analysis 
 
 
Difference 
(50/28mg- Matched 
Sham Control) in 
change in CHOP 
INTEND from 
baseline by visit 
ANCOVA using MI  
Matched Sham Set 
Difference 
(50/28mg- Matched 
Sham Control) in 
change in CHOP 
INTEND from 
baseline by visit 
ANCOVA using MI (Not assuming equality of 
variances) 
Matched Sham Set 
 
6.4. Secondary Efficacy Endpoints 
6.4.1. Proportion of motor milestone responders at Day 183: comparison: 
50/28mg versus CS3B sham control 
Hammersmith Infant Neurological Examination (HINE) section 2  
Motor milestones will be determined using Section 2 of the Hammersmith Infant 
Neurological Examination (HINE) which is comprised of eight motor milestone 
categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, 
crawling, standing and walking. 
 
Table 5: 
Hammersmith Infant Neurological Examination Section 2 - Motor 
Milestones 
Motor 
Milestone 
Category 
Milestone Level Progression Score 
(Age Expected in Heathy Infants1) 
Improvement 
  
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0 
1 
2 
3 
4 
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 
Rolls to 
side 
(4 months)
Prone to 
supine 
(6 months) 
Supine to 
prone 
(7 months) 
 
Sitting 
Cannot sit 
Sits with 
support at 
the 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) 
Crawls flat on 
the 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 
Walks 
independently 
(15 months) 
 
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on) 
[11 months]
 Values for healthy infants in [De Sanctis 2016; Haataja 1999] 
Within each motor milestone category (depicted as Motor Milestones in Table 5), there 
are 3 to 5 levels that can be achieved (depicted as Milestones Progression, or rows, in the 
Table above). All 8 Motor Milestones are 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, etc.) has not achieved any motor milestone. Motor milestone 
achievement is depicted by movement from the left side of the Table above to right side 
of the Table, as denoted by the Milestone Progression arrow in the Table. 
Missing Values 
Missing data will be imputed on an individual milestone level only if at least one 
milestone is assessed at the visit. 
If a motor milestone is missing at baseline, then the missing value will be imputed as the 
median of the non-missing values of the stratum to which the subjects belong to the four 
strata as defined above 
>12 weeks) by disease duration 
. The median value will be 
rounded up to the nearest integer value. 
If, for the subject with missing motor milestones at a particular visit, the corresponding 
visit is flanked by visits with non-missing Motor Milestones, the missing value for those 
motor milestones will be imputed using linear interpolation with the result rounded to the 
nearest integer score. Otherwise, if the missing visit is the last visit, missing motor 
milestone value will be imputed as the lowest value in the stratum (age at symptom onset 
by disease duration) to which the subject belongs within the same treatment group. 
In the event of no observed data for imputation, disease duration by treatment will be used 
as the classification factor for the purpose of identifying non-missing data for imputation. 
Of note, only observed data will be utilized for imputation purpose. Missing motor 
milestone items will be imputed first prior to any analysis. 
The definition of a motor milestones responder is based on the motor milestones 
categories in Section 2 of the Hammersmith Infant Neurological Exam with the exclusion 
of voluntary grasp using assessment at Day 183 study visit as follows: 
(a) Subject demonstrates at least a 2-point increase in the motor milestones 
category of ability to kick or maximal score on that category (touching 
toes) whilst having at baseline demonstrated touched leg, or a 1-point 
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CHOP INTEND will be used: age at symptom onset (:'.Sl2 weeks, 
(:'.Sl2 weeks,> 12 weeks) 


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increase in the motor milestones category of head control, rolling, 
sitting, crawling, standing, or walking, AND 
(b) Among the motor milestones categories with the exclusion of voluntary 
grasp, there are more categories where there is improvement as defined 
in (i) 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 lease 1-
point decrease.  
Main Analysis 
o The difference in the proportion of responders between treatment groups at 
Day 183 will be compared using logistic regression with the total number of 
motor milestones at baseline, baseline CHOP INTEND and disease duration at 
screening as covariates. Should the number of responders be less than 5 in 
either group, F
used, the unconditional confidence interval for the difference in response rates 
will be provided [Chan and Zhang 1999]. 
Sensitivity Analyses 
o Subjects who have neither died nor withdrawn with no assessment at Day 183 will 
be excluded from the analysis. 
o An alternative definition of a Motor Milestones responder with the exclusion of 
voluntary grasp will be used: 
(a) subject demonstrates at least a 2-point increase in the Motor Milestones 
category of ability to kick or maximal score on that category (touching 
toes) whilst having at baseline demonstrated touched leg, or a 1- point 
increase in the Motor Milestones category of head control, rolling, 
sitting, crawling, standing, or walking, and  
(b) among the motor milestone categories with the exclusion of voluntary 
grasp, the changes from baseline in total Motor Milestones score is at 
least 1-point. The total Motor Milestones score is calculated as the sum 
of scores across motor milestone categories, where 0 is lowest possible 
score within each Motor Milestones category.  
o A Motor Milestones responder is defined as a 2-point increase in the total Motor 
Milestones score, where voluntary grasp is excluded. For example, assuming no 
changes in other Motor Milestones categories 
(a) 1-point increase in head control and a 1-point increase in rolling is 
considered a response,  
(b) a 2-point increase in rolling is considered a response,  
(c) a 2-point increase in rolling with a 1-point decrease in head control is 
considered a non-response.  
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isher's exact test will be used instead. If Fisher's exact test is 


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Page 44
o
The main analysis will be conducted excluding subjects with any missing
baseline Motor Milestones assessment.
For the analysis at each visit, responder classifications will be based on the motor 
milestones assessment at the visit of interest. Subjects who die or withdraw prior to the 
visit of interest will be classified as non-responders. A subject is classified as having died 
or withdrawn prior to the visit of interest if the last visit prior to death or withdrawal is 
earlier than the visit of interest.  
Table 6: Proportion of Motor Milestones responders at Day 183: comparison: 50/28mg 
versus CS3B sham control 
Type 
Analysis Method 
 Analysis Population: Further Notes 
Main analysis 
Logistic regression or 
 
Matched Sham Set 
Sensitivity 
analysis 
Logistic regression or 
 
Matched Sham Set  
Subjects who have neither died nor withdrawn 
with no assessment at Day 183 will be 
excluded. 
Logistic regression or 
 
Matched Sham Set  
Net Positive improvement 
Logistic regression or 
 
Matched Sham Set  
responder defined as 2-point increase in total 
milestones score excluding voluntary grasp 
Logistic regression or 
 
Matched Sham Set  
(excluding subjects with missing baseline 
Motor Milestones assessment) 
6.4.2. Change in Motor Milestones total score from baseline to Day 183: 
comparison: 50/28mg versus CS3B sham control. 
A total Motor Milestones score for HINE Section 2 will be calculated as the sum of each level 
and will range from 0 to a maximum score of 26. 
Main Analysis 
o
The change from baseline to Day 183 in Motor Milestones total score will be
analyzed using the JRT methodology to account for mortality. The ANCOVA model
will include covariates for baseline Total Milestone score, baseline CHOP INTEND
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Fisher's Exact Test 
Fisher's Exact Test 
Fisher's Exact Test 
Fisher's Exact Test 
Fisher's Exact Test 


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total score and disease duration at screening. 
 
  
Sensitivity Analyses 
o In order to test sensitivity of data handling for withdrawals not due to death, ranking 
criteria will be adjusted in the JRT for withdrawals not due to death. 
o In order to test if permanent ventilation should be considered in evaluation of 
endpoint, ranking criteria will be adjusted for JRT to consider permanent ventilation 
in evaluation. 
o The MI model will be run for total score for the ITT population excluding data from 
any subjects who died.   
o Rank based implementation of joint rank method + MI 
o The main analysis will be repeated incorporating Jump to reference in the MI step. 
o Main analysis will be repeated using an ANCOVA model where the variance in each 
treatment group is estimated separately 
 
 
Supplementary analyses 
o ANCOVA 
o This will be repeated using an ANCOVA model where the variance in each treatment 
group is estimated separately. 
For more details refer to section 6.3. 
Table 7: Change from baseline to Day 183 in Motor Milestones total score: comparison: 
50/28mg versus CS3B sham control 
Type 
Analysis Method 
 Analysis Population: 
Further Notes 
Main analysis
Joint rank using multiple imputation (MI) 
Matched Sham Set 
Sensitivity analysis 
Adjustment of ranking criteria for JRT for 
withdrawals not due to death  
Matched Sham Set 
 
Adjustment of ranking criteria for JRT for 
permanent ventilation 
Matched Sham Set 
 
Subjects who died will be excluded from 
the MI model 
Matched Sham Set 
 
Rank based implementation of joint rank 
method + MI 
Matched Sham Set 
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Table 7: Change from baseline to Day 183 in Motor Milestones total score: comparison: 
50/28mg versus CS3B sham control 
Type 
Analysis Method 
 Analysis Population: 
Further Notes 
 
Joint rank using Jump to Control MI 
Matched Sham Set 
 
 
 
 
Joint rank test using multiple imputation 
(MI), ANCOVA model not assuming 
equality of variance 
Matched Sham Set 
 
 
 
Endpoint and 
Comparison  
Analysis Method 
Analysis Population: 
further notes 
Supplemental analysis 
 
 
Difference (50/28mg- 
Matched Sham Control) 
in change in HINE-2 
total milestones from 
baseline by visit  
ANCOVA using MI  
Matched Sham Set 
Difference (50/28mg- 
Matched Sham Control) 
in change in HINE-2 
total milestones from 
baseline by visit  
ANCOVA using MI (Not assuming 
equality of variances) 
Matched Sham Set 
 
 
6.4.3. Change in Plasma NF-L from (ratio to) baseline to Day 183: comparison: 
50/28mg versus CS3B sham control.  
Plasma Neurofilament  
The analysis will be performed on the ITT set but is it noted that neurofilament plasma samples 
from China sites were not analyzed due to export law complication.  The baseline and post 
baseline results for NF-L for these participants will be imputed in the MI step. 
For Plasma NF-L, if the baseline is missing than the first available assessment post dose, within 
Day 2, will be used instead as baseline. 
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Values that are BLQ will be set to half of the diluted LLOQ (2.6 pg/mL). 
The Neurofilament light chain (NF-L) plasma concentration change (including absolute and ratio 
to baseline) will be presented by visit. 
Summary tables and LS-mean (+- 95% CI) plots for geometric mean ratio to baseline using MI 
data +ANCOVA will be presented. 
Main Analysis 
o The change from baseline in Plasma NF-L from (ratio to) baseline to Day 183 will be 
analyzed using the JRT methodology to account for mortality.  The ANCOVA model 
will include covariates for baseline log plasma NF-L, baseline CHOP INTEND total 
score and disease duration at screening. 
 
  Ranking based on death will be performed as 
described earlier for CHOP INTEND. In terms of ranking based on the NF-L, 
progressively higher ranks will be given to subjects with a greater reduction in NF-L 
at Day 183. 
Sensitivity Analyses 
o In order to test sensitivity of data handling for withdrawals not due to death, ranking 
criteria will be adjusted in the JRT for withdrawals not due to death. 
o In order to test if permanent ventilation should be considered in evaluation of 
endpoint, ranking criteria will be adjusted for JRT to consider permanent ventilation 
in evaluation. 
o The MI model will be run for total score for the ITT population excluding data from 
any subjects who died.   
o Rank based implementation of joint rank method + MI 
Supplementary analysis 
o ANCOVA  
 
For more details refer to section 6.3. 
 
Table 8: Change in Plasma NF-L from (ratio to) baseline to Day 183: comparison: 
50/28mg versus matched CS3B sham control 
Analysis Method
Analysis Population: 
Further Notes 
Main analysis
Joint rank using multiple imputation (MI)
Matched Sham Set 
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Sensitivity analysis 
Adjustment of ranking criteria for JRT for 
withdrawals not due to death  
Matched Sham Set 
 
Adjustment of ranking criteria for JRT for 
permanent ventilation 
 Matched Sham Set 
 
Subjects who died will be excluded from 
the MI model 
Matched Sham Set 
Rank based implementation of joint rank 
method + MI 
Matched Sham Set 
Endpoint and 
Comparison  
Analysis Method 
Analysis 
Population: 
further notes 
Supplementary 
analysis 
 
 
Difference (50/28mg- 
Matched Sham Control) 
in change in Plasma 
NF-L from (ratio to) 
baseline by visit  
ANCOVA using MI  
Matched Sham Set 
6.4.4. Change from baseline to Day 302 in CHOP INTEND total score: 
comparison: 50/28mg versus 12 mg Group from 232SM203. 
Main Analysis 
o The change from baseline to Day 302 in CHOP INTEND total score will be analyzed 
using the JRT methodology to account for mortality.  
Sensitivity Analyses 
o In order to test sensitivity of data handling for withdrawals not due to death, ranking 
criteria will be adjusted in the JRT for withdrawals not due to death. 
o In order to test if permanent ventilation should be considered in evaluation of 
endpoint, ranking criteria will be adjusted for JRT to consider permanent ventilation 
in evaluation. 
o The MI model will be run for total score for the ITT population excluding data from 
any subjects who died. 
o Rank based implementation of joint rank method + MI. 
o The main analysis will be repeated incorporating Jump to reference in the MI step. 
o The main analysis will be repeated using PPS set. 
Supplementary analyses 
o ANCOVA 
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for more details section 6.3. 
Table 9: Change from baseline to Day 302 in CHOP INTEND total score comparison: 
50/28mg versus 12 mg Group from 232SM203 
Type 
Analysis Method  
Analysis 
Population: 
Further Notes 
Main analysis
Joint rank using multiple imputation (MI) 
ITT Set 
Sensitivity analysis 
Adjustment of ranking criteria for JRT for withdrawals 
not due to death 
ITT Set 
Adjustment of ranking criteria for JRT for permanent 
ventilation 
ITT Set 
Subjects who died will be excluded from the MI model ITT Set 
 
Rank based implementation of joint rank method + MI 
ITT Set 
 
Joint rank using multiple imputation (MI) 
PPS Set 
 
Main analysis repeated using Jump to reference in the 
MI step 
ITT Set 
 
Joint rank using multiple imputation (MI) 
by disease duration 
ITT Set 
 
Log-rank test stratified by disease duration at 
Screening; by baseline CHOP INTEND 
 
ITT Set 
 
Endpoint and 
Comparison  
Analysis Method 
Analysis 
Population: 
further 
notes 
Supplemental analysis 
 
 
Difference (50/28mg- 12 
mg Group from 
232SM203) in change in 
ANCOVA using MI  
ITT Set 
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CHOP INTEND from 
baseline by visit 
 
6.4.5. Change from baseline to Day 302 in HINE Section 2 motor milestones 
total score: comparison: 50/28mg versus 12 mg Group from 232SM203. 
Main, sensitivity and supplementary analyses 
Main, sensitivity and supplementary analyses will be analyzed in the same way as similar 
secondary endpoint described in 6.4.4. 
Table 10: Change from baseline to Day 302 in HINE Section 2 motor milestones total 
score: comparison: 50/28mg versus 12 mg Group from 232SM203 
Type 
Analysis Method  
Analysis 
Population: 
Further 
Notes 
Main analysis 
Joint rank using multiple imputation (MI) 
ITT Set 
Sensitivity analysis 
Adjustment of ranking criteria for JRT for withdrawals 
not due to death 
ITT Set 
 
Adjustment of ranking criteria for JRT for permanent 
ventilation 
ITT Set 
  
Rank based implementation of joint rank method + MI 
ITT Set 
 
Main analysis repeated using Jump to reference in the 
MI step 
ITT Set 
 
Endpoint and 
Comparison  
Analysis Method 
Analysis 
Population: 
further notes 
Supplemental analysis 
 
 
Difference (50/28mg- 12 
mg Group from 
232SM203) in change in 
ANCOVA using MI  
ITT Set 
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HINE section 2 from 
baseline by visit 
 
 
 
6.4.6. Change in Plasma NF-L from (ratio to) baseline to Day 64: comparison: 
50/28mg versus 12 mg Group from 232SM203. 
Main and   sensitivity analyses  
The analysis will be performed on the ITT set but is it noted that neurofilament plasma samples 
from China sites were not analyzed due to export law complication.  The baseline and post 
baseline results for NF-L for these participants will be imputed in the MI step. 
Main and sensitivity will be analyzed in the same way as described in section 6.4.3. 
Supplementary analyses 
o Population level summary  ANCOVA 
 
Table 11: Change in Plasma NF-L from (ratio to) baseline to Day 64: comparison: 50/28mg 
versus 12 mg Group from 232SM203. 
Type  
Analysis Method  
Analysis 
Population: 
Further Notes 
Main analysis
Joint rank using multiple imputation (MI) 
ITT Set 
Sensitivity analysis 
Adjustment of ranking criteria for JRT for 
withdrawals not due to death 
ITT Set 
Rank based implementation of joint rank method 
+ MI 
ITT Set 
 
Endpoint and 
Comparison  
Analysis Method 
Analysis 
Population: 
further 
notes 
Supplemental 
analysis 
 
 
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Difference 
(50/28mg- 12 mg 
Group from 
232SM203) in 
change in Plasma 
NF-L from baseline 
by visit 
ANCOVA using MI  
ITT Set 
 
 
6.4.7. 
continuously for > 21 days in the absence of an acute reversible event, or 
tracheostomy): comparison: 50/28mg versus CS3B sham control 
 
Permanent ventilation is defined as tracheostomy or >=16 hours of ventilation/day continuously 
for > 21 days in the absence of an acute reversible event (Appendix B). Note that it was 
originally planned to include additional follow-up data from extension study in the analysis, but 
in order to focus this analysis plan on 232SM203 this will now be analyzed as part of the 
integrated 232SM203/232SM302 analysis plan.  
An independent endpoint adjudication committee (EAC) will determine, in a blinded fashion, the 
date at which a participant is considered to have met the definition of an event. The procedures 
for reviewing and adjudicating event will be described in a charter. 
The main analysis is to compare the time to death or permanent ventilation between the two 
treatment groups with the log-rank test stratified by disease duration at Screening (<=12 weeks 
or >12 weeks). Only events that were adjudicated by the EAC as meeting the protocol defined 
criteria for permanent ventilation or death will be included in the main analysis. Participants who 
do not meet the endpoint definition will be censored on the last occasion the participant was seen 
(either in-person visit or by telephone contact), irrespective of whether the participant has 
completed the full course of treatment and whether the participant has completed the study or 
permanently withdrawn. The exception is time to death or permanent ventilation cases in which a 
participant has begun a ventilator diary, in which case the latest entry in the diary will be used as 
the date of censoring.  
 
Kaplan-Meier estimates of the cumulative probability of the time to death or permanent 
ventilation over time will be determined for the ITT population. Treatment comparisons of time 
to death or permanent ventilation will be based on a stratified log rank test. Stratification factor 
will be disease duration at Screening (<=12 weeks or >12 weeks). Kaplan-Meier plots will be 
presented. The median time to death or permanent ventilation, percentiles (5th, 10th, 25th, 75th, 
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90th) and associated 95% confidence limits, and proportion of subjects who meet an event by 
fixed time points (i.e. Day 183 and Day 302) will be estimated using Kaplan-Meier.  
 
The start date for calculating time to death or permanent ventilation in days i.e. death, permanent 
ventilation or censoring will be date of first dose. If a subject is adjudicated as having an event, 
the date they were considered to meet the endpoint either death or reach the definition of 
permanent ventilation will be provided as part of the adjudication.  
 
The proportion of subjects meeting the endpoint of time to death or permanent ventilation will be 
presented by treatment group. For subjects who met the endpoint the number of days per subject 
at which ventilation use was at least 16 hours per day will be summarized. 
 
 
Main analysis 
Log-rank test stratified by disease duration at Screening. 
Sensitivity Analyses 
o The main analysis will be repeated using the actual treatment assignment. If 
participant, randomized to 12 mg nusinersen, receives 50 or 28 mg nusinersen at any 
point during the study, then the participant will be counted in the 50 mg nusinersen 
group. 
o The treatment groups will be compared using a Cox proportional hazards model for 
 and 
baseline CHOP INTEND total score. Only events that were adjudicated by the EAC 
will be included in this sensitivity analysis. This analysis allows estimation of a hazard 
ratio of nusinersen relative to the CS3B sham with its associated 95% confidence 
intervals. 
o The main analysis will be repeated for the following subgroups: disease duration and 
Baseline CHOP INTEND 
Table 12: Time to death or permanent ventilation: comparison: 50/28mg versus CS3B 
sham control 
Type 
Analysis Method 
Analysis Population: 
further notes 
Main Analysis 
Log-rank test stratified by disease 
duration at Screening 
Matched Sham Set 
 
 
 
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time to death or permanent ventilation, adjusted for each subject's disease duration at 
Screening (rather than the binary stratification factor, ::S 12 weeks/> 12 weeks) 


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Sensitivity Analysis 
Cox proportional hazards with treatment 
Screening and baseline CHOP INTEND 
total score as terms in the model 
Matched Sham Set 
 
Log-rank test stratified by disease 
duration at Screening; by disease duration
at Screening 
Matched Sham Set 
 
Log-rank test stratified by disease 
duration at Screening; by baseline CHOP 
INTEND 
 
Matched Sham Set 
 
 
6.4.8. Time to death (overall survival): comparison: 50/28mg versus CS3B 
sham control 
Overall survival will be analyzed in the same way as time to death or permanent ventilation. 
Table 13: Time to death: comparison: 50/28mg versus CS3B sham control 
Type 
Analysis Method 
Analysis 
Population: further 
notes 
Main Analysis 
Log-rank test stratified by disease duration at 
Screening 
Matched Sham Set 
Sensitivity 
Analysis 
Cox proportional hazards with treatment and each 
 and 
baseline CHOP INTEND total score as terms in 
the model 
Matched Sham Set 
Log-rank test stratified by disease duration at 
Screening; by disease duration at Screening 
Matched Sham Set 
 
 
Log-rank test stratified by disease duration at 
Screening; by baseline CHOP INTEND total 
score. 
 
Matched Sham Set 
 
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and each subject's disease duration at 
subject's disease duration at Screening 


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Table 13: Time to death: comparison: 50/28mg versus CS3B sham control 
Type 
Analysis Method 
Analysis 
Population: further 
notes 
 
 
 
 
6.4.9. Time 
ventilation/day continuously for > 21 days in the absence of an acute 
reversible event): comparison: 50/28mg versus 12 mg Group from 
232SM203 
Main and sensitivity analyses will be analyzed in the same way as similar secondary endpoint 
described in section 6.4.7. 
Table 14: Time to death or permanent ventilation: comparison: 50/28mg versus 12 mg 
Group from 232SM203 
Type 
Analysis Method 
Analysis 
Population: further 
notes 
Main Analysis 
Log-rank test stratified by disease duration at 
Screening 
ITT Set 
Sensitivity Analysis 
Cox proportional hazards with treatment and 
and baseline CHOP INTEND total score as 
terms in the model 
ITT Set 
Log-rank test stratified by disease duration at 
Screening; by disease duration 
ITT Set 
 
Log-rank test stratified by disease duration at 
Screening; by Baseline CHOP INTEND 
ITT Set 
 
Joint rank using multiple imputation (MI) 
PPS Set 
 
6.4.10. Time to death (overall survival) - comparison: 50/28mg versus 12 mg 
Group from 232SM203 
Main, sensitivity analyses will be analyzed in the same way as similar secondary endpoint 
described in section 6.4.8. 
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to death or permanent ventilation (tracheostomy or> 16 hours of 
each subject's disease duration at Screening 


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Table 15: Time to death: comparison: 50/28mg versus 12 mg Group from 232SM203 
Type 
Analysis Method 
Analysis Population: 
further notes 
Main Analysis 
Log-rank test stratified by disease duration at 
Screening  
ITT Set 
Sensitivity Analysis 
Cox proportional hazards with treatment and 
Screening 
and baseline CHOP INTEND total score as 
terms in the model 
ITT Set 
Log-rank test stratified by disease duration at 
Screening; by disease duration 
ITT Set 
Log-rank test stratified by disease duration at 
Screening; by baseline CHOP INTEND 
ITT Set 
Joint rank using multiple imputation (MI) 
PPS Set 
6.5. Supplemental analyses supporting primary and secondary endpoints. 
6.5.1. Comparison: 50/28 mg Group versus CS3B sham control 
The main analysis for the primary endpoint of CHOP INTEND: Change from baseline to Day 
183 will be repeated for the Day 64 timepoint see table below for the specific analyses. 
The Proportion of CHOP INTEND Responders at Day 183 will also be analyzed. 
A subject is defined as a CHOP INTEND responder if the change from baseline in CHOP 
INTEND total score is greater than or equal to 4 points based on assessment at Day 183.  
Subjects who die or withdraw from the study will be counted as non-responders and will be 
included in the denominator for the calculation of the proportion. Proportions of CHOP INTEND 
responders will be analyzed using logistic regression as described in the MI description in 
Section 6.1 and if due to low counts this is not possible then Fishers Exact test will be used. 
Table 16: Supplemental Endpoints - comparison: 50/28mg versus CS3B sham control 
Endpoint and Comparison 
Analysis Method 
Analysis 
Population: 
further notes 
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each subject's disease duration at 


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CHOP INTEND: Change from baseline 
to Day 64, accounting for 
mortality/dropout   
Joint rank using multiple 
imputation (MI) 
Matched Sham 
Set 
 
Proportion of Motor Milestones 
responders at Day 64 
Logistic regression or 
 
Matched Sham 
Set 
 
The Proportion of CHOP INTEND 
Responders at Day 183   
Logistic regression or 
 
Matched Sham 
Set 
 
 
 
 
6.5.2.  Comparison: 50/28mg versus 12 mg Group from 232SM203 
For the comparison of higher dose and 12 mg Group from 232SM203, some of the secondary 
endpoints will be repeated as listed below, also the proportion of CHOP INTEND responders at 
Day 183 and Day 302 and proportion of Motor Milestones responders at Day 302 will be 
analyzed.  
 
Table 17: Supplemental endpoints 50/28mg versus 12 mg Group from 232SM203 
Endpoint    
Analysis Method 
Analysis 
Population: 
further notes 
Change in CHOP INTEND from baseline to Day 183 
Joint rank using 
multiple imputation 
(MI) 
 ITT set  
Repeat for Day 
29 and 64. 
  
Change in Motor Milestones total score from baseline 
to Day 183 
Joint rank using 
multiple imputation 
(MI) 
 ITT set  
  
 
The Proportion of CHOP INTEND Responders at Day 
183   
Logistic regression or 
 
ITT set  
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Fisher's Exact Test 
Fisher's Exact Test 
Fisher's Exact Test 


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The Proportion of CHOP INTEND Responders at Day 
302   
Logistic regression or 
 
ITT set  
Proportion of Motor Milestones responders at Day 302  Logistic regression or 
 
ITT set  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
                                                                                                                                                                                    
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Fisher's Exact Test 
Fisher's Exact Test 
• 
• 
• 


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6.6. Analysis of the Remaining Secondary Endpoints - comparison: 50/28mg 
versus 12 mg Group from 232SM203 
6.6.1. Change in CSF NF-L from (ratio to) baseline to Day 279 
The analysis will be performed on the ITT set but is it noted that neurofilament CSF samples 
from China sites were not analyzed due to export law complication.  The baseline and post 
baseline results for NF-L for these participants will be imputed in the MI step.  Only baseline, 
Day 29 and Day 279 visits will be included as visits in the MI. 
Values that are BLQ will be set to half of the diluted LLOQ (65 pg/mL). 
The Neurofilament light chain (NF-L) CSF concentration change (including absolute and ratio to 
baseline) will be presented by visit.  
Summary tables and LS-mean (+- 95% CI) plots for geometric mean ratio to baseline using MI 
data and ANCOVA will be presented. 
 
6.6.2.  Number and Length of Hospitalizations 
The number of hospitalizations during the study will be analyzed using the rate at which they 
occur. For descriptive purposes, the aggregate hospitalization rate will be calculated for each 
group by dividing the total number of hospitalizations that occurred in the group by the total 
number of subject-years on study.  
Annualized hospitalization rate will be calculated for each subject as the number of 
hospitalizations that the subject experienced divided by the number of days on study and this 
ratio multiplied by 365.25. Annualized hospitalization rate will be analyzed by a negative 
binomial regression model, adjusted for disease duration at screening and baseline CHOP 
INTEND total score. The logarithmic transformation of the time on the study will be included in 
regression model does not converge, a Poisson regression model with the same covariate will be 
used instead of the negative binomial regression model. Dispersion will be evaluated from the 
Pearson chi-squared statistic. 
For each subject, the total time spent in hospital during the study will be calculated and prorated 
according to number of days on study. Based on the prorated time in hospital, treatment groups 
Screening and baseline CHOP INTEND total score. 
Analyses will be performed on the ITT Set. 
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the model as the "offset" parameter. If the data are under dispersed, or if the negative binomial 
will be compared to an analysis of covariance adjusting for each subject's disease duration at 


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6.6.3. Clinical Global Impression of Change (CGIC) [Physician, Caregiver] at 
Day 302 
CGIC will be assessed at Days 29, 64, 183 and 302.  The CGIC rating scale was developed as a 
participant
initiating a study medication [Guy 1976]. The CGIC provides an overall clinician-determined 
summary measure that takes into account all available information, including knowledge of the 
participant
symptoms on the participant
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 participant at each visit: the 
severity of the illness, the participant
that any clinical changes are or are not due to medication and without consideration of the 
etiology of the symptoms. 
The CGIC is a 7-point scale that requires the clinician to assess how much the participant
illness has changed 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.  
CGIC should be assessed consistently by the same rater for each study participant. A separate 
CGIC assessment will be performed by the Investigator (Principal Investigator or Sub 
investigator) and caregiver. 
Clinical Global Impression of Change (CGIC) for the physician and caregiver at Day 302 will be 
analyzed as an ordered categorical score and as a dichotomized 
 
The proportion of subjects with each CGIC score and with the dichotomized response of either 
  
The difference in CGIC dichotomized response rate between 50/28 mg Group and Control Group 
will be analyzed using a logistic regression model with terms for treatment group and disease 
duration at screening and baseline CHOP INTEND total score. Participants who die or withdraw 
 
The odds ratio, its 95% CI and the p-value for 50/28 mg Group compared to the Control Group 
will be presented. The proportion of CGIC responders at other visits will also be analyzed in a 
similar way. 
Analyses will be performed on the ITT Set. 
6.6.4. Number of Serious Respiratory Events 
All adverse events that are coded into the System Organ Class (SOC) of respiratory, thoracic, 
and mediastinal disorders, as their primary SOC will be considered respiratory events. Only 
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brief standalone assessment of the clinician's view of the 
's global functioning after 
's history, psychosocial circumstances, symptoms, behavior, and the impact of the 
's ability to function. The CGIC is administered by an experienced 
's level of distress and other aspects of impairment, and the 
impact of the illness on functioning. The CGIC is rated without regard to the clinician's belief 
's 
response: "much improved" or 
"very much improved" versus other responses. 
"much improved" or "very much improved" will be summarized by visit and treatment group. 
from the study, prior Day 302, will be counted as 'non responders'. 


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those classified as serious will be analyzed. By utilizing the above approach, rare occurrence of 
serious respiratory events in the Infection and Infestation SOC and Investigation SOC (if any) 
may not be included. However, a detailed review of the AE listing will be conducted to identify 
such events. 
The number of serious respiratory events during the study will be analyzed using the rate at 
which they occur. For descriptive purposes, the aggregate rate will be calculated for each group 
by dividing the total number of serious respiratory events that occurred in the group by the total 
number of subject-years on study.  
Annualized serious respiratory event rate will be calculated for each subject as the number of 
serious respiratory events that the subject experienced divided by the number of days on study 
and this ratio multiplied by 365.5.  
Although serious respiratory events occur as a stochastic process and can be assumed to be from 
a Poisson distribution, studies in other therapeutic areas have shown that data of this type are 
typically over-dispersed, i.e., the variation seen is greater than that predicted by the Poisson 
model. To account for over-dispersion in the annualized rate of serious respiratory events, the 
negative binomial distribution will be used. Thus, on the basis of annualized serious respiratory 
event rate, treatment groups will be compared using a negative binomial model adjusting for 
disease duration at Screening and baseline CHOP INTEND total score
the logarithm of the time on study, will be included in the model. If the data are under dispersed, 
or if the negative binomial regression model does not converge, a Poisson regression model with 
the same covariate will be used instead of the negative binomial regression model. Dispersion 
will be evaluated from the Pearson chi-squared statistic.  
Analyses will be performed on the ITT Set. 
6.6.5. Proportion of Time on Ventilation  
The ventilation use during the study will also be collected via the daily ventilation diary. Daily 
ventilation use data that are missing will be imputed using the greater of the days that flank the 
missing day(s).  
For each subject, the total number of hours of ventilation support required during the study will 
be calculated and prorated according to number of days on study. Based on the prorated number 
of hours of ventilation support, treatment groups will be compared via an analysis of covariance 
reening and baseline CHOP INTEND total 
score.  
An additional analysis of the number of days in which each subject required ventilation support 
required will be a
at Screening and baseline CHOP INTEND total score.  
Analyses will be performed on the ITT Set. 
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. An "offset" parameter, 
adjusting for each subject's disease duration at Sc 
of 2: 16 hours per day will be performed. The number of days that this level of ventilation was 
nalyzed by analysis of covariance adjusting for each subject's disease duration 


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6.6.6. Ventilator Use 
 and respiratory aids will be collected at every study visit  
The ventilation use will be summarized by visit and listed.  
6.6.7. Change in the Parent Assessment of Swallowing Ability Scale (PASA) 
Parent Assessment of Swallowing Ability (PASA) Dysphagia will be assessed using the PASA 
questionnaire. Caregivers will be asked a series of questions regarding the mealtime behavior of 
the participant.  
The PASA questionnaire was developed by a Biogen team in order to assess the signs and 
symptoms of dysphagia. This questionnaire consists of 33 items across 4 domains that cover 
general feeding, drinking liquids, eating solid foods, and assessment of swallowing concerns. 
The first 3 of these domains are generally assessed with 5 levels of response (Never, Rarely, 
Sometime
answer. In the final domain, the assessment of swallowing concerns has 4 levels of response: 
Strongly Agree, Agree, Disagree, and Strongly Disagree. In answering each item, the caregiver is 
directed to consider the previous 7 days. 
The number, mean score, and percentage of subjects scoring each category in the PASA Section 
1  General Feeding will be presented by visit. In addition, a stacked bar chart will be used to 
summarize the proportion of subjects in each category over time for each item. Depending on the 
number of subjects who complete PASA Sections 1,2, 3, and 4, similar presentations may also be 
made or alternatively the results from these visits will be listed. 
7. 
Safety Endpoints 
7.1.1. Adverse events  
The analysis of safety will be performed using the respective Safety Sets and presenting by 
232SM203 treatment groups.  The sham participants from safety sets from CS3B will be 
included for the analysis of adverse events.  
All AEs will be analyzed based on the principle of treatment emergence where treatment 
emergence will be relative to the first dose of nusinersen. An AE will be regarded as treatment-
emergent if it was present prior to receiving the first dose of nusinersen and subsequently 
worsened in severity or was not present prior to receiving the first dose of nusinersen but 
subsequently appear. Refer to Appendix A for more details about AE with missing start or stop 
dates.  
A participant having the same AE preferred term more than once will be counted only once in 
the incidence for that event. Multiple occurrences of the same adverse event for the same subject 
will all be counted in the frequency for that adverse event. 
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The participant's ventilator use 
s, Often, and Always), although 2 items are assessed with a simple "Yes"/"No" 


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The occurrence of the AE with the greatest severity will be used in the calculation of incidence 
by severity.  The AE relationship to treatment or LP/sham procedure is captured as related or not 
related. In the event the relationship is missing then this will be considered related.  
Due to the long half-life of nusinersen, analyses of treatment-emergent adverse events will 
include all events reported during the study. Adverse Events will be coded using the Medical 
Dictionary for Regulatory Activities.  
 
The following presentations will be shown:  
an overall summary showing, for each treatment group, the number and percentage of subjects 
with an adverse event, a mild, moderate or severe event, an event related to study drug, an event 
related to lumbar puncture /sham procedure, a serious event, a serious event related to study 
drug, an event leading to study drug withdrawal, an event leading to study withdrawal, and a 
fatal event. 
incidence and frequency by system organ class and preferred term  
incidence and frequency by preferred term  
incidence and frequency, by preferred term, in at least 5% of subjects in any treatment group 
incidence of adverse events by maximum severity by preferred term  
incidence and frequency of severe events by system organ class and preferred term  
incidence and frequency of events related to study drug by system organ class and preferred term  
incidence and frequency of events related to lumbar puncture /sham procedure (as assessed by 
the investigator) by system organ class and preferred term 
incidence by system organ class and preferred term that occurred within 24 hours of Dosing or 
Sham Procedure 
incidence by system organ class and preferred term that occurred within 72 hours of Dosing or 
Sham Procedure 
incidence and frequency of serious adverse events by system organ class and preferred term  
incidence and frequency of serious adverse events related to study drug by system organ class 
and preferred term  
incidence of events that led to fatal outcome 
incidence of events leading to study drug withdrawal by system organ class and preferred term  
incidence of events leading to withdrawal from study by system organ class and preferred term   
incidence and frequency of adverse events over time by system organ class and preferred term.  
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incidence and frequency of adverse events antibody status by system organ class and preferred 
term.  
A separate table will also be presented to show an overall summary of COVID-19 pandemic 
related AEs. 
Listings of the following events will be produced.  
AEs 
SAEs  
AE with fatal outcome 
AEs led to study drug withdrawal   
AEs led to withdrawal from study  
AEs related to lumbar puncture/sham procedure  
AEs related to study drug 
 
Follow-up adjusted incidence rate.  
Follow-up adjusted incidence rate will be summarized by system organ class and preferred term 
by study group. Follow-up adjusted incidence rate  defined as the number of subjects who 
experienced an event divided by the total of entire follow-up time among the subjects in the 
analysis population. The entire follow-up time for subject is defined as the time from the first 
dose until the end of study day. Each subject will be counted only once within each category. A 
similar table will also be based on total number of events divided by the total of entire follow-up 
time among the subjects in the analysis population. This may count a subject more than once 
within each category of they experienced an event more than once.  
Note on capture of severity and seriousness in CS3B.  
In CS3B the eCRF captured detail for each investigator term for decreases in severity and 
changes from serious to non-serious. In 232SM203, the decrease in severity and change from 
serious to non-serious is not captured.  In all studies worsening in severity and moving from non-
serious to serious is captured. 
In presenting CS3B as part of 232SM203 reporting, consistent with how these studies were 
originally reported in the following two scenarios: 
1) where the severity decreases 
2) where a serious event becomes non-serious  
Only the first record will be considered treatment emergent so the actual reporting approach will 
be consistent with 232SM203.  
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7.1.2. Concomitant therapy and Procedure 
A concomitant therapy is any drug or substance administered between screening and the final 
study visit/telephone call. Participants are instructed to contact their Investigators before taking 
any new medications, including nonprescription drugs and herbal preparations. 
Throughout the study, Investigators or designated licensed physicians involved in the study may 
prescribe concomitant therapies (procedures) or treatments deemed necessary for AEs or to 
provide adequate supportive care. 
Participants are prohibited from receiving other experimental or approved agents for the 
treatment of SMA, including gene therapy, biological agent, or device, during the study. This 
includes marketed agents at experimental doses that are being tested for the treatment of SMA 
(oral albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea, 
etc.). 
All concomitant therapies will be coded using the World Health Organization drug 
dictionary (WHO Drug). A concomitant procedure is any therapeutic intervention (e.g., 
surgery/biopsy, physical therapy) or diagnostic assessment (e.g., blood gas measurement, 
bacterial cultures) performed between Screening and the final study visit/telephone call. 
Concomitant procedures will be coded using MedDRA. 
For the purposes of analysis, a concomitant therapy (including medication or procedure) is 
defined as any therapy that was taken or administered on or after the first injection of nusinersen 
(see appendix A). This includes therapies and procedures that were started prior to the initiation 
of injection of nusinersen if their use continued on or after the first injection of nusinersen. The 
number and percentage of subjects who were taking each type of concomitant therapy and 
procedures at baseline and during the study will be presented by preferred term. 
The number and percentage of subjects who underwent each type of concomitant procedure 
during the study will be presented.  
Concomitant therapies related to LP/Sham procedure will be summarized separately.   
If there are a sufficient number of tests or treatments reported with indication of COVID-19, a 
separate summary of these will be provided.  
Concomitant medications will also be reviewed by a medical reviewer prior to the lock to 
determine disallowed medications according to the protocol. These will be summarized 
separately. 
 
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7.1.3. Clinical laboratory data 
Laboratory data will be evaluated to determine the incidence of abnormalities that emerge during 
the course of the study. Changes in laboratory evaluations will be presented relative to baseline, 
which is defined as the closest visit prior to the first dose. 
The following clinical laboratory parameters are to be assessed: 
Hematology panel: complete blood count with differential and platelet count (hematocrit, 
hemoglobin, platelets, red blood cell count [RBC], white blood cell count [WBC], basophils, 
eosinophils, lymphocytes, monocytes, neutrophils) 
Blood chemistry panel: albumin, total bilirubin, direct and indirect bilirubin, alkaline 
phosphatase, alanine aminotransferase (ALT) (SGPT), aspartate aminotransferase (AST) 
(SGOT), gamma-glutamyl transferase (GGT), sodium, potassium, calcium, chloride, phosphate, 
blood urea nitrogen (BUN), creatinine, cystatin, creatine phosphokinase, creatine kinase, 
bicarbonate (CO2), glucose, total protein. 
Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, blood, red blood cells, white 
blood cells, epithelial cells, bacteria, casts and crystals 
Urine total protein assessed by local laboratories CSF analysis: RBC, WBC, protein, glucose.  
Coagulation: PT (prothrombin time), aPTT (activated partial thromboplastin time), and INR 
(international normalized ratio).  
Each hematology, blood chemistry, coagulation and CSF laboratory parameter will be flagged as 
if no result 
is available. 
For each urinalysis laboratory parameter, the number and percentage of subjects experiencing 
postdose shifts to abnormal will be summarized.  
For each hematology, blood chemistry, coagulation and CSF parameter, the number and 
per
each summary, the denominator for the percentage is the number of subjects at risk for the shift. 
The number at risk for the shift to low is the number of subjects whose baseline value was not 
low and who had at least one post baseline value. The number at risk for the shift to high is the 
number of subjects whose baseline value was not high and who had at least one-post baseline 
value. Subjects will be counted only once for each parameter and each shift regardless of how 
many postdosing assessments had that type of shift. All post baseline data will be used in the 
shift tables, regardless of whether a scheduled or unscheduled visit.  
Also, for each parameter, the incidence of shift to low will be summarized using the minimum 
post baseline values. Shift to low includes subjects with a normal, high, or unknown baseline 
value and at least one post baseline value of the given test. Similarly, the incidence of shift to 
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"low", "normal" or "high" relative to the parameter's normal range or as "unknown" 
centage of subjects experiencing postdose shifts to 'low' or 'high' will be summarized. In 


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high will be summarized using the maximum post baseline values. Shift to high includes subjects 
with a low, normal, or unknown baseline value and at least one post baseline value. 
To evaluate potential serious hepatotoxicity subjects with a post baseline AST and/or ALT value 
any time, not necessarily concurrent, will be listed with their values. In addition, a plot will be 
presented wit
have to be concurrent. All post baseline data will be used to identify abnormalities, regardless of 
whether a scheduled or unscheduled visit. 
Summary statistics for actual values and change from baseline in laboratory values will be 
summarized by treatment group and visit. Box plots for chemistry, hematology and CSF showing 
mean value for each treatment group at each visit will also be presented.  
Due to the impact of the COVID-19 pandemic on transport infrastructure, public health or 
humanitarian emergencies, certain sites may only be able to test blood and urine samples at a 
local laboratory instead of central one.  The use of local labs which will use different 
techniques/equipment and reference ranges may introduce variability in the results.  
To assess the variability of the results two summaries will be presented for actual and change 
from baseline by visit: 
 summarize local laboratory and central laboratory results together  
 summarize only central laboratory results 
Listings of all chemistry, hematology, coagulation, CSF, urinalysis values and pregnancy test 
(serum and urine) will be provided.  
For platelets a summary of the proportion of participants with a post baseline platelet count 
below the lower limit of normal on at least 2 consecutive measurements will be presented. 
For study 232SM203, the urine protein positive (trace, +1, +2, +3, +4 or >0.2g/L) results will be 
presented, number of subjects with positive result at baseline, with a negative result at baseline 
and at least one and at least two positive post baseline result respectively.  This display will not 
be presented for CS3B and CS4 since the total protein from local laboratories was not collected 
per protocol.  
 
7.1.4. Neurological Examinations   
Hammersmith infant Neurological Examination (Sections 1 and 3) (HINE 1 and 3)  
Sections 1 (neurological items) and 3 (behavior) of the HINE serve as the basis for neurological 
examinations. These are to be assessed at Screening, predose and at 3, 6, and 24 hours postdose 
on dosing days (Days 1, 15, 29, 64, 135, 183 and 279) and on Day 302/ET.  
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2:3 times the upper limit of normal (ULN) and a post baseline bilirubin value >2 times ULN at 
h each subject's maximum post baseline AST or ALT value relative to the ULN 
against the subject's maximum post baseline bilirubin value relative to the ULN; values do not 
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The neurological items comprise cranial nerve function (facial appearance, eye appearance, 
auditory response, visual response, sucking/swallowing), posture (head in sitting position, trunk 
in sitting position, arms at rest, hands, legs in sitting position, legs in supine and standing 
positions, feet in supine and standing positions), movements (quantity, quality), tone (scarf sign, 
passive shoulder elevation, pronation/supination, adductors, popliteal angle, ankle dorsiflexion, 
pulled to sit, ventral suspension), and reflexes and reactions (tendon reflexes, arm protection, 
vertical suspension, lateral tilting, forward parachute). Behavior is comprised of state of 
consciousness, emotional state, and social orientation. For each item, for each subject, the worst 
post-baseline and the best post-baseline out
the shifts from baseline to the worst and from baseline to the best post-baseline value will be 
presented. In this analysis, all assessments post the first dose at baseline will be considering post 
baseline visits. For any item where the investigators have entered scores outside the set of 
expected values the scores will be mapped prior to determining shifts as follows: for baseline 
values, to the next highest expected value and for post-baseline values to the next lowest 
expected value. 
Reflex assessments 
Acute effects after dosing: Reflex  
On each dosing day, each predosing reflex will be compared with all the post dosing assessments 
with 24 hours to see if the subject has changed (gained or lost) or maintained, reflexes. For this 
comparison the pre-dose reflex status will be categorized into two categories: 0 and >=1. For 
each reflex, visit, pre-dose category the number and proportion of subjects who change or 
maintained will be presented. 
Acute effects after dosing: Reflex and other assessments 
On each dosing day, the shifts from predose assessment on that day to postdose (i.e., from 
predose to 3, 6 and 24 hours postdose) will be determined and shifts the lowest post dose and the 
highest post baseline for each dose will be presented. 
Chronic effects: Reflex and other assessments 
For each item and subject, the lowest predose post baseline and the highest predose post baseline 
baseline (predose value 
on Day 1) to the lowest predose post baseline and from baseline to the highest predose post 
baseline value will be presented. In this analysis, all assessments after the first dose will be 
considered post baseline visits. 
For all the assessments the summary statistics for actual values and change from baseline in each 
parameter will be presented by treatment group and visit.  Line plots for each item mean value 
for each treatment group at each visit and timepoint will also be presented.  
 
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comes will be determined and 'shift' tables showing 
outcomes will be determined and 'shift' tables showing the shifts from 


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7.1.5. ECG 
ECGs are to be recorded at Days 1, 15, 29, 135, 183, 279 and 302/ET, predose and post dosing at 
various time points on dosing days and end predose at 302/ET. The ECGs are assessed at a 
central reading laboratory and the results provided as external vendor data. On the eCRF the 
investigator interpretation is collected as normal, abnormal and abnormal AE and the 
investigator determination will be used in analyses. 
The ECG test includes heart rate, QT interval, QTcF interval and RR interval. Summary statistics 
for actual values and change from baseline in each ECG parameter will be presented by 
treatment group and visit.  
ECGs will be analyzed using two approaches. 
Qualitative analysis 
The determination of whether an ECG is abnormal not AE, abnormal AE made by the 
Investigator will be used for this qualitative analysis. 
The number and percentage of subjects with shifts from normal to each of the categorical values 
denoting an abnormal scan (abnormal not AE, abnormal AE) will be summarized by treatment 
group. All post baseline data will be used to identify abnormalities, regardless of whether a 
scheduled or unscheduled visit.  
Corrected Fridericia QT interval QTcF abnormalities (outliers) 
QTcF will be examined to determine the incidence of clinically relevant abnormalities. The 
number of subjects evaluated and the number of subjects with clinically relevant abnormalities 
will be presented. 
The first criteria for clinically relevant post dosing abnormalities (secondary safety endpoint) that 
will be considered is: 
Post baseline QTcF of > 500 msec and Maximum increase from baseline to post baseline QTcF 
>60 msec. 
 
Other criteria are:  
Maximum increase from baseline QTcF > 30 to 60 msec  
Maximum increase from baseline QTcF > 60 msec  
Maximum post baseline QTcF > 480 to 500 msec  
Maximum post baseline QTcF > 500 msec  
ECG summaries will be presented for all subjects and for subjects with post baseline. Listings 
will include both the central and eCRF information. 
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7.1.6. Vital Signs 
The analysis of vital signs will be approached in two ways. 
Vital signs are to be measured at Screening, predose and at 1, 2, 4, 6, and 24 hours postdose on 
dosing days (Days 1, 15, 29, 64, 135, 183 and 279) and on Day 302/ET. At each of these times, 
temperature, heart rate, respiratory rate, systolic and diastolic blood pressure, and pulse oximetry 
will be measured. If multiple evaluations are on the same visit day and visit time, then the mean 
of multiple evaluations will be selected for inclusion in the analysis.  
Acute Effects After Dosing  
On each dosing day, the change in each vital sign from predose on that day to postdose (i.e., 
from predose to 1 hour postdose, to 2 hours postdose, etc.) will be calculated. Summaries of 
actual values and change from predose for each dosing day will be presented.  
Chronic Effects  
To examine for possible chronic effects, the change from baseline (the predose value on Day 1) 
to the predose value on later dosing days and to Day 302/ET will be determined. Summaries of 
actual values and change from baseline for subsequent dosing days (Days 15, 29, 64,135, 183, 
and 279) and for Day 302/ET will be presented. 
Vital signs (temperature, pulse, systolic and diastolic blood pressure and pulse oximetry) will 
also be examined to determine the incidence of potentially clinically relevant abnormalities.  
Shift analysis 
The number of subjects evaluated and the number of subjects with potentially clinically relevant 
abnormalities will be presented. All post baseline data will be used to identify abnormalities, 
regardless of whether a scheduled or unscheduled visit. The criteria for potentially clinically 
relevant postdose abnormalities are shown in Table 19 below. 
Table 20: Criteria to determine potentially clinically relevant abnormalities in vital signs. 
 
 
Vital Sign 
Criteria for Abnormalities 
Temperature 
<36°C 
>38°C  
Pulse 
<60 bpm 
>100 bpm 
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Systolic Blood Pressure 
<90 mmHg 
>140 mmHg 
>160 mmHg 
 
Diastolic Blood Pressure 
<50 mmHg 
>90 mmHg 
>100 mmHg 
  
Weight 
7% or more decrease from baseline 
7% or more increase from baseline 
Respiratory Rate 
<12 breaths/min 
>20 breaths/min 
 
7.1.7. Growth parameters 
Growth parameters include length for age, weight for age, weight for length, head circumference 
for age, chest circumference, head to chest circumference ratio, and arm circumference. 
The growth parameters are to be assessed during screening, on dosing days (Days 1, 15, 29, 64, 
135, 183 and 279) and on Day 302/ET. 
The weight for age and length for age will be summarized using the WHO child growth 
standards (WHO Child Growth Standards, 2006) for subjects aged up to 5 years and similarly the 
WHO growth reference data (WHO, 2007) for older subjects. These standards comprise 
percentiles for weight and length for age by sex and are available on a website (www.who.int) in 
txt files. Subjects will be cross referenced with these files, given the age and sex of the subject to 
determine below which percentile they lie for each parameter. 
Summary statistics for actual values and change from baseline in each growth parameter will be 
presented by treatment group and visit. 
Baseline growth parameters will be summarized and also the frequency and percentage for 
weight and length 
th percentile.  
 
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for age will also be presented for each of in the following categories: :S 1st, :S 
3rd, :S5th, :Sl 5th, :S25th, :S50th and > 50 


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7.1.8. LP opening pressure 
LP opening pressure will only be measured at Days 1, 15, and 279 to avoid potential unblinding. 
A lack of published data exists in terms of the variability of opening pressure between and within 
subjects. It is suspected that a simple change in position of a subject during the measurement or 
change of instrument used contributes to variability in the measurement.  
 
7.1.9. X-ray Examination of Spine 
N/A 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
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10. Pharmacodynamic Endpoints 
As detailed earlier NF-L is defined as a secondary endpoint. 
 
In addition, plasma and CSF PK 
concentrations will be analyzed with plasma and CSF biomarkers to establish PK/PD correlation. 
PK/PD and exposure-response may also be conducted on efficacy. The results of this study may 
be combined with other nusinersen studies to perform population PK/PD analyses, including 
exposure-response analysis. 
Other Analyses 
Not applicable. 
Statistical Considerations for Interim Analysis 
Not applicable 
 
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Changes from Protocol-Specified Analyses 
The secondary endpoint for plasma NF-L comparing Higher dose nusinersen to 12mg nusinersen 
was changed from Day 29 in the protocol to be Day 64 in this Statistical Analysis Plan 
Summary of Changes from the Previous Version 1.0 of the SAP 
Added in the per protocol set definition: Participants who had a previous diagnosis that would 
confound the data/conflict with SMA. 
Added text to Section 6.4.1 to clarify that if baseline is missing, the median used in the 
imputation will be rounded up to the nearest integer value. 
Added clarification to Section 6.4.3 that Ranking based on death will be performed as described 
earlier for CHOP INTEND. In terms of ranking based on the NF-L, progressively higher ranks 
will be given to subjects with a greater reduction in NF-L at Day 183. 
Removed the analysis of CSF NFL with the joint rank test at Day 64 in Section 6.6.1.  Day 64 is 
not feasible to use since the 50/28mg received a sham procedure at Day 64. 
Two sensitivity analyses added to Section 6.1 based on comments from the FDA: 
 Use of an ANCOVA model where the variance is estimated in each treatment arm 
separately for the main analyses of the change in CHOP INTEND and HINE-2 total score 
to Day 183 comparing sham to Higher dose. 
 Implementation of Jump To Reference (J2R) and the joint rank test for the main analyses 
of CHOP INTEND and HINE2 total score for sham compared to higher dose and 12mg 
compared to higher dose. 
Summary of Changes from the Previous Version 2.0 of the SAP 
Based on comment from FDA added a sensitivity analysis for the main analyses using joint rank 
test of the change in CHOP INTEND and HINE-2 total score to Day 183 comparing sham to 
higher dose where the variance is estimated in each treatment arm separately. 
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. 
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Berry JD, Miller R, Moore DH, et al. The Combined Assessment of Function and Survival 
(CAFS): a new endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal 
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-Based Exact Confidence Intervals for the Difference
1209. Coovert DD, Le TT, McAndrew PE, 
et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet. 
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De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular 
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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. 
Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: 
Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ 
systems; and ethics. Neuromuscul Disord. 2017 Epub 2017/11/23. 
Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: 
Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ 
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Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical 
trials. Stat Med 1999; 18 (11):1341-54.f 
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. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. 
Department of Health, Education, and Welfare; 1976. 
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. 
ICH E9 (R1) Addendum 2017 
Docusign Envelope ID: 7DCA7D24-7D1 B-4516-ABE7-DC0913457365 
Chan, I. S. F., and Zhang, Z. (1999). "Test 
of Two Binomial Proportions." Biometrics 55:1202-


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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. 
 
 
 
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. 
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. 
Little RJA, Rubin DB. Statistical Analysis with Missing Data. 2 nd ed. New York: John Wiley & 
Sons, Inc; 2002. 
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. 
 
 
Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: 
Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. 
Neuromuscul Disord. 2018;28(2):103-115. Epub 2017/11/23. 
 
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. 
Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat. 2017;16(1):20-
28. Epub 2016/08/15. 
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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-
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Rosenbaum 2010, Design of Observational Studies 
 
 
Schafer JL. Analysis of Incomplete Multivariate Data. 1 ed. London: Chapman & Hall/CRC 
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Schafer JL. Multiple imputation: a primer. Stat Methods Med Res. 1999;8(1):3-15 
 
 
 
 
 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
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2006;450:56-65. 
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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APPENDICES 
APPENDIX A. 
i 
Adverse Events 
In the situation where worsening in severity (including seriousness) occurs for an adverse event, 
study sites are instructed to enter an end date and start a new record for the adverse event. In the 
new record, the changed severity is to be recorded and the start date will be set to be the end date 
of the previous record. Data linking those records are collected in the data base. Consider three 
scenarios:  
The first AE record occurs prior to the first dose, the second AE record occurs on or after 
the first dose, and the severity increases: Only the second record will be counted as 
treatment emergent.  
Both records occur on or after the first dose: If the AE severity on the second record is 
worse than the severity on the first record, then count both records as treatment emergent. 
Both records occur on or after the first dose: If the AE one is severe and the other serious 
then count both records as treatment emergent. 
Of note, when counting the total number of treatment-emergent events, events linked through 
change in severity will still be counted as separate events. 
For events with missing start or stop dates, the following criteria will be used for the purpose of 
identifying treatment-emergent adverse events:  
If both the start and stop date for a particular event are missing, then the event is considered to 
have occurred on or after the first dose of study treatment. 
If the start date for a particular event is missing and the stop date/time falls after the first dose 
date/time, then the event is considered to have occurred on or after the first dose of study 
treatment. 
If the start time is missing and the start date is same as the first dosing date, then the event is 
considered to have occurred on or after the first dose of study treatment. 
If it cannot be determined whether or not an event has occurred on or after dosing due to a 
missing or partial date, then the event will be assumed to have occurred on or after the first dose 
for the purpose of identifying treatment-emergent adverse events. 
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Statistical Analysis Plan 
Version: 3.0 Final
Page 82
Specifically, let AESTDT denote the start date of an adverse event and TRTSTDT be the start 
date of study treatment. For the purpose of identifying the treatment emergent adverse events, the 
following algorithm will be used for the imputation of missing or partial date: 
If AESTDT is completely missing or the year is missing, then impute AESTDT to TRTSTDT. 
If, in AESTDT, year is present and month/day are missing and year is equal to the year portion 
of TRTSTDT, then impute the month/day portion of AESTDT to the month/day portion of 
TRTSTDT. 
If, in AESTDT, year is present and month/day are missing and year is not equal to the year 
portion of TRTSTDT, then impute the month/day portion of AESTDT to January 01. 
Consider the situation in AESTDT where year and month are present with only day missing. If 
the year and month are the same as those for TRTSTDT, then impute day in AESTDT with day 
in TRTSTDT. Otherwise, impute the day in AESTDT with the first day of the month. 
It is important to emphasize that the imputed date will not be used for calculations such as onset 
and duration of an adverse event.  
ii 
Concomitant Therapy and Procedure 
In order to define concomitant therapies with missing start or stop dates, the following additional 
criteria will be used: 
If both the start and stop dates of a particular therapy were missing, that therapy is 
considered concomitant. 
If the start date of a therapy was missing and the stop date of that therapy fell on or after 
the date of dosing, that therapy is considered concomitant. 
If the start date of a therapy was prior to the date of dosing and the stop date of that 
therapy was missing and the therapy was listed as continuing, that therapy is considered 
concomitant. 
If the start date of a therapy was prior to the date of dosing and the stop date of that 
therapy was missing and the therapy was listed as not continuing, that therapy is 
considered concomitant.  
If the start/stop date of a therapy is partial then where it is not possible to rule out that it 
was not taken concomitantly it will be considered concomitant. 
Denote the end date of medications as CMENDT and the study treatment start date as 
TRTSTDT. The medication is classified concomitant provided any of the following is NOT true: 
CMENDT is complete and CMENDT is less than TRTSTDT. 
Day of CMENDT missing and year/month of CMENDT is strictly before year-month of 
TRTSTDT. 
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Product: Nusinersen 
Study: 232SM203 
Statistical Analysis Plan 
Version: 3.0 Final
Page 83
Month of CMENDT is missing and year of CMENDT is strictly before year of 
TRTSTDT. 
APPENDIX B. 
PERMANENT VENTILATION DEFINITION CRITERIA: ACUTE REVERSIBLE EVENT 
Purpose: Acute, intercurrent events may result in transient utilization of increased respiratory 
support for participants with spinal muscular atrophy (SMA) in this study. Such events may not 
reflect irreversible SMA disease progression and may complicate the ability to detect the effects 
of nusinersen on SMA disease progression.  
16 hours of ventilation/day continuously for > 21 days in the absence of an acute reversible 
event). 
The purpose of this appendix is to define an acute reversible event and to indicate how this 
prespecified definition will be used in this study.  
Any one of the following that occur between 7 days before and 7 days after the onset of 
threshold-leve
event: 
1. 
2.
Infection
Blood, sputum, throat, or cerebrospinal fluid (CSF) culture positive × 2 for virus, bacteria, or 
fungus 
Blood, throat, sputum, or CSF viral polymerase chain reaction positive 
Blood, throat, sputum, or CSF for infectious antigen diagnostic (e.g., streptococcus+ or hepatitis 
B surface antigen positive)  
Blood, throat, sputum, or CSF positive for direct microscopic visualization (e.g., bronchoalveolar 
lavage or Gram stain revealing the presence of bacteria by tissue biopsy 
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A secondary endpoint is defined as the time to death or permanent ventilation (tracheostomy or~ 
1 respiratory support(~ 16 hours/day) meet the definition of an acute reversible 
Fever~ 102°F/38.9°C (tympanic, rectal, axillary, skin, sublingual) 


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Product: Nusinersen 
Study: 232SM203 
Statistical Analysis Plan 
Version: 1.0 
1 
PART B LATER-ONSET SMA STATISTICAL 
ANALYSIS PLAN 
Version No.: 1.0 
Date: 10April2024 
 Author: 
 
Study Title:  
Escalating Dose and Randomized, Controlled Study of Nusinersen 
(BIIB058) in Participants With Spinal Muscular Atrophy 
Name of Study Treatment: Nusinersen 
Protocol No.: 232SM203 
Study Phase: 2/3 
Confidential Information 
The information contained in this Statistical Analysis Plan (SAP) is confidential and may not be 
reproduced or otherwise disseminated without the approval of Biogen, Inc.   
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Product: Nusinersen 
Study: 232SM203 
Statistical Analysis Plan  
Version: 1.0 
 
2 
 
APPROVAL 
 
 
This document has been reviewed and approved by: 
 
 
 
 
  
SMT Statistician 
 
 
Date 
 
 
 
 
  
Program Statistician 
 
 
Date 
 
 
 
 
  
SMT Medical Director 
 
Signature 
 
Date 
 
 
 
 
 
 
VERSION HISTORY 
 
SAP Version 
Date 
Primary Reasons for 
Amendment 
 
 
 
 
 
 
 
 
 
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11-Apr-2024
11-Apr-2024


Product: Nusinersen 
Study: 232SM203 
Statistical Analysis Plan  
Version: 1.0 
 
3 
 
Table of Contents 
PART B LATER-ONSET SMA STATISTICAL ANALYSIS PLAN ............................. 1 
APPROVAL ...................................................................................................................... 2 
VERSION HISTORY ........................................................................................................ 2 
Table of Contents ............................................................................................................... 3 
LIST OF ABBREVIATIONS ............................................................................................ 6 
1. 
Introduction ................................................................................................... 10 
2. 
Study Overview ............................................................................................. 10 
2.1. 
Study Design............................................................................................................... 12 
2.2. 
Sample Size Considerations ....................................................................................... 13 
2.3. 
General Trial Conduct Mitigation Strategy under COVID-19 Pandemic or 
humanitarian emergencies ......................................................................................................... 13 
2.4. 
External Data .............................................................................................................. 14 
2.4.1. 
CS4 Study ............................................................................................................... 14 
2.4.2. 
CS11 Study ............................................................................................................. 14 
2.4.3. 
Japan PMS Study .................................................................................................... 14 
2.4.4. 
Summary of external data ....................................................................................... 15 
2.4.5. 
Summary of How External Data Will be Used in the Analysis .............................. 15 
3. 
Definitions ..................................................................................................... 16 
3.1. 
Dates and Points of Reference .................................................................................... 16 
3.2. 
Study Treatments ........................................................................................................ 16 
3.3. 
Key Derived Variables ............................................................................................... 17 
3.4. 
Stratification Factors and Subgroup Variables ........................................................... 17 
3.5. 
Analysis Sets............................................................................................................... 17 
3.5.1. 
Within 232SM203 ................................................................................................... 17 
3.5.2. 
External data ........................................................................................................... 18 
4. 
List of Planned Study Analyses ..................................................................... 20 
4.1. 
Interim Analysis ......................................................................................................... 20 
4.2. 
Primary Analysis ........................................................................................................ 20 
4.3. 
Final Analysis ............................................................................................................. 20 
4.4. 
General Principles ....................................................................................................... 20 
4.5. 
Participant Accountability .......................................................................................... 22 
4.6. 
Demographic and Baseline Characteristics ................................................................ 22 
4.7. 
Protocol Deviations .................................................................................................... 22 
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Statistical Analysis Plan  
Version: 1.0 
 
4 
 
4.8. 
Study Treatment Exposure ......................................................................................... 23 
5. 
Efficacy Endpoints ........................................................................................ 23 
5.1. 
General Analysis Methods for Efficacy Endpoints .................................................... 23 
5.1.1. 
Multiple imputation (MI) ........................................................................................ 23 
5.1.2. 
Matching external data ............................................................................................ 24 
 
. 25 
5.1.4. 
Primary Efficacy Endpoints .................................................................................... 28 
5.1.5. 
Secondary Efficacy Endpoints ................................................................................ 28 
5.1.6. 
Number and Length of Hospitalizations ................................................................. 34 
5.1.7. 
Clinical Global Impression of Change (CGIC) [Physician, Caregiver] at Day 
302 
34 
5.1.8. 
Number of Serious Respiratory Events................................................................... 35 
5.1.9. 
Ventilator Use ......................................................................................................... 36 
5.1.10. Change in the Parent Assessment of Swallowing Ability Scale (PASA) ............... 36 
 
 36 
5.1.12. Subgroup analyses .................................................................................................. 37 
37 
5.2. 
Comparisons to external data ..................................................................................... 37 
6. 
Safety Endpoints ............................................................................................ 40 
6.1.1. 
Concomitant therapy and Procedure ....................................................................... 43 
6.1.2. 
Clinical laboratory data ........................................................................................... 43 
6.1.3. 
Neurological Examinations ..................................................................................... 45 
6.1.4. 
ECG......................................................................................................................... 46 
6.1.5. 
Vital Signs ............................................................................................................... 47 
6.1.6. 
Growth parameters .................................................................................................. 48 
6.1.7. 
LP opening pressure ................................................................................................ 49 
6.1.8. 
X-ray Examination of Spine ................................................................................... 49 
9 
1 
9. 
Pharmacodynamic Endpoints ........................................................................ 53 
10. 
Other Analyses .............................................................................................. 53 
11. 
Statistical Considerations for Interim Analysis ............................................. 53 
12. 
Changes from Protocol-Specified Analyses .................................................. 53 
13. 
Summary of Changes from the Previous Version of the SAP ....................... 53 
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Study: 232SM203 
Statistical Analysis Plan  
Version: 1.0 
 
5 
 
14. 
References ..................................................................................................... 53 
15. 
APPENDICES ............................................................................................... 57 
APPENDIX A. ................................................................................................................. 57 
 
 
 
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Statistical Analysis Plan  
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6 
 
 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
  
 
   
 
 
ACEND  
Assessment of Caregiver Experience with Neuromuscular Disease 
 
 
AE   
Adverse event 
ALT 
Alanine Aminotransferase (SGPT) 
ANCOVA 
analysis of covariance   
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase (SGOT) 
AUC 
Area under the curve 
BLQ 
Below limit of quantification 
BUN 
Blood Urea Nitrogen 
CGIC  
Clinical Global Impression of Change 
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Product: Nusinersen 
Study: 232SM203 
Statistical Analysis Plan  
Version: 1.0 
 
7 
 
CGIC  
Clinical Global Impression of Change 
CHOP INTEND   
Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders 
   
 
CO2 
Carbon dioxide 
COVID-19   
Coronavirus disease 2019 
CRF  
Case report form 
CSF   
Cerebrospinal fluid 
 
 
CV 
Coefficient of variance 
EAC  
Endpoint adjudication committee 
ECG   
Electrocardiogram 
GGT 
Gamma-Glutamyl Transferase 
HFMSE   
Hammersmith Functional Motor Scale – Expanded 
HINE   
Hammersmith Infant Neurological Examination 
HRQOL   
Health-related quality of life 
ICF   
Informed consent form 
ICH   
International Council for Harmonization 
IDMC   
Independent data monitoring committee 
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Statistical Analysis Plan  
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8 
 
INR 
International Normalized Ratio 
IRT  
Interactive response technology 
ITT   
Intent-to-Treat 
JRT 
Joint Rank Test 
LLOQ 
Lower Limit of Quantification 
LP   
Lumbar puncture 
L3M6  
3 loading doses maintenance dose every 6 months 
MI 
Multiple imputation  
NfL   
Neurofilament Light chain 
PASA   
Parent Assessment of Swallowing Ability 
PD   
Pharmacodynamic(s) 
PedsQL   
Pediatric Quality of Life Inventory™ 
   
 
PMS 
Post-marketing surveillance  
  
 
 
 
PPS 
Per protocol Set 
PT 
Prothrombin Time 
QoL  
Quality-of-life 
QTcF  
Corrected QT interval using Fridericia’s formula 
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Study: 232SM203 
Statistical Analysis Plan  
Version: 1.0 
 
9 
 
RULM   
Revised Upper Limb Module 
SAE   
Serious adverse event 
SD 
Standard deviation 
SE 
Standard error 
SMA 
Spinal muscular atrophy 
SMN  
Survival motor neuron 
SMN1  
Survival motor neuron 1 
SMN2  
Survival motor neuron 2 
SOC 
System Organ Class 
 
 
ULN 
Upper Limit of Normal 
US  
United States 
WHO 
World A12:B65Health Organization 
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Product: Nusinersen 
Study: 232SM203 
Statistical Analysis Plan  
Version: 1.0 
 
10 
 
1. 
Introduction 
This Statistical Analysis Plan is based on Version 6 of the protocol, dated 05May2022. All 
references to the protocol refer to Version 6. 
 
Nusinersen is an antisense oligonucleotide administered intrathecally via lumbar puncture 
(LP); it increases survival motor neuron (SMN) protein expression and significantly improves 
motor function in patients with spinal muscular atrophy (SMA). Nusinersen was approved for 
the treatment of SMA under the tradename Spinraza™ in the United States (US), European 
Union, and other countries. The population for this study includes participants with infantile-
onset and later-onset SMA.  
Efficacy and safety results across the nusinersen clinical development program have 
demonstrated an overall positive benefit-risk profile of nusinersen across a broad range of 
SMA phenotypes and patient populations. Nusinersen is approved in the US, Europe, and 
other countries and regions for the treatment of SMA in paediatric and adult patients at a 
recommended dosage of 12 mg administered in 3 loading doses at 14-day intervals, a fourth 
loading dose 30 days after the third dose, and maintenance doses every 4 months thereafter in 
most countries and regions. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses 
indicate that nusinersen drug exposure higher than that achieved with 12 mg in patients with 
SMA may produce an even greater benefit in motor function. Additionally, PK modelling and 
simulations identified dosing regimens that achieve higher drug exposure more rapidly. 
Therefore, this study is being conducted to investigate the efficacy, safety, tolerability, and 
 of a 50/28-mg dose of nusinersen (50-mg loading dose/28-mg maintenance dose) and a 
dosing regimen targeted to achieve higher drug exposure more rapidly. This study will be 
conducted in participants with genetically confirmed SMA. 
This is a 3-part study Part A, Part B (infantile-onset and later-onset), and Part C. 
Part A was an open label safety evaluation in which later-onset SMA subjects received 3 
loading doses of 28 mg of nusinersen and 2 maintenance doses of 28 mg. All 6 participants 
enrolled in Part A completed. 
Part B was double-blind, active-controlled controlled study designed to evaluate the proposed 
higher dosing regimen and included infantile and   later-onset SMA participants. 
Part C was an open label safety evaluation in which infantile and later-onset SMA of the 
participants, who were on the currently approved dose of nusinersen (12-mg maintenance for 
at least 1 year after the initiation of treatment) received  higher dosing regimen via the 
administration of a single bolus dose of 50 mg of nusinersen (which should be administered 4 
months ± 14 days after their most recent maintenance dose of 12 mg), with maintenance 
dosing at 28 mg thereafter. All 40 participants enrolled in Part C completed. 
 
2. 
Study Overview 
Study Objectives and Endpoints applicable to Part B later-onset. 
This analysis plan it is only for Part B Later-onset analyses. Separate SAPs will cover the 
planned analyses for other parts of DEVOTE and the Part B infantile onset population. 
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Study: 232SM203 
Statistical Analysis Plan  
Version: 1.0 
 
11 
 
 
The Part B primary objective is not applicable to the later-onset population. 
Secondary Objectives  
To examine the clinical efficacy of nusinersen administered intrathecally at higher doses 
compared to the currently approved dose in participants with SMA. 
Secondary Endpoints 
 Change from baseline in Hammersmith Functional Motor Scale – Expanded (HFMSE) 
score. 
 Change from baseline in Revised Upper Limb Module (RULM) score. 
 Total number of new World Health Organization (WHO) motor milestones 
 Change from baseline in neurofilament light chain (NfL) concentration in plasma. 
 Change from baseline in neurofilament light chain (NfL) concentration in CSF. 
 Change from baseline in Assessment of Caregiver Experience with Neuromuscular 
Disease (ACEND)  
 Change from baseline in Pediatric Quality of Life Inventory™ (PedsQL)  
 Number and duration of hospitalizations. 
 Clinical Global Impression of Change (CGIC) [physician, caregiver] at Day 302 
 Number of serious respiratory events  
 Ventilator use 
 Change in the Parent Assessment of Swallowing Ability (PASA) scale. 
 
Secondary Safety Objectives 
To examine the safety and tolerability of nusinersen administered intrathecally at higher 
doses to participants with SMA. 
 Secondary Safety Endpoints 
 Incidence of AEs, including SAEs 
 Shifts from baseline in clinical laboratory parameters, ECGs, and vital signs  
 Change in growth parameters  
 Shifts from baseline in coagulation parameters (aPTT, PT, and INR)  
 Change in urine total protein  
 Change from baseline in neurological examination outcomes  
 The proportion of participants with a post baseline platelet count below the lower limit 
of normal on at least 2 consecutive measurements  
 The proportion of participants with a post baseline QTcF of > 500 msec and an 
increase from baseline to any post baseline timepoint in QTcF of > 60 msec 
 
 
 
 
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Product: Nusinersen 
Study: 232SM203 
Statistical Analysis Plan 
Version: 1.0 
12 
 



 
 
 


2.1. Study Design 
This 3-part study will evaluate the efficacy and safety of a higher dosing regimen of 
nusinersen in approximately 145 participants. The study will be conducted at approximately 
65 sites globally. Following the completion of this study, all eligible participants may elect to 
enrol in a separate long-term extension study (232SM302), pending study approval by ethics 
committees and the appropriate regulatory authorities. In regard to participants rolling over 
from Part B, this will be done without unblinding the participant’s treatment group. 
Part B will consist of a pivotal, double-blind, active-controlled treatment period with either 2 
or 4 loading doses of nusinersen (for the 50/28-mg Group and Control Group, respectively) 
administered intrathecally followed by maintenance doses approximately every 4 months 
thereafter. Approximately 75 participants with infantile-onset SMA and 24 participants with 
later-onset SMA will be randomized in a 1:2 ratio to receive either the currently approved 
dosing regimen or a 50/28-mg dosing regimen.  
In the Control Group, up to a total of 8 participants will receive 4 loading doses of 12 mg of 
nusinersen administered intrathecally (Days 1, 15, 29, and 64), followed by maintenance 
doses of 12 mg on Days 183 and 279 (and a sham procedure on Day 135). 
In the 50/28-mg Group, up to a total of 16 participants will receive 2 loading doses of 50 mg 
of nusinersen administered intrathecally (Days 1 and 15) and 2 sham procedures on Days 29 
and 64, followed by maintenance doses of 28 mg on Days 135 and 279 (and a sham 
procedure on Day 183). In order to maintain blinding sham procedures will be used as shown 
in the table below.  
Arm 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Dose 6 
Dose 7 
50/28-mg 
Group 
D1 
(50 mg) 
D15 
(50 mg) 
D29 
(sham) 
D64 
(sham) 
D135 
(28 mg) 
D183 
(sham) 
D279 
(28 mg) 
Control (12/12 
mg) 
Group 
D1 
(12 mg) 
D15 
(12 mg) 
D29 
(12 mg) 
D64 
(12 mg) 
D135 
(sham) 
D183 
(12 mg) 
D279 
(12 mg) 
Randomization in Part B will be performed using interactive response technology (IRT). 
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Product: Nusinersen 
Study: 232SM203 
Statistical Analysis Plan  
Version: 1.0 
 
13 
 
For Part B later-onset participants, the randomization will be stratified by age at informed 
consent as follows:  
< 6 years and 
 ≥ 6 years 
Blinded safety data will be reviewed on an ongoing basis by the Sponsor and the Medical 
Monitor. Unblinded safety data will be reviewed on an ongoing basis by an Independent Data 
Monitoring Committee (IDMC).  
2.2. Sample Size Considerations   
The sample size for Later-onset SMA in Part B is not based on statistical considerations. 
A total of 24 participants with later-onset SMA will be randomized to the Control Group and 
50/28-mg Group in Part B in a ratio of 1:2; this will allow the exploration of the safety, 
tolerability, 
, and efficacy of the 50/28-mg dose of nusinersen in this population. If 
any participants with later-onset SMA enrolled in Part B do not complete the Day 183 dose 
and assessments (e.g., due to withdrawal) as a result of a public health or humanitarian 
emergency, up to 4 additional participants may be enrolled at the Sponsor’s discretion. 
2.3. General Trial Conduct Mitigation Strategy under COVID-19 
Pandemic or humanitarian emergencies 
In order to mitigate risk of missing dosing or assessments during the time of the COVID-19 
pandemic, the following has been put into place: 
 If a site is not closed due to COVID-19 or humanitarian emergencies and the site 
enables the participant to attend the visit in-clinic, then delayed visits within a 
reasonable timeframe are allowed.  
 Site transfers are encouraged where possible, so that participants can be transferred to 
another site for assessment. Instructions are in place to enable sites to do this 
including transfer of the database and source documents for the patient from the 
transferring site to the receiving site. This will allow the participant to receive dosing 
and protocol defined assessments to be made.  Dosing can only be performed in the 
clinic setting due to intrathecal administration. In particular, if screening cannot be 
performed in the clinic, participants will be screened at a screening site and 
subsequently transferred to another site to perform dosing and all assessments for the 
participant, since dosing can only be performed in the clinic setting due to intrathecal 
administration.  
 A phone visit can be used to collect safety data (AEs, concomitant 
therapies/procedures) 
 Transferring sites are encouraged to enter and clean all data before transferring the 
participant to the receiving site. The database for a participant will remain with the 
transferring site until data are entered and cleaned as much as possible, but the 
transferring site must have access to the participant in IRT and copies of all source 
documents. Blinding of staff will be maintained as appropriate. Any queries raised 
later on for data belonging to visits at the transferring site will be cleaned by the 
receiving site through the source documents, and interaction between monitors at the 
receiving and transferring sites. The transferring site will no longer have access to the 
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Product: Nusinersen 
Study: 232SM203 
Statistical Analysis Plan  
Version: 1.0 
 
14 
 
database for a participant they have transferred but the monitors will. The Subject ID 
will remain the same when a participant is transferred to another site, but the transfer 
site can be tracked via the Site ID. 
2.4. External Data 
Three external datasets will be utilized to provide additional comparisons to the higher dose 
arm.  These will include the CS4 study, CS11 (CS4 extension study) and the Japan PMS 
study. 
2.4.1. CS4 Study  
CS4 was a phase 3, randomized, double-blind, sham-procedure controlled study to assess the 
clinical efficacy and safety of nusinersen administered intrathecally in patients with later-
onset spinal muscular atrophy.  The study had a planned follow-up from first dose of 15 
months.  
Key eligibility criteria were onset of symptoms of SMA at > 6 months of age, aged between 2 
and 12 years and ability to sit but never have achieved the ability to walk independently.  The 
primary endpoint was the change in HFMSE score from baseline to Month 15 and secondary 
endpoints included the proportion of participants achieving a 3 point improvement on the 
HFMSE, change in RULM and proportion of participants achieving new WHO motor 
milestones.  
The first patient was dosed in November 2014 and the last patient visit was February 2017.  
The study was stopped early based on the results of an interim safety and efficacy analysis 
and the study results were published (Mercuri et al. 2018). 
A difference between CS4 and later-onset part B of 232SM203 was that in CS4, patients 
received 3 loading doses of 12 mg at days 1, 29, and 85 and then a dose at Day 274 in 
contrast to 232SM203 where 4 loading doses at Days 1, 15, 29 and 64 and then a dose at Day 
183 is administered consistent with the nusinersen label in the majority of geographies. 
2.4.2. CS11 Study 
This was an open-label extension study in participants with SMA who previously participated 
in investigational studies of nusinersen. The last participant completed the study on 
21Aug2023. The primary purpose of this study was to gather additional information on the 
long-term safety, tolerability, and efficacy of repeated doses of nusinersen. Participants who 
were randomized to receive sham control in CS4 switched to receive 12 mg nusinersen at the 
start of CS11, so this dataset provides additional patients who were naïve to treatment. 
2.4.3. Japan PMS Study 
This is an ongoing, observational study to survey all the SMA patients treated with 
nusinersen after the launch in Japan for the purpose of understanding the safety and 
effectiveness in Japanese patients. Patients are followed up to death, discontinuation of the 
treatment or the end of the study period (8 years after the launch), whichever occurs first. The 
dosing regimen approved in Japan for later onset participants is the 3 loading doses and 6 
monthly maintenance dosing. As part of the effectiveness assessment, HFMSE has been 
collected at Day 274 dosing for later-onset patients. The latest data cut was at 30th of May 
2023. 
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2.4.4. Summary of external data 
The study design for 232SM203 included inclusion/exclusion criteria and efficacy 
assessments which are consistent with CS4, CS11 and the PMS study.  Although the same 
dose of 12 mg is administered a number of differences exist and these are summarized in the 
following table. 
 
Summary table of external data 
 
 
232SM203 
Higher Dose 
232SM203 
Standard dose 
CS4 
nusinersen 
CS4 
Sham 
CS11  
 
PMS 
Loading regimen 
2 x 50mg doses 
4 x 12mg doses 
3 x 12mg 
doses 
 
3 x 12mg 
doses 
3 x 12mg 
doses 
Maintenance regimen 
28mg every 4 
months 
12 mg every 4 
months 
12mg every 6 
months 
 
12mg every 6 
months 
12mg every 6 
months 
Label for regimen 
 
12mg L4M4 
12mg L3M6 
 
12mg L3M6 
12mg L3M6 
Timepoints efficacy 
collected (a) 
 
 
 
 
 
 
     Month 6 
     Month 9 
Day 183  
Day 279 
Day 183 [4]  
Day 279 [5] 
Day 169 [3] 
Day 274 [3] 
Day 169  
Day 274 
NA 
Day 265 [3] 
NA 
Day 274 [3] 
HFMSE collected 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
RULM collected 
Yes 
Yes 
Yes 
Yes 
Yes 
No 
WHO motor milestones 
collected  
Yes 
Yes 
Yes 
Yes 
Yes 
No(b) 
Estimated number of 
subjects  
16 
8 
84 
42 
38(c) 
27 (d) 
 
 
 
 
 
 
 
a) 
Number in square brackets denotes the number of 12mg doses received prior to timepoint. So although in 232SM203 a dose 
is administered at Day 183 this is not counted in the 4 doses shown at Month 6. 
b) 
WHO as collected in the PMS study uses different questions and is not considered comparable. 
c) 
Subjects with baseline age 2 to <=10 years with HFMSE >=10 and <=54 and able to sit and never walked alone per WHO 
motor milestones. 
d) 
Estimated based on data received Jan 2024. SMA type 2 patients, baseline age 2 to <=10 years with HFMSE >=10 and <=54. 
 
2.4.5. Summary of How External Data Will be Used in the Analysis 
In addition to the main comparison between the two active arms in study 232SM203, external 
data will be utilized for the following supportive analyses: 
 
Comparison  
How matching performed 
Time point for efficacy 
comparison 
Analyses 
 
Higher dose versus sham control 
 
Month 9, Month 6 
Safety and efficacy (HFMSE, 
RULM, WHO, plasma NfL) 
Higher dose versus nusinersen 
3LM6 – CS4 only 
 
Month 9, Month 6 
Efficacy (HFMSE, RULM, WHO, 
plasma NfL) 
Higher dose versus nusinersen 
3LM6 – CS4 and CS11 
 
Month 9 
Efficacy (HFMSE, RULM, WHO) 
Higher dose versus nusinersen 
3LM6 – CS4, CS11, PMS study 
 
  
Month 9 
Efficacy (HFMSE) 
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Higher dose versus nusinersen 
3LM6 – CS4 and CS11 
 
 
Month 9 
Efficacy (HFMSE, RULM, WHO) 
Higher dose versus nusinersen 
3LM6 – CS4  
 
 
Month 9, Month 6 
Efficacy (HFMSE, RULM, WHO, 
plasma NfL) 
Higher dose versus sham control 
 
 
Month 9, Month 6 
Efficacy (HFMSE, RULM, WHO, 
plasma NfL) 
 
3. 
Definitions 
3.1. Dates and Points of Reference 
 Study Day 1: the date of the first dose of study treatment in 232SM203 
 Study Day  
o For a date on or after Study Day 1  
Study Day = (Date of Interest) – (Study Day 1) + 1  
o For a date before Study Day 1  
Study Day = (Date of Interest) – (Study Day 1) 
In order to distinguish nominal visit names from duration defined in days, visit names will be 
referred to as “Day 15”, “Day 29”, etc., and “15 days” or “29 days”, etc. will be used to 
define time intervals. 
Overall time on study will be defined as the total number of days a participant is known to be 
followed on study calculated as follows: 
Overall time on Study = (Last date on study) – (Date of first dose) +1 
Last date on study is defined as the date of the latest visit or evaluation or telephone contact, 
or time of death from all available data for a given participant. 
Disease duration is defined as time from age at symptom onset to age at informed consent. 
3.2. Study Treatments 
The main presentations of data will be as follows: 
Baseline characteristics, disposition, exposure, time on study and adverse event displays 
 
 
232SM203 
 
12/12 mg nusinersen 
50/28 mg nusinersen 
Total 
 
For baseline summaries including external data, all patients available in the pool will be 
included in the first column and then the matched patients, in the 2nd column.   
 
 
Matched CS4              232SM203 
CS4 
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    Sham  
Sham 
50/28 mg nusinersen  
 
For efficacy endpoints, safety other than AES, 
:  
 
 
 
232SM203 
 
 
12/12 mg nusinersen 
50/28 mg nusinersen 
   
For summaries of adverse events and efficacy including external data: 
 
 
 
Matched CS4                232SM203 
 
 
     sham 
50/28 mg nusinersen 
 
The total study duration for each participant will be approximately 323 to 420 days:   
 
Screening: 21 days  
 
Loading period: 64 days  
 
Maintenance period: 215 days 
 
Follow-up: 23 to 120 days 
3.3. Key Derived Variables 
Not applicable. 
3.4. Stratification Factors and Subgroup Variables 
Randomization was stratified as follows: 
 Age at informed consent:  
 
< 6 years and  
 
≥ 6 years. 
The subgroup categories are the following: 
 
One group comprising North America, Taiwan and Europe (excluding Russia) 
(regions contributing participants to original 12mg studies) versus another group 
comprising all other countries.  
3.5. Analysis Sets 
3.5.1. Within 232SM203 
The Safety Set 
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The Safety Set is defined as all participants who receive at least one dose of nusinersen; 
participants will be analyzed in the treatment group based on what treatment they actually 
received.  
The Intent-to-Treat (ITT) Set  
The Intent-to-Treat (ITT) Set is defined as all participants who are randomized and receive at 
least one dose of nusinersen; participants will be analyzed in the treatment group to which 
they are randomized. This will be the primary population for the analysis of efficacy endpoints. 
 
 
 
 
  
 
 
Per Protocol Set 
A Per Protocol Set will include the subset of the ITT Set who have no significant protocol 
deviations that would be expected to affect efficacy assessments. 
Significant protocol deviations will be determined prior to database lock and will include: 
 Participants who had onset of signs and symptoms consistent with SMA at less 
than or equal to 6 months of age,  
 who were younger than 2 years or older than 10 years,  
 who cannot sit independently at screening,  
 whose HFMSE is <10 or >54 at screening,  
 who had respiratory insufficiency at Screening (defined as medical necessity for 
invasive or non-invasive ventilation for >6 hours during a 24-hour period) gtube 
at screening or severe scoliosis (Cobb angle > 40). 
 Participants who took experimental or approved agents for the treatment of 
SMA, including gene therapy, biological agent, or device, during the study. This 
includes marketed agents at experimental doses that are being tested for the 
treatment of SMA (oral albuterol/salbutamol, riluzole, carnitine, sodium 
phenylbutyrate, valproate, hydroxyurea, etc.). 
If participants have missed planned doses/sham but still completed study. 
 
3.5.2. External data  
The ITT Set as defined in the final analysis of CS4 will be used for the sham and nusinersen 
12mg groups.  
For CS11, the CS4 patients sham participants who received from the start of CS11 will be 
reassessed to determine if they would have qualified for 232SM203 based on fulfilling all the 
following conditions: 
 Aged 2 to <=10 years at first dose 
 Baseline HFMSE score ≥ 10 and ≤ 54 
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 Able to achieve WHO motor milestone of sitting without support and never 
achieved WHO walking alone. 
Only patients who satisfy these criteria will be considered from CS11 in the matching pool. 
For the PMS study a participant will need to meet all the following conditions to be included 
in the pool of participants: 
 SMA type 2. 
 Age at onset of symptoms > 0.5 years or missing. 
 Aged 2 to <= 10 years at first dose. 
 Baseline HFMSE score ≥ 10 and ≤ 54. 
 
The following labels will be used to reference external data. 
 
Label  
Description 
PS matched: CS4 Sham  
Formed from the CS4 ITT set of sham control 
treated patients using a PS matching to select at 
least 16 comparable to the higher dose group 
 
 
PS matched: nusinersen - CS4+CS11  
Formed from the CS4 and CS11 ITT set of 
nusinersen treated patients using a PS matching 
to select at least 16 comparable to higher dose 
group 
 
 
PS matched: nusinersen - CS4 only 
Formed from the CS4 ITT set of nusinersen 
treated patients using a PS matching to select at 
least 16 comparable to higher dose group  
 
 
PS matched with caliper: nusinersen A 
(Clinical trials and PMS) 
12mg nusinersen participants from CS4, CS11 
and Japan PMS study selected to match 
232SM203 higher dose using 
 
 
 
 
PS matched with caliper: nusinersen B (Clinical 
trials) 
12mg nusinersen participants from CS4 and 
CS11 studies selected to match 232SM203 
higher dose using 
 
 
 
PS matched with caliper: CS4 Sham  
 
CS4 sham participants selected to match 
232SM203 higher dose using 
 
 
 
 
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4. 
List of Planned Study Analyses 
4.1. Interim Analysis 
No interim analysis is planned.  Within Part B, when later-onset patients are completed then 
the final analysis will be performed on the later-onset patients. The unblinding plan details 
the steps to ensure that the blind is maintained throughout the entire study and for the 
infantile-onset patients should the later-onset patients be unblinded. 
4.2. Primary Analysis 
N/A 
 
4.3. Final Analysis 
The final analysis will be performed when all later-onset participants in Part B have 
completed the follow-up period.  
4.4. General Principles  
Descriptive summary statistics will be presented for all endpoints collected. Unless otherwise 
specified, for continuous endpoints, the summary statistics will generally include number of 
participants with data, mean, standard deviation, median, 25th percentile, 75th percentile, 
minimum and maximum. For categorical endpoints, the summary statistics will generally 
include number of participants with data, and the percentage of those with data in each 
category. 
 
All summaries and listings will be presented by study groups unless otherwise specified. 
Visits in listings will be displayed as per CRF data collection rather than analysis visits. 
 
The statistical software, SAS®(Version 9.4) will be used for all summaries and statistical 
analyses.  
 
Visit Windows for Early Withdrawal, Unscheduled Visits 
Data from early withdrawal visits and post baseline unscheduled assessments will be assigned 
to an appropriate scheduled post baseline visit using a windowing scheme for assessments 
that are tabulated or summarized by visit. Scheduled visits will not be windowed. 
The visit windowing will be performed for efficacy and safety endpoints.  
For safety endpoints the following windows will be utilized. 
 
Table 2: Visit windows for safety Endpoints in 232SM203 
Visit 
Lower Bound  
Upper Bound  
Target Day 
Baseline 
 
 
<=1 
Day 15 
2 
21 
 
Day 29 
22 
47 
29 
Day 64 
48 
99 
64 
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Day 135 
100 
159 
135 
Day 183 
160 
232 
183 
Day 279 
233 
290 
279 
Day 302 
291 
348 
302 
 
For efficacy endpoints, the actual day of the unscheduled or end of study visits will be 
considered. 
For post baseline visits up to and including Day 64 a +/- 7 day window will be used and for 
visits between Day 135 and Day 302 a +/- 14 day window will be used. 
The following rules will be implemented for windowing: 
 If more than one observation is within the same window, data from the regular 
scheduled visit will be used for that visit.  
 If neither of the observations are from a regular scheduled visit the observation closest 
to the planned target date will be used. However, if both the observations are 
equidistant from the target date, the latest one will be used; if repeated measurements 
are on the same day, then the last measurement will be used. 
 If windowing safety data safety data and there is more than one observation in a 
window for a dosing visit the observation on the day of dosing will be chosen over the 
observation where dosing did not occur on the same day. 
 In windowing laboratory data, if a central and local result is available within the 
window then the central laboratory result will be chosen.  
 
Summary table of windowing for the external data 
 
 
Study 
Windowing  
 
CS4 
All dosed subjects will be included, and the 
Month 6 and Month 9 values collected will be 
utilized.  
 
CS11 
All dosed subjects meeting the re-evaluated 
conditions will be included. The protocol defined 
Day 265 visit will be used. If this was not 
collected since the subject moved to MMDR 
dosing, then Day 265 will be missing. 
 
PMS study 
The HFMSE visit data will be windowed to give 
Month 9 as study day 274  +/- 15 days. Therefore, 
study days between 259 and 289 will be 
considered, if >1 lie in the window the one closest 
to Day 274 will be selected. If two are equally 
close, the latest one will be selected. 
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4.5.  Participant Accountability  
The number (and percentage) of participants screened, screening failure, randomized, 
withdrew prior to dosing, dosed, completed treatment, discontinued treatment and the reasons 
for discontinuation from treatment, completed the study, withdrew from the study and reason 
for withdrawal will be summarized in a table.  
A listing of participants who discontinued treatment/withdrew from study and the associated 
reasons for discontinuation/withdrawal will be presented. A separate listing will also be 
presented for participants who discontinued treatment/withdrew from study due to the 
COVID-19 pandemic or to humanitarian emergencies if applicable. 
4.6. Demographic and Baseline Characteristics 
Baseline data (demography, medical history, SMA history, and baseline disease 
characteristics) will be summarized.  
Formal statistical analyses will not be done to test for homogeneity between treatment 
groups. If there are apparent heterogeneities between the groups in any of the participant 
characteristics that are of clinical importance or could affect the treatment outcome, the 
impact of the imbalances will be investigated and, if appropriate, adjustments made in the 
efficacy and safety analyses. 
Demography includes age at screening, age at first dose, sex, ethnicity, race, country and 
geographic region. Medical history will be coded in MedDRA and the number and 
percentage of participants with each medical history presented by preferred term.  
SMA history includes age of symptom onset, time from disease onset to enrollment, age at 
SMA diagnosis, time from diagnosis to enrollment, number of copies of the SMN1 and 
SMN2 gene, highest motor function achieved and maintained, wheelchair use. 
Baseline disease characteristics will be assessed by HFMSE, WHO motor milestones, 
Revised Upper Limb Module Test Total score and Entry item, growth parameters and Cobb 
angle. These assessments are further described in the next paragraph and Section 5. 
Demographic and baseline disease characteristics will be presented for the ITT Set, the PPS 
and the Safety Set as appropriate. 
4.7. Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a protocol deviation 
log and categorized as major or minor deviations. These deviations will be listed. Major 
protocol deviations will be summarized including those that lead to exclusion from the Per 
protocol Set. 
Participants with incorrect stratification i.e. any mismatch between the stratification used for 
randomization on the IRT system and the actual stratification according to the eCRF will also 
be listed. A separate summary of major protocol deviations related to the COVID-19 
pandemic will be presented.  
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4.8. Study Treatment Exposure  
The number of doses received, and the number of sham procedures performed will be 
displayed using frequency distributions. The cumulative amount of nusinersen received will 
be summarized using summary statistics. 
The overall time on study will be summarized descriptively by treatment. Overall time on 
study will be calculated (section 3.1). The duration will also be categorized and summarized 
using the following categories: <29 days, >=29 to 64 days, >=64 to 99 days, >=99 to 135 
days, >=135 to 183 days, >=183 to 218 days, >=218 to <260, >=260 to 302 and >=302 days 
Given the long half-life of nusinersen, participants are considered to be exposed from the 
time the first dose of nusinersen was administered (in or before the start of study) to the date 
of last visit or contact. 
Separate listings will be provided showing what participants were randomized to as well as 
study drug administration data which will include lot numbers, actual treatment received, 
cumulative number of doses and cumulative doses. A listing of dosing errors will also be 
provided i.e. where either the incorrect dose was administered compared with the kit 
description from IRT system. A listing will also be presented to show whether any of the 
missed doses are related to COVID-19. If any of the doses are due to COVID-19, then the 
number of impacted doses will be presented. 
5. 
Efficacy Endpoints 
5.1. General Analysis Methods for Efficacy Endpoints 
5.1.1. Multiple imputation (MI)  
In the event of missing data for post baseline visits then multiple imputation will be 
performed.   
For secondary, 
 endpoints the multiple imputation method [Schafer 1997, 
Schafer 1999] will be used for patients who discontinue for a reason other than death or have 
a missing efficacy result at the timepoint of interest.  This will be performed for HFMSE, 
RULM, NfL CSF and plasma concentration, ACEND, and PedsQL.  
The imputations will be performed on total scores for post baseline visits. All available data 
will be used i.e., where participants have missed doses but continued to perform assessments; 
otherwise, any missing values will be imputed using MI. 
If the MI procedure imputes any values outside the expected range for the scale e.g. from 0 to 66 
for HFMS-E then values below 0 will be set to 0 and values above 66 will be set to be 66, and for 
NfL the minimum will be set to LLOQ/2. 
The Markov Chain Monte Carlo (MCMC) method will be used to impute the missing score.   
The treatment variable will be coded so that the Higher dose group is the first in the sort 
order. Prior to the Proc MI step the dataset will be sorted by treatment and then ascending 
unique subject identifier (USUBJID). The variable list in the model for imputations will 
include: 
 treatment group, age at screening, baseline plasma NfL baseline value for the 
endpoint, and all available post baseline values 
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A set of 100 complete imputed datasets will be generated and the relative efficiency 
parameter will also be checked to determine the acceptability of the imputed results i.e. it 
should be close to 98% or higher.   
For each of the 100 imputed datasets, the endpoint will be compared between treatment 
groups using an ANCOVA model for continuous endpoints or logistic regression for binary 
endpoints as described in the main analysis for each endpoint.   
The estimates from the 100 fitted models will be combined to provide an overall estimate 
with corresponding confidence intervals and p-value using PROC MIANALYZE [Little et al, 
2002]. 
For the continuous endpoints, the difference between treatments and the corresponding CI 
will be presented. For the analyses using logistic regression the odds ratio and corresponding 
CI will be presented. In addition, the estimates of the binomial proportions in each treatment 
arm and the differences between treatments will be presented (Ratitch, 2013). 
In the presentation of results from multiple imputed data, the number of subjects with missing 
data will be summarized. 
For any given endpoint such as HFMSE, a number of different comparisons are planned such 
as within study 232SM203: 12mg to higher dose, sham versus higher dose, L3Q6 compared 
to higher dose.  For each comparison a separate multiple imputation procedure will be 
performed including the 2 corresponding treatment groups. Only visits in common between 
the two arms will be included in the multiple imputation step.  This will mean that for any 
comparisons including CS4, CS11 and the PMS study, only baseline and Month 9 HFMSE 
visits will be included in the imputation step and for comparisons including CS4 only, 
baseline, Month 6 and Month 9 will be included. 
5.1.2. Matching external data 
Due to the wide range of matching algorithms available and the difficulty in foreseeing all 
challenges upfront an additional operational step will be implemented as follows as part of 
the comparisons to external data: 
An independent statistician will be identified. This statistician will be considered independent 
as they will have no knowledge or ability to access Part B later-onset post-baseline data in 
DEVOTE. 
 The independent statistician will be provided with:232SM203 baseline covariates, 
baseline efficacy data and be unblinded to he assigned treatments.  They will not have 
access to any on-treatment efficacy data for 232SM203Baseline data from CS4, Japan 
PMS, CS11.  
 The following process will be followed: 
1) The independent statistician will be provided with code to perform matching per this 
analysis plan and attempt to find the best match they can per the matching designs. In 
a situation where the matching approach is not successful then the statistician may 
implement an alternative matching algorithm.  
2) If a match is found, then the independent statistician will create a dataset which 
identifies which groups of subjects were matched between studies. 
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3) Following the unblinding of 232SM203 the statistician responsible for the efficacy 
analysis will be provided with the file in (2) and perform the planned efficacy analysis 
using the groups of subjects identified. Since this statistician will have access to post-
baseline efficacy data, they will not be permitted to perform the matching step (1,2). 
This operational sequence is considered important in order to increase the chance of making a 
reasonable match, but also to protect the integrity of matching and minimize the bias which 
could occur if the statistician performing the matching had access to the efficacy data (or vice 
versa).  Further details on this are described in the unblinding plan. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
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Matching designs 
1. Comparison of higher dose versus 12 mg nusinersen L3M6 dosing regimen 
The intent is to match the 16 subjects in 232SM203 who received higher dose with a subset 
of subjects selected from the pool of subjects who received 12mg from baseline in: CS4, 
CS11 or the Japan PMS study.  The matching design will follow the steps and number of 
subjects outlined in the following table: 
Design 
 
232SM203 higher dose 
 
CS4 or CS11 or Japan PMS     
12 mg 
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1) Match 1 to 3 
N= 16  
N= 48 
 
 
 
2) Match 1 to 2 
N= 16  
N= 32 
 
 
 
3) Match 1 to 1 
N= 16  
N=16  
 
2. Higher dose versus 12 mg nusinersen from CS4 and CS11 controlled clinical trials 
L3M6 dosing regimen. 
The matching design will be the same design as the design for comparison 2 but will use a 
smaller pool of patients as Japan PMS patients will not be included.  In this analysis, baseline 
RULM will also be included as a covariate for matching 
 
. 
3. Matching design for comparison 4: higher dose versus CS4 Sham control  
The matching design will be as shown in the table below. In this analysis baseline RULM 
will also be included as a covariate for matching 
.  
Design 
 
232SM203 higher dose 
CS4 Sham 
1) Match 1 to 2 
N= 16 
N= 32 
 
 
 
2) Match 1 to 1 
N= 16 
N= 16 
 
 
 
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5.1.4. Primary Efficacy Endpoints  
N/A 
5.1.5. Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be evaluated for later-onset SMA population 
between 50/28 mg Group and 12/12 mg Group: 
 Change from baseline in Hammersmith Functional Motor Scale – Expanded (HFMSE) 
score 
 Change from baseline in Revised Upper Limb Module (RULM) score 
 Total number of new World Health Organization (WHO) motor milestones 
 Change from baseline in neurofilament light chain (NfL) concentration in plasma 
 Change from baseline in neurofilament light chain (NfL) concentration in CSF 
 Change from baseline in Assessment of Caregiver Experience with Neuromuscular 
Disease (ACEND) 
 Change from baseline in Pediatric Quality of Life Inventory™ (PedsQL) 
 Number and duration of hospitalizations 
 Clinical Global Impression of Change (CGIC) [physician, caregiver] at Day 302 
 Number of serious respiratory events  
 Ventilator use 
 Change in the Parent Assessment of Swallowing Ability (PASA) scale 
 
Analysis Methods for HFMSE 
The HFMSE is a tool used to assess motor function in children >2 years or older with later-onset 
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. The expanded scale includes an additional module of 13 
items developed to alleviate the ceiling effect and allow evaluation of higher functioning and 
ambulatory SMA patients. Each item is scored 0 (unable), 1 (performs with modification or 
adaption) or 2 (able) and the total score is calculated by summing the 33 items and ranges from 0 
to 66 with higher scores indicating greater motor function. If 6 or fewer items are missing, then 
these items will be imputed to 0 when summing all 33 items. If greater than 6 items are missing, 
then the total score will be set to missing.  
Baseline is defined as the last non-missing total score prior to the first dose of nusinersen. 
In order to further explore the response as measured by HFMSE score a number of thresholds 
will be evaluated:  The proportion of subjects achieving: worsening of >= 4, >= 3, >=2, >=1 
points, any worsening, no change (=0 points), any improvement, >=1, >=2, >=3,>=4 points 
improvement will be presented. 
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The main analysis is to compare the change from baseline HFMSE score at Day 302 between 
50/28 mg Group and 12/12 mg Group using an ANCOVA model with treatment group as a 
factor and age at screening, baseline Plasma NfL and baseline HFMSE score as covariates. 
Missing post baseline HFMSE data will be handled using the multiple imputation method. 
Several sensitivities will be performed for change from baseline HFMSE: 
 The main analysis will be repeated using the PPS. 
 The analysis will be performed using a Mixed Effect Model with Repeated Measures 
(MMRM) with an unstructured covariance matrix, where the treatment group, time (as a 
categorical variable), treatment by time interaction, and age at screening, baseline Plasma 
NfL, baseline HFMSE and baseline by time interaction will be included as covariates. No 
imputation for missing visit data will be performed and the analysis will be performed on 
the ITT set. 
 The missing Day 302 values will be imputed by “last observation carried forward”. This 
will be performed on the ITT set. 
 Multiple imputation will be repeated, but for subjects who have a missing Day 302 
assessment due to discontinuation for any reason, the worst of the subjects last observed 
value or the baseline value will be imputed. For subjects who completed but have a 
missing Day 302 value the imputed values will be used. 
In order to further explore the change in HFMSE score during the study and the difference between 
treatment groups the change from baseline to each visit will be analyzed as described for the main 
analysis. A plot of mean change from baseline (based on the estimates from the ANCOVA model) 
over time will be provided by treatment group. 
 
Proportion of subjects achieving>=3 point improvement in HFMSE from baseline at Day 
302: 
The multiple imputation datasets produced for the main analysis will be utilized. If a subject 
terminates the study prior to Day 302 assessment, then the imputed value from the multiple 
imputation will be ignored and the subject will be considered a non-responder. Any subject in the 
ITT Set who has an increase from baseline HFMSE score of 3 or more points at Day 302 will be 
defined as a responder; otherwise, a subject will be considered a non-responder.  Treatment 
groups will be compared using logistic regression adjusting for each subject’s age at screening 
and baseline HFMSE.  
If the logistic regression model does not converge then a Cochran–Mantel–Haenszel test will be 
performed instead.  
Analysis Methods for RULM 
The upper limb module test (Mazzone et al. 2011) was developed to assess the upper limb 
functional abilities in SMA patients using 9 items. However, a revised version of the upper limb 
module test developed by the Upper Limb Module Working Group will be performed in this 
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study consisting of 20 items. The first item is assessed on a seven point scale ranging from 0 – 
“No useful function” to 6 – “Can abduct both arms simultaneously elbows in extension in a full 
circle until they touch above the head”. This first item will not contribute to the total score. For 
the remaining 19 items, 18 items are assessed on a three point scale using the following criteria: 
0 – Unable to achieve independently; 1 – Modified method but achieves goal independent of 
physical assistance from another person; 2 – Normal – achieves goal without any assistance. The 
one remaining item is assessed as either 0 or 1.  For each item, a score will be collected on the 
left and right side. A derived total score will be calculated by summing the scores from these 19 
individual items and ranges from 0 if the subject fails all activities to 37 if the subject achieves 
all activities. If, for an individual item, a response is recorded for both he left and right side the 
highest score will be used in calculating the total.  If 3 or fewer items are still missing responses, 
then it will be assumed that the score was 0. If greater than 3 items are missing, then the total 
score will be set to be missing.  
Baseline is defined as the last non-missing total score prior to the first dose of nusinersen. 
In order to further explore the response as measured by upper limb score a number of thresholds 
will be evaluated:  The proportion of participants achieving worsening of >= 4, >= 3, >=2, >=1 
points, any worsening, no change, any improvement, >=1, >=2, >=3,>=4 points improvement 
will be presented. 
The main analysis is to compare the change from baseline RULM total score at Day 302 between 
50/28 mg Group and 12/12 mg Group using an ANCOVA model with treatment group as a 
factor and age at screening, baseline Plasma NfL and baseline RULM score as covariates. 
Missing post baseline RULM data will be handled using the multiple imputation method.  
Sensitivity analyses as described for the HFMSE will be performed. 
 
Analysis Methods for Total Number of New WHO Motor Milestones 
The WHO motor milestones are a set of six milestones in motor development, all of which 
would be expected to be attained by age 24 months in healthy children. The individual 
milestones are: 
 Sitting without support 
 Standing with assistance 
 Hands and knees crawling 
 Walking with assistance 
 Standing alone 
 Walking alone 
Per the study inclusion criterion number 16, subjects would be expected to all have achieved and 
maintained at baseline the milestone “Sitting without support” but none would have achieved the 
milestone of “Walking alone”. The motor milestones are assessed using the WHO motor 
milestone criteria [WHO Multicentre Growth Reference Study Group 2006]. As part of the 
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assessment, the examiner records an overall rating of the subject’s emotional state and then for 
each milestone one of the following four classifications: 
 No (inability) – Child tried but failed to perform the milestone 
 No (refusal) – Child refused to perform despite being calm and alert 
 Yes – Child was able to perform the milestone 
 Unable to test – Could not be tested because of irritability, drowsiness or sickness. 
Imputation for motor milestones 
If for a milestone either “No (refusal)” or “Unable to test” are observed at a visit, then the result 
will be first set to missing. Imputation will be performed for missing data considering each 
milestone separately using the following rules for scheduled visits. 
For baseline, the closest non-missing milestone prior to or at first dose will be selected. If the 
motor milestone is still missing, then the missing value will be imputed as the median of the non-
missing values of the stratum to which the subject belongs to: Age at screening <6 years or Age 
at screening >=6 years. In the event that the median at baseline is 0.5 then the missing value will 
be imputed as 1. If, for the subject with a missing value at a particular visit the corresponding 
visit is flanked by visits with non-missing milestones, the missing value will be imputed by using 
the worst result from the flanking visits. Otherwise, if the imputation is the last visit, the missing 
value will be imputed as the lowest value observed across all subjects who have a non-missing 
value at this visit within the stratum: Age at screening <6 years or Age at screening >= 6 years 
within the treatment group. Of note, only observed data will be utilized for imputation purposes 
and in situation where unscheduled visit data is available these values will be utilized if these 
flank a missing visit. Missing motor milestone items will be imputed first prior to any analysis. 
Main Analysis 
The main analysis is to compare the total number of new motor milestones achieved at Day 302 
between 50/28 mg Group and 12/12 mg Group, based on the ITT set. Missing data will be 
handled as described above and a total score for each visit calculated by summing the six 
milestones. 
For each milestone the Day 302 and baseline values will be compared and if the subject can 
achieve a new milestone compared to baseline, then it will be counted +1, if the subject is unable 
to achieve the milestone, then it will be scored -1 and if the milestone has been maintained then 
it will be scored 0. These scores will then be summed to give a total score which could range 
between -6 (if a subject was able to perform all milestones at baseline but lost the ability and 
could not perform any milestones at Day 302) and +6 (if a subject was unable to achieve any 
milestones at baseline but could achieve all at Day 302). 
The total number of new milestones achieved by each subject at Day 302 will be compared 
between treatment groups by ANCOVA with treatment group as the factor and subject age at 
screening, baseline Plasma NfL, and baseline number of milestones as covariates.  
The following sensitivity analyses will be performed: 
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 The main analysis will be repeated using the PPS. 
 The analysis will be repeated in the ITT, with an exception to assign the worst of last 
available observation and zero (0) new motor milestones achieved for subjects who 
terminate the study prior to the Day 302 assessment.  
Biomarker 
The baseline for NfL is defined as the last non missing assessment prior to the first dose of study 
treatment. For Plasma NfL, if the baseline is missing and a NF-L result is available post dose at 
Day 1 or Day 2 than the first available assessment post dose, will be used as baseline. 
Values that are BLQ will be set to half of the diluted LLOQ (34.5 pg/mL NfL in CSF and 2.76 
pg/mL for NfL in plasma). 
Neurofilament light chain (NfL) concentration in CSF and in plasma will be analyzed. 
The baseline concentrations and the change (including absolute and ratio to baseline) will be 
presented by visit. 
The analysis is to compare the adjusted mean change from (ratio to) baseline to Day 302 between 
50/28 mg Group and 12/12 mg Group using an ANCOVA model with treatment group as a 
factor and age at screening, baseline CSF/Plasma NFL and baseline HFMSE score as covariates. 
Summary tables and LS-mean plots (±SE) for geometric mean ratio to baseline in NfL in 
CSF/plasma using MI data +ANCOVA. 
 
Spaghetti plots by visit for NfL in CSF/plasma using observed data will be plotted for all 
subjects. 
Analysis Methods for ACEND 
Parents of subjects will complete the Assessment of Caregiver Experience with Neuromuscular 
Disease (ACEND) questionnaire at screening on Day 183 and Day 302. 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 et al. 
2011). 
The ACEND includes a total of seven domains assessing physical impact (including 
feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact 
(including time, emotion, and finance) and each domain comprises several items. The total score 
for a domain with n items, each item assessed on ordinal scale from 1 to z, is derived as follows: 
100 multiplied by (Mean of the n items in the domain -1) divided by (z-1). This total score will 
be on a scale of 0 to 100 with a higher score indicating a greater impact on the caregiver. At least 
two items for the time domain and one item for the remaining domains need to be non-missing 
for a total to be calculated; else the total score will be set to be missing. 
The baseline for ACEND is defined as the last non missing assessment prior to the first dose of 
study treatment. 
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The main analysis is to compare the change from baseline for each domain at Day 302 between 
50/28 mg Group and 12/12 mg Group using an ANCOVA model with treatment group as a 
factor and age at screening, baseline plasma NfL and baseline score as covariates. Missing data 
will be handled using the multiple imputation method.  
Analysis Methods for PedsQL 
Subjects will be evaluated using the Pediatric Quality of Life Inventory (PedsQLTM) 
Measurement 4.0 Generic Core Scales and 3.0 Neuromuscular Module (Vami et al. 1999) at 
screening (the baseline assessment) , Day 183 and Day 302.  
The questionnaires are specific to the age of the subject, and sites are instructed to get both 
subjects and caregivers to complete the same age specific questionnaire as was collected at 
baseline irrespective of whether or not the subjects cross an age boundary at a subsequent visit. 
The PedsQL parent questionnaire is collected for children in the following age categories: 2-4, 5-
7, 8-12. Four dimensions are collected: Physical, Emotional, Social and School functioning and 
each item is scored on a 5 point ordinal scale (0=Never, 1=Almost Never, 2=Sometimes, 
3=Often, 4=Almost Always). The PedsQL patient questionnaire is collected for children in the 
following categories: 5-7, 8-12. Similar dimensions and 5-point ordinal scale are used as for the 
parents but for subjects aged 5-7 years a 3-point ordinal scale is collected, omitting the response 
levels of 1 and 3. 
In the neuromuscular module, one parent questionnaire is collected for all subjects irrespective of 
age with three dimensions: “About my child’s neuromuscular disease”, “Communication” and 
“Family resources”. The same 5-point ordinal scale is collected for each question.  
The patient neuromuscular disease questionnaire is collected for subjects in the following age 
categories: 5-7, 8-12. The questionnaire for subjects aged 5-7 years uses the 3-point ordinal scale 
as above and has only one dimension – “About my Neuromuscular disease”.  
The questionnaires for the remaining two categories cover dimensions for “Communication” and 
“Family resources” and use the 5-point ordinal scale. 
In scoring a dimension the first step is to reverse and linearly transform to a 0-100 scale (0=100, 
1=75, 2=50, 3=25, 4=0), so higher score is indicative of a better health related quality of life. If 
greater than 50 percent of the items within a dimension are missing then the dimension score will 
not be computed, otherwise the mean score for the dimension will be calculated as the sum of 
items over the number of items answered. 
A psychosocial health summary score, constructed from three dimensions, will be calculated as 
the sum of items over the number of items answered in the emotional, social and school 
functioning scales. A total score will be calculated as the sum of all the items over the number of 
items answered on all the scales. If greater than 50 percent of the items are missing, then the 
summary score or total score will be set to be missing. 
For the neuromuscular module, a score for each dimension and then total score will be calculated 
in the same manner, no health summary scores are evaluated.  
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The baseline for PedsQL is defined as the last non missing assessment prior to the first dose of 
study treatment. 
For the generic PedsQL and neuromuscular module, the change from baseline in the total score 
will be presented by visit and treatment group for both the parent and subject assessments. 
Similarly, the changes in the individual dimensions and health summary score will also be 
presented.  
The change from baseline score (each total score and parent/subject evaluation separately) at 
Day 302 50/28 mg Group and 12/12 mg Group will be analyzed using ANCOVA model with 
treatment group as a factor and age at screening, baseline plasma NfL and baseline score as 
covariates. Missing data will be handled using the multiple imputation method. The imputation 
will be performed separately for each dimension and total and psychosocial summary scores. 
Due to the age specific nature of these questionnaires, subjects aged 2-4 years would not be 
expected to complete the self-evaluation and if this is the case then imputations will not be 
performed, and the subjects will be excluded from the analysis.  
5.1.6. Number and Length of Hospitalizations 
If the number of hospitalizations during the study is greater than 5 in total then an analysis will 
be performed as described in the following section using the rate at which they occur, otherwise 
just a listing will be provided.  
For descriptive purposes, the aggregate hospitalization rate will be calculated for each group by 
dividing the total number of hospitalizations that occurred in the group by the total number of 
subject-years on study.  
Annualized hospitalization rate will be calculated for each subject as the number of 
hospitalizations that the subject experienced divided by the number of days on study and this 
ratio multiplied by 365. Annualized hospitalization rate will be analyzed by a negative binomial 
regression model, adjusted for disease duration at Baseline. The logarithmic transformation of 
the time on the study will be included in the model as the “offset” parameter. If the data are 
under dispersed, or if the negative binomial regression model does not converge, a Poisson 
regression model with the same covariate will be used instead of the negative binomial 
regression model. Dispersion will be evaluated from the Pearson chi-squared statistic. 
For each subject, the total time spent in hospital during the study will be calculated and prorated 
according to number of days on study. Based on the prorated time in hospital, treatment groups 
will be compared to an ANCOVA adjusting for each subject’s disease duration at Screening, age 
at symptom onset and baseline Plasma NfL. 
5.1.7. Clinical Global Impression of Change (CGIC) [Physician, Caregiver] at 
Day 302 
CGIC will be assessed at Days 29, 64, 183 and 302.  The CGIC rating scale was developed as a 
brief standalone assessment of the clinician’s view of the patient’s global functioning after 
initiating a study medication [Guy 1976]. The CGIC provides an overall clinician-determined 
summary measure that takes into account all available information, including knowledge of the 
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patient’s history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the patient’s ability to function. The CGIC 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 
the illness, the patient’s level of distress and other aspects of impairment, and the impact of the 
illness on functioning. The CGIC 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 CGIC is a 7-point scale that requires the clinician to assess how much the patient’s illness 
has changed 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.  
CGIC should be assessed consistently by the same rater for each study participant. A separate 
CGIC assessment will be performed by the Investigator (Principal Investigator or Sub 
investigator) and caregiver. 
Clinical Global Impression of Change (CGIC) for the physician and caregiver at Day 302 will be 
analyzed as an ordered categorical score and as a dichotomized response: “much improved” or 
“very much improved” versus other responses.  
The proportion of subjects with each CGIC score and with the dichotomized response of either 
“much improved” or “very much improved” will be summarized by visit and treatment group.  
The difference in CGIC dichotomized response rate between 50/28 mg Group and Control Group 
will be analyzed using a logistic regression model with terms for treatment group and disease 
duration. Participants who die or withdraw from the study, prior Day 302, will be counted as 
‘non responders’. 
The odds ratio, its 95% CI and the p-value for 50/28 mg Group compared to the Control Group 
will be presented. The proportion of CGIC responders at other visits will also be analyzed in a 
similar way. In a situation where the model does not converge then exact logistic regression (Hirji, 
K. F. 2005) will be performed. 
5.1.8. Number of Serious Respiratory Events 
All adverse events that are coded into the System Organ Class (SOC) of respiratory, thoracic, 
and mediastinal disorders, either as their primary SOC will be considered respiratory events. 
Only those classified as serious will be analyzed. By utilizing the above approach, rare 
occurrence of serious respiratory events in the Infection and Infestation SOC and Investigation 
SOC (if any) may not be included. However, a detailed review of the AE listing will be 
conducted to identify such events. 
The number of serious respiratory events during the study will be analyzed using the rate at 
which they occur. For descriptive purposes, the aggregate rate will be calculated for each group 
by dividing the total number of serious respiratory events that occurred in the group by the total 
number of subject-years on study.  
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Annualized serious respiratory event rate will be calculated for each subject as the number of 
serious respiratory events that the subject experienced divided by the number of days on study 
and this ratio multiplied by 365.  
No formal statistical comparison is planned. 
5.1.9. Ventilator Use 
The participant’s ventilator use and respiratory aids will be collected at every study visit. If 
ventilation is used daily, the average number of hours per day for the past 7 days will be 
recorded.  
The ventilation use will be summarized by visit and listed.  
5.1.10. Change in the Parent Assessment of Swallowing Ability Scale (PASA) 
Parent Assessment of Swallowing Ability (PASA) will be assessed using the PASA 
questionnaire. Caregivers will be asked a series of questions regarding the mealtime behavior of 
the participant.  
The PASA questionnaire was developed by a Biogen team in order to assess the signs and 
symptoms of dysphagia. This questionnaire consists of 33 items across 4 domains that cover 
general feeding, drinking liquids, eating solid foods, and assessment of swallowing concerns. 
The first 3 of these domains are generally assessed with 5 levels of response (Never, Rarely, 
Sometimes, Often, and Always), although 2 items are assessed with a simple “Yes”/“No” 
answer. In the final domain, the assessment of swallowing concerns has 4 levels of response: 
Strongly Agree, Agree, Disagree, and Strongly Disagree. In answering each item, the caregiver is 
directed to consider the previous 7 days. 
The number, mean score, and percentage of subjects scoring each category in the PASA Section 
1 – General Feeding will be presented by visit. In addition, a stacked bar chart will be used to 
summarize the proportion of subjects in each category over time for each item. Depending on the 
number of subjects who complete PASA Sections 1,2, 3, and 4, similar presentations may also be 
made or alternatively the results from these visits will be listed. 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.1.12. Subgroup analyses 
Summary statistics by visit for the endpoints of HFMSE, RULM and number of new WHO 
milestones will be presented by age category and by region.  It is not planned to do ANCOVA 
analysis due to the small patient numbers. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
  
 
5.2.   Comparisons to external data 
The following table summarizes the endpoints, group compared, timepoint and analysis method 
where additional supplementary comparisons to the DEVOTE higher dose group will be 
performed: 
 
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Time points 
 
Matched group 
compared 
Analysis 
Plasma NfL 
 
Plasma NfL at Month 6 
PS matched CS4 
Sham  
MI +ANCOVA [Age at first dose, Baseline 
Plasma NfL, Baseline HFMSE] 
 
PS matched 
nusinersen - CS4 
only 
MI +ANCOVA [Age at first dose, Baseline 
Plasma NfL, Baseline HFMSE] 
HFMSE 
Change to Month 9 [Repeated 
for Month 6] 
PS matched CS4 
Sham  
MI +ANCOVA [Age at first dose, Baseline 
Plasma NfL, Baseline HFMSE] 
Change to Month 9 
PS matched 
nusinersen – 
CS4+CS11 
MI +ANCOVA [Age at first dose, Baseline 
HFMSE] 
Change to Month 9 [Repeated 
for Month 6] 
PS matched 
nusinersen – CS4 
only 
MI +ANCOVA [Age at first dose, Baseline 
Plasma N-FL, Baseline HFMSE] 
 
 
 
Change to Month 9 
PS with caliper 
matched nusinersen 
A (Clinical trials and 
PMS) 
MI +ANCOVA [Age at first dose, Baseline 
HFMSE] 
Change to Month 9  
PS with caliper 
matched nusinersen 
B (Clinical trials) 
MI +ANCOVA [Age at first dose, Baseline 
HFMSE] 
Change to Month 9 [Repeated 
for Month 6] 
PS with caliper 
matched CS4 Sham  
 
MI +ANCOVA [Age at first dose, Baseline 
Plasma NfL, Baseline HFMSE] 
Proportion of subjects 
achieving: >=3 point 
improvement from baseline at 
Month 9[Repeated for Month 6] 
PS matched CS4 
Sham  
MI + logistic regression [Age at first dose, 
Baseline Plasma NfL, Baseline HFMSE] 
Proportion of subjects 
achieving: >=3 point 
improvement from baseline at 
Month 9 
PS matched 
nusinersen – 
CS4+CS11 
MI + logistic regression [Age at first dose, 
Baseline HFMSE] 
Proportion of subjects 
PS matched 
MI + logistic regression [Age at first dose, 
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Time points 
 
Matched group 
compared 
Analysis 
achieving: >=3 point 
improvement from baseline at 
Month 9[Repeated for Month 6] 
nusinersen – CS4 
only 
Baseline Plasma NfL and Baseline HFMSE] 
Proportion of subjects 
achieving: >=3 point 
improvement from baseline at 
Month 9 
PS with caliper 
matched nusinersen 
A (Clinical trials and 
PMS) 
MI + logistic regression [Age at first dose, 
Baseline HFMSE] 
Proportion of subjects 
achieving: >=3 point 
improvement from baseline at 
Month 9  
PS with caliper 
matched nusinersen 
B (Clinical trials) 
MI + logistic regression [Age at first dose, 
Baseline HFMSE] 
Proportion of subjects 
achieving: >=3 point 
improvement from baseline at 
Month 9[Repeated for Month 6] 
PS with caliper 
matched CS4 Sham  
 
MI + logistic regression [Age at first dose, 
Baseline Plasma NfL, Baseline HFMSE] 
RULM 
 
 
Change to Month 9 [Repeated 
for Month 6] 
PS matched CS4 
Sham  
MI +ANCOVA [Age at first dose, Baseline 
Plasma NfL, Baseline RULM] 
 
 
 
Change to Month 9 
PS matched 
nusinersen – 
CS4+CS11 
MI +ANCOVA [Age at first dose, Baseline 
RULM] 
 
 
 
Change to Month 9 [Repeated 
for Month 6] 
PS matched 
nusinersen – CS4 
only 
MI +ANCOVA [Age at first dose, Baseline 
Plasma NfL, Baseline RULM] 
 
 
 
 
 
Change to Month 9  
PS with caliper 
matched nusinersen 
B (Clinical trials) 
MI +ANCOVA [Age at first dose, Baseline 
RULM] 
Change to Month 9 [Repeated 
for Month 6] 
 
PS with caliper 
matched CS4 Sham  
 
MI +ANCOVA [Age at first dose, Baseline 
Plasma NfL, Baseline RULM] 
Total number of new WHO motor milestones 
 
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Time points 
 
Matched group 
compared 
Analysis 
 
Change to Month 9 [Repeated 
for Month 6] 
PS matched CS4 
Sham  
 
ANCOVA [Age at first dose, Baseline 
plasma NfL, Baseline number of WHO 
milestones] 
Change to Month 9  
PS matched 
nusinersen – 
CS4+CS11 
 
ANCOVA [Age at first dose, Baseline 
number of WHO milestones] 
Change to Month 9 [Repeated 
for Month 6] 
PS matched 
nusinersen – CS4 
only 
 
ANCOVA [Age at first dose, Baseline 
plasma NfL, Baseline number of WHO 
milestones 
Change to Month 9  
PS with caliper 
matched nusinersen 
B (Clinical trials) 
ANCOVA [Age at first dose, Baseline 
number of WHO milestones] 
Change to Month 9 [Repeated 
for Month 6] 
PS with caliper 
matched CS4 Sham  
 
ANCOVA [Age at first dose, Baseline 
number of WHO milestones] 
Square brackets in the 3rd column denotes the covariates to include in the ANCOVA/Logistic 
regression model.  If analysis is also using multiple imputation, then these covariates will be 
included in the imputation step. 
 
6. 
Safety Endpoints 
The analysis of safety will be performed using the Safety Set.  The main analysis will be to 
compare the two arms of 232SM203.  Presentations will also be included for AEs, SAEs and 
related AEs comparing sham from the matched CS4 Sham to the 232SM203 higher dose arm.  
AEs will be analyzed based on the principle of treatment emergence where treatment emergence 
will be relative to the first dose of nusinersen. An AE will be regarded as treatment-emergent if it 
was present prior to receiving the first dose of nusinersen and subsequently worsened in severity 
or was not present prior to receiving the first dose of nusinersen but subsequently appear. Refer 
to Appendix A for more details about AE with missing start or stop dates.  
A participant having the same AE preferred term more than once will be counted only once in 
the incidence for that event. Multiple occurrences of the same adverse event for the same subject 
will all be counted in the frequency for that adverse event. 
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The occurrence of the AE with the greatest severity will be used in the calculation of incidence 
by severity.  The AE relationship to treatment or LP/sham procedure is captured as related or not 
related. In the event the relationship is missing then this will be considered related.  
Due to the long half-life of nusinersen, analyses of treatment-emergent adverse events will 
include all events reported during the study. Adverse Events will be coded using the Medical 
Dictionary for Regulatory Activities.  
The following presentations will be shown:  
 an overall summary showing, for each treatment group, the number and percentage of 
subjects with an adverse event, a mild, moderate or severe event, an event related to 
study drug, an event related to lumbar puncture /sham procedure, a serious event, a 
serious event related to study drug, an event leading to study drug withdrawal, an 
event leading to study withdrawal, and a fatal event. 
 incidence and frequency by system organ class and preferred term  
 incidence and frequency by preferred term  
 incidence and frequency, by preferred term, in at least 2 subjects in any treatment 
group 
 incidence of adverse events by maximum severity by preferred term  
 incidence and frequency of severe events by system organ class and preferred term  
 incidence and frequency of events related to study drug by system organ class and 
preferred term  
 incidence and frequency of events related to lumbar puncture /sham procedure (as 
assessed by the investigator) by system organ class and preferred term 
 incidence by system organ class and preferred term that occurred within 24 hours of 
Dosing or Sham Procedure 
 incidence by system organ class and preferred term that occurred within 72 hours of 
Dosing or Sham Procedure 
 incidence and frequency of serious adverse events by system organ class and 
preferred term  
 incidence and frequency of serious adverse events related to study drug by system 
organ class and preferred term  
 incidence of events that led to fatal outcome 
 incidence of events leading to study drug withdrawal by system organ class and 
preferred term  
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 incidence of events leading to withdrawal from study by system organ class and 
preferred term   
 incidence and frequency of adverse events over time by system organ class and 
preferred term.  
 incidence and frequency of adverse events antibody status by system organ class and 
preferred term.  
A separate table will also be presented to show an overall summary of COVID-19 pandemic 
related AEs. 
Listings of the following events will be produced.  
 AEs 
 SAEs  
 AE with fatal outcome 
 AEs led to study drug withdrawal   
 AEs led to withdrawal from study  
 AEs related to lumbar puncture/sham procedure  
 AEs related to study drug 
Follow-up adjusted incidence rate  
Follow-up adjusted incidence rate will be summarized by system organ class and preferred term 
by study group. Follow-up adjusted incidence rate, defined as the number of subjects who 
experienced an event divided by the total of entire follow-up time among the subjects in the 
analysis population. The entire follow-up time for subject is defined as the time from the first 
dose until the end of study day. Each subject will be counted only once within each category. A 
similar table will also be based on total number of events divided by the total of entire follow-up 
time among the subjects in the analysis population. This may count a subject more than once 
within each category if they experienced an event more than once.  
Note on capture of severity and seriousness in CS4  
In CS4 the eCRF captured detail for each investigator term for decreases in severity and changes 
from serious to non-serious. In 232SM203, the decrease in severity and change from serious to 
non-serious is not captured.  In all studies worsening in severity and moving from non-serious to 
serious is captured. 
In presenting CS4 as part of 232SM203 reporting, consistent with how these studies were 
originally reported in the following two scenarios: 
1) where the severity decreases 
2) where a serious event becomes non-serious  
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Only the first record will be considered treatment emergent so the actual reporting approach will 
be consistent with 232SM203.  
6.1.1. Concomitant therapy and Procedure 
A concomitant therapy is any drug or substance administered between screening and the final 
study visit/telephone call. Participants are instructed to contact their Investigators before taking 
any new medications, including nonprescription drugs and herbal preparations. 
Throughout the study, Investigators or designated licensed physicians involved in the study may 
prescribe concomitant therapies (procedures) or treatments deemed necessary for AEs or to 
provide adequate supportive care. 
Participants are prohibited from receiving other experimental or approved agents for the 
treatment of SMA, including gene therapy, biological agent, or device, during the study. This 
includes marketed agents at experimental doses that are being tested for the treatment of SMA 
(oral albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea, 
etc.). 
All concomitant therapies will be coded using the World Health Organization drug 
dictionary (WHO Drug). A concomitant procedure is any therapeutic intervention (e.g., 
surgery/biopsy, physical therapy) or diagnostic assessment (e.g., blood gas measurement, 
bacterial cultures) performed between Screening and the final study visit/telephone call. 
Concomitant procedures will be coded using MedDRA. 
For the purposes of analysis, a concomitant therapy (including medication or procedure) is 
defined as any therapy that was taken or administered on or after the first injection of nusinersen. 
(appendix A). This includes therapies and procedures that were started prior to the initiation of 
injection of nusinersen if their use continued on or after the first injection of nusinersen. The 
number and percentage of subjects who were taking each type of concomitant therapy and 
procedures at baseline and during the study will be presented by preferred term. 
The number and percentage of subjects who underwent each type of concomitant procedure 
during the study will be presented.  
Concomitant therapies related to LP/Sham procedure will be summarized separately.   
If there are a sufficient number of tests or treatments reported with indication of COVID-19, a 
separate summary of these will be provided.  
Concomitant medications will also be reviewed by a medical reviewer prior to the lock to 
determine disallowed medications according to the protocol. These will be summarized 
separately. 
6.1.2. Clinical laboratory data 
Laboratory data will be evaluated to determine the incidence of abnormalities that emerge during 
the course of the study. Changes in laboratory evaluations will be presented relative to baseline, 
which is defined as the closest visit prior to the first dose. 
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The following clinical laboratory parameters are to be assessed: 
 Hematology panel: complete blood count with differential and platelet count 
(hematocrit, hemoglobin, platelets, red blood cell count [RBC], white blood cell 
count [WBC], basophils, eosinophils, lymphocytes, monocytes, neutrophils) 
 Blood chemistry panel: albumin, total bilirubin, direct and indirect bilirubin, alkaline 
phosphatase, alanine aminotransferase (ALT) (SGPT), aspartate aminotransferase 
(AST) (SGOT), gamma-glutamyl transferase (GGT), sodium, potassium, calcium, 
chloride, phosphate, blood urea nitrogen (BUN), creatinine, cystatin, creatine 
phosphokinase, creatine kinase, bicarbonate (CO2), glucose, total protein. 
 Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, blood, red blood 
cells, white blood cells, epithelial cells, bacteria, casts and crystals 
 Urine total protein assessed by local laboratories CSF analysis: RBC, WBC, protein, 
glucose.  
 Coagulation: PT (prothrombin time), aPTT (activated partial thromboplastin time), 
and INR (international normalized ratio).  
Each hematology, blood chemistry, coagulation and CSF laboratory parameter will be flagged as 
“low”, “normal” or “high” relative to the parameter’s normal range or as “unknown” if no result 
is available. 
For each urinalysis laboratory parameter, the number and percentage of subjects experiencing 
postdose shifts to abnormal will be summarized.  
For each hematology, blood chemistry, coagulation and CSF parameter, the number and 
percentage of subjects experiencing postdose shifts to ‘low’ or ‘high’ will be summarized. In 
each summary, the denominator for the percentage is the number of subjects at risk for the shift. 
The number at risk for the shift to low is the number of subjects whose baseline value was not 
low and who had at least one post baseline value. The number at risk for the shift to high is the 
number of subjects whose baseline value was not high and who had at least one-post baseline 
value. Subjects will be counted only once for each parameter and each shift regardless of how 
many postdosing assessments had that type of shift. All post baseline data will be used in the 
shift tables, regardless of whether a scheduled or unscheduled visit.  
Also, for each parameter, the incidence of shift to low will be summarized using the minimum 
post baseline values. Shift to low includes subjects with a normal, high, or unknown baseline 
value and at least one post baseline value of the given test. Similarly, the incidence of shift to 
high will be summarized using the maximum post baseline values. Shift to high includes subjects 
with a low, normal, or unknown baseline value and at least one post baseline value. 
To evaluate potential serious hepatotoxicity subjects with a post baseline AST and/or ALT value 
≥3 times the upper limit of normal (ULN) and a post baseline bilirubin value >2 times ULN at 
any time, not necessarily concurrent, will be listed with their values. In addition, a plot will be 
presented with each subject’s maximum post baseline AST or ALT value relative to the ULN 
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against the subject’s maximum post baseline bilirubin value relative to the ULN; values do not 
have to be concurrent. All post baseline data will be used to identify abnormalities, regardless of 
whether a scheduled or unscheduled visit. 
Summary statistics for actual values and change from baseline in laboratory values will be 
summarized by treatment group and visit. Box plots for chemistry, hematology and CSF showing 
mean value for each treatment group at each visit will also be presented.  
Due to the impact of the COVID-19 pandemic on transport infrastructure, public health or 
humanitarian emergencies, certain sites may only be able to test blood and urine samples at a 
local laboratory instead of central one.  The use of local labs which will use different 
techniques/equipment and reference ranges may introduce variability in the results.  
To assess the variability of the results two summaries will be presented for actual and change 
from baseline by visit: 
 summarize local laboratory and central laboratory results together  
 summarize only central laboratory results 
Listings of all chemistry, hematology, coagulation, CSF, urinalysis values and pregnancy test 
(serum and urine) will be provided.  
For platelets a summary of the proportion of participants with a post baseline platelet count 
below the lower limit of normal on at least 2 consecutive measurements will be presented. 
For study 232SM203, the urine protein positive (trace, +1, +2, +3, +4 or >0.2g/L) results will be 
presented, number of subjects with positive result at baseline, with a negative result at baseline 
and at least one and at least two positive post baseline result respectively.   
6.1.3. Neurological Examinations   
Neurological examinations include assessment of mental status, level of consciousness, cranial 
nerves, reflexes, motor system, coordination/cerebellar function and sensation – temperature and 
vibration. These are to be assessed at Screening, predose and at 3, 6, and 24 hours postdose on 
dosing Days 1, 15, predose and at 1 and 3 hours postdose on Days 29, 64, 135, 183, and 279; and 
at Day 302/ET. 
 
The results collected for the majority of the tests are classified as ‘normal’ or ‘abnormal’, 
however the assessment of sensations is reported as ‘present’ or ‘absent’ and the assessment of 
reflexes is captured on an ordinal scale. For each test it is recorded if secondary to SMA. 
Acute Effects After Dosing: Reflex assessments 
On each dosing day, each predose reflex will be compared with all the post dosing assessments 
with 24 hours to see if the subject has changed (gained or lost) or maintained, reflexes. For this 
comparison the predose reflex status will be categorized into two categories: 0 and >=1. For each 
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reflex, visit, predose category the number and proportion of subjects who change or maintained 
will be presented. 
Acute Effects After Dosing: Other assessments with binary response (Normal/Abnormal) 
On each dosing day, the shifts from predose assessment on that day to postdose (i.e., from 
predose to 3, 6 and 24 hours postdose) will be determined. For each test and post dosing time 
point, the number and proportion of subjects who moved from ‘Normal’ to ‘Abnormal’ will be 
presented, for sensations the number and proportion who move from ‘Present’ to ‘Absent’ will 
be presented.  
Chronic effects: Reflex assessments 
For each reflex the baseline reflex will be compared (the predose value on Day 1) to the pre dose 
value on later dosing days (Day 1, 15, 29, 64, 135,183, 279 and on Day 302/ET)  to see if the 
subject has changed (gained or lost) or maintained, reflexes. For this comparison the predose 
reflex status will be categorized into two categories: 0 and >=1. For each reflex, visit, predose 
category the number and proportion of subjects who change or maintained will be presented. 
Chronic effects: Other assessments with binary response (Normal/Abnormal) 
For each test the shift from baseline to (the predose value on Day 1) the predose value on later 
dosing days ( Day 1, 15, 29, 64, 135,183, 279 and on Day 302/ET )to determine, the number and 
proportion of subjects who moved from ‘Normal’ to ‘Abnormal’ will be presented, for sensations 
the number and proportion who move from ‘Present’ to ‘Absent’ will be presented. 
Figures of subjects neurological exams will also presented.  
6.1.4. ECG 
ECGs are to be recorded at Days 1, 15, 29, 64, 135, 183, 279 and 302/ET, predose and post 
dosing at various time points on dosing days and end predose at 302/ET. The ECGs are assessed 
at a central reading laboratory and the results provided as external vendor data. On the eCRF the 
investigator interpretation is collected as normal, abnormal and abnormal AE and the 
investigator determination will be used in analyses. 
The ECG test includes heart rate, QT interval, QTcF interval and RR interval. Summary statistics 
for actual values and change from baseline in each ECG parameter will be presented by 
treatment group and visit.  
ECGs will be analyzed using two approaches. 
Qualitative analysis 
The determination of whether an ECG is abnormal not AE, abnormal AE made by the 
Investigator will be used for this qualitative analysis. 
The number and percentage of subjects with shifts from normal to each of the categorical values 
denoting an abnormal scan (abnormal not AE, abnormal AE) will be summarized by treatment 
group. All post baseline data will be used to identify abnormalities, regardless of whether a 
scheduled or unscheduled visit.  
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Corrected Fridericia QT interval QTcF abnormalities (outliers) 
QTcF will be examined to determine the incidence of clinically relevant abnormalities. The 
number of subjects evaluated and the number of subjects with clinically relevant abnormalities 
will be presented. 
The first criteria for clinically relevant post dosing abnormalities (secondary safety endpoint) that 
will be considered is: 
 Post baseline QTcF of > 500 msec and Maximum increase from baseline to post 
baseline QTcF >60 msec 
Other criteria are:  
 Maximum increase from baseline QTcF > 30 to 60 msec  
 Maximum increase from baseline QTcF > 60 msec  
 Maximum post baseline QTcF > 480 to 500 msec  
 Maximum post baseline QTcF > 500 msec  
ECG summaries will be presented for all subjects and for subjects with post baseline. Listings 
will include both the central and eCRF information. 
6.1.5. Vital Signs 
The analysis of vital signs will be approached in two ways. 
Vital signs are to be measured at Screening, predose and at 1, 2, 4, 6, and 24 hours postdose on 
dosing Days 1, 15, predose at 1 and 6 hours postdose on Days 29, 64, 135, 183, and 279 and on 
Day 302/ET At each of these times, temperature, heart rate, respiratory rate, systolic and 
diastolic blood pressure, and pulse oximetry will be measured.  
Acute Effects After Dosing  
On each dosing day, the change in each vital sign from predose on that day to postdose (i.e., 
from predose to 1 hour postdose, to 2 hours postdose, etc.) will be calculated. Summaries of 
actual values and change from predose for each dosing day will be presented.  
Chronic Effects  
To examine for possible chronic effects, the change from baseline (the predose value on Day 1) 
to the predose value on later dosing days and to Day 302/ET will be determined. Summaries of 
actual values and change from baseline for subsequent dosing days (Days 15, 29, 64,135, 183, 
and 279) and for Day 302/ET will be presented. 
Vital signs (temperature, pulse, systolic and diastolic blood pressure and pulse oximetry) will 
also be examined to determine the incidence of potentially clinically relevant abnormalities.  
Shift analysis 
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The number of subjects evaluated and the number of subjects with potentially clinically relevant 
abnormalities will be presented. All post baseline data will be used to identify abnormalities, 
regardless of whether a scheduled or unscheduled visit. The criteria for potentially clinically 
relevant postdose abnormalities are shown in Table 6 below: 
Table 6: Criteria to determine potentially clinically relevant abnormalities in vital signs. 
 
Vital Sign 
Criteria for Abnormalities 
Temperature 
<36°C 
>38°C  
Pulse 
<60 bpm 
>100 bpm 
Systolic Blood Pressure 
<90 mmHg 
>140 mmHg 
>160 mmHg 
 
Diastolic Blood Pressure 
<50 mmHg 
>90 mmHg 
>100 mmHg 
  
Weight 
7% or more decrease from baseline 
7% or more increase from baseline 
Respiratory Rate 
<12 breaths/min 
>20 breaths/min 
 
6.1.6. Growth parameters 
Growth parameters include weight for age, and ulnar length.  
The growth parameters are to be assessed during screening, on dosing days (Days 1, 15, 29, 64, 
135, 183 and 279) and on Day 302/ET. 
The 2000 CDC Growth Charts (ages 2 to <20 years) will be used to assess the weight change for 
older subjects. The National Center for Health Statistics provides a SAS macro which can be 
downloaded from their website [https://www.cdc.gov/growthcharts/clinicalcharts.htm] and this 
will be utilized to calculate the weight for age percentiles for each participant in the later onset 
population. 
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Summary statistics for actual values and change from baseline in each growth parameter will be 
presented by treatment group and visit. 
Baseline growth parameters will be summarized and also the frequency and percentage for 
weight and height for age will also be presented for each of in the following categories: ≤ 1st, ≤ 
3rd, ≤5th, ≤15th, ≤25th, ≤50th and > 50th percentile.  
6.1.7. LP opening pressure 
LP opening pressure will only be measured at Days 1, 15, and 279 to avoid potential unblinding. 
A lack of published data exists in terms of the variability of opening pressure between and within 
subjects. It is suspected that a simple change in position of a subject during the measurement or 
change of instrument used contributes to variability in the measurement.  
The actual value and change from baseline to each visit will be summarized by treatment groups 
all the data collected will be listed.  
6.1.8. X-ray Examination of Spine 
The X-rays will be used to determine the severity of scoliosis by measuring the Cobb angle in 
the later-onset SMA subjects. The spine X-ray is performed at screening with the participant in a 
sitting or supported sitting position following an image acquisition guideline. Summary and 
listing of baseline Cobb angle will be presented.  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
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• 
 
  
• 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
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9. 
Pharmacodynamic Endpoints 
As detailed earlier NfL is defined as a secondary endpoint. 
 
 In addition, plasma and CSF PK 
concentrations will be analyzed with plasma and CSF biomarkers to establish PK/PD correlation. 
PK/PD and exposure-response may also be conducted on efficacy. The results of this study may 
be combined with other nusinersen studies to perform population PK/PD analyses, including 
exposure-response analysis.  
10. Other Analyses 
Not applicable. 
11. Statistical Considerations for Interim Analysis 
Not applicable 
12. Changes from Protocol-Specified Analyses 
Added NF-L as a secondary endpoint. 
13. Summary of Changes from the Previous Version of the SAP 
14. 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. 
 
 
 
Berry JD, Miller R, Moore DH, et al. The Combined Assessment of Function and Survival 
(CAFS): a new endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal 
Degener. 2013;14(3):162-8. Epub 2013/01/17. 
Bohdana Ratitch, Ilya Lipkovich, Michael O'Kelly. Combining Analysis Results from Multiply 
Imputed Categorical Data. PharmaSUG 2013 - Paper SP03. 
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. 
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De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular 
atrophy. Neuromuscul Disord. 2016;26(11):754-759. Epub 2016/10/05. 
Elizabeth A. Stuart. "Matching Methods for Causal Inference: A Review and a Look Forward." 
Statistical Science, 25(1) 1-21 February 2010 
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. 
Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: 
Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ 
systems; and ethics. Neuromuscul Disord. 2017 Epub 2017/11/23. 
Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: 
Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ 
systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207. Epub 2017/11/23. 
Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical 
trials. Stat Med 1999; 18 (11):1341-54.f 
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. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. 
Department of Health, Education, and Welfare; 1976. 
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. 
Hirji, K. F. (2005).  Exact Analysis of Discrete Data. Boca Raton: Chapman and Hall. 
ICH E9 (R1) Addendum 2017 
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. 
 
 
 
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. 
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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. 
Little RJA, Rubin DB. Statistical Analysis with Missing Data. 2 nd ed. New York: John Wiley & 
Sons, Inc; 2002. 
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. 
 
 
Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: 
Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. 
Neuromuscul Disord. 2018;28(2):103-115. Epub 2017/11/23. 
 
 
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. 
Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat. 2017;16(1):20-
28. Epub 2016/08/15. 
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. 
Rosenbaum 2010, Design of Observational Studies 
 
 
Santner TJ, Snell MK. Small-Sample Confidence Intervals for p 1 - p 2 and p 1 /p 2 in 2 × 2 
Contingency Tables. J Am Statist Assoc. 1980;75:386-94. 
Schafer JL. Analysis of Incomplete Multivariate Data. 1 ed. London: Chapman & Hall/CRC 
Press; 1997. 430 p.  
Schafer JL. Multiple imputation: a primer. Stat Methods Med Res. 1999;8(1):3-15 
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Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
inventory. Med Care. 1999;37(2):126-39. 
WHO Multicentre Growth Reference Study Group. Assessment of differences in linear growth 
among populations in the WHO Multicentre Growth Reference Study. Acta Paediatr Suppl. 
2006;450:56-65. 
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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15. APPENDICES 
APPENDIX A. 
i 
Seeds for MI 
Table 9: Seeds used for each endpoint in MI for Later-Onset SMA population 
Endpoint 
Seed 
HFMSE 
25980495 
RULM 
47886416 
NfL in plasma 
7953683 
NfL in CSF 
4711630 
PedsQL  
12676424 
ACEND 
 
68757534 
 
ii 
Adverse Events 
In the situation where worsening in severity (including seriousness) occurs for an adverse event, 
study sites are instructed to enter an end date and start a new record for the adverse event. In the 
new record, the changed severity is to be recorded and the start date will be set to be the end date 
of the previous record. Data linking those records are collected in the data base. Consider three 
scenarios:  
 The first AE record occurs prior to the first dose, the second AE record occurs on or after 
the first dose, and the severity increases: Only the second record will be counted as 
treatment-emergent.  
 Both records occur on or after the first dose: If the AE severity on the second record is 
worse than the severity on the first record, then count both records as treatment-emergent. 
 Both records occur on or after the first dose: If the AE one is severe and the other serious 
then count both records as treatment-emergent. 
Of note, when counting the total number of treatment-emergent events, events linked through 
change in severity will still be counted as separate events. 
For events with missing start or stop dates, the following criteria will be used for the purpose of 
identifying treatment-emergent adverse events:  
 If both the start and stop date for a particular event are missing, then the event is 
considered to have occurred on or after the first dose of study treatment. 
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
If the start date for a particular event is missing and the stop date/time falls after the
first dose date/time, then the event is considered to have occurred on or after the first
dose of study treatment.

If the start time is missing and the start date is same as the first dosing date, then the
event is considered to have occurred on or after the first dose of study treatment.

If it cannot be determined whether or not an event has occurred on or after dosing due
to a missing or partial date, then the event will be assumed to have occurred on or
after the first dose for the purpose of identifying treatment-emergent adverse events.
Specifically, let AESTDT denote the start date of an adverse event and TRTSTDT be the start 
date of study treatment. For the purpose of identifying the treatment emergent adverse events, the 
following algorithm will be used for the imputation of missing or partial date: 

If AESTDT is completely missing or the year is missing, then impute AESTDT to
TRTSTDT.

If, in AESTDT, year is present and month/day are missing and year is equal to the
year portion of TRTSTDT, then impute the month/day portion of AESTDT to the
month/day portion of TRTSTDT.

If, in AESTDT, year is present and month/day are missing and year is not equal to the
year portion of TRTSTDT, then impute the month/day portion of AESTDT to
January 01.

Consider the situation in AESTDT where year and month are present with only day
missing. If the year and month are the same as those for TRTSTDT, then impute day
in AESTDT with day in TRTSTDT. Otherwise, impute the day in AESTDT with the
first day of the month.
It is important to emphasize that the imputed date will not be used for calculations such as onset 
and duration of an adverse event.  
iii 
Concomitant Therapy and Procedure 
In order to define concomitant therapies with missing start or stop dates, the following additional 
criteria will be used: 

If both the start and stop dates of a particular therapy were missing, that therapy is
considered concomitant.

If the start date of a therapy was missing and the stop date of that therapy fell on or after
the date of dosing, that therapy is considered concomitant.

If the start date of a therapy was prior to the date of dosing and the stop date of that
therapy was missing and the therapy was listed as continuing, that therapy is considered
concomitant.
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 If the start date of a therapy was prior to the date of dosing and the stop date of that 
therapy was missing and the therapy was listed as not continuing, that therapy is 
considered concomitant.  
 If the start/stop date of a therapy is partial then where it is not possible to rule out that it 
was not taken concomitantly it will be considered concomitant. 
Denote the end date of medications as CMENDT and the study treatment start date as 
TRTSTDT. The medication is classified concomitant provided any of the following is NOT true: 
 CMENDT is complete and CMENDT is less than TRTSTDT. 
 Day of CMENDT missing and year/month of CMENDT is strictly before year-month of 
TRTSTDT. 
 Month of CMENDT is missing and year of CMENDT is strictly before year of 
TRTSTDT. 
 
 
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Statistical Analysis Plan 
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Page 1 
PART C STATISTICAL ANALYSIS PLAN 
Version No.: 1.0 
Date: 06 October 2023 
 Author: 
 
Study Title:  
Escalating Dose and Randomized, Controlled Study of Nusinersen 
(BIIB058) in Participants With Spinal Muscular Atrophy 
Name of Study Treatment: Nusinersen 
Protocol No.: 232SM203 
Study Phase: 2/3 
Confidential Information 
The information contained in this Statistical Analysis Plan (SAP) is confidential and may not be 
reproduced or otherwise disseminated without the approval of Biogen, Inc.   
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APPROVAL 
This document has been reviewed and approved by: 
 
SMT Statistician 
Signature 
Date 
 
Program Statistician 
Date 
 
SMT Medical Director 
Date 
VERSION HISTORY 
SAP Version 
Date 
Primary Reasons for 
Amendment 
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Statistical Analysis Plan 
Version: 1.0 Final 
Page 3 
Table of Contents 
PART C STATISTICAL ANALYSIS PLAN ................................................................... 1 
APPROVAL ...................................................................................................................... 2 
VERSION HISTORY ........................................................................................................ 2 
Table of Contents ............................................................................................................... 3 
LIST OF ABBREVIATIONS ............................................................................................ 5 
1.
Introduction ..................................................................................................... 8 
2.
Study Overview ............................................................................................... 9 
2.1. 
Study Objectives and Endpoints ................................................................................... 9 
2.2. 
Study Design............................................................................................................... 10 
2.3. 
Sample Size Considerations ....................................................................................... 11 
2.4. 
General Trial Conduct Mitigation Strategy under COVID-19 Pandemic or 
humanitarian emergencies ......................................................................................................... 11 
3.
Definitions ..................................................................................................... 12 
3.1. 
Dates and Points of Reference .................................................................................... 12 
3.2. 
Study Treatment ......................................................................................................... 13 
3.3. 
Study Groups .............................................................................................................. 13 
3.4. 
Study Periods .............................................................................................................. 13 
3.5. 
Key Derived Variables ............................................................................................... 14 
3.6. 
Stratification Factors and Subgroup Variables ........................................................... 14 
3.6.1. 
Stratification Factors ............................................................................................... 14 
3.6.2. 
Subgroup Variables ................................................................................................. 14 
3.7. 
Analysis Sets............................................................................................................... 14 
4.
List of Planned Study Analyses ..................................................................... 14 
4.1. 
Interim Analysis ......................................................................................................... 14 
4.2. 
Primary Analysis ........................................................................................................ 15 
4.3. 
Final Analysis ............................................................................................................. 15 
5.
Statistics Methods for Planned Analyses ....................................................... 15 
5.1. 
General Principles ....................................................................................................... 15 
5.2. 
Participant Accountability .......................................................................................... 16 
5.3. 
Demographic and Baseline Characteristics ................................................................ 16 
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5.4. 
Protocol Deviations .................................................................................................... 17 
5.5. 
Study Treatment Exposure and Concomitant Medications ........................................ 17 
5.6. 
Efficacy Endpoints ..................................................................................................... 18 
5.6.1. 
General Analysis Methods for Efficacy Endpoints ................................................ 18 
5.6.2. 
Imputation ............................................................................................................... 19 
5.6.3. 
Primary Efficacy Endpoints .................................................................................... 20 
5.6.4. 
Secondary Efficacy Endpoints ................................................................................ 20 
29 
5.7. 
Safety Endpoints ......................................................................................................... 34 
5.7.1. 
Adverse events ........................................................................................................ 35 
5.7.2. 
Clinical laboratory data ........................................................................................... 36 
5.7.3. 
Neurological Examinations ..................................................................................... 38 
5.7.4. 
ECG......................................................................................................................... 39 
5.7.5. 
Vital Signs ............................................................................................................... 40 
5.7.6. 
Growth parameters .................................................................................................. 42 
 
 42 
5.7.8. 
LP opening pressure ................................................................................................ 42 
5.7.9. 
X-ray Examination of Spine ................................................................................... 43 
43 
43 
45 
5.8. 
Other Analyses ........................................................................................................... 47 
5.9. 
Statistical Considerations for Interim Analysis .......................................................... 47 
6.
Changes from Protocol-Specified Analyses .................................................. 47 
7.
Summary of Changes from the Previous Version of the SAP ....................... 47 
8.
References ..................................................................................................... 47 
9.
APPENDICES ............................................................................................... 49
APPENDIX A. Derivation of the dates ........................................................................... 49 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
  
 
aPTT 
activated partial thromboplastin time 
ACEND Assessment of 
Caregiver Experience with 
Neuromuscular Disease 
Assessment of Caregiver Experience with Neuromuscular 
Disease 
 
 
AE  
Adverse event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
BLQ 
Below limit of quantification 
BUN 
blood urea nitrogen 
CGIC 
Clinical Global Impression of Change 
CHOP INTEND  
Children’s Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders 
  
 
CO2 
bicarbonate 
COVID-19  
Coronavirus disease 2019 
CSF  
Cerebrospinal fluid 
CV 
Coefficient of variance 
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ECG   
Electrocardiogram 
eCRF  
electronic Case report form 
 
 
GGT 
gamma-glutamyl transferase 
HFMSE   
Hammersmith Functional Motor Scale – Expanded 
HINE   
Hammersmith Infant Neurological Examination 
HRQOL   
Health-related quality of life 
ICH   
International Council for Harmonization 
INR 
International normalized ratio 
 
 
IRT  
Interactive response technology 
ITT   
Intent-to-Treat 
LLOQ 
lower limit of quantification 
LP   
Lumbar puncture 
MET 
Metabolic equivalent task 
   
 
   
 
PT 
prothrombin time 
PedsQL   
Pediatric Quality of Life Inventory™ 
PK   
Pharmacokinetic(s) 
PPS 
Per protocol Set 
QoL  
Quality-of-life 
QTcF  
Corrected QT interval using Fridericia’s formula 
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Page 7 
 
 
RULM   
Revised Upper Limb Module 
SAE   
Serious adverse event 
SD 
Standard deviation 
SE 
Standard error 
SMA 
Spinal muscular atrophy 
 
 
SMN  
Survival motor neuron 
SMN1  
Survival motor neuron 1 
SMN2  
Survival motor neuron 2 
SOC 
System Organ Class 
ULN 
upper limit of normal 
 
 
WHO 
World Health Organization 
 
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1. Introduction 
This Statistical Analysis Plan is based on Version 6 of the protocol, dated 05May2022. All 
references to the protocol refer to Version 6. 
 
Nusinersen is an antisense oligonucleotide administered intrathecally via lumbar puncture (LP); it 
increases survival motor neuron (SMN) protein expression and significantly improves motor 
function in patients with spinal muscular atrophy (SMA). Nusinersen was approved for the 
treatment of SMA under the tradename Spinraza™ in the United States (US), European Union, 
and other countries. The population for this study includes participants with infantile-onset and 
later-onset SMA.  
Efficacy and safety results across the nusinersen clinical development program have demonstrated 
an overall positive benefit-risk profile of nusinersen across a broad range of SMA phenotypes and 
patient populations. Nusinersen is approved in the US, Europe, and other countries and regions for 
the treatment of SMA in paediatric and adult patients at a recommended dosage of 12 mg 
administered in 3 loading doses at 14-day intervals, a fourth loading dose 30 days after the third 
dose, and maintenance doses every 4 months thereafter in most countries and regions. 
Pharmacokinetic (PK) and pharmacodynamic (PD) analyses indicate that nusinersen drug 
exposure higher than that achieved with 12 mg in patients with SMA may produce an even greater 
benefit in motor function. Additionally, PK modelling and simulations identified dosing regimens 
that achieve higher drug exposure more rapidly. Therefore, this study is being conducted to 
investigate the efficacy, safety, tolerability, 
 of a 50/28-mg dose of nusinersen (50-mg 
loading dose/28-mg maintenance dose) and a dosing regimen targeted to achieve higher drug 
exposure more rapidly. This study will be conducted in participants with genetically confirmed 
SMA. 
This is a 3-part study Part A, Part B (infantile-onset and later-onset), and Part C. 
Part A was an open label safety evaluation in which later-onset SMA subjects received 3 loading 
doses of 28 mg of nusinersen and 2 maintenance doses of 28 mg. All 6 participants enrolled in 
Part A completed the study. 
 
In Part B, in order to evaluate the proposed higher dosing regimen, an active-controlled design is 
being used, with participants randomized either to the investigational dosing regimen (50-mg 
loading/28-mg maintenance) or to the currently approved dosing regimen (12-mg loading/12-mg 
maintenance). In order to supplement the number of participants available for the analysis in Part 
B of this study, historical data from the existing data set for Study CS3B, a Phase 3 efficacy and 
safety study of nusinersen in participants with infantile-onset SMA, may be borrowed to 
augment the control arm.  
 
Part C of the study will allow safety evaluation of transitioning participants who are on the 
currently approved dose of nusinersen (12-mg maintenance for at least 1 year after the initiation 
of treatment) to the proposed higher dosing regimen via the administration of a single bolus dose 
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of 50 mg of nusinersen (which should be administered 4 months ± 14 days after their most recent 
maintenance dose of 12 mg), with maintenance dosing at 28 mg thereafter. 
This SAP will cover the planned analysis of Part C. 
2. Study Overview 
2.1. 
Study Objectives and Endpoints 
Study Primary Objective (Part C) 
To examine the safety and tolerability of nusinersen administered intrathecally at higher doses 
to participants with SMA.  
Study Primary Endpoints (Part C) 
 
Incidence of adverse events (AEs), including serious adverse events (SAEs) 
 
Shifts from baseline in clinical laboratory parameters, electrocardiograms (ECGs), 
and vital signs 
 
Change in growth parameters 
 
Shifts from baseline in coagulation parameters (activated partial thromboplastin time 
[aPTT], prothrombin time [PT], and international normalized ratio [INR]) 
 
Change in urine total protein 
 
Change from baseline in neurological examination outcomes 
 
The proportion of participants with a post-baseline platelet count below the lower 
limit of normal on at least 2 consecutive measurements 
 
The proportion of participants with a post-baseline QT interval using Fridericia’s 
formula (QTcF) of > 500 msec and an increase from baseline to any post-baseline 
timepoint in QTcF of > 60 msec 
Study Secondary Objective (Part C) 
 To examine the clinical efficacy of nusinersen administered intrathecally at higher 
doses to participants with SMA.  
 To examine the effect of nusinersen administered intrathecally at higher doses to 
participants with SMA 
Study Secondary Endpoint (Part C) 
 
Change from baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) 
score 
 
Change from baseline in Revised Upper Limb Module (RULM) score  
 
Total number of new World Health Organization (WHO) motor milestones 
 
Change from baseline in Assessment of Caregiver Experience with Neuromuscular 
Disease (ACEND) 
 
Change from baseline in Pediatric Quality of Life Inventory™ (PedsQL) 
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 
Change from baseline in Children’s Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders (CHOP-INTEND) (Cohort 1 only) 
 
Change from baseline in Hammersmith Infant Neurological Examination (HINE) 
Section 2 motor milestones (Cohort 1 only) 
 
Number and duration of hospitalizations 
 
Clinical Global Impression of Change (CGIC) [physician, caregiver] at Day 302 
 
Number of serious respiratory events 
 
Ventilator use 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
2.2. 
Study Design 
This 3-part study will evaluate the efficacy and safety of a higher dosing regimen of nusinersen 
in approximately 145 participants. The study will be conducted at approximately 65 sites 
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Page 11 
 
 
globally. Following the completion of this study, all eligible participants may elect to enrol in a 
separate long-term extension study (232SM302), pending study approval by ethics committees 
and the appropriate regulatory authorities. In regard to participants rolling over from Part B, this 
will be done without unblinding the participant’s treatment group. 
In Part C, up to approximately 40 participants who have already initiated treatment with 
nusinersen and have been receiving the approved dose of 12 mg for at least 1 year prior to entry 
will be enrolled in Part C. The initial cohort in Part C (i.e., Cohort 1) consists of up to 
approximately 20 participants of any age and of any SMA status. For Cohort 1, an attempt will 
be made to enroll at least 8 but no more than 12 participants ≥ 18 years of age (participants in 
Cohort 1 ≥ 18 years of age must be ambulatory). Up to 5 participants with severe scoliosis and/or 
severe contractures may be enrolled in Cohort 1 of Part C after consultation with the Medical 
Monitor. An additional cohort (i.e., Cohort 2) consisting of up to approximately 20 adult 
participants (≥ 18 years of age) was subsequently added to Part C in Protocol Version 5, in order 
to enable collection of data in adults transitioning from the currently approved nusinersen dosing 
regimen to a higher dose. Participants in Cohort 2 can be either ambulatory or non-ambulatory. 
All participants in Part C will receive a single bolus dose of 50 mg (which should be 
administered 4 months ± 14 days after their most recent maintenance dose of 12 mg) followed by 
2 maintenance doses of 28 mg on Days 121 and 241. Participants in Part C will remain at the 
clinic for at least 24 hours after the first (bolus) dose for the purpose of completing study 
assessments. 
2.3. 
Sample Size Considerations   
For Cohort 1 of Part C, an attempt was made to enroll at least 8 but no more than 
12 participants ≥ 18 years of age (participants ≥ 18 years of age must be ambulatory). For 
Cohort 2 of Part C, all participants must be ≥ 18 years of age and can be either ambulatory or 
non-ambulatory. 
2.4. 
General Trial Conduct Mitigation Strategy under COVID-19 Pandemic or 
humanitarian emergencies 
In order to mitigate risk of missing dosing or assessments during the time of the COVID-19 
pandemic, the following has been put into place: 
 If a site is not closed due to COVID-19 or humanitarian emergencies and the site enables 
the participant to attend the visit in-clinic, then delayed visits within a reasonable 
timeframe are allowed.  
 Site transfers are encouraged where possible, so that subjects can be transferred to 
another site for assessment. Instructions are in place to enable sites to do this including 
transfer of the database and source documents for the patient from the transferring site to 
the receiving site. This will allow the participant to receive dosing and protocol defined 
assessments to be made.  Dosing can only be performed in the clinic setting due to 
intrathecal administration. In particular, if screening cannot be performed in the clinic, 
participants will be screened at a screening site and subsequently transferred to another 
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Page 12 
 
 
site to perform dosing and all assessments for the participant, since dosing can only be 
performed in the clinic setting due to intrathecal administration.  
 A phone visit can be used to collect safety data (AEs, concomitant therapies/procedures) 
 Transferring sites are encouraged to enter and clean all data before transferring the 
participant to the receiving site. The database for a participant will remain with the 
transferring site until data are entered and cleaned as much as possible, but the 
transferring site must have access to the participant in IRT and copies of all source 
documents. Any queries raised later on for data belonging to visits at the transferring site 
will be cleaned by the receiving site through the source documents, and interaction 
between monitors at the receiving and transferring sites. The transferring site will no 
longer have access to the database for a participant they have transferred, but the 
monitors will. The Subject ID will remain the same when a participant is transferred to 
another site, but the transfer site can be tracked via the Site ID. 
3. Definitions 
3.1. 
Dates and Points of Reference 
In the remainder of this analysis plan only Part C analyses will be described.  Separate SAPs will 
be developed for other parts of the study, (Parts A open label and B randomized double-blind). 
Therefore ‘Part C’ will not be stated throughout this document. 
 Study Day 1: the date of the first dose of study treatment in 232SM203 
 Study Day  
o For a date on or after Study Day 1  
Study Day = (Date of Interest) – (Study Day 1) + 1  
o For a date before Study Day 1  
Study Day = (Date of Interest) – (Study Day 1) 
In order to distinguish nominal visit names from duration defined in days, visit names will be 
referred to as “Day 121”, “Day 241”, etc., and “121 days” or “241 days”, etc. will be used to 
define time intervals. 
Overall time on commercial nusinersen prior to first study dose= (Date of first study dose) – 
(Date of first commercial dose)  
 
Overall time on study will be defined as the total number of days a participant is known to be 
followed on study calculated as follows: 
Overall time on Study = (Last date on study) – (Date of first study dose) +1 
Last date on study is defined as the date of the latest visit or evaluation or telephone contact, or 
time of death from all available data for a given participant. 
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Statistical Analysis Plan  
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Page 13 
 
 
Disease duration at informed consent is defined as time from age at symptom onset to age at 
informed consent. 
3.2. 
Study Treatment 
All participants will receive a single bolus dose of 50 mg of nusinersen administered 
intrathecally on Day 1 of this study (which should be administered 4 months ± 14 days after their 
most recent maintenance dose of 12 mg), followed by 2 maintenance doses of 28 mg of 
nusinersen on Days 121 and 241. 
3.3. 
Study Groups 
All the summaries will be using display ‘a’ below, only selected analysis will be repeated using 
displays ‘b’ and ‘c’and will include baseline characteristics, disposition, exposure, time on study 
incidence of adverse events and secondary endpoints. 
a.  
Nusinersen 50/28 mg 
Infantile-
onset SMA 
 
Later-onset SMA 
Total 
Age < 18 years 
Age>= 18 years 
 
b. 
 
Nusinersen 50/28 mg 
Non-Ambulatory 
Ambulatory 
Age <18 years 
Age >=18 
years 
Total 
Age< 18 years 
Age>= 18 
years 
Total 
 
 
 
 
 
 
 
c. 
 
Nusinersen 50/28 mg 
< median time on commercial nusinersen 
prior first dose 
>= median time on commercial nusinersen 
prior first dose 
Age <18 years 
Age >=18 
years 
Total 
Age < 18 years 
Age >= 18 
years 
Total 
3.4. 
Study Periods 
The total study duration for each participant will be a maximum of 323 to 382 days with 5 to 6 
visits.   
 
Screening: 21 days  
 
Loading period: 1 day  
 
Maintenance period: 240 days 
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 
Follow-up: 61 to 120 days 
3.5. 
Key Derived Variables 
Not applicable. 
3.6. 
Stratification Factors and Subgroup Variables 
3.6.1. Stratification Factors 
Not applicable. 
3.6.2. Subgroup Variables 
Not applicable.  
3.7. 
Analysis Sets 
The Intent-to-Treat (ITT) Set is defined as all participants who receive at least one dose of 
nusinersen in 232SM203.  
The Safety Analysis will be performed on the ITT Set. 
 
  
 
  
 
 
A Per Protocol Set (PPS) will include the subset of the ITT Set who have no significant protocol 
deviations that would be expected to affect efficacy assessments 
Significant protocol deviations will be determined prior to database lock and will include: 
Participants with missing baseline results  for the following assessments: HFMSE or RULM. 
Participants who took experimental or approved agents for the treatment of SMA, including gene 
therapy, biological agent, any disease modifying therapy, or device, during the study. This 
includes marketed agents at experimental doses that are being tested for the treatment of SMA 
(oral albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea, 
etc.). 
4. List of Planned Study Analyses 
4.1. 
Interim Analysis 
No Interim analysis is planned. 
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4.2. 
Primary Analysis 
Not applicable. 
 
4.3. 
Final Analysis 
The final analysis will be conducted after all Part C subjects have completed the study. 
5. Statistics Methods for Planned Analyses 
5.1. 
General Principles  
Descriptive summary statistics will be presented for all primary, secondary 
 
endpoints collected. Unless otherwise specified, for continuous endpoints, the summary statistics 
will generally include number of participants with data, mean, standard deviation, median, 25th 
percentile, 75th percentile, minimum and maximum. For categorical endpoints, the summary 
statistics will generally include number of participants with data, and the percentage of those 
with data in each category. 
 
All summaries and listings will be presented by study groups unless otherwise specified. Visits 
in listings will be displayed as per CRF data collection rather than analysis visits. 
The statistical software, SAS®(Version 9.4) will be used for all summaries and statistical 
analyses.  
 
Visit Windows for Early Withdrawal, Unscheduled Visits 
Data from early withdrawal visits and post baseline unscheduled assessments will be mapped to 
a planned visit using a windowing scheme for assessments that are tabulated by visit. Scheduled 
visits will not be windowed. 
The visit windowing will be performed for safety and efficacy endpoints as shown below.  
Table 2: Visit Windows for safety and efficacy Endpoints in 232SM203: 
Visit 
Lower Bound  
Upper Bound  
Target Day 
Baseline 
 
 
<=1 
Day 121 
2 
181 
121 
Day 241 
182 
271 
241 
Day 302 
272 
422 
302 
Any postdose assessments with specific time associated to it (i.e vital signs collected at 1,2,4,6 
and 24 hours) will be associated to the windowed visit at which they belong. 
The following rules will be implemented for windowing of these visits for both safety and 
efficacy. 
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 If more than one observation is within the same window, data from the regular scheduled 
visit will be used for that visit.  
 If neither of the observations are from a regular scheduled visit the observation closest to 
the planned target date will be used. However, if both the observations are equidistant 
from the target date, the latest one will be used; if repeated measurements are on the same 
day, then the last measurement will be used. 
 If there is more than one observation in a window for a dosing visit the observation on 
the day of dosing will be chosen over the observation where dosing did not occur on the 
same day. 
 In windowing laboratory data, if a central and local result is available within the window 
then the central laboratory result will be chosen  
 
5.2. 
Participant Accountability  
The number (and percentage) of subjects screened, enrolled, dosed, completed treatment and 
study, along with the reasons for discontinuing treatment and withdrawing from the study, will 
be presented.  
If there are any subjects who discontinued from treatment or withdrew from study due to reasons 
associated with the COVID-19 pandemic or reasons associated with humanitarian emergencies, a 
separate summary will be presented to summarize these reasons. Adverse events, deaths, and 
other reasons may fall into COVID-19 related categories.  
A listing of subjects who discontinued treatment/withdrew from study and the associated reasons 
for discontinuation/withdrawal will be presented. Subjects who died during the study will be 
listed separately. Two separate listings will also be presented for subjects who discontinued 
treatment/withdrew from study due to the COVID-19 pandemic or to humanitarian emergencies 
if applicable. 
5.3. 
Demographic and Baseline Characteristics 
Baseline data (demography, medical history, SMA history, and baseline disease characteristics) 
will be summarized.  
Demography includes age at screening, age at first dose in the study, sex, ethnicity, and race. 
Medical history will be coded in MedDRA and the number and percentage of subjects with each 
medical history presented by preferred term.  
Demographic, baseline disease characteristics will be presented for the ITT Set and PPS. 
SMA history includes age of symptom onset, time from disease onset to enrollment, age at SMA 
diagnosis, time from diagnosis to enrollment, number of copies of the SMN1 and SMN2 gene, 
highest motor function achieved, wheelchair use, and walker/cane/crutches/braces use. 
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Baseline disease characteristics presented include HFMSE, WHO motor milestones, Revised 
Upper Limb Module Test, growth parameters, CHOP INTEND, COBB angle and Neurological 
Examination (HINE) Section 2 motor milestone if available. These assessments are further 
described in the next paragraph and Section 5. 
Commercial nusinersen prior first dose  
The number of commercial nusinersen doses received, prior to the first study dose, will be 
displayed using frequency distributions. The cumulative amount of commercial nusinersen 
received, will be summarized using summary statistics. The overall time on commercial 
nusinersen will be summarized descriptively (see section 3.1 for calculation). 
5.4. 
Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a protocol deviation log 
and categorized as major or minor deviations. These deviations will be listed. Major protocol 
deviations will be summarized including those that lead to exclusion from the Per protocol Set. 
5.5. 
Study Treatment Exposure and Concomitant Medications 
Exposure on Study  
The number of doses received will be displayed using frequency distributions. The cumulative 
amount of nusinersen received will be summarized using summary statistics. 
The overall time on study will be summarized descriptively (see section 3.1 for calculation). The 
duration will also be categorized and summarized using the following categories: <121 days, 
>=121 to 241 days, >=241 to 302 days, >=302 days 
Given the long half-life of nusinersen, participants are considered to be exposed to the date of 
last visit or contact. 
Separate listings will be provided showing study drug administration data which will include lot 
numbers, actual treatment received, cumulative number of doses and cumulative doses. 
 
The cumulative, prior and during study, time on nusinersen will also be summarized as above. 
  
Concomitant Medications and Procedure 
A concomitant therapy is any drug or substance administered between screening and the final 
study visit/telephone call. Participants should be instructed to contact their Investigators before 
taking any new medications, including nonprescription drugs and herbal preparations. 
Throughout the study, Investigators or designated licensed physicians involved in the study may 
prescribe concomitant therapies (procedures) or treatments deemed necessary for AEs or to 
provide adequate supportive care. 
Participants are prohibited from receiving other experimental or approved agents for the 
treatment of SMA, including gene therapy, biological agent, or device, during the study. This 
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includes marketed agents at experimental doses that are being tested for the treatment of SMA 
(oral albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea, 
etc.). 
All concomitant medications will be coded using the World Health Organization drug dictionary 
(WHO Drug).  
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
Screening and the final study visit/telephone call. Concomitant procedures will be coded using 
MedDRA. 
For the purposes of analysis, a concomitant therapy (including medication or procedure) is 
defined as any therapy that was taken or administered on or after the first injection of nusinersen 
received in the study.  This includes therapies that were started prior to the initiation of injection 
of nusinersen if their use continued on or after the first injection of nusinersen received in the 
study. Refer to Appendix A for more details about missing start or stop dates.  
The number and percentage of subjects who were taking each type of concomitant medication at 
baseline and during the study will be presented. The number and percentage of subjects taking 
each type of concomitant procedure will be presented by preferred term. 
If there are a sufficient number of tests or treatments reported with indication of COVID-19, a 
separate summary of these will be provided. 
Concomitant medications will also be reviewed by a medical reviewer prior to the final lock to 
determine disallowed medications according to the protocol. These will be summarized 
separately. 
5.6. 
Efficacy Endpoints 
5.6.1. General Analysis Methods for Efficacy Endpoints 
  
The following secondary 
 efficacy assessments will be evaluated:  
 HFMSE 
 RULM 
 WHO Motor Milestones  
 ACEND 
 PedsQL 
 Hospitalizations  
 CGIC 
 Serious respiratory events 
 Ventilator use 
 
 
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Cohort 1 only: 
 CHOP INTEND 
 HINE Section 2 motor milestones  
 
 
 
 
 
 
 
 
 
Unless otherwise specified, the baseline for the clinical function endpoints and QoL 
questionnaires are defined as the last non missing assessment prior to the first dose of study 
treatment. 
5.6.2. Imputation   
Multiple imputation (MI)  
In the event more than two subjects have missing data for an endpoint at a post baseline visit 
then multiple imputation will be performed.  If applicable  imputed data summaries will be 
presented and also the  summaries of observed data. 
For  multiple imputation method [Schafer 1997, Schafer 1999] will be used for patients who 
discontinue for a reason other than death or have a missing efficacy result at the timepoint of 
interest.  
For HFMSE and RULM the imputations will be performed on total scores for post baseline visit. 
The imputations will be performed on total scores for post baseline visits. Missing baseline will 
not be imputed. All available data will be used i.e., where subjects have missed doses but 
continued to perform assessments; otherwise, any missing values will be imputed using MI.  
The Markov Chain Monte Carlo (MCMC) method will be used. 
Prior to the Proc MI step the dataset will be sorted by ascending unique subject identifier 
(USUBJID). The variable list in the model for imputations will include: 
 Age at onset of symptoms, age at first dose, baseline ambulatory status, baseline value for 
the endpoint, and all available post baseline values 
A set of 100 complete imputed datasets will be generated and the relative efficiency parameter 
will also be checked to determine the acceptability of the imputed results i.e. it should be close to 
98% or higher.   
For continuous variables, each of the 100 imputed datasets will be used to calculate the change 
from baseline and subsequently the correspondent means, and standard errors. These summaries 
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will be used to calculate a combined estimate of mean and mean change from baseline using 
PROC MIANALYZE [Little et al, 2002] for each visit.  
 In the presentation of results from multiple imputed data, the number of subjects with missing 
data and the degree to which it is missing will be summarized. 
Imputation for WHO motor milestones  
If for a milestone either ‘No (refusal)’ or ‘Unable to test’ are observed at a visit then the result 
will be first set to missing. Imputation will be performed for missing data considering each 
milestone separately using the following rules for scheduled visits.  
 
For baseline, the closest non-missing milestone prior to or at first dose will be selected. If this 
results in a subject having no baseline for all six milestones, then this will be left missing, and no 
imputation will be performed.  If at least one milestone is evaluable as either Yes or No and the 
remainder are missing, then other assessments or SMA history will be used to impute a baseline 
result. 
 
For post baseline visits, if a subject has at least one milestone assessed but the remainder are 
missing the missing value will be imputed by using the worst result from the flanking visits. 
Otherwise, if the imputation is the last visit, the missing value will be imputed as the last 
observed value for the subject. Of note, only observed data will be utilized for imputation 
purposes and in a situation where unscheduled visit data is available these values will be utilized 
if these flank a missing visit. Missing motor milestone items will be imputed first prior to any 
analysis. 
5.6.3. Primary Efficacy Endpoints  
Not applicable.  
5.6.4. Secondary Efficacy Endpoints  
For each endpoint the main analysis will be performed on the ITT set and be repeated for PPS 
Set. 
5.6.4.1. 
HFMSE 
The HFMSE is a tool used to assess motor function in children 2 years or older 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 alleviate the ceiling effect and allow evaluation of higher functioning and 
ambulatory SMA patients [O'Hagen 2007]. Each item is scored 0 (unable), 1 (performs with 
modification or adaption) or 2 (able) and the total score is calculated by summing the 33 items 
and ranges from 0 to 66 with higher scores indicating greater motor function.  
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If 6 or fewer items are missing, then these items will be imputed to 0 when summing all 33 
items. If greater than 6 items are missing, then the total score will be set to missing. 
In order to further explore the response as measured by HFMSE score a number of thresholds 
will be evaluated:  The proportion of subjects achieving: worsening of >= 4, >= 3, >=2, >=1 
points, any worsening, no change (=0 points), any improvement, >=1, >=2, >=3, >=4 points 
improvement will be presented. 
Analyses:  
 Total score and change from baseline by visit  
 Thresholds of change from baseline by visit 
 Thresholds of change from baseline to last observed assessment 
 Mean (-/+ SE) plots of total score and change from baseline over time  
 
Sensitivity analyses 
 The above analyses will be repeated excluding subjects with a baseline cobb angle >=40. 
 Total score and change from visit displays will be repeated including patients with 
baseline HFMSE consistent with the CS4 study:  baseline HFMSE >=10 and <= 54 
 
 
5.6.4.2. 
RULM 
The upper limb module test (Mazzone et al. 2011) was developed to assess the upper limb 
functional abilities in SMA patients using 9 items. However, a revised version of the upper limb 
module test developed by the Upper Limb Module Working Group will be performed in this 
study consisting of 20 items. The first item is assessed on a seven point scale ranging from 0 – 
“No useful function” to 6 – “Can abduct both arms simultaneously elbows in extension in a full 
circle until they touch above the head”. This first item will not contribute to the total score.  
For the remaining 19 items, 18 items are assessed on a three point scale using the following 
criteria: 0 – Unable to achieve independently; 1 – Modified method but achieves goal 
independent of physical assistance from another person; 2 – Normal – achieves goal without any 
assistance. The one remaining item is assessed as either 0 or 1.  For each item, a score will be 
collected on the left and right side. A derived total score will be calculated by summing the 
scores from these 19 individual items and ranges from 0 if the subject fails all activities to 37 if 
the subject achieves all activities. If, for an individual item, a response is recorded for both he 
left and right side the highest score will be used in calculating the total.  If 3 or fewer items are 
still missing responses then it will be assumed that the score was 0. If greater than 3 items are 
missing, then the total score will be set to be missing. 
Missing baseline will not be imputed.  
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In order to further explore the response as measured by upper limb score a number of thresholds 
will be evaluated:  The proportion of participants achieving: worsening of >= 4, >= 3, >=2, >=1 
points, any worsening, no change, any improvement, >=1, >=2, >=3,>=4 points improvement 
will be presented. 
Analyses 
 Total score and change from baseline by visit  
 Thresholds of change from baseline by visit 
 Thresholds of change from baseline to last observed assessment 
 Mean (-/+ SE) plots of total score and change from baseline over time  
Sensitivity analyses 
 The above analyses will be repeated excluding subjects with a baseline cobb angle 
>=40 . 
 Total score and change from visit will be repeated including patients with baseline 
RULM: >=5 and <= 30 
 
 
5.6.4.3. 
WHO motor milestones 
The WHO motor milestones criteria [WHO Multicentre Growth Reference Study Group 2006; 
Wijnhoven 2004] are a set of six milestones in motor development, all of which would be 
expected to be attained by age 24 months in healthy children. The individual milestones are: 
 Sitting without support 
 Standing with assistance 
 Hands and knees crawling 
 Walking with assistance 
 Standing alone 
 Walking alone 
As part of the assessment, the examiner records an overall rating of the subject’s emotional state 
and then for each milestone one of the following four classifications: 
 No (inability) – Child tried but failed to perform the milestone 
 No (refusal) – Child refused to perform despite being calm and alert 
 Yes – Child was able to perform the milestone 
 Unable to test – Could not be tested because of irritability, drowsiness or sickness 
WHO motor milestones will be assessed by the site clinical evaluator and caregiver. Adult 
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participants who do not require a caregiver during the study visit may self-report WHO motor 
milestone achievement. Whenever possible, for each participant, motor milestone assessments 
across all study visits should be conducted consistently by the same clinical evaluator. 
 
If for a milestone either ‘No (refusal)’ or ‘Unable to test’ are observed at a visit then the result 
will be set to missing.  
New motor milestones 
For each milestone at a visit and baseline values will be compared and if the subject can achieve 
a new milestone compared to baseline then it will be counted +1, if the subject is unable to 
achieve the milestone then it will be scored -1 and if the milestone has been maintained then it 
will be scored 0. These scores will then be summed to give a total score which could range 
between -6 (if a subject was able to perform all milestones at baseline but lost the ability and 
could not perform any milestones at the specific visit) and + 6 (if a subject was unable to achieve 
any milestones at baseline but could achieve all at the specific visit).  
 
Analyses  
 Summary of motor milestones at baseline  
 Number of new motor milestones achieved per subject by visit 
 Summary of motor milestones status at last observed assessment 
5.6.4.4. 
PedsQL 
Subjects who are ≥ 2 years of age in cohort 1 at Screening will be evaluated using the 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, adolescents and adults. The PedsQL consists of brief, practical, generic 
core scales, as well as condition-specific modules for use in designated clinical populations. The 
PedsQL4.0 Generic Core Scales include an assessment of physical functioning, emotional 
functioning, social functioning, and school functioning and will be assessed for participants 2 to ≥ 
26 years of age. The PedsQL 3.0 Neuromuscular Module was designed to measure HRQOL 
dimensions specific to patient with neuromuscular disorders, including SMA, and will be assessed 
in participants 2 to 25 years of age. Patient self-report will be measured in participants starting at 
5 years of age, while parent proxy-report of HRQOL will be measured for participants starting at 
2 years of age. 
 
If a participant is assessed on PedsQL at baseline, then the age range of the scale used at 
Screening for that participant will continue to be used up to Day 302, regardless of changes in 
the participant’s age. 
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The PedsQL Core Scales parent questionnaire is collected for children in the following age 
categories: 2-4, 5-7, 8-12, 13-18, 18-25, and ≥26. Four dimensions are collected: Physical, 
Emotional, Social and School functioning and each item is scored on a 5-point ordinal scale (0= 
Never, 1 = Almost Never, 2= Sometimes, 3 = Often, 4 = Almost Always). 
The PedsQL Core Scales patient questionnaire is collected for children in the following 
categories: 5-7, 8-12, 13-18, 18-25, and ≥26. Similar dimensions and 5-point ordinal scale are 
used as for the parents but for subjects aged 5 to 18 years a 3-point ordinal scale is collected, 
omitting the response levels of 1 and 3.  
In the neuromuscular module, one parent questionnaire is collected for all subjects irrespective of 
age with three dimensions: ‘About my child’s neuromuscular disease’, ’Communication’ and 
‘Family resources’. The same 5-point ordinal scale is collected for each question.  
The patient neuromuscular disease questionnaire is collected for subjects in the following age 
categories: 5-7, 8-12, 13-18 and 18-25. The questionnaire for subjects aged 5-7 years uses the 3-
point ordinal scale as above and has only one dimension - ‘About my Neuromuscular disease’. 
The questionnaires for other age categories use 5-point ordinal scale with three dimensions.  
In scoring a dimension (physical functioning, emotional functioning, social functioning, and 
school functioning) the first step is to reverse and linearly transform to a 0-100 scale (0 = 100, 1 
=75, 2=50, 3= 25, 4= 0), so a higher score is indicative of a better health related quality of life. If 
greater than 50 percent of the items within a dimension are missing then the dimension score will 
not be computed, otherwise the mean score for the dimension will be calculated as the sum of 
items over the number of items answered. 
A psychosocial health summary score, constructed from three dimensions, will be calculated as 
the sum of items over the number of items answered in the emotional, social and school 
functioning scales. A total score will be calculated as the sum of all the items over the number of 
items answered on all the scales. If greater than 50 percent of the items are missing, then the 
summary score or total score will be set to be missing. 
For the neuromuscular module, a score for each dimension and then total score will be calculated 
in the same manner, no health summary scores are evaluated.  
 Due to the age specific nature of these questionnaires, subjects aged 2-4 years would not be 
expected to complete the self-evaluation. 
Analyses  
 Total score and change from baseline by visit 
 Total score and change (parent/subject evaluation separately) from baseline by visit 
 Mean (-/+ SE) plots of total score and change from baseline. 
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5.6.4.5. 
ACEND 
Parents/caregivers of participants will complete the ACEND questionnaire. The ACEND 
questionnaire will not be collected for adult participants who do not require a caregiver during 
the study visits. For cohort 1, only the parents/caregivers of the participants older than 2 years 
will complete this questionnaire. This assessment instrument has been designed to quantify the 
caregiver impact experienced by parents/caregivers of children affected with severe 
neuromuscular diseases, including children with SMA [Matsumoto 2011]. ACEND includes 
seven domains assessing physical impact (including feeding/grooming/dressing, sitting/play, 
transfers, and mobility) and general caregiver impact (including time, emotion, and finance). and 
each domain comprises several items.   
The total score for a domain with n items, each item assessed on ordinal scale from 1 to z, is 
derived as follows: 100 multiplied by (Mean of the n items in the domain -1) divided by (z-1).   
This total score will be on a scale of 0 to 100 with a higher score indicating a greater impact on 
the caregiver. 
At least two items for the time domain and one item for the remaining domains need to be non-
missing for a total to be calculated; else the total score will be set to be missing. 
 
Analyses 
 Total score and change from baseline by visit 
 Domain total score and change from baseline by visit 
 Mean (-/+ SE) plots of total score and change from baseline. 
5.6.4.6. 
CHOP INTEND 
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]. 
The CHOP INTEND infant motor function scale is comprised of 16 test items, nine of which are 
scored 0, 1, 2, 3, or 4 with greater scores indicating greater muscle strength, five are scored as 0, 
2, or 4, one is scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4. This can result in a worst possible 
total score of 0 to a best possible total score of 64. CHOP INTEND is used to assess spontaneous 
movement in the upper extremities, spontaneous movement in the lower extremities, hand grip, 
head in midline with visual stimulation, hip adductors, rolling elicited from the legs, rolling 
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elicited from the arms, shoulder and elbow flexion and horizontal abduction, shoulder flexion 
and elbow flexion, knee extension, hip flexion and foot dorsiflexion, head control, elbow flexion, 
neck flexion, head/neck extension, and spinal incurvation. CHOP INTEND is to be evaluated 
during the study for cohort 1. For each item, a score will be collected on the left and right side. 
In order to examine if the response is consistent with a range of thresholds, the proportion of 
participants achieving: worsening of >=6, >=5, >=4, >=3, >=2, >=1 points, no change (=0 
points), and improvement of >=1, >=2, >=3, >=4 (endpoint for main analysis), >=5, >=6 points 
will be presented. If a subject has moved scales and/or reached maximum score of 64 will be 
summarized on a different row in the tables.  
Depending on data availability the following displays will be presented showing the following 
 Total score and change from baseline by visit 
 Thresholds of change from baseline by visit 
5.6.4.7. 
HINE Section 2 
Hammersmith Infant Neurological Examination (HINE) is collected for cohort 1 infantile-onset 
SMA subjects, that are less than 2 years of age at the time of informed consent.  
The assessment is comprised of eight motor milestone categories: voluntary grasp, ability to kick 
in supine position, head control, rolling, sitting, crawling, standing and walking. 
Within each motor milestone category (depicted as Motor Milestones in Table 5), there are 3 to 5 
levels that can be achieved (depicted as Milestones Progression, or rows, in the Table above). All 
8 Motor Milestones are 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, etc.) has not 
achieved any motor milestone. Motor milestone achievement is depicted by movement from the 
left side of the Table above to right side of the Table, as denoted by the Milestone Progression 
arrow in the Table.  
The 8 categories of HINE Section 2 can be summed to give a total score that ranges from 0 to 26. 
Depending on data availability the following displays:  
 Total motor milestone score and change from baseline by visit 
 Summary of highest motor milestones item achieved at last observed assessment. 
 The proportion of subjects who have achieved specific individual item at last analysis visit. 
 Mean (-/+ SE) plots of total score and change from baseline.  
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Table 5:Hammersmith Infant Neurological Examination Section 2 - Motor Milestones 
Motor 
Milestone 
Category 
Milestone Level Progression Score 
(Age Expected in Heathy Infants1) 
Improvement 
0 
1 
2 
3 
4 
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 
Rolls to 
side 
(4 months) 
Prone to 
supine 
(6 months) 
Supine to 
prone 
(7 months) 
 
Sitting 
Cannot sit 
Sits with 
support at 
the 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) 
Crawls flat on 
the 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) 
 
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Motor 
Milestone 
Category 
Milestone Level Progression Score 
(Age Expected in Heathy Infants1) 
Improvement 
0 
1 
2 
3 
4 
Walking 
No walking 
Bouncing 
(6 months) 
Cruising 
(holding on) 
[11 months] 
Walks 
independently 
(15 months) 
 
 Values for healthy infants in [De Sanctis 2016; Haataja 1999] 
 
5.6.4.8. 
Number and Length of Hospitalizations 
The number of hospitalizations during the study will be analyzed using the rate at which they 
occur. For descriptive purposes, the aggregate hospitalization rate will be calculated for each 
group by dividing the total number of hospitalizations that occurred in the group by the total 
number of subject-years on study.  
Annualized hospitalization rate will be calculated for each subject as the number of 
hospitalizations that the subject experienced divided by the number of days on study and this 
ratio multiplied by 365.  
For each subject, the total time spent in hospital during the study will be calculated and prorated 
according to number of days on study.  
5.6.4.9. 
CGIC 
The CGIC rating scale was developed as a brief standalone assessment of the clinician’s view of 
the patient’s global functioning after initiating a study medication [Guy 1976]. The CGIC 
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. The 
CGIC 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 the illness, the patient’s level of distress and other aspects 
of impairment, and the impact of the illness on functioning. The CGIC 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 CGIC is a 7-point scale that requires the clinician to assess how much the patient’s illness 
has changed 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, 
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minimally worse; 6, much worse; or 7, very much worse. CGIC should be assessed consistently 
by the same rater for each study participant. A separate CGIC assessment will be performed by 
the Investigator (Principal Investigator or Sub investigator) and caregiver.  
In order to investigate response on these scales, three definitions of responder will be defined: 
“Much improved”: Responder (<=2) versus Non-responder (>=3), “Any improvement”: 
Responder (<=3) versus Non-responder (>=4), “No worsening”: Responder (<=4) versus Non-
responder (>=5). 
Analyses 
 Proportion of participants achieving each responder definitions above by visit  
5.6.4.10. 
Number of Serious Respiratory Events 
All adverse events that are coded into the System Organ Class (SOC) of respiratory, thoracic, 
and mediastinal disorders, either as their primary SOC or their secondary SOC will be 
considered respiratory events. Only those classified as serious will be analyzed. By utilizing the 
above approach, rare occurrence of serious respiratory events in the Infection and Infestation 
SOC and Investigation SOC (if any) may not be included. However, a detailed review of the AE 
listing will be conducted to identify such events. 
The number of serious respiratory events during the study will be analyzed using the rate at 
which they occur. For descriptive purposes, the aggregate rate will be calculated for each group 
by dividing the total number of serious respiratory events that occurred in the group by the total 
number of subject-years on study.  
In order to evaluate if there is any change in the number of serious respiratory events overtime, 
the events will be presented in periods of 120 days. 
5.6.4.11. 
Ventilator Use 
The participant’s use of ventilators and respiratory aids will be collected at every study visit.  
The ventilation/respiratory aid use will be summarized by visit and listed. 
  
  
 
 
 
 
 
 
 
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5.7. 
Safety Endpoints 
Analyses of safety data will include adverse events and serious adverse events, laboratory data, 
ECGs, growth parameters, vital signs, and neurological examinations. Worsening or new 
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findings noted from the physical or neurological examinations will be reported as AEs as 
appropriate. 
5.7.1. Adverse events 
All adverse events (AEs) will be analyzed based on the principle of treatment emergence. An 
adverse event will be regarded as treatment-emergent if it was present prior to receiving the first 
dose of nusinersen in 232SM203 and subsequently worsened in severity or was not present prior 
to receiving the first dose of nusinersen and subsequently appeared. Refer to Appendix A for 
more details about AE with missing start or stop dates.  
The incidence and frequency (event count) of treatment-emergent adverse events will be 
summarized.  A participant having the same adverse event more than once will be counted only 
once in the incidence for that adverse event; multiple occurrences of the same adverse event for 
the same subject will all be counted in the frequency for that adverse event. Incidence will be 
presented by decreasing order by system organ class and by decreasing order by preferred term 
within each system organ class.   
The occurrence of the AE with the greatest severity will be used in the calculation of incidence 
by severity.  The AE relationship to treatment or LP procedure is captured as related or not 
related. In the event the relationship is missing then this will be considered related.  
Due to the long half-life of nusinersen, analyses of adverse events will include all events reported 
during the study per the treatment emergent definition. Adverse Events will be coded using the 
Medical Dictionary for Regulatory Activities.  
The following presentations will be shown:  
 an overall summary showing, the number and percentage of subjects with an adverse 
event, a mild, moderate or severe event, an event related to study drug, an event 
related to lumbar puncture procedure, a serious event, a serious event related to study 
drug, an event leading to study drug withdrawal, an event leading to study 
withdrawal, and a fatal event. 
 incidence and frequency by system organ class and preferred term  
 incidence and frequency by preferred term  
 incidence and frequency, by preferred term, at least 5% of subjects in either study 
group 
 incidence of adverse events by maximum severity by preferred term  
 incidence and frequency of severe events by system organ class and preferred term  
 incidence and frequency of events related to study drug by system organ class and 
preferred term  
 incidence and frequency of events related to lumbar puncture (as assessed by the 
investigator) by system organ class and preferred term 
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 incidence by system organ class and preferred term that occurred within 24 hours of 
dosing procedure 
 incidence by system organ class and preferred term that occurred within 72 hours of 
dosing procedure 
 incidence and frequency of serious adverse events by system organ class and 
preferred term  
 incidence and frequency of serious adverse events related to study drug by system 
organ class and preferred term  
 incidence of events that led to fatal outcome 
 incidence of events leading to study drug withdrawal by system organ class and 
preferred term  
 incidence and frequency of adverse events over time by system organ class and 
preferred term.  
 
 incidence of events leading to withdrawal from study by system organ class and 
preferred term   
 incidence and frequency of adverse events antibody status by system organ class and 
preferred term.  
A separate table will also be presented to show an overall summary of COVID-19 pandemic 
related AEs. 
Listings of the following events will be produced.  
 AEs 
 SAEs  
 AE with fatal outcome 
 AEs led to study drug withdrawal   
 AEs led to withdrawal from study  
 AEs related to lumbar puncture procedure  
 AEs related to study drug 
 
5.7.2. 
Clinical laboratory data 
Laboratory data will be evaluated to determine the incidence of abnormalities that emerge during 
the course of the study. Changes in laboratory evaluations will be presented relative to baseline, 
which is defined as the closest non-missing visit prior to the first dose. 
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The following clinical laboratory parameters are to be assessed: 
 Hematology panel: complete blood count with differential and platelet count 
(hematocrit, hemoglobin, platelets, red blood cell count [RBC], white blood cell 
count [WBC], basophils, eosinophils, lymphocytes, monocytes, neutrophils) 
 Blood chemistry panel: albumin, total bilirubin, direct and indirect bilirubin, alkaline 
phosphatase, alanine aminotransferase (ALT) (SGPT), aspartate aminotransferase 
(AST) (SGOT), gamma-glutamyl transferase (GGT), sodium, potassium, calcium, 
chloride, phosphate, blood urea nitrogen (BUN), creatinine, cystatin, creatine 
phosphokinase, creatine kinase, bicarbonate (CO2), glucose, total protein. 
 Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, blood, red blood 
cells, white blood cells, epithelial cells, bacteria, casts and crystals 
 Urine total protein assessed by local laboratories  
 CSF analysis: RBC, WBC, protein, glucose.  
 Coagulation: PT (prothrombin time), aPTT (activated partial thromboplastin time), 
and INR (international normalized ratio).  
Each hematology, blood chemistry, coagulation and CSF laboratory parameter will be flagged as 
“low”, “normal” or “high” relative to the parameter’s normal range or as “unknown” if no result 
is available. 
For each urinalysis laboratory parameter, the number and percentage of subjects experiencing 
postdose shifts to abnormal will be summarized.  
For each hematology, blood chemistry, coagulation and CSF parameter, the number and 
percentage of subjects experiencing postdose shifts to ‘low’ or ‘high’ will be summarized. In 
each summary, the denominator for the percentage is the number of subjects at risk for the shift. 
The number at risk for the shift to low is the number of subjects whose baseline value was not 
low and who had at least one post baseline value. The number at risk for the shift to high is the 
number of subjects whose baseline value was not high and who had at least one-post baseline 
value. Subjects will be counted only once for each parameter and each shift regardless of how 
many postdosing assessments had that type of shift. All post baseline data will be used in the 
shift tables, regardless of whether a scheduled or unscheduled visit.  
Also, for each parameter, the incidence of shift to low will be summarized using the minimum 
post baseline values. Shift to low includes subjects with a normal, high, or unknown baseline 
value and at least one post baseline value of the given test. Similarly, the incidence of shift to 
high will be summarized using the maximum post baseline values. Shift to high includes subjects 
with a low, normal, or unknown baseline value and at least one post baseline value. 
To evaluate potential serious hepatotoxicity subjects with a post baseline AST and/or ALT value 
≥3 times the upper limit of normal (ULN) and a post baseline bilirubin value >2 times ULN at 
any time, not necessarily concurrent, will be listed with their values. In addition, a plot will be 
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presented with each subject’s maximum post baseline AST or ALT value relative to the ULN 
against the subject’s maximum post baseline bilirubin value relative to the ULN; values do not 
have to be concurrent. All post baseline data will be used to identify abnormalities, regardless of 
whether a scheduled or unscheduled visit. 
Summary statistics for actual values and change from baseline in laboratory values will be 
summarized by study group and visit. Line plots for chemistry, hematology and CSF showing 
median value for each study group at each visit will also be presented.  
For a parameter if the local and central result are available with the same date and time then only 
the central analysis result will be considered for presentations by visit. In a situation where two 
or more results have the same date and time and are both central (or both local) then we will 
check with the Safety physician if it would be more appropriate or take the highest or lowest 
value. 
Listings of all chemistry, hematology, coagulation, CSF, urinalysis values and pregnancy test 
(serum and urine) will be provided.  
For platelets a summary of the proportion of participants with a post baseline platelet count 
below the lower limit of normal on at least 2 consecutive measurements will be presented. 
The urine protein positive (trace, +1, +2, +3, +4 or >0.2g/L) results will be presented, number of 
subjects with positive result at baseline, with a negative result at baseline and at least one and at 
least two positive post baseline result respectively.   
 
5.7.3. Neurological Examinations   
5.7.3.1. 
Hammersmith infant Neurological Examination (Sections 1 and 3) (HINE 1 
and 3) in infantile-onset SMA population 
Sections 1 (neurological items) and 3 (behavior) of the HINE serve as the basis for neurological 
examinations for infantile-onset SMA subjects < 2 years old in cohort 1. These are to be assessed 
at Screening, predose and at 3, 6, and 24 hours postdose on Day 1, predose and 1, 3 hours 
postdose on Days 121 and 241, and on Day 302/ET 
The neurological items comprise cranial nerve function (facial appearance, eye appearance, 
auditory response, visual response, sucking/swallowing), posture (head in sitting position, trunk in 
sitting position, arms at rest, hands, legs in sitting position, legs in supine and standing positions, 
feet in supine and standing positions), movements (quantity, quality), tone (scarf sign, passive 
shoulder elevation, pronation/supination, adductors, popliteal angle, ankle dorsiflexion, pulled to 
sit, ventral suspension), and reflexes and reactions (tendon reflexes, arm protection, vertical 
suspension, lateral tilting, forward parachute). Behavior is comprised of state of consciousness, 
emotional state, and social orientation. 
Since the number of patients below 2 years of age is expected to be small the results of HINE 1 
and 3 testing will be listed only. 
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5.7.3.2. 
Neurological Examination in patients 2 years or older  
Neurological examinations include assessment of mental status, level of consciousness, cranial 
nerves, reflexes, motor system, coordination/cerebellar function and sensation – temperature and 
vibration. These are to be assessed at Screening, predose and at 3, 6, and 24 hours postdose on 
Day 1, predose and at 1, 3 hours on Days 121 and 241, and on Day 302/ET. 
The results collected for the majority of the tests are classified as ‘normal’ or ‘abnormal’, 
however the assessment of sensations is reported as ‘present’ or ‘absent’ and the assessment of 
reflexes is captured on an ordinal scale. For each test it is recorded if secondary to SMA.  
 
Acute Effects After Dosing: Reflex assessments 
On each dosing day, each predose reflex will be compared with all the post dosing assessments 
with 24 hours to see if the subject has changed (gained or lost) or maintained, reflexes. For this 
comparison the predose reflex status will be categorized into two categories: 0 and >=1. For each 
reflex, visit, predose category the number and proportion of subjects who change or maintained 
will be presented. 
Acute Effects After Dosing: Other assessments with binary response (normal/abnormal; 
present/absent) 
On each dosing day, the shifts from predose assessment on that day to postdose (i.e., from 
predose to 3, 6 and 24 hours postdose) will be determined. For each test and post dosing time 
point, the number and proportion of subjects who moved from ‘normal’ to ‘abnormal’ will be 
presented, for sensations the number and proportion who move from ‘present’ to ‘absent’ will be 
presented.  
Chronic effects: Other assessments with binary response (normal/abnormal; 
present/absent) 
For each test the shift from baseline to (the predose value on Day 1) to the predose value on later 
dosing days and to Day 1, 121, 241 and on Day 302/ET will be determined, the number and 
proportion of subjects who moved from ‘normal’ to ‘abnormal’ will be presented, for sensations 
the number and proportion who move from ‘present’ to ‘absent’ will be presented.   
5.7.4. ECG 
ECGs are to be recorded at Days 1, 121, 241, and 302/ET, predose (Day 1) and post dosing 
(Days 1, 121, 241) at various time points on dosing days and end predose at 302/ET. The ECGs 
are assessed at a central reading laboratory and the results provided as external vendor data. On 
the eCRF the investigator interpretation is collected as normal, abnormal and abnormal AE and 
the investigator determination will be used in analyses. 
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The ECG test includes heart rate, QT interval, QTcF interval and RR interval. Summary statistics 
for actual values and change from baseline in each ECG parameter will be presented by study 
group and visit.  
ECGs will be analyzed using two approaches. 
Qualitative analysis 
The determination of whether an ECG is abnormal not AE, abnormal AE made by the 
Investigator will be used for this qualitative analysis. 
The number and percentage of subjects with shifts from normal to each of the categorical values 
denoting an abnormal scan (abnormal not AE, abnormal AE) will be summarized by study 
group. All post baseline data will be used to identify abnormalities, regardless of whether a 
scheduled or unscheduled visit.  
Corrected Fridericia QT interval QTcF abnormalities (outliers) 
QTcF will be examined to determine the incidence of clinically relevant abnormalities. The 
number of subjects evaluated and the number of subjects with clinically relevant abnormalities 
will be presented. 
The first criteria for clinically relevant post dosing abnormalities (secondary safety endpoint) that 
will be considered is: 
 Post baseline QTcF of > 500 msec and Maximum increase from baseline to post 
baseline QTcF >60 msec 
Other criteria are:  
 Maximum increase from baseline QTcF > 30 to 60 msec  
 Maximum increase from baseline QTcF > 60 msec  
 Maximum post baseline QTcF > 480 to 500 msec  
 Maximum post baseline QTcF > 500 msec  
ECG summaries will be presented for all subjects and for subjects with post baseline. Listings 
will include both the central and eCRF information. 
5.7.5. Vital Signs 
The analysis of vital signs will be approached in two ways. 
Vital signs are to be measured at Screening, predose and at 1, 2, 4, 6, 8 and 24 hours postdose on 
Day 1, predose and at 1 and 6 hours postdose on Days 121 and 241  At each of these times, 
temperature, heart rate, respiratory rate, systolic and diastolic blood pressure, and pulse oximetry 
will be measured.  
Acute Effects After Dosing  
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On each dosing day, the change in each vital sign from predose on that day to postdose (i.e., 
from predose to 1 hour postdose, to 2 hours postdose, etc.) will be calculated. Summaries of 
actual values and change from predose for each dosing day will be presented.  
Chronic Effects  
To examine for possible chronic effects, the change from baseline (the predose value on Day 1) 
to the predose value on later dosing days and to Day 302/ET will be determined. Summaries of 
actual values and changes from baseline for subsequent dosing days (Days 121 and 241) and for 
Day 302/ET will be presented. 
Vital signs (temperature, pulse, systolic and diastolic blood pressure and pulse oximetry) will 
also be examined to determine the incidence of potentially clinically relevant abnormalities.  
Shift analysis 
The number of subjects evaluated and the number of subjects with potentially clinically relevant 
abnormalities will be presented. All post baseline data will be used to identify abnormalities, 
regardless of whether a scheduled or unscheduled visit. The criteria for potentially clinically 
relevant postdose abnormalities are shown in Table 6 below 
Table 6: Criteria to determine potentially clinically relevant abnormalities in vital signs 
Vital Sign 
Criteria for Abnormalities 
Temperature 
<36°C 
>38°C  
Pulse 
<60 bpm 
>100 bpm 
Systolic Blood Pressure 
<90 mmHg 
>140 mmHg 
>160 mmHg 
 
Diastolic Blood Pressure 
<50 mmHg 
>90 mmHg 
>100 mmHg 
  
Weight 
7% or more decrease from baseline  
7% or more increase from baseline  
Respiratory Rate 
<12 breaths/min 
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>20 breaths/min 
 
5.7.6. Growth parameters 
Growth parameters for infantile-onset and  later-onset SMA population include weight, 
height/length ulnar length, length for age (<18 years of age) and weight for age (<18 years of 
age).  
The growth parameters are to be assessed during screening, on dosing days (Days 1, 121, and 
241) and on Day 302/ET. 
 
The 2000 CDC Growth Charts (ages 2 to <20 years) will be used to assess the weight change  
for older subjects. The National Center for Health Statistics provides a SAS macro which  
can be downloaded from their website [https://www.cdc.gov/growthcharts/clinical_ 
charts.htm] and this will be utilized to calculate the weight for age percentiles for each  
participant in the later onset population. 
Subjects will be cross referenced with these files, given the age and sex of the subject to  
determine below which percentile they lie for each parameter.  
 
For patients <18 years of age the weight and length for age percentiles will be determined and 
summarized over time. 
Summary statistics for actual values and change from baseline in each growth parameter will be 
presented by visit. 
Baseline growth parameters for subjects <18 years of age at baseline, will be summarized and 
also the frequency and percentage for weight and height for age will also be presented for each 
of in the following categories: ≤ 1st, ≤ 3rd, ≤5th, ≤15th, ≤25th, ≤50th and > 50th percentile.  
 
  
  
 
 
 
  
 
5.7.8. LP opening pressure 
LP opening pressure will only be measured at dosing days (Days 1, 121, and 241). A lack of 
published data exists in terms of the variability of opening pressure between and within subjects. 
It is suspected that a simple change in position of a subject during the measurement or change of 
instrument used contributes to variability in the measurement.  
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The actual value and change from baseline to each visit will be summarized, all the data 
collected will be listed.  
5.7.9. X-ray Examination of Spine 
The X-rays will be used to determine the severity of scoliosis by measuring the Cobb angle of 
later onset patients in Cohort 1 and all patients in Cohort 2. The spine X-ray is performed at 
screening with the participant in a sitting or supported sitting position following an image 
acquisition guideline. Summary and listing of baseline Cobb angle will be presented.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
   
 
 
 
 
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5.8. 
Other Analyses 
Not applicable. 
5.9. 
Statistical Considerations for Interim Analysis 
Not applicable 
6. Changes from Protocol-Specified Analyses 
 
 
 
7. Summary of Changes from the Previous Version of the SAP 
8. References 
 
 
 
 
 
Bohdana Ratitch, Ilya Lipkovich, Michael O'Kelly. Combining Analysis Results from Multiply 
Imputed Categorical Data. PharmaSUG 2013 - Paper SP03. 
De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular 
atrophy. Neuromuscul Disord. 2016;26(11):754-759. Epub 2016/10/05. 
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. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. 
Department of Health, Education, and Welfare; 1976. 
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. 
 
 
 
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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. 
 
 
 
 
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. 
 
 
 
 
 
 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
inventory. Med Care. 1999;37(2):126-39. 
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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9. APPENDICES 
APPENDIX A. Derivation of the dates 
 
 
i 
Table 9: Seeds used for each endpoint in MI  
Endpoint 
Seed 
HFMSE 
25980495 
RULM 
47886416 
 
ii 
Adverse Events 
In the situation where worsening in severity (including seriousness) occurs for an adverse event, 
study sites are instructed to enter an end date and start a new record for the adverse event. In the 
new record, the changed severity is to be recorded and the start date will be set to be the end date 
of the previous record. Data linking those records are collected in the data base. Consider three 
scenarios:  
• The first AE record occurs prior to the first dose, the second AE record occurs on or 
after the first dose, and the severity increases: Only the second record will be counted as 
treatment-emergent.  
• Both records occur on or after the first dose: If the AE severity on the second record is 
worse than the severity on the first record, then count both records as treatment-emergent.  
 Both records occur on or after the first dose: If worsening in severity and and 
seriousness  then count both records as treatment-emergent. 
Of note, when counting the total number of treatment-emergent events, events linked through 
change in severity will still be counted as separate events. 
For events with missing start or stop dates, the following criteria will be used for the purpose of 
identifying treatment-emergent adverse events:  
 If both the start and stop date for a particular event are missing, then the event is 
considered to have occurred on or after the first dose of study treatment. 
 If the start date for a particular event is missing and the stop date/time falls after the 
first dose date/time, then the event is considered to have occurred on or after the first 
dose of study treatment. 
 If the start time is missing and the start date is same as the first dosing date, then the 
event is considered to have occurred on or after the first dose of study treatment. 
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 If it cannot be determined whether or not an event has occurred on or after dosing due 
to a missing or partial date, then the event will be assumed to have occurred on or 
after the first dose for the purpose of identifying treatment-emergent adverse events. 
 
Specifically, let AESTDT denote the start date of an adverse event and TRTSTDT be the start 
date of study treatment. For the purpose of identifying the treatment emergent adverse events, the 
following algorithm will be used for the imputation of missing or partial date: 
 If AESTDT is completely missing or the year is missing, then impute AESTDT to 
TRTSTDT. 
 If, in AESTDT, year is present and month/day are missing and year is equal to the 
year portion of TRTSTDT, then impute the month/day portion of AESTDT to the 
month/day portion of TRTSTDT. 
 If, in AESTDT, year is present and month/day are missing and year is not equal to the 
year portion of TRTSTDT, then impute the month/day portion of AESTDT to 
January 01. 
 Consider the situation in AESTDT where year and month are present with only day 
missing. If the year and month are the same as those for TRTSTDT, then impute day 
in AESTDT with day in TRTSTDT. Otherwise, impute the day in AESTDT with the 
first day of the month. 
It is important to emphasize that the imputed date will not be used for calculations such as onset 
and duration of an adverse event.  
 
iii 
Concomitant Therapy and Procedure 
In order to define concomitant therapies with missing start or stop dates, the following additional 
criteria will be used: 
 If both the start and stop dates of a particular therapy were missing, that therapy is 
considered concomitant. 
 If the start date of a therapy was missing and the stop date of that therapy fell on or after 
the date of dosing, that therapy is considered concomitant. 
 If the start date of a therapy was prior to the date of dosing and the stop date of that 
therapy was missing and the therapy was listed as continuing, that therapy is considered 
concomitant. 
 If the start date of a therapy was prior to the date of dosing and the stop date of that 
therapy was missing and the therapy was listed as not continuing, that therapy is 
considered concomitant.  
 If the start/stop date of a therapy is partial then where it is not possible to rule out that it 
was not taken concomitantly it will be considered concomitant. 
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Denote the end date of medications as CMENDT and the study treatment start date as 
TRTSTDT. The medication is classified concomitant provided any of the following is NOT true: 
 CMENDT is complete and CMENDT is less than TRTSTDT. 
 Day of CMENDT missing and year/month of CMENDT is strictly before year-month of 
TRTSTDT. 
 Month of CMENDT is missing and year of CMENDT is strictly before year of 
TRTSTDT. 
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