Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
Phase: PHASE3
Conditions: Muscular Atrophy, Spinal
Sponsor: Biogen

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 
CONFIDENTIAL 
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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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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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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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.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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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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 

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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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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). 

Protocol 232SM203, Version 7 
Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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25 
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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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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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29 
 
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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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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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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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33 
 
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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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34 
 
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). 

Protocol 232SM203, Version 7 
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 
 

Protocol 232SM203, Version 7 
Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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38 
 
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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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40 
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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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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). 
 

Protocol 232SM203, Version 7 
Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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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 
 

Protocol 232SM203, Version 7 
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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Escalating Dose and Randomized, Controlled Study of Nusinersen in SMA 
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44 
 
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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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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United States 
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Maidenhead, Berkshire 
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United Kingdom 
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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 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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2 
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 
 

Amendment Summary for Protocol 232SM203, Version 6 
 
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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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16 
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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______________________________________________________________________ 
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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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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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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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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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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13 
 
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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18 
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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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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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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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.
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 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.

Amendment Summary for Protocol 232SM203, Version 4
CONFIDENTIAL
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Biogen MA Inc.
3
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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Biogen MA Inc.
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 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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(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.

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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.

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.

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
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.

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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

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1
Biogen MA Inc.
225 Binney Street
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Biogen Idec Research Limited
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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 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
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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
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 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
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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 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
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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.

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.