An Open-Label Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
Phase: PHASE2
Conditions: Muscular Atrophy, Spinal
Sponsor: Hoffmann-La Roche

 
Official Title: An Open-Label Study of Risdiplam in Infants With Genetically 
Diagnosed and Presymptomatic Spinal Muscular Atrophy 
NCT Number: NCT03779334 
Document Dates: Protocol Version 4: 30-March-2021 
 
 
 

PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Risdiplam—F. Hoffmann-La Roche Ltd
Protocol BN40703, Version 4
PROTOCOL
TITLE:
AN OPEN-LABEL STUDY OF RISDIPLAM IN 
INFANTS WITH GENETICALLY DIAGNOSED AND 
PRESYMPTOMATIC SPINAL MUSCULAR 
ATROPHY
PROTOCOL NUMBER:
BN40703
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-002087-12
IND NUMBER:
128972
TEST PRODUCT:
Risdiplam (RO7034067)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below
30-Mar-2021 20:51:05
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Risdiplam—F. Hoffmann-La Roche Ltd
2/Protocol BN40703, Version 4
PROTOCOL HISTORY
Version
Date Final
4
See electronic date 
stamp on title page
3
18 September 2020
2
26 February 2019
1
13 July 2018

 
Risdiplam—F. Hoffmann-La Roche Ltd 
3/Protocol BN40703, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol BN40703 has been amended primarily to reduce the overall number of 
ophthalmological assessments, including revision of the ophthalmological assessment 
requirements at baseline, and to modify the conditions for closure of recruitment. These 
changes were based on ophthalmological results from Study BP39056 (FIREFISH) and 
the overall risdiplam clinical development program.   Changes to the protocol, along with 
the rationale for key changes, are summarized below: 
• 
Ophthalmological monitoring conducted in 461 patients has not revealed any 
ophthalmological safety concerns. This dataset includes 62 patients from Study 
BP39056 (FIREFISH) aged 2.2 months to 6.9 months at enrollment, thus 
establishing retinal safety in infants older than 2 months.  Moreover, 
ophthalmological follow-up has been conducted for at least 1 year in 3 patients in 
the present study without any risdiplam-induced findings. Therefore, in order to 
reduce burden on patients and their families and caregivers, ophthalmological 
assessments will be conducted at the following visits: screening, Weeks 8, 28, and 
52, and yearly thereafter (Section 1.3.2 and Appendix 3). 
• 
A high number of repeat optical coherence tomography (OCT) images may be 
required to gain optimal OCT quality and in order not to delay the start of treatment 
in presymptomatic SMA infants, the time window for obtaining high quality screening 
ophthalmologic assessments is expanded from Day −42 to Day 14.  In the event 
that an OCT of sufficient quality cannot be obtained prior to enrollment, one must be 
obtained by Day 14 (Section 4.1.2, Appendix 1and Appendix 3). 
• 
The conditions for the closure of recruitment have been updated in order to facilitate 
completion of the study in a reasonable timeframe.  Recruitment has been 
challenging because patients having other treatment options, particularly those 
patients who have two copies of the SMN2 gene as they are the most likely 
candidates for alternative therapies.  Previously, recruitment would have closed 
when a minimum of 10 patients who meet criteria for  the primary efficacy population 
had been enrolled (two SMN2 copies (excluding the known SMN2 gene modifier 
mutation c.859G>C) and a baseline CMAP amplitude ≥ 1.5 mV). This has been 
updated so that recruitment will now close when either at least 25 patients, including 
a minimum of 5 patients who meet the criteria for the primary efficacy population 
(Section 6.3.3) are enrolled, OR when a total of 10 patients who meet the criteria for 
the primary efficacy population are enrolled (Sections 3.1, 3.3 and 4.1).  
Additional changes include the following: 
• 
Safety data for Study BN40703 have been updated (Section 1.2.2.4)   
• 
The timing of the primary analysis has been updated to account for the possibility 
that recruitment may be completed prior to 10 primary efficacy population 
patients being enrolled. Instead of the primary analysis occurring when the last 
patient with two SMN2 copies and a baseline CMAP amplitude ≥ 1.5 mV reaches 

 
Risdiplam—F. Hoffmann-La Roche Ltd 
4/Protocol BN40703, Version 4 
Month 12 of treatment, it will occur when the last patient enrolled overall reaches 
Month 12 of treatment (Sections 3.1 and 6).   
• 
The description of the sample size has been updated to include the requirements 
for a statistically significant result in the event that recruitment stops prior to 
enrolling 10 patients with two SMN2 copies and a baseline CMAP 
amplitude ≥ 1.5 mV (Sections 6.1 and 6.5.1). 
• 
At the request of the Belgian Health Authority (FAMHP), language regarding the 
monitoring of potential toxicities of co-administered CYP3A substrates removed 
with protocol version 3 has been restored (Section 4.4.1). 
• 
At the request of the FAMHP, language prohibiting grapefruit or Seville orange 
juice, which was removed with protocol version 3, has been restored because 
during the study, patients will reach the age where drinking these products may 
become possible (Section 4.4.3).   
• 
It has been clarified that home nursing will only be used in exceptional 
circumstances that prevent a patient from attending the study visit at the site 
(Section 4.5).   
• 
Language has been added to clarify that, regarding the stopping of the 
Hammersmith Infant Neurological Examination (HINE-2), the earliest final HINE-2 
evaluation will be at Week 104 . Previously, it was stated that from Week 104, 
this assessment will be stopped for each infant once the maximum score is 
reached at two consecutive visits, however, it was not clear at which visit this 
could first be achieved (Section 4.5.9.2 and Appendix 1).   
• 
It has been clarified that the Hammersmith Functional Motor Scale Expanded 
(HFMSE) may be video recorded for quality control purposes (Section 4.5.9.4).  
• 
It has been clarified that Bayley Scales of Infant and Toddler Development, Third 
Edition (BSID-III) is not required at study completion/early withdrawal visits that 
occur after Week 182 (Appendix 1). 
 
Additional minor changes and corrections have been made to improve clarity and 
consistency.  Substantive new information appears in italics.  This amendment 
represents cumulative changes to the original protocol.  

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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 24
1.1
Background on Spinal Muscular Atrophy............................... 24
1.2
Background on Risdiplam...................................................... 26
1.2.1
Nonclinical Studies ................................................................ 26
1.2.1.1
Pharmacokinetics .................................................................. 26
1.2.1.2
Toxicology ............................................................................. 27
1.2.2
Clinical Studies...................................................................... 28
1.2.2.1
Pharmacokinetics .................................................................. 28
1.2.2.2
Pharmacodynamics ............................................................... 29
1.2.2.3
Efficacy.................................................................................. 30
1.2.2.4
Safety .................................................................................... 30
1.3
Study Rationale and Benefit–Risk Assessment..................... 31
1.3.1
Study Rationale ..................................................................... 31
1.3.2
Benefit–Risk Assessment...................................................... 32
2.
OBJECTIVES AND ENDPOINTS ............................................................... 34
2.1
Efficacy Objectives ................................................................ 34
2.1.1
Primary Efficacy Objective..................................................... 34
2.1.2
Secondary Efficacy Objectives .............................................. 35
2.1.3
Exploratory Efficacy Objective............................................... 37
2.2
Safety Objectives................................................................... 38
2.3
Pharmacokinetic Objective .................................................... 38
2.4
Biomarker Objective .............................................................. 38
2.5
Health Status Utility Objective ............................................... 39
3.
STUDY DESIGN......................................................................................... 39
3.1
Description of the Study......................................................... 39
3.1.1
Independent Data Monitoring Committee .............................. 40
3.1.2
Permanent Ventilation Adjudication Committee..................... 41
3.2
End of Study and Length of Study......................................... 42

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3.3
Rationale for Study Design.................................................... 42
3.3.1
Rationale for Risdiplam Dose and Schedule ......................... 43
3.3.2
Rationale for Patient Population ............................................ 45
3.3.3
Rationale for Control Group................................................... 46
3.3.4
Rationale for Biomarker Assessments................................... 47
4.
MATERIALS AND METHODS .................................................................... 47
4.1
Patients.................................................................................. 47
4.1.1
Inclusion Criteria.................................................................... 47
4.1.2
Exclusion Criteria................................................................... 48
4.2
Method of Treatment Assignment and Blinding..................... 50
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 50
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 50
4.3.1.1
Risdiplam............................................................................... 50
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 50
4.3.3
Investigational Medicinal Product Accountability ................... 51
4.3.4
Continued Access to Risdiplam............................................. 52
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 52
4.4.1
Permitted Therapy................................................................. 52
4.4.2
Prohibited Therapy ................................................................ 53
4.4.3
Prohibited Food ..................................................................... 55
4.5
Study Assessments ............................................................... 55
4.5.1
Informed Consent Forms and Screening Log........................ 56
4.5.2
Medical History, Concomitant Medication, and
Demographic Data................................................................. 56
4.5.3
Anthropometric Measurements.............................................. 57
4.5.4
Physical and Neurological Examinations............................... 58
4.5.5
Vital Signs.............................................................................. 58
4.5.6
Electrocardiograms................................................................ 59
4.5.7
Ophthalmological Examination .............................................. 59
4.5.8
Nutritional Check ................................................................... 61

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4.5.9
Motor Function and Motor Development 
Assessments ......................................................................... 61
4.5.9.1
Bayley Scales of Infant and Toddler 
Development, Third Edition (BSID-III) ................................... 61
4.5.9.2
Hammersmith Infant Neurological 
ExaminationModule 2 (HINE-2)........................................... 63
4.5.9.3
Children's Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders (CHOP INTEND).......................... 63
4.5.9.4
Hammersmith Functional Motor Scale Expanded 
(HFMSE)................................................................................ 64
4.5.9.5
World Health Organisation (WHO) Milestones ...................... 65
4.5.9.6
Six-Minute Walk Test (6MWT; Ambulant Patients 
Only)...................................................................................... 65
4.5.10
Compound Muscle Action Potential....................................... 66
4.5.11
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 66
4.5.11.1
Clinical Genotyping Samples................................................. 68
4.5.11.2
Fluid Pharmacodynamic Assessments.................................. 68
4.5.11.3
Safety Laboratory Assessments............................................ 68
4.5.11.4
Plasma Protein Binding ......................................................... 69
4.5.11.5
Pharmacokinetic Assessments.............................................. 69
4.5.12
Parent/Caregiver-Reported Outcomes .................................. 70
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 70
4.6.1
Study Treatment Discontinuation........................................... 70
4.6.2
Patient Discontinuation from Study........................................ 71
4.6.3
Study Discontinuation............................................................ 71
4.6.4
Site Discontinuation............................................................... 71
4.6.5
Assessments at Study Completion/Early 
Withdrawal Visit..................................................................... 72
4.6.6
Follow-up Assessments......................................................... 72
5.
ASSESSMENT OF SAFETY....................................................................... 72
5.1
Safety Plan ............................................................................ 72
5.1.1
Risks Associated with Risdiplam ........................................... 73
5.1.1.1
Skin Toxicity .......................................................................... 73

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5.1.1.2
Oral and Larynx Mucous Membranes.................................... 73
5.1.1.3
Effects on Hematology Parameters ....................................... 73
5.1.1.4
Conjunctival Mucous Membranes.......................................... 74
5.1.1.5
Visual Impairments ................................................................ 74
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 74
5.1.2.1
Dose Modifications ................................................................ 74
5.1.3
Stopping Rules ...................................................................... 74
5.1.3.1
Individual Patient Stopping Rules.......................................... 74
5.1.3.2
Management Guidelines........................................................ 76
5.1.4
Safety Monitoring................................................................... 76
5.2
Safety Parameters and Definitions ........................................ 77
5.2.1
Adverse Events ..................................................................... 77
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 77
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 78
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 79
5.3.1
Adverse Event Reporting Period ........................................... 79
5.3.2
Eliciting Adverse Event Information....................................... 79
5.3.3
Assessment of Severity of Adverse Events ........................... 79
5.3.4
Assessment of Causality of Adverse Events ......................... 80
5.3.5
Procedures for Recording Adverse Events............................ 81
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 81
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 81
5.3.5.3
Persistent or Recurrent Adverse Events................................ 81
5.3.5.4
Abnormal Laboratory Values ................................................. 82
5.3.5.5
Abnormal Vital Sign Values ................................................... 83
5.3.5.6
Abnormal Liver Function Tests.............................................. 83
5.3.5.7
Deaths ................................................................................... 83
5.3.5.8
Preexisting Medical Conditions.............................................. 84
5.3.5.9
Lack of Efficacy or Worsening of Spinal Muscular 
Atrophy .................................................................................. 84

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5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 84
5.3.5.11
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 85
5.3.5.12
Patient/Caregiver-Reported Outcome Data........................... 87
5.3.5.13
Safety Biomarker Data........................................................... 87
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 87
5.4.1
Emergency Medical Contacts................................................ 88
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 88
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 88
5.4.2.2
Events That Occur after Study Drug Initiation........................ 88
5.4.3
Reporting Requirements for Medical Device 
Complaints............................................................................. 89
5.5
Follow-Up of Patients after Adverse Events .......................... 89
5.5.1
Investigator Follow-Up........................................................... 89
5.5.2
Sponsor Follow-Up ................................................................ 89
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 89
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 90
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 90
6.1
Determination of Sample Size ............................................... 90
6.2
Summaries of Conduct of Study............................................ 92
6.3
Analysis Population ............................................................... 92
6.3.1
Safety Analysis Population .................................................... 92
6.3.2
Pharmacokinetic and Pharmacodynamic Analysis 
Population.............................................................................. 92
6.3.3
Intent-to-Treat and Primary Efficacy Analysis 
Population.............................................................................. 92
6.4
Summaries of Treatment Group Comparability ..................... 92
6.5
Efficacy Analyses .................................................................. 93
6.5.1
Primary Efficacy Endpoint...................................................... 93
6.5.2
Secondary Efficacy Endpoints............................................... 94

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6.5.3
Exploratory Efficacy Endpoints.............................................. 97
6.5.4
Subgroup Analyses ............................................................... 98
6.6
Safety Analyses..................................................................... 98
6.6.1
Adverse Events ..................................................................... 99
6.6.2
Clinical Laboratory Test Results............................................ 99
6.6.3
Vital Signs.............................................................................. 99
6.6.4
Electrocardiogram Data Analysis........................................... 99
6.6.5
Concomitant Medications ...................................................... 99
6.7
Pharmacodynamic analyses.................................................. 99
6.8
Pharmacokinetic Analyses................................................... 100
6.9
Interim Analysis ................................................................... 100
7.
DATA COLLECTION AND MANAGEMENT ............................................. 101
7.1
Data Quality Assurance....................................................... 101
7.2
Electronic Case Report Forms............................................. 101
7.3
Source Data Documentation................................................ 101
7.4
Use of Computerized Systems ............................................ 102
7.5
Retention of Records........................................................... 102
8.
ETHICAL CONSIDERATIONS.................................................................. 103
8.1
Compliance with Laws and Regulations .............................. 103
8.2
Informed Consent................................................................ 103
8.3
Institutional Review Board or Ethics Committee.................. 104
8.4
Confidentiality...................................................................... 104
8.5
Financial Disclosure ............................................................ 105
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 105
9.1
Study Documentation .......................................................... 105
9.2
Protocol Deviations.............................................................. 106
9.3
Site Inspections ................................................................... 106
9.4
Administrative Structure....................................................... 106
9.5
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 106
9.6
Protocol Amendments ......................................................... 107

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10. REFERENCES ......................................................................................... 108
LIST OF TABLES
Table 1
Prioritization Order for Blood Samples........................................ 67
Table 2
Guidelines for Management of Patients Who Experience 
Adverse Events........................................................................... 76
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 80
Table 4:
Number of Patients in the Primary Analysis Population 
Needed to Achieve the Primary Endpoint ................................... 91
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 40
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 112
Appendix 2
Blood Samples.......................................................................... 118
Appendix 3
Ophthalmology Assessments.................................................... 120
Appendix 4
Order and Blocks of Assessments at Visits When Efficacy 
Measurements Are Performed up to and Including 
Week 104 ................................................................................. 121

Risdiplam—F. Hoffmann-La Roche Ltd
12/Protocol BN40703, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL STUDY OF RISDIPLAM IN 
INFANTS WITH GENETICALLY DIAGNOSED AND 
PRESYMPTOMATIC SPINAL MUSCULAR 
ATROPHY
PROTOCOL NUMBER:
BN40703
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-002087-12
IND NUMBER:
128972
TEST PRODUCT:
Risdiplam (RO7034067)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.

Risdiplam—F. Hoffmann-La Roche Ltd
13/Protocol BN40703, Version 4
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL STUDY OF RISDIPLAM IN INFANTS WITH 
GENETICALLY DIAGNOSED AND PRESYMPTOMATIC SPINAL 
MUSCULAR ATROPHY
PROTOCOL NUMBER:
BN40703
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-002087-12
IND NUMBER:
128972
TEST PRODUCT:
Risdiplam (RO7034067)
PHASE:
II
INDICATION:
Spinal muscular atrophy
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of 
risdiplam in infants genetically diagnosed with spinal muscular atrophy (SMA) but not yet 
presenting with symptoms.  Specific objectives and corresponding endpoints for the study are 
outlined below.
Efficacy Objectives
Primary Efficacy Objective
In line with the study population expected to predominantly include presymptomatic infants who, 
without any treatment, would develop a phenotype of Type 1 SMA, the primary efficacy 
objective for this study is to evaluate the efficacy of risdiplam in patients with two copies of the 
survival motor neuron (SMN)2 gene (excluding the known SMN2 gene modifier mutation 
c.859G C) and baseline compound muscle action potential (CMAP) ) amplitude 1.5 mV, as 
determined by the proportion of patients who are sitting without support after 12 months of 
treatment.  Sitting is defined as “sits without support for 5 seconds” as assessed in Item 22 of 
the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Gross Motor 
Scale.
Secondary Efficacy Objectives
The secondary efficacy objectives along with the corresponding endpoints for this study are as 
follows:
To evaluate the efficacy of risdiplam on the development of clinically manifested SMA on the 
basis of the following endpoints:
Proportion of patients developing clinically manifested SMA (at Month 12 and 
Month 24 of treatment)
To evaluate the efficacy of risdiplam on survival and permanent ventilation on the basis of the 
following endpoints
Time to death
Time to permanent ventilation 
Time to death or permanent ventilation
Proportion of patients alive without permanent ventilation (at Month 12 and Month 24 
of treatment) 
Proportion of patients alive (at Month 12 and Month 24 of treatment)

 
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To evaluate the efficacy of risdiplam on the achievement of motor milestones defined in the 
BSID-III and by the Hammersmith Infant Neurological Examination (HINE) on the basis of 
the following endpoints: 
Proportion of patients who achieve the attainment levels of the motor milestones 
assessed in the HINE-2 (head control, sitting, voluntary grasp, ability to kick, rolling, 
crawling, standing, and walking) (at Month 12 and Month 24 of treatment) 
Proportion of patients with two copies of the SMN2 gene sitting without support (at 
Month 12 of treatment [as assessed in Item 22 of BSID-III Gross Motor Scale]) for 
5 seconds (independent of the CMAP value at baseline)  
Proportion of patients sitting without support (at Month 24 of treatment [as assessed in 
Item 22 of BSID-III Gross Motor Scale] for 5 second 
Proportion of patients sitting without support (at Month 12 and Month 24 of treatment 
[as assessed in Item 26 of BSID-III Gross Motor Scale]) for 30 seconds 
Proportion of patients standing (at Month 24 [defined as “Stands Alone” for at least 
3 seconds as assessed in Item 40 of the BSID-III Gross Motor Scale]) 
Proportion of infants walking (at Month 24 [defined as “Walks Alone” takes at least 
3 steps as assessed in Item 42 of the BSID-III Gross Motor Scale]) 
Proportion of patients demonstrating the ability to achieve a scaled score within 
1.5 standard deviations of the chronological reference standard (at Months 24 and 42 
[as assessed through the use of the BSID−III Gross Motor Scale]) 
 
To evaluate the efficacy of risdiplam on motor function on the basis of the following endpoints: 
Change from baseline in the Children's Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders (CHOP INTEND) motor function scale (at Month 12 and 
Month 24 of treatment)  
Proportion of patients who achieve a score of 40 or higher, 50 or higher, and 60 or 
higher in the CHOP INTEND motor function scale (at Month 12 of treatment)  
Proportion of patients who meet CHOP INTEND stopping criteria at any point up to 
Month 24 of treatment  
Change from baseline (Month 24) in the Hammersmith Functional Motor Scale 
Expanded (HFMSE) (at Month 60 of treatment). 
To evaluate the efficacy of risdiplam on growth measures upon treatment on the basis of the 
following endpoints: 
Number and proportion of patients within 3rd percentile of normal range for 
weight-for-age, length/height-for-age and weight-for-length/height (at Months 12, 24, 
36, 48, and 60 of treatment based on the WHO Child Growth Standards) (WHO 2019)  
Number and proportion of patients within 3rd percentile of normal range for head 
circumference-for-age (at Month 12 and Month 24 of treatment, based on the WHO 
Child Growth Standards) (WHO 2019) 
Change from baseline percentiles for weight-for-age, length/height-for-age and 
weight-for-length/height (at Months 12, 24, 36, 48 and 60 of treatment)  
Change from baseline percentiles for head circumference-for-age (at Month 12 and 
Month 24 of treatment)  
Change from baseline in chest circumference (at Month 12 and Month 24 of treatment)  
Ratio between chest and head circumferences (at Month 12 and Month 24 of 
treatment) 
To evaluate the efficacy of risdiplam on the nutritional status of the patients upon treatment with 
risdiplam on the basis of the following endpoint: 
Ability to swallow and to feed orally (at Months 12, 24, 36, 48, and 60 of treatment) 
To evaluate the efficacy of risdiplam on the degree of innervation upon treatment with risdiplam 
on the basis of the following endpoint: 
Change from baseline in CMAP amplitude (at Month 12 and 24 of treatment) 

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To evaluate the pharmacodynamic (PD) effects of risdiplam on the basis of the following 
endpoints:
SMN mRNA levels in blood
SMN protein levels in blood
Exploratory Efficacy Objectives
The exploratory efficacy objectives along with the corresponding endpoint for this study are as 
follows:
To evaluate the efficacy of risdiplam to achieve other developmental milestones as defined by 
BSID-III and WHO milestones on the basis of the following endpoints:
Cognition assessed through the use of the BSIDIII Cognitive Scale (at Months 12, 24, 
and 42 of treatment)
Proportion of patients demonstrating the ability to achieve a scaled score within 
1.5 standard deviations of chronological reference standard (at Months 24 and 42 of 
treatment [as assessed through the use of the BSIDIII Cognitive Scale])
Fine motor function assessed through the use of the BSIDIII Fine Motor Scale (at 
Months 12, 24, and 42 of treatment)
Proportion of patients demonstrating the ability to achieve a scaled score within 
1.5 standard deviations of chronological reference standard (at Months 24 and 42 of 
treatment [as assessed through the use of the BSIDIII Fine Motor Scale])
Proportion of patients who attain motor milestones as assessed by WHO criteria (at 
Months 48 and 60 of treatment)
To evaluate the efficacy of risdiplam on motor function on the basis of the following endpoint:
Total Walk Distance in the six-minute walk test (6MWT; ambulant patients only) (at 
Month 60 of treatment)
To explore the treatment effect on speech development on the basis of the following endpoint:
Speech development as assessed during the neurological examination (at Months 12, 
24, 36, 48, and 60 of treatment).

To explore the effect of treatment with risdiplam on the number of hospitalizations on the 
basis of the following endpoints: 
Number of hospitalizations (for any reason, except if for study purpose only [e.g., to 
facilitate study assessments]) per patient-year and number of nights admitted to 
hospital per patient (at 12, 24, 36, 48, and 60 months of treatment).
Proportion of patients with no hospitalizations (at 12, 24, 36, 48, and 60 months of 
treatment).
To explore the treatment effect on pre-specified disease-related adverse events on basis on the 
following endpoint: 
Pre-specified disease-related adverse events by 12 and 24 months of treatment
Safety Objectives
The safety objective for this study is to evaluate the safety of risdiplam on the basis of the 
following endpoints:
Incidence and severity of adverse events, with severity determined according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5
Incidence and severity of serious adverse events
Incidence of treatment discontinuation due to adverse events
Incidence of abnormal laboratory values
Incidence of abnormal ECG values

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Vital signs abnormalities, including body temperature, systolic and diastolic blood pressure, 
heart rate, respiratory rate
Ophthalmological examination as appropriate for age (e.g., red reflex, external ocular 
examination, pupillary examination/response, cover/uncover, fix and follow test, corneal 
light reflex, fundus examination including ophthalmoscopy/slit lamp examination, SD-OCT, 
and fundus photography)
Physical examination, including detailed examination of the skin and mouth
Pharmacokinetic Objective
The pharmacodynamic (PK) objective for this study is to characterize the PK profile of risdiplam 
on the basis of the following endpoints:
Plasma concentration of risdiplam and its metabolite(s), as appropriate, at specified timepoints
Area under the concentration–time curve (AUC)
Concentration at the end of a dosing interval to assess steady-state
Other PK parameters as appropriate
Biomarker Objective
The exploratory biomarker objective for this study is to identify biomarkers that are predictive of 
response to risdiplam (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), are 
associated with susceptibility to developing adverse events or can lead to improved adverse 
event monitoring or investigation (i.e., safety biomarkers), can provide additional evidence of 
risdiplam activity (i.e., PD biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints:
Relationship between exploratory biomarkers in blood and efficacy, safety, PK, or other 
biomarker endpoints
Relationship of genetic, epigenetic, or genomic markers with efficacy, safety, PK, or other 
biomarker endpoints related to SMA
Health Status Utility Objective
The exploratory health status utility objective for this study is to evaluate parent (or 
caregiver)-rated health status and health-related quality of life on the basis of the following 
endpoint:
Change from baseline in Infant/Toddler Quality of Life Questionnaire(at 12 and 24 months of 
treatment)
Study Design
Description of Study
The study is an open-label, single-arm, multicenter clinical study to investigate the efficacy, 
safety, pharmacokinetics, and pharmacodynamics of risdiplam in infants aged from birth to 
6 weeks who have been (at first dose) genetically diagnosed with SMA but are not yet 
presenting with symptoms.
There will be a screening, treatment, open-label extension (OLE) phase, and a follow-up.  
Screening will be up to 42 days prior to first dose, bearing in mind the maximum age of the 
patient at first dose of study drug is 42 days.  Screening assessments may be repeated before 
enrollment to confirm eligibility.  Patients will be enrolled in the study regardless of SMN2 copy 
number.  Recruitment will be global (e.g., at sites in United States, European Union, Russia, 
Brazil, Australia, Taiwan, Saudi Arabia and National Medical Products Administration 
recognized sites in China).  All patients will receive risdiplam orally once daily for 2 years at a 
dose selected to achieve the targeted exposure range of close to 2000 ng hr/mL (the dose 
may be adapted as patients grow and mature), followed by an OLE phase of at least 36 months 

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Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Concomitant or previous participation in any investigational drug or device study at any time
Concomitant or previous administration of an SMN2-targeting antisense oligonucleotide, 
SMN2-splicing modifier, or gene therapy either in a clinical study or as part of medical care
Presence of significant concurrent syndromes or diseases
In the opinion of the investigator, inadequate venous or capillary blood access for the study 
procedures
Requiring invasive ventilation or tracheostomy
Requiring awake non-invasive ventilation
Awake hypoxemia (SaO2 95%) with or without ventilator support
Multiple or fixed contractures and/or hip subluxation or dislocation at birth
Systolic blood pressure or diastolic blood pressure or heart rate considered to be clinically 
significant by the investigator
Presence of clinically relevant ECG abnormalities before study drug administration; corrected 
QT interval using Bazett’s method 460 ms; personal or family history (first degree 
relatives) of congenital long QT syndrome indicating a safety risk for patients as determined 
by the investigator.  First-degree atrioventricular block or isolated right bundle branch block 
are allowed.
The infant (and the mother, if breastfeeding the infant) taking any of the following:
Any inhibitor of CYP3A4 taken within 2 weeks (or within 5 times the elimination 
half-life, whichever is longer) prior to dosing, including but not limited to:  ketoconazole, 
miconazole, itraconazole, fluconazole, erythromycin, clarithromycin, ranitidine, 
cimetidine
Any inducer of CYP3A4 taken within 4 weeks (or within 5 times the elimination half-life, 
whichever is longer) prior to dosing, including but not limited to: rifampicin, rifabutin, 
glucocorticoids, carbamazepine, phenytoin, phenobarbital, St. John's wort
Use of any OCT 2 and MATE substrates within 2 weeks prior to dosing (including but 
not limited to: amantadine, cimetidine, memantine, amiloride, famotidine, metformin, 
pindolol, ranitidine, procainamide, varenicline, acyclovir, ganciclovir, oxaliplatin, 
cephalexin, cephradine, fexofenadine)
Use of any known FMO1 or FMO3 inhibitors or substrates
Clinically significant abnormalities in laboratory test results (e.g., Grade 1 anemia, ALT values 
exceeding 1.5 the upper limit of normal unless the elevated ALT level is considered of 
muscular origin [i.e., in the absence of other evidence of liver disease that is confirmed by 
elevated creatine kinase and lactate dehydrogenase]).  Out of range creatine kinase levels 
should be reviewed in light of the underlying SMA pathology of the patient; elevated levels 
per se do not disqualify the patient from the study.  In the case of uncertain or questionable 
results, tests performed during screening may be repeated before enrollment to confirm 
eligibility.
Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to risdiplam or to the 
constituents of its formulation (see the Risdiplam Investigator’s Brochure)
Treatment with oral salbutamol or another 2 adrenergic agonist taken orally for SMA is not 
allowed.  Use of inhaled 2 adrenergic agonists (e.g., for the treatment of asthma) is 
allowed.
Anticipated need for thioridazine, vigabatrin, retigabine, or any other drug known to cause 
retinal toxicity during the study.  Infants exposed to thioridazine, vigabatrin, retigabine, or 
drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should 
not be enrolled.

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Diagnosis of ophthalmic diseases (e.g., glaucoma, central serous retinopathy,
inflammatory/infectious retinitis unless clearly inactive, retinal detachment, intraocular 
trauma, retinal dystrophy or degeneration, optic neuropathy, or optic neuritis) that would 
interfere with the conduct of the study as assessed by an ophthalmologist.  Any other 
abnormalities detected with SD-OCT during screening prior to enrollment (e.g., retinal 
layer abnormalities, edema, cystic or atrophic changes) must be discussed with the 
investigator, ophthalmologist, and with the Sponsor, who will jointly determine if the infant 
may be enrolled in the study.  Infants in whom SD-OCT measurement of sufficient quality 
cannot be obtained at screening will not be enrolled.  In the event that an OCT of 
sufficient quality cannot be obtained prior to enrollment, one must be obtained by Day 14.
End of Study
The end of study (EOS) is defined as the date when the last patient, last visit (LPLV) occurs.  
Length of Study
The study will continue until the EOS, or as per local regulation, or per the Sponsor’s decision to 
terminate risdiplam development.  However, the length of the study will not exceed a total of 
5 years after the last patient is enrolled in the study. 
After completion of 2 years treatment, each patient will continue to receive treatment in the OLE 
phase for at least 3 years.  After a patient has completed 3 years in the OLE, the patient may 
continue until EOS, provided that risdiplam is not commercially available in the country of the 
site.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product for this study is risdiplam.
Throughout the study, the study drug (risdiplam) should be taken orally once daily in the 
morning, except when site visits are planned and study medication will be administered at the 
clinical site.  In patients able to swallow, study drug will be administered with a syringe inserted 
between gum and cheek of the patient as described in the study drug administration instructions 
for use.  Patients unable to swallow the study medication and who have a naso-gastric or 
gastrostomy tube in situ should receive the study medication by bolus via the tube.
Statistical Methods
Primary Analysis
All enrolled infants with two SMN2 copies (excluding the known SMN2 gene modifier mutation 
c.859G C) and a baseline CMAP amplitude 1.5 mV will be included in the primary efficacy 
analysis.  The primary endpoint of the study is the proportion of infants who are sitting without 
support after 12 months of treatment.  Infants who do not achieve sitting, or have not 
maintained sitting achieved earlier, have been withdrawn, or died, will be classified as 
non-responders (i.e., non-sitters) for the primary analysis.  Sitting is defined as “sits without 
support for 5 seconds” as assessed in Item 22 of the BSID-III Gross Motor Scale.  The 
assessment of the independent central readers will be used for the primary analysis.
The proportion of infants who are alive and sitting after 12 months of treatment will be presented 
with a two-sided 90% Clopper-Pearson (Exact) confidence interval.  An exact binomial test will 
be performed.  The hypothesis to be tested will be that the proportion of infants who sit on 
treatment (p) is:
Ho: p 5% (null) versus Ha: p 5% (alternative).
If the one-sided p-value is 5% (Type 1 error rate), then the null hypothesis will be rejected.  
If the lower limit of the two-sided 90% confidence interval is above the 5% threshold, the 
primary objective of the study will be considered achieved.  The number and percentage of 
infants sitting at each timepoint will also be presented, using the same 
responder/non-responder definition described above.
As this is an open-label study, once at least 3 out of 10 infants (if 10 patients in the primary 
analysis population are enrolled) have met the primary endpoint of sitting without support at 
Month 12 (as assessed by the independent central readers), the minimum number of infants 
needed for a statistically significant result will have been achieved and the primary objective of 

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the study will be considered achieved at this earlier timepoint.  The primary analysis will be 
conducted once the last patient enrolled (irrespective of SMN2 copy number) has reached 
12 months of treatment, in order to assess the primary endpoint, and to allow the assessment 
of the 12 month secondary and exploratory endpoints in all patients. The study will not be 
stopped early if the primary objective has been reached, and all infants enrolled will continue to 
receive 12 months of treatment to provide an unbiased estimate of the proportion of infants 
sitting at Month 12.
Determination of Sample Size
The purpose of the study is to estimate the proportion of infants with two SMN2 copies 
(excluding the known SMN2 gene modifier mutation c.859G C) and a baseline CMAP 
amplitude 1.5 mV who are sitting without support after 12 months of treatment and to test 
whether this proportion is higher than a performance criterion set at 5%.  The 5% threshold was 
chosen based on the natural history of the disease (typically patients with Type 1 SMA never 
achieve sitting without support by definition) and based on the assumption that there is a 97% 
chance that a presymptomatic infant with two SMN2 copies develops Type 1 SMA.
The target sample size to be enrolled in the study is 10 patients with two SMN2 copies and a 
baseline CMAP amplitude 1.5 mV.  The sample size of 10 patients provides 83% power to test 
the null hypothesis Ho:  p 5% versus alternative hypothesis Ha:  p 5%, if the true proportion 
of infants who would sit after 12 months on treatment is 40%.  This is based on an exact 
binomial test with a one-sided 5% significance level.  The minimum number of infants needed to 
be observed sitting without support is 3 out of 10 for a statistically significant result.  If 3 out of 
10 infants sit without support, the lower limit of the two-sided 90% Clopper-Pearson (Exact) 
confidence interval would be above 5%.
If recruitment is completed prior to enrolling 10 patients with two SMN2 copies and a 
baseline CMAP amplitude 1.5 mV, the number of patients needed to be observed sitting 
without support for a statistically significant result may differ. The table below shows the 
minimum number of patients that would need to achieve the primary endpoint (based on the 
number enrolled), in order for the endpoint to meet statistical significance (the critical value).  
In each case, the lower limit of the two-sided 90% Clopper-Pearson (Exact) confidence interval 
would be above 5%. 
Number of Patients in the Primary Analysis Population Needed to Achieve 
the Primary Endpoint  
Number of Patients in 
the Primary 
Population
Critical Value
Power (%)
5
2
66.3
6
2
76.7
7
2
84.1
8
3
68.5
9
3
76.8
10
3
83.3

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Interim Analyses
As this study is open-label, once at least 3 of the 10 infants (if 10 of these patients have been 
enrolled) have met the primary endpoint of sitting without support at Month 12 (as assessed by 
the independent central readers), the minimum number of infants needed for a statistically 
significant result will have been achieved and the primary objective of the study will be 
considered achieved at this earlier timepoint.  The study will not be stopped and all infants 
enrolled will continue to receive 12 months of treatment in order to provide an unbiased 
estimate of the proportion of infants sitting at Month 12.
An interim analysis may also be performed to summarize descriptively the safety and efficacy 
data to support the initial filing and registration of risdiplam in pre-symptomatic patients and 
patients below the age of 2 months. 
Interim analyses for efficacy will be performed by the Sponsor and the results presented to the 
iDMC.  The iDMC will be requested to review all available safety data and asked to provide an 
independent assessment of the benefit–risk profile of risdiplam in the pre-symptomatic 
SMA population at this earlier timepoint.

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
6MWT
six-minute walk test
AUC
area under the concentration–time curve
AUC0-24
area under the concentration–time curve from time 0 to 24 hours
AUC0-24,ss
area under the concentration–time curve from time 0 to 24 hours at 
steady state
BSID-III
Bayley Scales of Infant and Toddler Development,Third Edition
CDC
Centers for Disease Control and Prevention
CHOP INTEND
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders
CMAP
compound muscle action potential
Cmax
maximum plasma concentration observed
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
DAP
Data Analysis Plan
DDI
drugdrug interaction
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EOS
end of study
FDA
Food and Drug Administration
FMO
flavin-containing monooxygenase
HFMSE
Hammersmith Functional Motor Scale Expanded
HINE
Hammersmith Infant Neurological Examination
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
health-related quality of life
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ITQOL
Infant Toddler Quality of Life Questionnaire
ITQOL-SF47
Infant Toddler Quality of Life Questionnaire47-item short-form
version
ITT
intent-to-treat (population)
IxRS
interactive voice or web-based response system
LPLV
last patient, last visit

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Abbreviation
Definition
MATE
multidrug and toxin extrusion
MN
mobile nursing
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NOAEL
no-observed-adverse-effect level
NOEL
no-observed-effect level
OCT 2
organic cation transporter 2
OLE
open-label extension
OTC
over-the-counter
PD
pharmacodynamic
PK
pharmacokinetic
PRO
patient-reported outcome
QTc
corrected QT interval
QTcF
QT interval corrected through use of Fridericia’s formula
SD-OCT
spectral-domain optical coherence tomography
SMA
spinal muscular atrophy
SMN
survival motor neuron (protein)
SMN
survival motor neuron (gene)
ULN
upper limit of normal
WHO
World Health Organisation

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1.
BACKGROUND
1.1
BACKGROUND ON SPINAL MUSCULAR ATROPHY
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder 
characterized by the progressive loss of proximal motor neurons leading to muscle 
weakness and profound neuromotor disability beginning in infancy (Crawford and Pardo
1996; Lunn and Wang 2008). It is the leading genetic cause of mortality in infants and 
young children, with an incidence of 1 in ~11,000 live births and a carrier frequency 
estimated at 1 in 5070 individuals (Sugarman et al. 2012).
Clinically, SMA ranges in disease severity. For classification purposes, patients are 
usually categorized into four main subtypes based on clinical criteria, including achieving 
(or failing to achieve) physical motor milestones, age of onset, and life span (Munsat and 
Davies 1992): Type 1 SMA or Werdnig-Hoffmann disease (severe infantile type with 
onset before 6 months of age; infants never sit without support, with death due to 
respiratory distress usually within 2 years), Type 2 SMA (intermediate chronic infantile 
type with onset after the age of 6 months, children unable to stand or walk without 
support), Type 3 SMA or Kugelberg-Welander disease (chronic juvenile type with onset 
around the age of 18 months, children able to walk until the disease progresses), and 
Type 4 SMA (adult onset). 
SMA is caused by a homozygous deletion (95% of cases) or mutation of the survival of 
motor neuron (SMN) 1 gene on chromosome 5q (locus 5q13), which encodes SMN, an 
essential protein expressed in both neuronal and non-neuronal cells (Lefebvre et al.
1995). In humans, there are two SMN genes, the SMN1 gene and its paralog SMN2. 
Species other than human have only one SMN gene, which is equivalent to the human 
SMN1 gene. Due to a translationally synonymous C to T mutation at nucleotide 6 in
exon 7, the SMN2 pre-mRNA undergoes alternative splicing, which excludes exon 7 
from 85%90% of mature SMN2 transcripts producing an unstable SMN7 protein that 
is rapidly degraded (Lorson et al. 1999; Cho and Dreyfuss 2010). Accordingly, 
full-length SMN2 mRNA is generated in only 10%15% of splicing events. Because
patients with SMA only have the SMN2 gene, their SMN protein levels are significantly 
decreased (Kolb and Kissel 2011).
Consistent with this mechanism, several studies have reported a phenotype-genotype 
relationship among patients with SMA, showing that an increased SMN2 copy number is 
correlated with improved survival outcomes and maintenance of motor function 
(Feldkotter et al. 2002; Mailman et al. 2002): The majority of patients with Type 1 
SMA have two SMN2 copies, though some have three and even four or five copies; 
patients with Type 2 SMA usually have three SMN2 copies; patients with Type 3 
SMA have three or four SMN2 copies; and patients with Type 4 SMA have four or more 
SMN2 copies (Crawford et al. 2012). Considering the number of studies that have 
confirmed a positive correlation between SMN2 copy number and a milder phenotype, 

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SMN2 copy number is currently regarded as a determinant of SMA disease severity (yet 
it is not the only phenotype modifier; see Prior et al. 2009 for example).
Although the exact mechanism by which SMN protein deficiency leads to motor neuron 
loss as observed in patients with SMA is currently unclear (Nurputra et al. 2013), the 
elucidation of the molecular basis of SMA suggests several therapeutic approaches 
based on the general principle of increasing SMN protein expression (Kolb and Kissel 
2011). In fact, considering that SMN protein levels in patients with SMA Type 1, Type 2,
and Type 3 are ~30%40%, ~50%60% and ~60%80%, respectively, of the normal 
level (i.e., level in SMN1carrier individuals) (Kolb et al. 2006; Sumner et al. 2006;
Nguyen et al. 2008), even moderate changes in SMN protein levels are expected to 
have a substantial clinical benefit in patients with SMA, turning more severe phenotypes 
into milder forms. In addition, nonclinical data suggest that greater than 100% SMN 
protein increase is likely to result in better efficacy in patients with SMA.
The timing of therapeutic intervention is crucial since most of the degeneration in motor 
neurons occurs in the first months of life in patients with Type 1 SMA.  It has been 
demonstrated that infants with Type 1 SMA undergo a rapid loss of motor units in the 
first 3 months of life. Results from recent clinical trials in presymptomatic patients have
shown a more rapid achievement of motor milestones and diminished disease severity 
when therapy was administered at an early age and earlier in the disease course
(Hwu et al. 2017).
In all types of SMA, as the disease progresses, clinical symptoms include hypotonia, 
symmetrical muscle weakness and atrophy (predominantly of the proximal muscles of 
the shoulder and pelvic girdle), diminished or absent deep tendon reflexes, tremor of 
fingers and hands, fasciculation of the tongue muscles, and hyporeflexia with orthopedic 
deformities (contractures, scoliosis). Progressive respiratory failure and frequent 
pulmonary infections and superinfections are common in Types 1 and 2 SMA. Other 
common comorbidities include failure to thrive, sleep difficulties, pneumonia, osteopenia 
and osteoporosis with pathological fractures, poor cough and secretion clearance, 
reduced vital capacity, gastroesophageal dysmotility, urinary incontinence, hip 
dislocation, and joint and muscle pain.
Nusinersen (Spinraza™) is currently licensed for the treatment of SMA. This 
intrathecally administered antisense oligonucleotide acts by binding downstream of 
exon 7 in the SMN2 pre-mRNA, allowing for its inclusion in the mRNA message, thus 
enhancing translation into fully functional SMN2 encoded protein (Hua et al. 2010). 
However, the medical need in SMA is still high, and there is currently no approved oral 
treatment for SMA that provides stabilization or improvement of motor function. Several 
drug candidates are currently under investigation in the clinical setting (Kariyawasam 
et al. 2018).

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Alternative management strategies focus on prevention and treatment of comorbidities, 
such as failure to thrive, surgical and non-surgical treatment of scoliosis and 
contractures, pulmonary hygiene, non-invasive ventilation, mobility and seating support, 
and physical and occupational therapy.
More recent and detailed information is provided in the Risdiplam Investigator’s 
Brochure.
1.2
BACKGROUND ON RISDIPLAM
One of the promising pharmacological strategies currently being pursued is to restore 
functional SMN protein levels in patients with SMA by modulating SMN2 splicing to favor 
the inclusion of exon 7 into the mRNA transcript, thereby increasing expression of stable 
full-length protein from the SMN2 gene (Kolb and Kissel 2011; Nurputra et al. 2013). 
This approach is supported by the recent approval of nusinersen, an antisense 
oligonucleotide promoting inclusion of exon 7 in SMN2 pre-mRNA, thereby increasing 
the amount of full-length SMN protein expressed by the SMN2 gene. Risdiplam 
(formerly known as RO7034067) is an orally bioavailable small-molecule compound, 
which directly targets the underlying molecular deficiency of the disease, promoting the 
inclusion of exon 7 to generate full-length SMN2 mRNA and thereby increasing the 
production of the functional SMN protein. The specificity for SMN2 over other transcripts 
was elucidated in a study with SMN2 splicing modifier tool molecules of the same 
chemical series and closely related to risdiplam (Sivaramakrishnan et al. 2017). These 
data demonstrate that risdiplam modifies alternative splicing rather than gene expression 
with high specificity.
Risdiplam has been investigated in five clinical pharmacology studies in healthy subjects 
and in three ongoing studies in patients with SMA. To date, treatment with risdiplam has 
been safe and well tolerated in all studies, and an exposure-dependent increase in SMN 
protein was observed in patients with SMA, confirming proof of mechanism. Risdiplam 
has been approved in the USA for patients 2 months of age and older.
Findings from nonclinical studies and clinical study data relevant to this study are 
summarized below.
Refer to the Risdiplam Investigator's Brochure for details on nonclinical and clinical 
studies.
1.2.1
Nonclinical Studies
1.2.1.1
Pharmacokinetics 
For a detailed summary of preclinical data, please refer to the Risdiplam Investigator's 
Brochure.
Risdiplam is cleared in animals and humans primarily through metabolism with minor 
contribution from renal clearance. The metabolizing enzymes involved are 

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flavin-containing monooxygenase (FMO) 1 and 3 and members of the CYP superfamily, 
especially CYP3A. Risdiplam is an inhibitor of organic cation transporter 2 (OCT 2), 
multidrug and toxin extrusion (MATE)1, and MATE2-K, and the potential for interaction 
with other drugs that are substrates of those transport proteins cannot be ruled out. 
Such drugs are therefore prohibited for patients participating in this study.
Risdiplam is a weak inhibitor of CYP3A. A small, but clinically not relevant, interaction 
was observed in adult subjects (increase in AUC 11% and Cmax 16%). Based on 
physiologically-based pharmacokinetic (PBPK) modeling a similar magnitude of the 
effect is expected in children and infants as young as 2 months old. Caution should be 
applied for co-administration of risdiplam and CYP3A substrates in infants 2 months of 
age.
1.2.1.2
Toxicology 
For a detailed summary of the toxicology data, please refer to the Risdiplam
Investigator's Brochure. 
Findings of toxicological significance for risdiplam were observed mainly in organs with 
rapid cell turnover in mice, rats, and monkeys.
A further finding of significance was noted in the retina from the 39-week toxicology
study in monkeys. Multifocal peripheral retina degeneration in the photoreceptor layer 
and microcystic spaces in the inner retinal layers in monkeys was detected by 
spectral-domain optical coherence tomography (SD-OCT). This was associated with 
depressed scotopic (rod) B-wave and somewhat less affected photopic (cone) B-wave in 
the electroretinogram. These findings were confirmed by histopathology. Experimental 
evidence suggests that the effect on the retina is not directly associated with effects on 
tissue proliferation but is related to in vitro evidence of high melanin binding and tissue 
retention in the retina. Despite high tissue accumulation and tissue retention of risdiplam
in monkey and pigmented rat retinal pigment epithelium/retina, no evidence for any 
retinal effects was present after 26 weeks of treatment in pigmented rats, at which time 
retinal changes were clearly seen in monkeys. Thus, melanin-bound risdiplam in the 
retina does not confer toxicity per se.
The doses for the clinical studies in patients with SMA were selected to result in a mean 
exposure (area under the concentration–time curve from time 0 to 24 hours at steady 
state [AUC0-24,ss]) of 2000 ng hr/mL. This corresponds to the mean exposure at the 
no-observed-adverse-effect level (NOAEL)/no-observed-effect level (NOEL) of the 
39-week toxicity study in monkeys with an area under the concentration–time curve from 
time 0 to 24 hours (AUC0-24) of 1870/2060 ng hr/mL in males and females, respectively.
Young/very young rats displayed a higher dose-based susceptibility to the subacute, 
life-threatening toxicity of risdiplam than older rats, likely based on a higher free fraction
and longer half-life. Thus, careful evaluation of the free fraction of risdiplam in plasma of 

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infants is warranted, with specific adaptation of the doses to be tested if differences in 
plasma protein binding similar to those seen in rats of different ages should be found.
In rats, risdiplam resulted in embryo-fetal toxicity with retarded fetal development, 
evidenced by lower fetal weights and minor differences in skeletal ossification.  There 
was no evidence of embryo-fetal death or fetal dysmorphology (teratogenicity) in rats.  
The NOAEL for rats was 3 mg/kg/day, corresponding to Cmax 319 ng/mL and AUC0-24h
4630 ng•h/mL on gestational day (GD) 15.  In rabbits, risdiplam administered from 
Days 6 to 19 of gestation resulted in maternal toxicity and embryo-fetal death and 
malformations (hydrocephaly).  The NOAEL for rabbits was 4 mg/kg/day for risdiplam 
(Cmax1500 ng/mL, AUC0-24h 7990 ng•h/mL on GD 15).
1.2.2
Clinical Studies
Risdiplam has been investigated in five clinical pharmacology studies; all five studies 
(BP29840, BP39122, NP39625, BP41361, and BP40995) have been completed (see the 
Risdiplam Investigator’s Brochure for available data):

Study BP29840 (single ascending dose, entry-into-human study in healthy male 
adults)

Study BP39122 (a mass-balance study in healthy male adults)

Study NP39625 (a pharmacokinetic [PK] study in healthy Japanese adults)

Study BP41361 (a drug-drug interaction [DDI] study with the CYP3A substrate 
midazolam)

Study BP40995 (a hepatic impairment study)
Additionally, there are three ongoing studies in patients with SMA:

Study BP39054 (an open-label study to evaluate safety, pharmacokinetics, and 
pharmacodynamics in non-naive patients with Type 1, 2, or 3 SMA) 

Study BP39055 (a study to evaluate safety, pharmacokinetics, pharmacodynamics,
and efficacy in patients with Type 2 or 3 SMA)

Study BP39056 (a study to evaluate safety, pharmacokinetics, pharmacodynamics, 
and efficacy in patients with Type 1 SMA)
Current data for ongoing studies is provided in the Risdiplam Investigator Brochure.
1.2.2.1
Pharmacokinetics 
In the completed single ascending dose study in healthy adults (BP29840), risdiplam
was rapidly absorbed with a median time of maximum concentration between 23 hours 
under fasted conditions. Food had no relevant effect on the pharmacokinetics.
Maximum plasma concentration (Cmax) and total plasma exposure (area under the 
concentrationtime curve [AUC]) increased in a dose-proportional manner. The 
elimination half-life was approximately 4164 hours. On average, a small fraction 
(10%) of the administered dose was excreted unchanged into urine. Itraconazole

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(CYP3A4 inhibitor) had only a minor effect on the pharmacokinetics. A mass-balance 
study (BP39122) showed that the major pathway of elimination was fecal excretion with
on average 53.2% of the dose administered; urinary excretion of [14C]-radioactivity 
accounted for on average 28.2% of the dose administered. Study NP39625 showed that 
there was no difference in plasma or urine PK parameters, or the pharmacodynamic 
(PD) effects of risdiplam on SMN mRNA and SMN protein, between Japanese and 
Caucasian healthy subjects.
In Part 1 of Study BP39055 in patients with Type 2 or 3 SMA, pharmacokinetics was 
linear (i.e., there was a corresponding increase in risdiplam plasma concentrations with 
increase in dose). The median AUC0-24,ss at the highest evaluated dose of 5 mg was 
1610 ng hr/mL (range: 11401950 ng hr/mL) in the 1225-year-old group. In the 
group of patients with SMA aged 211 years, the highest evaluated dose of 0.25 mg/kg 
led to a median AUC0-24,ss of 1450 ng hr/mL (range: 12302090 ng hr/mL). There was 
no indication of nonlinear pharmacokinetics versus dose or a change in 
pharmacokinetics with time after multiple-dose administration. Steady state was 
attained after 714 days of treatment with risdiplam once daily.
In Study BP39056 in infants with Type 1 SMA, the final dose level selected was 
0.2 mg/kg for all infants 2 years old. The mean AUC0-24,ss at 0.2 mg/kg was 
1930 ng hr/mL (range: 12303300) at the Month 12 visit.
Please see Section 3.3.1 for details on dose selection.
1.2.2.2
Pharmacodynamics 
In healthy adults (Studies BP29840 and NP39625), risdiplam had a dose-dependent 
effect on SMN2 splicing, as shown by a change in the ratio of full-length SMN2 mRNA to 
SMNΔ7 mRNA.
In Part 1 of Study BP39055 in patients with Type 2 or 3 SMA, a median SMN protein 
increase of 151% (range: 49%251%) versus baseline was observed for the highest 
evaluated dose of 5 mg in patients 1225 years old, and a 96% (range: 17%150%) 
increase in SMN protein was noted for the highest tested dose of 0.25 mg/kg in the 
211 year age group.
In Part 1 of Study BP39056 in infants with Type 1 SMA, a 2-fold increase (median;
range 1.05.4) in SMN protein versus baseline was observed for infants with an 
exposure (AUC0-24) 1000 ng hr/mL and a 3.2-fold increase (median; range 1.66.5) in 
infants with an exposure (AUC0-24) 1000 ng hr/mL. 
More recent and detailed information is provided in the Risdiplam Investigator’s 
Brochure.

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1.2.2.3
Efficacy
The objectives for Study BP39056 Part 1 were to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of risdiplam in infants with Type 1 SMA and 
to select the dose for Part 2.  As of 2 May 2018, preliminary review of efficacy data from 
Part 1 indicates benefits of treatment.
More recent and detailed information is provided in the Risdiplam Investigator’s
Brochure.
1.2.2.4
Safety
In healthy adults, single doses of risdiplam have been well tolerated at all dose levels 
(Studies BP29840, NP39625, and BP39122) and in combination with itraconazole 
(Study BP29840, Part 3). There were no deaths, withdrawals due to adverse events, or 
any severe adverse events. One serious adverse event of pneumonia was reported in 
Study BP39122, which resolved upon supportive treatment and was assessed as 
unrelated to study treatment by the investigator. No clinically relevant changes in 
laboratory safety parameters, vital signs, adverse events, ECG parameters, or 
ophthalmological assessments related to risdiplam were observed in any study.
In Part 1 of Study BP39055 as of 2 May 2018, risdiplam was well tolerated in patients 
with Types 2 and 3 SMA across all dose levels tested. Adverse events reported during
active treatment in Part 1 were mostly mild in intensity and resolved without any change 
to study treatment. In Part 1, eight serious adverse events were reported during active 
treatment in 5 patients; all were reported as unrelated to study drug. No deaths have 
been reported, and 1 patient discontinued due to withdrawal of consent, but not due to 
adverse events.
In Part 1 of Study BP39056, the dose finding part of the study, risdiplam has been well 
tolerated in all 21 patients with Type 1 SMA across all dose levels tested. The pivotal 
Part 2 of the study has started. As of 2 May 2018, adverse events reported for all 
21 patients in Part 1 were mostly mild or moderate in intensity and resolved without 
change in study treatment.  Nine patients experienced at least one serious adverse 
event; 2 of the 9 patients had a serious adverse event with a fatal outcome. The two 
fatal events reported were viral respiratory tract infection in 1 patient, and cardiac arrest 
and respiratory failure in the other patient; both were considered to be unrelated to study 
treatment. Seven additional patients experienced serious adverse events:  pneumonia 
(two events) and neutropenia and influenza; acute respiratory failure; hypoxia and 
aspiration pneumonia and respiratory distress; respiratory distress and atelectasis; 
upper respiratory tract infection; pneumonia and rash and pneumothorax; failure to 
thrive. All serious adverse events were reported as unrelated to study medication with 
the exception of neutropenia that occurred in the context of pneumonia and resolved 
3 days after onset despite ongoing treatment with risdiplam. There have been no 
adverse events leading to modification or permanent withdrawal of study treatment.

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No clinically significant adverse findings related to study medication have been observed 
in safety laboratory results, vital signs, and ECG. Ophthalmological assessments 
available to date from Part 1 and the ongoing Part 2 of Studies BP39055 and BP39056
did not show drug-related toxicity. 
No individual or cohort stopping rules have been met in any of the studies to date. 
Part 1 patients are now in the extension treatment periods of the respective studies.
In this study, BN40703, as of 21 January 2021 after 12 patients have been enrolled and 
treated for median duration of 6.4 months (range: 0.1–14.9), risdiplam was well 
tolerated. Adverse events were mostly mild in intensity.   There were no adverse events 
leading to discontinuation of study drug. A review of all available safety laboratory 
results, vital signs, ECGs, and ophthalmological assessments did not show any 
clinically significant adverse findings as compared with baseline.
More recent and detailed information is provided in the Risdiplam Investigator’s 
Brochure.
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
1.3.1
Study Rationale
SMA is the leading genetic cause of death in infants and young children. It is a 
devastating disease caused by a lack of functional SMN protein, resulting in almost 
inevitable mortality for patients with Type 1 SMA within the first 2 years of life. Among 
the different strategies that are currently being pursued to restore SMN protein levels in 
patients with SMA, modulation of SMN2 splicing to favor inclusion of exon 7 into the 
mRNA transcript, thereby increasing expression of stable full-length protein from SMN2, 
is one of the most promising (Kolb and Kissel 2011; Nurputra et al. 2013). This 
approach is supported by nusinersen, currently the only licensed treatment for SMA. 
Nusinersen is an intrathecally administered antisense oligonucleotide that promotes
inclusion of exon 7 in SMN2 pre-mRNA and thereby increases the amount of full-length 
SMN protein expressed by the SMN2 gene. However, there is currently no approved 
oral treatment for SMA that restores SMN protein levels in both the CNS and in 
peripheral tissue. Thus the medical need for SMA is still high.
The timing of therapeutic intervention is crucial since most of the degeneration in motor 
neurons occurs in the first months of life in patients with Type 1 SMA.  It has been 
demonstrated that infants with Type 1 SMA undergo a rapid loss of motor units in the 
first 3 months of life, with more than 95% of motor units lost within 6 months of age 
(Swoboda et al. 2005; Kolb et al. 2017; Govoni et al. 2018). Moreover, a recent clinical 
trial in patients with presymptomatic SMA who, without any treatment, would develop a 
phenotype of Type 1 SMA, have shown a more rapid achievement of motor milestones 

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and diminished disease severity when therapy was administered at an early age and 
earlier in the disease course (Hwu et al. 2017).
Small molecule SMN2 splicing modifiers such as risdiplam represent a potential 
treatment option for patients with SMA, as they increase the level of SMN protein. 
Deficiency of SMN protein is the fundamental pathophysiological mechanism of SMA. 
There is increasing nonclinical evidence to suggest that SMN restoration in the CNS 
results in significant improvements in survival, motor function, and disease pathology but 
is insufficient to fully ameliorate the SMA phenotype (Passini et al. 2011; Porensky et al. 
2012). By restoring SMN protein levels in both the CNS and in peripheral tissue, orally 
administered SMN2 splicing modifiers are hypothesized to provide improved efficacy 
over compounds administered intrathecally (i.e., to the CNS only; Hua et al. 2011).
The study is an open-label, single-arm, multicenter clinical study to investigate the 
efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in infants aged 
from birth to 6 weeks who have been (at first dose) genetically diagnosed with 
SMA (SMN1 deletion and any SMN2 copies) but are not yet presenting with symptoms.
Efficacy in terms of development milestones will be assessed with the Bayley Scales of 
Infant and Toddler Development, Third Edition (BSID-III), including the Gross Motor 
Scale, the Hammersmith Infant Neurological Examination (HINE) and the World Health 
Organisation (WHO) milestones. Efficacy in terms of motor function will be assessed 
with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders 
(CHOP INTEND), the Hammersmith Functional Motor Scale Expanded (HFMSE), and 
the six-minute walk test (6MWT). Other treatment effects will be measured by assessing 
quality of life and relevant biomarkers (see Section 4.5.12).
1.3.2
Benefit–Risk Assessment
The benefitrisk evaluation of risdiplam is based on nonclinical pharmacology and 
toxicology studies in rats and cynomolgus monkeys, as well as the clinical experience to 
date with risdiplam in healthy subjects and in patients with SMA. In healthy adults, 
single doses of risdiplam have been well tolerated at all dose levels (Studies BP29840, 
NP39625, and BP39122), and risdiplam had a dose-dependent effect on SMN2 splicing 
in healthy adults, as shown by a change in the ratio of full-length SMN2 mRNA to 
SMNΔ7 mRNA. In Part 1 of the ongoing Studies BP39055 and BP39056, treatment with 
risdiplam was safe and well tolerated at all dose levels, and an exposure-dependent 
increase in SMN protein (median 2 to 3 fold) was observed, confirming proof of 
mechanism in patients with SMA. The increase in SMN protein levels observed in Part 1 
of Studies BP39055 and BP39056 is expected to have a substantial clinical benefit in 
patients with SMA, turning more severe phenotypes into milder forms. No clinically 
relevant changes in laboratory safety parameters, vital signs, adverse events, ECG 
parameters, or ophthalmological assessments related to risdiplam were observed in any 
study, and no individual or cohort stopping rules have been met. Accordingly, available 
data to date suggest that risdiplam may provide benefit for patients with SMA.

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The doses selected for patients with SMA for the current study and for other ongoing 
studies (BP39054, BP39055, and BP39056) aim for a mean exposure at steady state
of AUC0-24,ss 2000 ng hr/mL. This corresponds to the mean exposure at the 
NOAEL/NOEL (multifocal peripheral retina degeneration) of the 39-week toxicity study in 
monkeys with an AUC0-24 of 1870/2060 ng hr/mL in males and females, respectively. 
This exposure cap has been selected to maximize the increase in SMN protein and 
subsequently the chance for clinical efficacy in patients with SMA, while still providing a 
safety margin versus the ophthalmology findings in the animal study. The individual
pharmacokinetics in all patients will be monitored closely and regularly, and the dose will 
be adjusted as required to maximize the likelihood of clinical benefit, while still being 
compliant with the exposure cap.
Safety precautions are provided and a thorough safety monitoring plan focusing on 
liabilities identified in the nonclinical toxicology studies will be implemented to address 
potential safety concerns for the patients enrolled in the trial. Toxicological findings 
observed in the nonclinical studies include toxicity involving skin, pharynx/larynx, and
fertility; potential for genotoxicity based on micronucleus induction; and potential 
irreversible retinal toxicity that could translate into some visual impairment (e.g., night 
tunnel vision).
With this regard, it is essential to note that the changes found by SD-OCT scan (and on 
histopathology) in the peripheral retina in the 39-week monkey study may produce 
peripheral visual field defects that initially may be asymptomatic. These defects would 
be similar to those found in early stage peripheral retinal degeneration, and pan-retinal 
photocoagulation for diabetic retinopathy; initially, central visual function is spared in 
these conditions and would normally not affect visually oriented behavior and quality of 
life. As of the clinical cutoff date of 21 January 2021, ophthalmological assessments did 
not show any retinal toxicity in any patient exposed to risdiplam at any dose.
Ophthalmological monitoring in this study includes SD-OCT at three post-baseline visits 
during the first year and every year thereafter until the end of the study in case of 
clinically relevant peripheral retinal toxicity, stopping rules will apply (see Section 5.1.3).
On the basis of these elements, the ophthalmological monitoring strategy and stopping 
rules included in this study appear appropriate to minimize the risk of irreversible 
symptomatic retinal injury and to detect peripheral retinal abnormalities early when 
peripheral visual field defects would likely be asymptomatic.
The key elements of risk management in this study, taking into consideration the
nonclinical findings and clinical experience so far, are summarized below:

Frequent PK assessments, including assessment of free fraction from a sample 
taken at screening as a precaution to take into account possible age-related 
differences in plasma protein binding, to ensure that risdiplam exposure remains in 
compliance with the exposure cap. The PK data will be regularly (every 2 weeks but 
may be adjusted on the basis of the data) reviewed by the Clinical Pharmacologist, 

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and on the basis of the PK monitoring, the dose of individual or all patients may be 
adjusted to ensure that the patients are in the targeted exposure range and in 
compliance with the exposure cap.

Safety monitoring throughout the study including ophthalmology, dermatology, and 
clinical laboratory measures (see Section 5.1.4)

Stopping rules at the individual patient level (see Section 5.1.3)

Guidelines for managing specific adverse events (see Section 5.2.3)

Implementation of an external independent Data Monitoring Committee (iDMC), who 
will review safety on a regular and ad-hoc basis at least until the last patient enrolled 
in this study has completed 12 months of treatment together with data from other 
ongoing studies (see Section 3.1.1)

Appropriate inclusion/exclusion criteria and guidance regarding prohibited therapy
(including CYP3A4 inhibitors/inducers/substrates, OCT 2 and MATE substrates, 
FMO inhibitors and substrates, and medications with potential retinal toxicity; see 
Section 4.1)
The potential benefit of early treatment with risdiplam for patients with SMA would be an 
increase in functional SMN protein levels in the CNS and peripheral tissues, such as 
muscles and endothelial cells. This early pharmacological effect is hypothesized to 
translate into an improvement or even normalization of developmental milestone
acquisitions, including major motor milestones such as sitting without support, standing,
and possibly walking. 
The study population is expected to predominantly include presymptomatic infants who, 
without any treatment, would develop a phenotype of Type 1 SMA. Given the potential 
for these patients to benefit from treatment with risdiplam, the safety margins in this 
study are considered appropriate.  Data from ongoing SMA studies with risdiplam justify 
the benefitrisk of treatment with risdiplam in infants aged from birth to 6 weeks of age 
(at first dose) who have been genetically diagnosed with SMA but are not yet presenting 
with symptoms.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics 
of risdiplam in infants genetically diagnosed with SMA but not yet presenting with 
symptoms.  Specific objectives and corresponding endpoints for the study are outlined 
below. 
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
In line with the study population expected to predominantly include presymptomatic 
infants who, without any treatment, would develop a phenotype of Type 1 SMA, the 
primary efficacy objective for this study is to evaluate the efficacy of risdiplam in patients 

 
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with two copies of the SMN2 gene (excluding the known SMN2 gene modifier mutation 
c.859G > C) and baseline compound muscle action potential (CMAP) amplitude 
≥ 1.5 mV, as determined by the proportion of patients who are sitting without support 
after 12 months of treatment.  Sitting is defined as “sits without support for 5 seconds” as 
assessed in Item 22 of the BSID-III Gross Motor Scale. 
2.1.2 
Secondary Efficacy Objectives 
The secondary efficacy objectives along with the corresponding endpoints for this study 
are as follows: 
• 
To evaluate the efficacy of risdiplam on the development of clinically manifested 
SMA on the basis of the following endpoints: 
– 
Proportion of patients developing clinically manifested SMA (at Month 12 and 
Month 24 of treatment) 
• 
To evaluate the efficacy of risdiplam on survival and permanent ventilation on the 
basis of the following endpoints: 
– 
Time to death 
– 
Time to permanent ventilation 
– 
Time to death or permanent ventilation  
– 
Proportion of patients alive without permanent ventilation (at Month 12 and 
Month 24 of treatment) 
– 
Proportion of patients alive (at Month 12 and Month 24 of treatment) 
• 
To evaluate the efficacy of risdiplam on the achievement of motor milestones 
defined in the BSID-III and by the HINE-2 on the basis of the following endpoints: 
– 
Proportion of patients who achieve the attainment levels of the motor 
milestones assessed in the HINE-2 (head control, sitting, voluntary grasp, 
ability to kick, rolling, crawling, standing, and walking) (at Month 12 and 
Month 24 of treatment) 
– 
Proportion of patients sitting without support (at Month 24 of treatment [as 
assessed in Item 22 of BSID-III Gross Motor Scale]) for 5 seconds 
– 
Proportion of patients with two copies of the SMN2 gene sitting without support 
(at Month 12 of treatment [as assessed in Item 22 of BSID-III Gross Motor 
Scale]) for 5 seconds (independent of the CMAP value at baseline)  
– 
Proportion of patients sitting without support (at Month 12 and Month 24 of 
treatment [as assessed in Item 26 of BSID-III Gross Motor Scale]) for 
30 seconds 
– 
Proportion of patients standing (at Month 24 of treatment [defined as “Stands 
Alone” for at least 3 seconds as assessed in Item 40 of the BSID-III Gross 
Motor Scale]) 
– 
Proportion of patients walking (at Month 24 of treatment [defined as “Walks 
Alone” takes at least 3 steps as assessed in Item 42 of the BSID-III Gross 
Motor Scale]) 
– 
Proportion of patients demonstrating the ability to achieve a scaled score within 
1.5 standard deviations of the chronological reference standard (at Months 24 

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and 42 of treatment [as assessed through the use of the BSIDIII Gross Motor 
Scale])

To evaluate the efficacy of risdiplam on motor function on the basis of the following 
endpoints:
–
Change from baseline in the Children's Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders (CHOP INTEND) motor function scale (at Month 12
of treatment)
–
Proportion of patients who achieve a score of 40 or higher, 50 or higher, and 60
or higher in the CHOP INTEND motor function scale (at Month 12 of treatment)
–
Proportion of patients who meet CHOP INTEND stopping criteria at any point 
up to Month 24 of treatment
–
Change from baseline (Month 24) in the Hammersmith Functional Motor Scale 
Expanded (HFMSE) (at Month 60 of treatment).

To evaluate the efficacy of risdiplam on growth measures on the basis of the 
following endpoints:
–
Number and proportion of patients within 3rd percentile of normal range for 
weight-for-age, length/height-for-age and weight-for-length/height (at Months
12, 24, 36, 48, and 60 of treatment based on the WHO Child Growth 
Standards) (WHO 2019)
–
Number and proportion of patients within 3rd percentile of normal range for 
head circumference-for-age (at Month 12 and Month 24 of treatment, based on 
the WHO Child Growth Standards) (WHO 2019)
–
Change from baseline percentiles for weight-for-age, length/height-for-age and
weight-for-length/height (at Months 12, 24, 36, 48 and 60 of treatment)
–
Change from baseline percentiles for head circumference-for-age (at Month 12 
and Month 24 of treatment)
–
Change from baseline in chest circumference (at Month 12 and Month 24 of 
treatment)
–
Ratio between chest and head circumferences (at Month 12 and Month 24 of 
treatment)

To evaluate the efficacy of risdiplam on the nutritional status of the patients on the 
basis of the following endpoint:
–
Ability to swallow and to feed orally (at Months 12, 24, 36, 48, and 60 of 
treatment)

To evaluate the efficacy of risdiplam on the degree of innervation on the basis of the 
following endpoint:
–
Change from baseline in CMAP amplitude (at Month 12 and 24 of treatment)

To evaluate the PD effects of risdiplam on the basis of the following endpoints:
–
SMN mRNA levels in blood

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–
SMN protein levels in blood
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objectives along with the corresponding endpoints for this study 
are as follows:

To evaluate the efficacy of risdiplam to achieve other developmental milestones as 
defined by BSID-III and WHO milestones on the basis of the following endpoints:
–
Cognition assessed through the use of the BSID-III Cognitive Scale (at 
Months 12, 24, and 42 of treatment) 
–
Proportion of patients demonstrating the ability to achieve a scaled score within
1.5 standard deviations of chronological reference standard (at Months 24 and 
42 of treatment [as assessed through the use of the BSIDIII Cognitive Scale])
–
Fine motor function assessed through the use of the BSIDIII Fine Motor Scale
(at Months 12, 24, and 42 of treatment)
–
Proportion of patients demonstrating the ability to achieve a scaled score within 
1.5 standard deviations of chronological reference standard (at Months 24 and 
42 of treatment [as assessed through the use of the BSIDIII Fine Motor Scale])
–
Proportion of patients who attain motor milestones as assessed by WHO 
criteria (at Months 48 and 60 of treatment) 

To evaluate the efficacy of risdiplam on motor function on the basis of the following 
endpoint:
–
Total Walk Distance in the six-minute walk test (6MWT; ambulant patients only) 
(at Month 60 of treatment)

To explore the treatment effect on speech development on the basis of the following 
endpoint:
Speech development as assessed during the neurological examination (at 
Months 12, 24, 36, 48, and 60 of treatment). 

To explore the effect of treatment with risdiplam on the number of hospitalizations on 
the basis of the following endpoints: 
–
Number of hospitalizations (for any reason, except if for study purpose only 
[e.g., to facilitate study assessments]) per patient-year and number of nights 
admitted to hospital per patient (at 12, 24, 36, 48, and 60 months of treatment).
–
Proportion of patients with no hospitalizations (at 12, 24, 36, 48, and 60 months 
of treatment).

To explore the treatment effect on pre-specified disease-related adverse events on 
the basis of the following endpoint: 
–
Pre-specified disease-related adverse events by 12 and 24 months of treatment

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2.2
SAFETY OBJECTIVES
The safety objective for this study is to evaluate the safety of risdiplam on the basis of 
the following endpoints:

Incidence and severity of adverse events, with severity determined according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5 (NCI CTCAE v5)

Incidence and severity of serious adverse events

Incidence of treatment discontinuation due to adverse events

Incidence of abnormal laboratory values

Incidence of abnormal ECG values

Vital signs abnormalities, including body temperature, systolic and diastolic blood 
pressure, heart rate, respiratory rate

Ophthalmological examination as appropriate for age (e.g., red reflex, external 
ocular examination, pupillary examination/response, cover/uncover, fix and follow 
test, corneal light reflex, fundus examination including ophthalmoscopy/slit lamp 
examination, SD-OCT, and fundus photography)

Physical examination, including detailed examination of the skin and mouth
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the PK profile of risdiplam on the basis 
of the following endpoints:

Plasma concentration of risdiplam and its metabolite(s), as appropriate, at specified 
timepoints

AUC

Concentration at the end of a dosing interval to assess steady-state

Other PK parameters as appropriate
2.4
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify biomarkers that are 
predictive of response to risdiplam (i.e., predictive biomarkers), are early surrogates of 
efficacy, are associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), are associated with susceptibility to developing adverse events or can lead 
to improved adverse event monitoring or investigation (i.e., safety biomarkers), can 
provide additional evidence of risdiplam activity (i.e., PD biomarkers), or can increase 
the knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoints:

Relationship between exploratory biomarkers in blood (listed in Section 4.5.11.5)
and efficacy, safety, PK, or other biomarker endpoints

Relationship of genetic, epigenetic, or genomic markers with efficacy, safety, PK, or 
other biomarker endpoints related to SMA

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The iDMC will be informed of any individual dose changes at the next scheduled iDMC 
meeting.
The roles, responsibilities, membership, scope of activities, time of meetings, and 
communication plan for the iDMC will be documented in the iDMC charter. The external 
iDMC will be chaired by a medically qualified individual with experience with SMA and 
will include at least one other physician experienced in neurology, a clinical 
pharmacologist, an ophthalmologic expert, and a biostatistician. No member of the 
iDMC will participate in the study as an investigator or sub-investigator.
3.1.2
Permanent Ventilation Adjudication Committee
Time to permanent ventilation will be determined by a central, independent Permanent 
Ventilation Adjudication Committee.  This committee will meet periodically to review all 
pertinent data for patients that may meet the definition of permanent ventilation 
(16 hours of non-invasive ventilation per day or intubation for21 consecutive days in 
the absence of, or following the resolution of, an acute reversible event or 
tracheostomy). 
An acute reversible event will include any of the following events that occur between 
7 days prior and 7 days after the onset of 16 hours of non-invasive ventilation per day 
or intubation:

Fever

Laboratory diagnosis of a viral, bacterial, or fungus infection either by direct 
examination of a sample (e.g., sputum, tissue etc.), culture, serology, or polymerase 
chain reaction

Leukocytosis

Imaging studies demonstrating an active infection

Surgical procedure
The infant will be given a period of 7 days after the event to recover and begin 
extubation or weaning off ventilation support before the endpoint of permanent 
ventilation can be confirmed (i.e., the endpoint will not be met until the infant requires 
16 hours of non-invasive ventilation per day or intubation for21 consecutive days
starting 7 days after the resolution of the acute reversible event).
The independent Permanent Ventilation Adjudication Committee will determine if this 
endpoint has been met and provide recommendations to the Sponsor. 
The procedures for reviewing and adjudicating events, and the governing and operation 
of the independent Permanent Ventilation Adjudication Committee will be described in a 
charter.

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3.2
END OF STUDY AND LENGTH OF STUDY
The end of study (EOS) is defined as the date when the last patient, last visit (LPLV) 
occurs. LPLV is expected to occur at the latest when the last patient enrolled in the 
study has completed 2 years in the treatment phase and 3 years in the OLE phase. 
The study will continue until the EOS, or as per local regulation, or per the Sponsor’s 
decision to terminate risdiplam development. However, the length of the study will not 
exceed a total of 5 years after the last patient is enrolled in the study. 
After completion of 2 years treatment, each patient will continue to receive treatment in
the OLE phase for at least 3 years. After a patient has completed 3 years in the OLE, 
the patient may continue until EOS, provided that risdiplam is not commercially available 
in the country of the site. 
3.3
RATIONALE FOR STUDY DESIGN
This study is designed to assess the efficacy and safety of risdiplam treatment in infants
aged from birth to 6 weeks of age (at first dose) genetically diagnosed with SMA but not
yet presenting with symptoms.
The target population for the primary efficacy analysis is patients who have two copies 
of the SMN2 gene and a baseline CMAP amplitude of 1.5mV, reflective of a Type 1 
population.  Nevertheless, infants with copy number 1, 3, or 4 will not be excluded and 
enrollment of infants into the study will continue until at least 25 patients, including a 
minimum of 5 patients who meet the criteria for the primary efficacy population are 
enrolled, OR when 10 patients who meet the criteria for the primary efficacy population
are enrolled.  All infants enrolled regardless of copy number (i.e., full population) will be 
used as the primary population for safety, while those infants with SMN2 copy number 2 
and baseline CMAP amplitude 1.5mV will form the primary efficacy population for the 
study.
In line with the study population expected to predominantly include presymptomatic 
infants who, without any treatment, would develop a phenotype of Type 1 SMA, the 
primary endpoint will be the achievement of a motor milestone that a Type 1 infant would 
not normally achieve according to natural history data (sitting without support).  
According to the WHO windows of achievement for motor milestones in healthy infants, 
sitting without support is expected to be achieved by 9 months of age and walking alone 
by 18 months of age; hence, a 24-month treatment period with the primary analysis and 
reporting after 12 months of treatment is planned.
Similar to the single-arm design of Study BP39056 in symptomatic Type 1 infants, a 
performance criteria approach for the primary analysis will be used (i.e., a threshold of 
achievement for the presymptomatic risdiplam-treated infants to be assessed against 
within this study).  The predefined performance criterion for the primary endpoint will be 
5%, based on the assumption that there is a 97% chance that a presymptomatic infant 

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with two SMN2 copies develops SMA Type 1 (Feldkotter et al. 2002).  If the lower limit of 
the two-sided 90% (exact) confidence interval is above this 5% threshold, the primary 
objective of the study will be considered achieved. 
The primary endpoint can be objectively measured, incorporates survival, and is 
clinically meaningful.  The evaluation of the primary endpoint will be video recorded in a 
standardized manner and centrally reviewed by two independent readers to confirm the 
investigators' assessments.  To reduce the risk of bias in the assessment of the 
endpoint, the central readers' assessment will be used for the primary analysis. 
3.3.1
Rationale for Risdiplam Dose and Schedule
The target exposure is an AUC0-24,ss of close to 2000 ng hr/mL, with the average 
exposure of all patients not predicted to exceed 2000 ng hr/mL.  This target AUC has 
been selected to maximize the likelihood of clinical benefit while maintaining a safety 
margin versus the findings in the animal toxicology studies (except effects on testes). 
This target exposure has been assessed and was well tolerated in all SMA patients in 
the ongoing clinical studies, including infants as young as 2.2 months (status:  
14 November 2019) at the start of treatment.
In Study BP39056 Part 1 (infants with Type 1 SMA), a median 2-fold increase (range:
1.05.4) in SMN protein in blood versus baseline was observed for infants with an
exposure (AUC0-24) 1000 ng hr/mL, and a median 3.2-fold increase (range: 1.66.5) 
was obtained in infants with an exposure (AUC0-24) 1000 ng hr/mL.  Thus, this 
exposure is predicted to provide clinical benefit to patients with SMA treated with 
risdiplam.
The mean AUC for all infants in Study BP39056 was 1930 ng hr/mL (range 
12303300) at the Month 12 visit at the 0.2 mg/kg dose.
The first patient enrolled into this study must be at least 7 days old at time of first dose. 
The first patient enrolled aged between 4 and 6 weeks (29 and 42 days) of age at first
dosing will receive a once daily oral dose of 0.04 mg/kg of risdiplam to assess safety, 
tolerability, and pharmacokinetics.  
The first patient enrolled aged between 7 days and 28 days of age at the time of first 
dose will receive a once daily oral dose of 0.004 mg/kg. A ten-fold safety factor has 
been applied to account for uncertainty of the metabolism and excretion of risdiplam in 
this young age range. However, during the course of this study, emerging PK data from 
the first patients enrolled in this study indicated that the very low dose of 0.004 mg/kg 
would not be required.

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The starting dose for all patients may be adjusted to the most appropriate dose based on 
the latest available data from the currently ongoing Study BP39056 in infants 
17 months and based on emerging PK data from this study BN40703.
Pharmacokinetics will be assessed at Days 1, 2, and 14 in the first infant (while the 
patient continues to receive once daily treatment), and at subsequent timepoints as 
detailed in the schedule of activities (Appendix 1).  PK samples obtained on each of 
Days 1, 2, and 14 will be shipped immediately for analysis, and on the basis of the PK 
data obtained, the dose for the first patient will be adjusted to reach the targeted 
exposure range.  Should the initial starting dose be too low to provide reliable PK 
measurements, the dose will be adjusted and two additional unscheduled PK samples 
may be taken (in addition to those specified in Appendix 1) to confirm pharmacokinetics 
at the adjusted dose.
Provided risdiplam is well tolerated in the first patient for at least 1 week and the 
pharmacokinetics have been reliably assessed, further patients in the respective age 
category may be enrolled.  The dose to be administered to the subsequently enrolled 
patients will be based on the PK data obtained from the first infant (and all other PK and 
safety data available from all other studies with risdiplam at that time) and will be in 
compliance with the specified exposure cap of an AUC0-24,ss 2000 ng hr/mL (mean). 
Pharmacokinetics will be regularly assessed in all patients, and the dose will be adjusted 
based on the observed PK data to achieve the targeted exposure range and to be in 
compliance with the exposure cap.
Dose adjustments between the scheduled visits based on weight change are allowed
(e.g., if weight change is 10% according to parent/caregiver). The change in weight 
may be discussed during the follow-up phone calls with the parent/caregiver. The 
weight used to perform dose calculations between visits should be taken at site (e.g., by 
bringing the patient in for an unscheduled visit). However, if the patient is unable to 
come to site for a scheduled or unscheduled visit, due to exceptional circumstances, the 
weight can be taken at an alternative location, provided suitable scales are used, as 
determined by the Sponsor. During OLE, as visits are 26 weeks apart, unscheduled 
visits to assess weight may be expected. If patients are attending site for any other 
reason during OLE, it is advisable to also take the opportunity to measure weight. Any 
dose adjustment has to be performed by the site and cannot be made by the 
parent/caregiver themselves. 
The fu of risdiplam will be measured in all patients from a sample taken at screening with 
an in vitro assay. If the measured free fraction in patients is different from the free
fraction observed in infants and adults in other ongoing studies, the dose will be adjusted 
for this difference.

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As the patients grow and develop, the dose may be adjusted for an individual or all 
patients, to maintain the exposure level over time in an individual growing patient, and to 
match individual exposure versus the target exposure (see Section 3.1).
3.3.2
Rationale for Patient Population
Patients with Type 1 SMA have a more severe clinical presentation and reduced survival 
rate compared with patients with Types 2 and 3 SMA. The clinical progression of the 
disease is more pronounced in patients with Type 1 SMA than those with Types 2 and 3 
SMA, and their comorbidities and complications (e.g., swallowing and breathing function) 
are usually more severe. The number of SMN2 copies and the presence of its 
c.859GC variant still remain as the major modiﬁers of SMA disease (Prior et al. 2009; 
Bernal et al. 2010). Distribution of the positive modifier of SMA phenotype, SMN2
c.859GC variant, is rare (2%4%) and mostly reported in Types 2 and 3 
SMA (Calucho et al. 2018).  Numerous studies show that the higher the SMN2 copy 
number the larger the amount of full-length SMN protein produced, the milder the 
associated SMA phenotype and vice versa (Feldkotter et al. 2002; Wirth et al. 2006). 
However, this inverse correlation is not absolute. The Type 1 SMA population usually 
has one (7%) or two (73%) copies of SMN2, but some patients with Type 1 SMA have
three (20%) and even four (1%) or 5 (1%) SMN2 copies (Calucho et al. 2018).
Feldkotter et al. (2002) calculated the posterior probability of a child with homozygous 
absence of SMN1 developing Type 1, Type 2, or Type 3 SMA, conditional on the 
number of SMN2 copies. A child with one SMN2 copy has a risk of 99%, and with two 
SMN2 copies, a risk of 97%, of developing Type 1 SMA. Thus, patients will be enrolled 
and treated in the study regardless of the SMN2 copy number, but the primary analysis 
will be performed in patients with two SMN2 copies and without the c.859GC variant to
increase homogeneity of the population in which to assess the efficacy of treatment.
It has been demonstrated that infants with Type 1 SMA undergo a rapid loss of motor 
units in the first 3 months of life, with more than 95% of motor units lost within 6 months
of age (Swoboda et al. 2005; Kolb et al. 2017; Govoni et al. 2018).
Based on data presented so far for the antisense oligonucleotides (nusinersen) and 
gene therapy (AAV9-SMN), patients with Type 1 SMA treated at an earlier age and even 
before SMA symptom onset achieved the best outcome measure results. NURTURE 
(NCT02386553) is an ongoing study, evaluating intrathecal nusinersen in infants with
presymptomatic SMA 6 weeks old at first dose. Twenty-five infants were enrolled in 
the study (n15 with two SMN2 copies and n10 with three SMN2 copies). At the time 
of the interim analysis, infants had been enrolled for a median of 317.5 days. All infants 
were alive without requiring chronic respiratory support and showed improvements and 
achievement of motor milestones over the expected natural history of Types 1 and 2
SMA. Most infants achieved motor milestones generally consistent with normal 
development (De Vivo et al. 2017).

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CMAP amplitude is an objective measure of the electrophysiologic output from muscle 
following stimulation of the innervating nerve and has shown to be useful to evaluate 
disease progression even before clinical symptom onset. Natural history studies among 
patients with Type 1 SMA demonstrate low ulnar CMAP amplitude levels that rapidly 
decreased in the first few months of life did not improve after symptom onset. The 
CMAP amplitude at the time of initial assessment is predictive of the clinical course of 
patients (Swoboda et al. 2005; Glanzman et al. 2010; Finkel 2013; Passini et al. 2014; 
Kolb et al. 2017). Kolb et al. (2017) compared ulnar CMAP in infants with Type 1 
SMA with two copies of SMN2 to controls and showed that CMAP amplitude in SMA was 
significantly reduced early in life (baseline) and rapidly fell over 24 months compared 
with being stable in controls (controls: mean baseline was 5.24 mV, 6-month visit was 
6.00 mV; SMA: mean baseline was 1.53 mV, 6-month visit was 0.23 mV). The CMAP 
amplitude over time from the 3-month visit was never higher than 0.6 mV in SMA infants.
To allow treatment for all patients (with confirmed deletion of the SMN1 gene and any
SMN2 copies), no CMAP amplitude criteria will be used for inclusion in the current study. 
However, only patients with baseline (Day 1) CMAP amplitude 1.5 mV and two SMN2
copies (excluding the known SMN2 gene modifier mutation c.859GC) will be included 
in the analysis for the primary endpoint.
Overall, very early initiation of an effective treatment is anticipated to counteract the 
deleterious effects of chronic SMN protein deficiency in the body. Thus initiation of 
treatment no later than 6 weeks from birth in patients genetically diagnosed with
SMA prior to clinical symptoms with a splicing modifier, as proposed in this study, may 
lead to a significant increase in SMN protein expression that could rescue partly or 
completely avoid the chronic SMN protein deficiency during the motor function 
development phase of these patients. This is expected to lead to a clinically relevant 
beneficial outcome in motor and respiratory function of treated patients
(e.g., achievement of sitting milestone).
3.3.3
Rationale for Control Group
This is an open-label study. A placebo-control group will not be included in this study, as 
the majority of patients with 2 SMN2 copies will develop Type 1 SMA and it is ethically 
debatable to treat patients with Type 1 SMA with placebo, considering the rapid decline 
and short life-expectancy of these patients. The open-label design is considered 
justified in the context of the choice of the primary endpoint that is minimally subject to 
bias and the known natural history of this endpoint (and developmental milestones) in 
patients with SMA Type 1.
All patients must receive the local clinical standard of care for SMA, as defined by each 
site investigator, except for the administration of SMN2-targeting oligonucleotides, which 
is not allowed.  

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3.3.4
Rationale for Biomarker Assessments
The putative target tissues for SMA treatment are spinal cord and muscle, tissues that 
cannot be easily sampled multiple times to evaluate drug effects. As SMA is due to 
decreased levels of SMN protein, changes in SMN mRNA and SMN protein levels will be 
measured in blood as fluid PD markers (see Section 4.5.11.2). Based on animal data, 
the increase in SMN protein in blood reflects the increase in brain, spinal cord, and 
muscle tissue. 
In addition to the SMN2 copy number analysis performed at screening, additional 
genetic, genomic, or epigenetic markers that influence the progression and severity of 
the disease or treatment response may be studied in the patients.
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
Blood samples for fluid PD markers will be taken from the Week 1 Day 1 visit and 
onwards (see schedule of activities in Appendix 1) and only if the limit on blood volume 
allows (see Section 4.5.11).
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 25 patients with SMA will be enrolled in this study. Enrollment will be 
closed when one of the following conditions have been met 
1.
At least 25 patients, including a minimum of 5 patients who meet the criteria for 
the primary efficacy population (Section 6.3.3) are enrolled, OR 
2.
A total of 10 patients who meet the criteria for the primary efficacy population are 
enrolled.  
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form by a legally authorized representative for the patient 
in accordance to International Council on Harmonisation (ICH) and local regulations

Males and females aged from birth (1 day) to 6 weeks (42 days) of age at the time 
of first dose (Day 1); a minimum age of 7 days at first dose is required for the first 
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
Gestational age of 3742 weeks for singleton births; gestational age of 
3442 weeks for twins

Body weight 3rd percentile for age, using appropriate country-specific guidelines 

Genetic diagnosis of 5q-autosomal recessive SMA, including confirmation of 
homozygous deletion or compound heterozygosity predictive of loss of function of 
the SMN1 gene

Absence of clinical signs or symptoms at screening (Day 42 to Day 2) or at 
baseline (Day 1) that are, in the opinion of the investigator, strongly suggestive 
of SMA

Receiving adequate nutrition and hydration at the time of screening, in the opinion of 
the investigator

Adequately recovered from any acute illness at baseline and considered well
enough to participate in the study, in the opinion of the investigator

Able and expected to be able to safely travel to the study site for the entire duration 
of the study and in accordance to the frequency of required study visits, in the 
opinion of the investigator

Able to complete all study procedures, measurements, and visits, and the parent 
(or caregiver), in the opinion of the investigator, has adequately supportive 
psychosocial circumstances

Parent (or caregiver) is willing to consider nasogastric, naso-jejunal, or gastrostomy 
tube placement during the study to maintain safe hydration, nutrition, and treatment 
delivery, if recommended by the investigator

Parent (or caregiver) is willing to consider the use of non-invasive ventilation during 
the study, if recommended by the investigator
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Concomitant or previous participation in any investigational drug or device study at 
any time

Concomitant or previous administration of an SMN2-targeting antisense 
oligonucleotide, SMN2-splicing modifier, or gene therapy either in a clinical study or 
as part of medical care

Presence of significant concurrent syndromes or diseases

In the opinion of the investigator, inadequate venous or capillary blood access for 
the study procedures

Requiring invasive ventilation or tracheostomy

Requiring awake non-invasive ventilation

Awake hypoxemia (SaO295%) with or without ventilator support

Multiple or fixed contractures and/or hip subluxation or dislocation at birth

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
Systolic blood pressure or diastolic blood pressure or heart rate considered to be 
clinically significant by the investigator

Presence of clinically relevant ECG abnormalities before study drug administration; 
corrected QT interval using Bazett’s method 460 ms; personal or family history 
(first-degree relatives) of congenital long QT syndrome indicating a safety risk for 
patients as determined by the investigator. First-degree atrioventricular block or 
isolated right bundle branch block are allowed.

The infant (and the mother, if breastfeeding the infant) taking any of the following:
–
Any inhibitor of CYP3A4 taken within 2 weeks (or within 5 times the elimination 
half-life, whichever is longer) prior to dosing, including but not limited to: 
ketoconazole, miconazole, itraconazole, fluconazole, erythromycin, 
clarithromycin, ranitidine, cimetidine
–
Any inducer of CYP3A4 taken within 4 weeks (or within 5 times the elimination 
half-life, whichever is longer) prior to dosing, including but not limited to: 
rifampicin, rifabutin, glucocorticoids, carbamazepine, phenytoin, phenobarbital, 
St. John's wort
–
Use of any OCT 2 and MATE substrates within 2 weeks prior to dosing 
(including but not limited to: amantadine, cimetidine, memantine, amiloride, 
famotidine, metformin, pindolol, ranitidine, procainamide, varenicline, acyclovir, 
ganciclovir, oxaliplatin, cephalexin, cephradine, fexofenadine)
–
Use of any known FMO1 or FMO3 inhibitors or substrates

Clinically significant abnormalities in laboratory test results (e.g., Grade 1 anemia, 
ALT values exceeding 1.5the upper limit of normal [ULN] unless the elevated ALT 
level is considered of muscular origin [i.e., in the absence of other evidence of liver 
disease that is confirmed by elevated creatine kinase and lactate dehydrogenase]). 
Out of range creatine kinase levels should be reviewed in light of the underlying 
SMA pathology of the patient; elevated levels per se do not disqualify the patient 
from the study. In the case of uncertain or questionable results, tests performed 
during screening may be repeated before enrollment to confirm eligibility.

Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to risdiplam
or to the constituents of its formulation (see the Risdiplam Investigator’s Brochure)

Treatment with oral salbutamol or another 2 adrenergic agonist taken orally for 
SMA is not allowed. Use of inhaled 2 adrenergic agonists (e.g., for the treatment 
of asthma) is allowed.

Anticipated need for thioridazine, vigabatrin, retigabine, or any other drug known to 
cause retinal toxicity during the study. Infants exposed to thioridazine, vigabatrin, 
retigabine, or drugs with known retinal toxicity given to mothers during pregnancy 
(and lactation) should not be enrolled.

Diagnosis of ophthalmic diseases (e.g., glaucoma, central serous retinopathy, 
inflammatory/infectious retinitis unless clearly inactive, retinal detachment, 
intraocular trauma, retinal dystrophy or degeneration, optic neuropathy, or optic 
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ophthalmologist. Any other abnormalities detected with SD-OCT during screening
prior to enrollment (e.g., retinal layer abnormalities, edema, cystic or atrophic 
changes) must be discussed with the investigator, ophthalmologist, and with the 
Sponsor, who will jointly determine if the infant may be enrolled in the study. In the 
event that an OCT of sufficient quality cannot be obtained prior to enrollment, one
must be obtained by Day 14.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is an open-label study and all patients will receive risdiplam.
An interactive (voice/web) response system (IxRS) will be used to manage patient 
screening, enrollment, and drug supply. The patient number will be allocated by IxRS 
and will be used in the clinical database and for recording data in the electronic case 
report form (eCRF). Sites should call the IxRS to enter the patient into screening and to 
register a screen failure. The enrollment call to the IxRS should occur on Day 1 after 
the patient’s eligibility (i.e., inclusion/exclusion criteria) has been confirmed.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is risdiplam.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Risdiplam
Risdiplam clinical formulation will be supplied by the Sponsor as a powder for 
constitution to an oral solution.  The powder is constituted with purified water (sourced 
locally) to yield an oral solution containing 0.25 mg/mL or 0.75 mg/mL of risdiplam, 
respectively, which can be administered orally (via mouth) or via a naso-gastric or 
gastrostomy tube.  For information on the formulation and handling of risdiplam, see the 
pharmacy manual and Investigator's Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.  The qualified individual 
responsible for dispensing the study drug will prepare the correct dose according to the 
Pharmacy Manual.
Throughout the study, the study drug (risdiplam) should be taken orally once daily in the 
morning, except when site visits are planned and study medication will be administered 
at the clinical site. In patients able to swallow, study drug will be administered with a 
syringe inserted between gum and cheek of the patient as described in the study drug 
administration instructions for use. The patient should be fed prior to dosing. In the 
case of breastfeeding, the patient should be fed prior to dosing, winded, and the study 
medication administered. Thereafter, water (approximately 1020 mL, if possible, but 
might need to be less for young babies) should be administered with a patient’s bottle or 
dispenser to prevent prolonged contact of study drug with buccal mucosa. Similarly, the 

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peribuccal area of the patient with SMA will be washed with water in case of drug 
drooling or spitting. Breastfeeding should be avoided within 1 hour after study drug 
administration. Patients unable to swallow the study medication and who have a 
naso-gastric or gastrostomy tube in situ should receive the study medication by bolus via 
the tube. Refer to the Study Drug Administration Instructions for Use.
If a parent (or caregiver) does not administer the dose at the regular time, but realizes 
prior to 12:00 (noon) local time, they will be instructed to administer the regular dose at 
that time. If a parent (or caregiver) realizes a missed administration only after 
12:00 (noon) local time, this will be considered a missed dose and parent (or caregiver) 
will be instructed to not administer study drug for that day. The regular amount should 
be given at the next scheduled time on the subsequent day, but the dose should not be 
doubled, and the event should be reported in the medication diary.
A patient diary will be required that will capture information related to drug administration
for all doses throughout the study. All bottles and unused drug and drug supplies will be
returned to the site during a study visit or collected during a home visit.
Any dose modification should be noted on the Study Drug Administration eCRF.  Cases 
of overdose, medication error, drug abuse, or drug misuse, along with any associated 
adverse events, should be reported as described in Section 5.3.5.11.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 4.6.2.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (risdiplam) will be provided by the Sponsor 
where required by local health authority regulations.  The study site will acknowledge 
receipt of IMPs supplied by the Sponsor using the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.

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4.3.4
Continued Access to Risdiplam
The Sponsor will offer continued access to Roche IMP (risdiplam) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (risdiplam) after completing the study if all
of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Roche IMP (risdiplam) after completing the study 
if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP
is not effective for SMA

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
SMA

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from date of 
birth (up to 42 days prior to dosing) up to, and including, the follow-up call, unless stated 
otherwise (see Section 4.1.2).  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Physiotherapy, occupational therapy, and other forms of exercise therapy are 
encouraged, but the frequency should remain the same during the clinical study. All 

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concomitant medication should be reported to the investigator and recorded on the 
Concomitant Medications page in the eCRF.
Examples of allowed medications include the following:

Inhaled corticosteroids

Other inhaled drugs for obstructive airways diseases (e.g., anticholinergics and 
anti-allergic agents)

Other systemic drugs for obstructive airways diseases (e.g., leukotriene receptor 
antagonists)

Laxatives and other drugs for functional gastrointestinal disorders

Occasional use of analgesics, including opioids (e.g., hydromorphone or codeine)

Any antibiotics, except those listed in Section 4.4.2

Antihistamines except those that are OCT 2 and MATE substrates (see 
Section 4.4.2)

Proton pump inhibitors

Any vaccine considered as part of the local standard of care for the patient

CYP3A substrates: Risdiplam is a weak inhibitor of CYP3A. A small, but clinically 
not relevant, interaction was observed in adult subjects (increase in AUC 11% and
Cmax 16%). Based on PBPK modeling, a similar magnitude of the effect is 
expected in children and infants as young as 2 months old. Caution shall be applied 
for co-administration of risdiplam and CYP3A substrates in infants 2 months of 
age; including monitoring patients for potential toxicities from co-administered 
CYP3A substrates (particularly those with a narrow therapeutic window), and
reducing the dosage of the co-administered drug if clinically indicated.
4.4.2
Prohibited Therapy
All medications (prescription and over-the-counter [OTC]) taken from date of birth (up to 
42 days prior to dosing) will be recorded on the Concomitant Medications eCRF.
The following medication is prohibited for patients for 2 weeks prior to and during the 
study (and for the mother during the study if breastfeeding the patient):

Any inhibitor of CYP3A4, including but not limited to: ketoconazole, miconazole, 
itraconazole, fluconazole, erythromycin, clarithromycin, ranitidine, cimetidine

Any OCT 2 and MATE substrates shall be avoided, including but not limited to: 
amantadine, cimetidine, memantine, amiloride, famotidine, metformin, pindolol, 
ranitidine, procainamide, varenicline, acyclovir, ganciclovir, oxaliplatin, cephalexin, 
cephradine, fexofenadine

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The following medication is prohibited for patients for 4 weeks prior to and during the 
study (and for the mother during the study if breastfeeding the patient):

Any inducer of CYP3A4, including but not limited to:  rifampicin, rifabutin, 
glucocorticoids, carbamazepine, phenytoin, phenobarbital, St. John's wort
Patients should not have received the following drugs at any time in their lives; the drugs
are prohibited for the infant (and the mother if breastfeeding the patient) during the 
study:

Any known FMO1 or FMO3 inhibitors or substrates

Medications intended for the treatment of SMA
–
Riluzole
–
Valproic acid
–
Hydroxycarbamide
–
Sodium phenylbutyrate
–
Butyrate derivatives
–
Creatine
–
Carnitine
–
Human growth hormone
–
Anabolic steroids
–
Probenecid
–
Bortezomib
–
Quercetin
–
Oral salbutamol or another β2 adrenergic agonist taken orally
–
Chronic oral or parenteral use of corticosteroids (inhaled corticosteroid use is 
allowed, see Section 4.4.1)
–
Agents anticipated to increase or decrease muscle strength or agents with 
known or presumed HDAC inhibition activity
–
Any prior use of nusinersen or any other SMN2-targeting antisense 
oligonucleotide, SMN2-splicing modifier or gene therapy

Medications with known phototoxicity liabilities
–
Oral or topical retinoids, including OTC formulations, amiodarone, 
phenothiazines, and chronic use of minocycline

Medications with potential retinal toxicity
–
Quinolines (chloroquine and hydroxychloroquine), thioridazine, vigabatrin and 
retigabine, deferoxamine, topiramate, latanoprost, niacin (not applicable if used 
as a nutritional supplement), rosiglitazone, tamoxifen, canthaxanthin, sildenafil, 
interferon, or any other drugs known to cause retinal toxicity

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4.4.3
Prohibited Food
Patients are to avoid grapefruit and Seville orange juices.
Breastfeeding of the patient is allowed if the mother is not consuming any prohibited 
medications (see Section 4.4.2). Breastfeeding should be avoided within 1 hour after 
study drug administration. Women breastfeeding will be advised to rinse their breasts 
with water if breastfeeding occurs shortly after (i.e., 1 hour) study drug administration. 
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1,
Appendix 2, and Appendix 3.  All activities should be performed and documented for 
each patient.
Prioritization of blood samples is described in Section 4.5.11.
The patient study visits when efficacy assessments are performed (see Appendix 1) will 
be the most extensive visits and include all efficacy assessments in addition to 
pharmacokinetics, pharmacodynamics, full physical examination, and safety 
assessments. Accordingly, these visits may be conducted either as a 1-day visit or over 
2 days, whichever is preferred by the parents (or caregiver) and possible for the clinical 
site. For these visits, three blocks of assessments have been identified that should 
ideally be conducted in the order described in Appendix 4. Flexibility is given to the site 
to perform the assessments in any order within each of these blocks. It is critical that in 
Block 1, the BSID-III, CHOP INTEND, and HINE-2 are always preceded by a break of at 
least 15 minutes. It is also recommended that assessments are conducted in the same 
order throughout the trial for a single patient.
Follow-up phone calls are planned in this study. Parents (or caregivers, as appropriate) 
will be called by the investigator or designee to monitor safety and tolerability when 
patients are not attending the clinic. Assessments will include review of adverse events, 
concomitant medications, and significant life events (see Appendix 1). If, in exceptional 
circumstances, patients are unable to go to site for a scheduled on-site visit, they may 
be able to have some study assessments, as defined by the Sponsor, by telephone or 
video call.
At applicable sites, if exceptional circumstances prevent a patient from attending an on-
site visit, some study assessments, as defined by the Sponsor, may be performed by a 
site team member or a mobile nursing (MN) professional at the patient's home or 
another suitable location to improve access and convenience for patients participating in 
the study. The Sponsor will select a healthcare company that will be responsible for 
providing MN services for participating sites (the MN vendor).  The MN vendor is 
responsible for ensuring that all MN professionals are licensed, qualified, and in good 
standing, as per applicable regulations, and that appropriate background checks have 
been performed.  If the investigator at a participating site determines that MN services 

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are appropriate for a patient, the MN network will communicate with the parents or
patient caregiver and the patient's site.  MN visits will be scheduled on specified 
visit days, to allow for relevant assessments to be performed by the MN professional.  
Delivery of study medication and supplies to the home of the patient or return of unused 
drug and supplies as required may be scheduled as appropriate. Alternatively, the
patients will visit the clinic on these dates.
The exact timing of all study assessments (e.g., PK or PD blood collection) may be 
shifted depending on emergent data.  However, the total number of assessments will not 
change unless additional PK samples are required to ensure the safety of the patient 
with regard to reaching the desired target exposure range versus the exposure cap, or 
additional safety assessments are required to ensure the patient’s safety.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations). Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent 
and within 42 days prior to Day 1 may be used upon agreement with the Sponsor.  
Informed Consent Forms from the parent (or caregiver) of the enrolled patients and from 
the parent (or caregiver) of the patients who are not subsequently enrolled will be 
maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients 
meet all eligibility criteria before enrollment.  The investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history including clinically significant diseases and all medications 
(e.g., prescription drugs, OTC drugs, herbal or homeopathic remedies, nutritional 
supplements; see Section 4.4) or physical/occupational/exercise therapy applied to the 
patient from date of birth will be recorded at baseline.
Demographic data will include age, sex, and self-reported/caregiver-reported
race/ethnicity.
Spinal Muscular Atrophy Family History
SMA family history from first-degree relatives (sibling or parent) will be collected as 
available in the medical records of the patient. The collected parameters will include (list 

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is not exhaustive, please refer to the eCRF) the following:  SMA type including age of 
onset.
4.5.3
Anthropometric Measurements
Anthropometric measurements include weight, height, head, and chest circumferences
and will be measured at the timepoints specified in the schedule of activities (see 
Appendix 1) as described below:

Body weight will be measured to the nearest 10 g using baby scales, the naked 
infant being placed centrally on the scales, until the patient reaches 1 year of age. 
For patients above 1 year of age, body weight will be measured to the nearest 100 g 
using appropriate scales. During OLE, as visits are 26 weeks apart, unscheduled 
visits to assess weight may be expected. If patients are attending site for any other 
reason during OLE, it is advisable to also measure weight.

Height (or length) will be measured to the nearest centimeter with the child in lying
position using an inflexible length board with fixed headboard and moveable
footboard.  For all patients who are able to stand, height will be measured while 
standing using a stadiometer.  If the patient is unable to stand, but they are too long
to be assessed by the fixed board, the height can be derived from ulna length to 
the nearest centimeter by the following method: ulnar length (from the tip of the 
olecranon process to that of the styloid process) will be measured using an 
anthropometer with the patient in sitting position, the left forearm resting comfortably 
on a table, elbow bent 90°to110, palm facing downwards and fingers extended but 
together.  Prior to using this method please discuss with the Sponsor.  Method of 
height measurement should be kept consistent for as long as possible.

Head and chest circumferences will be measured to the nearest centimeter using an 
automated flexible, non-stretchable tape device as follows:
Head circumference (or occipital-frontal circumference) will be measured at the level 
of the plane passing above the glabella (the most anterior protrusion of the 
forehead) and over the opisthocranion (the most posterior protrusion from glabella 
on the back of the head), perpendicular to the mid-sagittal plane. The patient's 
head should be supported away from the table surface. The measuring tape should 
remain above the ears and fully compress any hair (hair ornaments should be 
removed and large plaits or braids loosened). The measurement should be taken to 
the nearest millimeter and repeated three times with the largest measurement being 
recorded.
Chest circumference will be measured with the patient lying on the back, under the 
axilla and over the nipple line. The measurement should be taken to the nearest 
millimeter and repeated three times with the largest measurement being recorded.
Head-to-chest circumference ratio will be derived throughout the study (see 
Sections 6.5.2 and 6.6).

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4.5.4
Physical and Neurological Examinations
A full physical examination should include an evaluation of the head, eyes, ears, nose, 
throat, neck and lymph nodes, and the cardiovascular, dermatologic, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurologic systems. Full physical 
examination will be carried out at timepoints specified in the schedule of activities 
(see Appendix 1). If medically indicated, the physical examination should include the 
mouth (buccal cavity and mucosa), pharynx, and gastrointestinal and skin systems, as 
possible and appropriate according to the age of the patient. The physical examination
will not include pelvic or rectal examinations unless deemed necessary by the study site 
physician.
Any abnormality identified at baseline should be recorded on the Medical History eCRF.
Changes from baseline abnormalities should be recorded in the notes of the patient.  
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF.
Photographs may be taken to document the nature of skin findings (or other adverse 
events) from any patient in this study.  These photographs will be used to follow the 
resolution of adverse events, document their appearance, and to allow consultations 
with experts.  These photographs may be shared with the Sponsor to allow for safety 
monitoring.
A neurologic examination will be performed during the physical examination. Given the 
motor assessments will be performed in the other examinations, the neurologic
examination will focus on mental status and behavior, cognitive, and speech 
assessments. The examination will be performed by asking the parent (or caregiver) 
about the patient’s development, overall behavior, sleep, and mood (such as number of 
tantrums and vocalization). The investigator will observe and interact with the patient 
using tasks or paradigms adapted to the patient’s age and motor ability (e.g., observing 
patient’s reaction to a sound, speech development, shifting attention to a newly 
introduced toy, observing the patient interact with the parent [or caregiver]).
During the neurologic examination, any abnormality that may be related to SMA should 
be recorded on the neurologic examination page in the eCRF. 
4.5.5
Vital Signs
Vital signs will include measurements of blood pressure, pulse rate, respiratory rate,
and body temperature (oral or tympanic) and will be recorded at the timepoints specified 
in schedule of activities (see Appendix 1).  Measurements should be obtained in a quiet 
room at a comfortable temperature, with the patient positioned in a relaxed 
(e.g., semi-supine/supine) position with the arms unconstrained by clothing or other
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Throughout the study all blood pressure measurements will be obtained from the same 
arm (when not possible to measure it from the arm the lower leg may be used) and with 
the appropriate cuff size, using a well-calibrated automatic instrument with a digital
readout.
4.5.6
Electrocardiograms
Triplicate ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1).  ECGs acquired on different days should be as 
closely time-matched as feasible.  Three interpretable ECG recordings (e.g., without 
artifacts, 23 minutes apart) must be obtained. The average of the three readings will 
be used to determine ECG intervals (e.g., PR, QRS, QT).  Single ECG recordings may 
be obtained at unscheduled timepoints as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a relaxed (e.g., semi-supine/supine)
position for at least 10 minutes.  All ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws).  
Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, conversation), should be avoided during the pre-ECG 
resting period and during ECG recording.
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings.  Paper or electronic copies will be kept as part of the patient’s 
permanent study file at the site.  If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central reader.
ECG characteristics, including heart rate, QRS duration and PR, QT and RR intervals, 
will be recorded on the eCRF.  QTcB (Bazett’s correction; Phan et al. 2015) and QTcF 
(Fridericia’s correction) will be calculated by the Sponsor.  Both corrections of QTc will 
be tabulated and analyzed; although, in children, Bazett’s formula appears to provide a 
better correction of the QT interval.  Changes in T-wave and U-wave morphology and 
overall ECG interpretation will be documented on the eCRF, additionally as an adverse 
event as appropriate.  T-wave information will be captured as normal or abnormal, 
U-wave information will be captured in two categories:  absent/normal or abnormal.
4.5.7
Ophthalmological Examination
Ophthalmological examination will be performed at timepoints specified in the schedule 
of activities (see Appendix 3). Examinations will be carried out by a pediatric 

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ophthalmologist or neuro-ophthalmologist with the support of a pediatric ophthalmology 
imaging specialist. Ophthalmologic examination and retinal imaging include:

SD-OCT imaging will be recorded with the Envisu hand-held device from Bioptigen 
Inc. (or other hand-held device SD-OCT available approved by the central 
ophthalmic laboratory).  Alternative method may include the use of a Spectralis
(Heidelberg Engineering) converted to a hand-held system for supine imaging.  
Every attempt should be made to capture additional images after up, down, left, and 
right gaze.

Visual development

Red reflex: Performed with an ophthalmoscope or retinoscope from approximately 
30 cm/1 foot in a semi-darkened room, examination will assess brightness of pupil 
reflex (color and homogeneity, symmetry of the findings, absence, white, opacified).

External ocular examination: eyelids, conjunctiva, sclera, cornea

Pupillary response: Using a bright light, pupillary response of each eye will be 
assessed for direct and consensual response and when achievable accommodative 
response will be tested.

Cover/uncover test

Fix and follow test: Failure to fix and follow will be assessed in the context of the 
patient’s medical conditions and age.

Ocular examination under magnification (slit lamp/ophthalmoscope of anterior and 
posterior segments including assessment [with dilation or not] of the retina and optic 
nerve).

Color fundus photography should be attempted at least once at each scheduled 
visit. If unsuccessful, an image of the fundus may be captured during funduscopy.
The details of the visual tests will be included in a separate technical operating manual.
Additional ophthalmic assessments may be carried out as needed in case of 
abnormalities or upon recommendation from the site or central ophthalmologist.
The Central Reading Center will provide sites with the Central Reading Center Manual 
and training materials for study mandated ocular imaging. Before study images are 
obtained, site personnel, test images, and systems and software (where applicable) will 
be certified by the reading center as specified in the Central Reading Center Manual. 
All ocular images will be obtained only by trained and Central Reading Center/certified 
personnel at the study sites and forwarded to the Central Reading Center for storage 
and for independent analysis, including confirmation of eligibility for defined imaging 
criteria.

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4.5.8
Nutritional Check
Nutritional assessment will be performed for all patients at the timepoints indicated in the 
schedule of activities (see Appendix 1) and will include:

Head-to-chest circumference ratio from anthropometric measurements (see 
Section 4.5.3)

Nutritional status interview of the parent (or caregiver), including questions about 
ability to swallow and level of solid food intake

Standard swallowing assessment will be performed by a speech language 
pathologist or other suitably qualified individual according to local practice at the 
baseline visit and then according to the schedule of activities.  This will include 
assessing the ability of the patient to swallow age-appropriate foods.
On the basis of the assessment, specific nutritional advice may be given individually to 
the parent (or caregiver) by the investigator or nutritionist.
4.5.9
Motor Function and Motor Development Assessments
Assessments of motor function and motor development will be performed as detailed in 
the schedule of activities (see Appendix 1).
4.5.9.1
Bayley Scales of Infant and Toddler Development, Third 
Edition (BSID-III)
The BSID-III is the current version of the most extensively used measure of infant and 
toddler development (0 to 42 months) in clinical and research practice (Bayley 2006).
The normed-scores derived from the BSID-III are used in clinical practice to detect 
infants with developmental delays, as well as to evaluate developmental progress and 
the impact of therapeutic interventions. In addition, the generated T-scores and 
percentiles for developmental achievement allow direct clinical comparison of any 
stabilization of decline or improvement against normally developing children.
The BSID consists of a core battery of five scales. Three main scales are administered 
with child interaction: the Cognitive Scale, which includes items such as attention to 
familiar and unfamiliar objects, looking for a fallen object, and pretend play; the 
Language Scale, which taps understanding and expression of language
(e.g., recognition of objects and people, following directions, and naming objects and 
pictures); and the Motor Scale, which assesses gross and fine motor skills such as 
grasping, sitting, stacking blocks, and climbing stairs. In addition, two scales 
(social-emotional, adaptive behavior) are conducted with parent questionnaires. The 
BSID-III also includes a behavior observation inventory, a separate scale for validating 
examiner and parent perceptions of the child’s responses.
In this study, the two main scales will be administered as indicated in the schedule of 
activities: motor (gross and fine) and cognitive. The Gross Motor Scale of the BSID-III 
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thus, it will be administered before the other scales.  The sitting, standing, and walking 
series should be done separately prior to the full Gross Motor Scale at all visits.  The 
Gross Motor Scale test, which is expected to take about 25 minutes to be administered 
in this population, will assess static positioning (e.g., head control, sitting); dynamic 
movement, including locomotion (e.g., crawling); quality of movement (e.g., kicking); 
balance; and motor planning.
The scales will be administered using a standardized instrument kit, and the test will be 
administered by an experienced clinician specifically trained to the test procedures, 
which will be described in a separate manual.
The sitting, standing, and walking series and the BSID-III Gross Motor assessment will 
be video-recorded in a standardized manner and centrally reviewed by two independent 
readers. The assessment of the central readers will be used for the primary analysis.
The Fine Motor Scale, Gross Motor Scale and Cognitive Scale will be administered 
according to standard administration procedures as described in the BSID-III manual. 
Thus, starting criteria for testing will be performed in accordance with the age of the
patient, and the order of item administration will be fixed to allow direct clinical 
comparison of any stabilization of decline or improvement against normally developing 
children. Because the BSID-III is only designed to evaluate patients up to 42 months of 
age, these assessments will be stopped for each patient after they reach 42 months of 
age. The final BSID-III visit for all patients will be Week 182. The Fine Motor Scale may 
be video recorded upon request, but only where permitted by local regulations and 
where the optional consent has been given for the use of video recordings for purposes 
additional to assessment of the study objectives. 
4.5.9.1.1
Rescheduling of Sitting, Standing, Walking and Gross Motor 
Scale Assessments
If the patient is not cooperative during the assessment of the sitting, standing, walking 
assessment or the Gross Motor Scale, the action to be taken will depend on the 
situation. 
If the assessment has commenced and at least one item scored, then the assessment 
should be completed at that visit. It may be necessary for the patient to have a rest 
before continuing. 
If the assessment has not yet begun, but the patient is uncooperative and, in the 
judgment of the Clinical Evaluator, the assessment will not reflect the capabilities of the 
patient, the assessment can be rescheduled for another day. Before this decision is 
taken it must be checked that the caregiver is able to bring the patient back for an extra 
study appointment, and that the visit window is respected. To emphasize, this decision 
is at the discretion of the Clinical Evaluator, based on clinical judgment and knowledge 
of the individual patient.

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If the decision is made to reschedule the sitting, standing, walking assessment to a 
different day due to the patient being uncooperative, then the Gross Motor Scale should 
not be performed at the original visit, it should also be rescheduled to be performed on 
the same day as the sitting, standing, walking assessment.  
If the sitting, standing, walking assessment is successfully performed at the original visit 
but the Gross Motor Scale cannot be assessed, and needs to be rescheduled, then the 
sitting, standing, walking assessment should be performed again, at the rescheduled 
visit, prior to the Gross Motor Scale.  In this scenario, there will be two sitting, standing, 
walking assessments – one from the original visit, and one from the rescheduled visit.   
4.5.9.2 
Hammersmith Infant Neurological Examination−Module 2 
(HINE-2) 
The HINE is a neurologic examination initially designed to evaluate patients between 
2 months and 24 months of age.  It is a simple and scorable method that includes 
26 items assessing different aspects of neurologic examinations such as cranial nerves, 
posture, movements, tone, and reflexes.  The pro forma provides instructions for 
performing the individual items and diagrams to aid recording.  The HINE is easily 
performed and accessible to all clinicians; it can be completed in 5 to 10 minutes.  It has 
shown good inter-observer reliability, even in inexperienced staff. 
In this study, only Module 2 of the HINE, which evaluates 8 development milestones, will 
be assessed.  The assessment may be video recorded for quality control purposes as 
indicated in the Training and Quality assurance methodology manual.  The HINE is only 
designed to evaluate patients up to 24 months of age.  Therefore, from Week 104 in the 
study, this assessment will be stopped for each infant once the maximum score is 
reached at two consecutive visits.  At the earliest, the final HINE-2 evaluation will be 
at Week 104.   
4.5.9.3 
Children's Hospital of Philadelphia Infant Test of 
Neuromuscular Disorders (CHOP INTEND) 
The CHOP INTEND is a measure of motor function that was developed from the Test of 
Infant Motor Performance specifically for weak infants with neuromuscular disease.  
It includes both active and elicited reflexive movement (16 items in total each scored 
from 0 to 4), such as spontaneous movement of upper and lower extremity, hand 
grasping, rolling, head control, and others.  A total score is calculated by summing the 
item scores with lower scores indicating greater severity.  The CHOP INTEND 
demonstrates good intra- and inter-rater reliability in patients with Type 1 SMA 
(Glanzman et al. 2010; Glanzman et al. 2011). 
The CHOP INTEND has been used in several studies in patients with Type 1 SMA, 
including both non-drug longitudinal studies, such as the Pediatric Neuromuscular 
Clinical Research network (Glanzman et al. 2010) and the National Institute of 
Neurological Diseases and Stroke NeuroNext natural history studies in children with 
Type 1 SMA (Kolb et al. 2016), and interventional medicinal product studies, such as the 
IONIS study (ClinicalTrials.gov Identifier NCT01839656).  Scores on the CHOP INTEND 

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are correlated with clinical decline over time, requirement for ventilation and are 
associated with SMN2 copy number (Glanzman et al. 2011).
In this study, the CHOP INTEND will be administered by an experienced and specifically 
trained clinician. Refer to the CHOP INTEND test administration manual for specific 
instruction regarding administration. The assessment may be video recorded for quality 
control purposes as indicated in the Training and Quality assurance methodology 
manual. Because the CHOP INTEND is only designed to evaluate patients up to 
24 months of age, this assessment will be stopped after 24 months of treatment.  
However, after the Week 52 visit, the CHOP INTEND can be discontinued prior to 
Month 24, upon notification by the Sponsor, if the patient has demonstrated the ability
to sit independently (item 22 of the BSID-III) at two consecutive visits, and has achieved 
a CHOP INTEND score of at least 60, at the same two consecutive visits, at any point up 
to Month 24.
4.5.9.4
Hammersmith Functional Motor Scale Expanded (HFMSE)
The HFMSE was developed to assess the motor function ability of individuals aged two 
years or older, with Type 2 and 3 SMA (O’Hagen et al 2007). The scale contains 33 
items, which are scored on a 3-point Likert scale (0-2) and summed to derive the total 
score, with lower scores indicating greater impairment. The HFMSE contains a series of 
assessments designed to assess important functional abilities, including standing, 
transfers, ambulation, and proximal and axial function. The original Hammersmith 
Functional Motor Scale (HFMS) contained 20 items and was developed primarily to 
assess an SMA Type 2 population. Thirteen items, adapted from the Gross Motor 
Function Measure (GMFM), were added to improve the sensitivity of the scale, 
particularly for measuring motor function ability in Type 3 SMA patients. The HFMS and 
HFMSE have been used in previous and ongoing clinical trials for SMA, including as a 
primary endpoint (ClinicalTrials.gov Identifiers NCT02292537, NCT01302600; Chiriboga 
et al. 2016). The intra-rater reliability of the HFMSE was assessed in a sample of 
38 Type 2 and 3 SMA patients using data at baseline and 2 months, with strong 
evidence demonstrated: intra-class correlation coefficient0.99 (O’Hagen et al. 2007). 
The validity of the HFMSE was assessed in a sample of 70 individuals with Type 2 and 3 
SMA (Glanzman et al. 2011). Convergent validity was demonstrated by strong 
correlations with the GMFM (r0.98), forced vital capacity (percentage of predicted 
normal; r 0.87), functional rating (r0.92), measures of extension and flexion 
(r0.740.77). The HFMSE also demonstrated an ability to differentiate between groups 
defined by SMN2 copy number, bi-level positive airway pressure use, ambulatory status, 
and SMA type. In this sample, time of administration averaged 12 minutes.
A users’ manual and scoring sheet will be provided to the sites prior to the first 
assessment required (Week 104) (see Appendix 1 for HFMSE visit schedule). The scale 
will be administered by a Clinical Evaluator who has received training on the 
administration of the HFMSE according to the users’ manual. Scores will be recorded 
on the scoring sheet and on the eCRF and the total score will be derived. The 

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assessment may be video recorded for quality control purposes as indicated in the 
Training and Quality assurance methodology manual.  
4.5.9.5
World Health Organisation (WHO) Milestones
The WHO motor milestones evaluate gross motor development and comprise of the time 
windows of achievement for six gross motor milestones based on data derived from the 
WHO Multicenter Growth Reference Study (MGRS) (Acta Paediatrica Supplement 
2006;450:8695). The windows represent normal variation among healthy children and 
are recommended for descriptive comparisons among populations. 
The six gross motor milestones are:
sitting without support, hands-and-knees crawling, 
standing with assistance, walking with assistance, standing alone and walking alone. 
These items are considered fundamental to the acquisition of self-sufficient erect 
locomotion and are simple and quick to test (about 10 minutes). The milestones are 
assessed using standardized testing procedures and specific MGRS performance 
criteria (Wijnhoven et al. 2004). A milestone is considered achieved only if all criteria 
are met. The assessment can be carried out by a Clinical Evaluator who has received 
appropriate training.
In this study, the WHO motor milestones will be used to assess whether patients newly 
attain one or more of the six gross motor milestones at Months 48, 54, and 60. It will 
also provide information on maintenance of effect on gross motor milestone attainment 
during the long term OLE phase of the study. 
4.5.9.6
Six-Minute Walk Test (6MWT; Ambulant Patients Only)
The 6MWT is an objective evaluation of functional exercise capacity that measures the 
maximum distance a person can walk in 6 minutes over a 25-meter linear course. 
Originally developed for chronic respiratory disease and heart failure, the test has since 
then been widely used as a performance-based measure of functional exercise capacity 
in many other populations and diseases, and normative data are available for adults and 
children. In particular, the 6MWT has been widely used as an outcome measure in 
clinical trials in neuromuscular diseases, including Duchenne Muscular Dystrophy, 
Becker Muscular Dystrophy, and SMA. In addition to providing a clinically relevant 
measure of the patient’s walking ability that has a direct impact on autonomy, the 6MWT 
was shown to detect physiological fatigue in ambulatory SMA patients as demonstrated 
by a 17% decrease in gait velocity from the first minute to the last (Montes et al. 2010).
In this study, the 6MWT will be administered by a Clinical Evaluator who has received 
training on the administration of the 6MWT. Patients must be aged 3.5 years and must 
be able to walk unassisted (i.e., without braces, crutches or calipers, or person 
[e.g., hand-held] assistance) for at least 10 meters in order to perform this test. The 
6MWT procedure will be based on the American Thoracic Society guidelines 
(ATS 2002), adapted as required with age-appropriate (for young SMA patients) 
instructions and encouragement. The course is a 25-meter linear course in a quiet 

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corridor at least 30-meter long. It is marked with a horizontal line at the beginning, the 
end, and at each intervening meter. A cone is placed at each end. Participants will be 
instructed that the test aims to see how far they can walk over a 6-minute period going 
around the cones. They must not run or jog. The use of assisted devices, such as ankle 
foot orthoses, crutches, walkers, or canes, will not be permitted during the assessment. 
However, suitable shoes and socks are to be worn. Patients will be permitted to rest 
against the wall, without sitting, if necessary. The total distance walked is recorded as 
well as how far they walk in each minute of the test.
4.5.10
Compound Muscle Action Potential
Electrophysiological outcome measures obtained through nerve conduction studies, in 
particular CMAP, provide unique information regarding the function of the motor unit, 
which is central in the pathophysiological process in SMA.
CMAP, which is the measure of the total output of the motor units that supply a particular 
muscle, has been extensively used to monitor disease progression in amyotrophic lateral 
sclerosis and SMA; a number of studies have shown that it correlates with disease 
severity, functional status, SMN2 copy number, and age (Lewelt et al. 2010; Finkel 2013; 
Kolb et al. 2016). 
Maximum ulnar CMAP amplitude and area will be obtained by stimulating the ulnar 
nerve at the elbow and recording from the abductor digiti minimi muscle. The laterality 
of muscle groups studied with CMAP must remain consistent for each patient throughout 
the study.
CMAP will be performed by an electrophysiologist experienced in the assessment of 
pediatric patients. As much as possible, the same person should perform all the 
assessments for each patient throughout the study.
4.5.11
Laboratory, Biomarker, and Other Biological Samples
The following blood samples will be taken in the study at the timepoints specified in the 
schedule of activities (see Appendix 1):

Clinical genotyping (see Section 4.5.11.1)

Fluid PD samples (see Section 4.5.11.2)

Safety laboratory (see Section 4.5.11.3)

Plasma protein binding (see Section 4.5.11.4)

Pharmacokinetics (see Section 4.5.11.5)
The total blood volume to be collected at any timepoint should not exceed 0.8 mL/kg or 
2.4 mL/kg over any 4-week period throughout the study (E.U. 2008). However, should 
the total blood volume to be collected at any timepoint according to the schedule of 
activities exceed 0.8 mL/kg or the volume collected over any 4-week period throughout 

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the study exceed 2.4 mL/kg, the prioritization order indicated in Table 1 should be 
followed.
Table 1
Prioritization Order for Blood Samples
1
Any safety laboratory samples (scheduled or unscheduled and performed at 
the discretion of the Investigator)
2
PK samples, including assessment of free-fraction plasma protein binding
3
Fluid PD samples (SMN protein levels)
4
Fluid PD samples (SMN2 mRNA, exploratory biomarkers)
PDpharmacodynamic; PK pharmacokinetic; SMNsurvival motor neuron (protein).
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected does not produce useful information.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biological samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions:

Fluid PD samples will be destroyed no later than 5 years after the date of final lock
of the clinical database and may be used for additional exploratory analysis/assay
development related to SMA including, but not limited to, pathways related to SMN
function or treatment response.

Blood samples collected for clinical genotyping will be destroyed no later than
5 years after the date of final lock of the clinical database.
If a patient withdraws from the study, samples collected prior to the date of withdrawal 
may still be analyzed, unless the patient specifically requests that the samples be 
destroyed or local laws require destruction of the samples.  However, if samples have 
been tested prior to withdrawal, results from those tests will remain as part of the overall 
research data. 
Data arising from sample analysis, including data on mutations, will be subject to the 
confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.

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4.5.11.1
Clinical Genotyping Samples
A single mandatory whole blood sample will be taken from every patient at screening for 
DNA extraction. The DNA will be used to determine the number of copies of the SMN2
gene (see Section 4.1.1) and to confirm SMN1 gene mutation or deletion. The result of 
the mandatory genotyping sample may not be required prior to enrollment given that 
genetic diagnosis of 5q autosomal recessive SMA has already been confirmed by using 
local assays.
Samples may be used for exploratory analysis/assay development related to SMA, 
including, but not limited to, mitochondrial DNA, and genes related to SMN function or 
treatment response.
4.5.11.2
Fluid Pharmacodynamic Assessments
The following fluid PD assessments will be performed as detailed in the schedule of 
activities (see Appendix 1).

In vivo splicing modification of SMN2 mRNA in whole blood to measure:
In vivo splicing modification of SMN1, SMN2 full-length, and SMNΔ7 mRNA. 
Housekeeping genes for the quantitative analysis of RNA will be measured.

SMN protein levels (venous blood)

Exploratory biomarker for exploratory biomarker studies related to the pathology or
disease progression of SMA or treatment response to risdiplam
If blood volume allows, a serum sample will be taken for exploratory biomarker 
studies related to the pathology or disease progression of SMA or treatments 
response to risdiplam. 
4.5.11.3
Safety Laboratory Assessments
Timepoints for safety blood samples are indicated in the schedule of activities (see 
Appendix 1).
Normal ranges for the study laboratory parameters should be supplied to the Sponsor.
Laboratory safety tests shall be collected at timepoints specified in the schedule of 
activities (see Appendix 1 and Appendix 2).
At any time and as described in Section 4.5.11, safety laboratory samples will be given 
priority over any other sample, such that the volume of blood taken at any single 
timepoint will not exceed 0.8 mL/kg, and the volume collected over any 4-week period 
throughout the study will not exceed 2.4 mL/kg.
Additional blood samples may be taken at the discretion of the investigator if the results 
of any test fall outside the reference ranges, or clinical symptoms necessitate additional
testing to monitor patient safety. For safety laboratory samples only, use of 
micro-collection method should always be favored to limit the amount of blood collected.

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Where the clinical significance of abnormal laboratory results is considered uncertain, 
screening laboratory tests may be repeated before enrollment to confirm eligibility.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated and followed up in a timely manner until they have returned to 
the normal range and/or an adequate explanation of the abnormality is found. Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the local or central laboratory.
Laboratory test samples will be collected for the following analyses:

Hematology: hemoglobin, hematocrit, erythrocytes (RBC), platelets, leukocytes
(WBC), differentials (counts): neutrophils, eosinophils, lymphocytes, monocytes,
basophils, reticulocyte

Serum chemistry: AST, ALT, total and conjugated bilirubin, albumin, creatinine,
urea nitrogen, sodium, chloride, potassium, glucose
4.5.11.4
Plasma Protein Binding
A venous blood sample will be collected from all patients at screening to measure 
plasma protein binding (i.e., to measure the free fraction of the study drug; see 
Section 3.3.1). Results for a patient must be available and checked by the Sponsor 
before any study drug is administered (Day 1) to each individual patient, if the patient is 
below the age range for which free fraction data is already available from other patients.  
If free fraction data from other patients in this age range is already available, then 
treatment of the new enrolled patient may be initiated without free fraction being 
available, however, the result of the screening free fraction sample must be reviewed by 
the Sponsor within 4 weeks of treatment start for this patient.
Plasma protein binding (i.e., free fraction, fu) may also be measured from the PK 
samples collected during the study.
4.5.11.5
Pharmacokinetic Assessments
Blood for determination of plasma concentrations of risdiplam, and its metabolite(s) as 
applicable, will be collected as detailed in the schedule of activities (see Appendix 1 and
Appendix 2).
Additional PK samples may be taken if required for safety reasons, e.g., upon a 
requested dose change to confirm the new target exposure or to confirm unusual PK 
findings before requesting a dose change (see Appendix 1 and Appendix 2).
Venous blood will be collected for PK samples. If venous blood cannot be obtained after 
two attempts, capillary blood collection should be attempted for pharmacokinetics.
Plasma concentrations of risdiplam and derived metabolite(s) as applicable will be 
measured by appropriate assays, and PK samples may also be used for exploratory 

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metabolite identification.  Actual PK sampling times must be documented in the eCRF. 
Actual date and time of dosing on the day of PK sampling (and the two preceding dosing 
occasions if possible) must be documented in the eCRF.
4.5.12
Parent/Caregiver-Reported Outcomes
The infant/toddler quality of life questionnaireshort-form 47-item version (ITQOL-SF47) 
is a parent (or caregiver)-completed measure that was developed to assess health 
status and health-related quality of life (HRQoL) of children between 2 months and 
5 years old (Landgraf et al. 2013). It also assesses the HRQoL of the parent. The 
ITQOL-SF47 contains three single-item scores (Overall Health, Change in Health, and 
Family Cohesion) and eight multi-item domains (Physical Abilities [6 items], Growth and 
Development [5 items], Bodily Pain [2 items], Temperament and Moods [6 items], 
Behavior [12 items], General Health Perception [5 items], Parent-Emotional Health 
[4 items] and Parent-Time Limitations [4 items]). Items are scored using a Likert-type 
scale with five levels (except Parent-Time limitations which has 4 response options).
Where applicable, item scores are reversed so that higher scores indicate better health. 
For each domain, items are summed and converted to a 0 (worst health)100 (best 
health) scale.
Throughout the study, the same parent (or caregiver) should complete the ITQOL-SF47.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following: 

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Unable to continue to comply with study requirements

Any event that meets stopping criteria defined in Section 5.1.3
For patients who discontinue study drug prematurely, their parents (or caregiver) will be
asked to return with the patient to the clinic for a study completion/early withdrawal visit
and participate in the follow-up call 30 days later (see Appendix 1). The primary reason 
for premature study drug discontinuation should be documented on the appropriate 
eCRF.
If a patient needs to stop administration of study drug (e.g., immediate need for surgery,
required treatment with a drug known to or suspected to have an interaction with
risdiplam, etc.), the investigator must discuss the situation with the Sponsor to determine 
whether the patient should withdraw from the study or temporarily discontinue study 
drug.

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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
4.6.2
Patient Discontinuation from Study
Parent (or caregiver) has the right to voluntarily withdraw the patient from the study at 
any time for any reason.  In addition, the investigator has the right to withdraw a patient 
from the study at any time.  Reasons for withdrawal from the study may include, but are 
not limited to, the following:

The parent (or caregiver) withdrawals consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent. The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.
If a parent (or caregiver) requests the patient to be withdrawn from the study, this 
request must be documented in the source documents and signed by the investigator.  
Patients who are withdrawn from the study will not be replaced.
Patients will not be followed for any reason after consent has been withdrawn.
When the parent (or caregiver) voluntarily withdraws the patient from the study, or the 
patient is withdrawn by the investigator, samples collected until the date of withdrawal 
will be analyzed, unless the parent (or caregiver) specifically requests for these to be 
discarded or local laws require their immediate destruction.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

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
Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the ICH guideline for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
4.6.5
Assessments at Study Completion/Early Withdrawal Visit
The EOS is when the last patient completes 5 years in the study. All patients should
attend a study completion/early withdrawal visit when they either complete the study or 
discontinue study drug early, as shown in the schedule of activities (Appendix 1, 
Appendix 2, and Appendix 3). If risdiplam is approved in the country of the site before 
the Week 260 (Year 5) visit, then the final visit for the patient will be at 260 weeks in the 
study – in this case the study completion/early withdrawal visit will be performed in place 
of the Week 260 visit. If risdiplam is not approved in the country of the site at the time of 
the Week 260 visit, the patient should attend the Week 260 visit, and all OLE visits 
beyond Week 260 until risdiplam is approved or until EOS (whichever occurs first), 
ensuring that the final site visit is the study completion/early withdrawal visit.  
4.6.6
Follow-up Assessments
A follow-up phone call should occur 30 days after the study completion/early withdrawal 
visit to collect information on adverse events and use of respiratory support as outlined 
in Section 5.5, Section 5.6 and the schedule of activities(Appendix 1, Appendix 2, and 
Appendix 3).
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Risdiplam has only been approved in the USA for patients 2 months of age and older.
Clinical development is ongoing.  The safety plan for patients in this study aims at 
managing potential risks that were identified following findings in preclinical studies with 
risdiplam. The potential safety risks for risdiplam are outlined below.  Please refer to the 
Risdiplam Investigator's Brochure for a complete summary of safety information.
The exposure cap of a mean AUC0-24,ss 2000 ng hr/mL corresponds to the NOAEL in 
the 39-week toxicology study in cynomolgus monkey (i.e., the exposure level at which no 
adverse events were observed).  Only effects on the testes were observed at those 
exposure levels in another study in rats (effects on testes could not be assessed in 
cynomolgus monkey due to sexual immaturity of the animals; see Risdiplam 
Investigator’s Brochure); parents of male subjects will be informed accordingly.  
In humans, the pachytene stage of meiosis is completed towards the end of fetal 
development. In this study, effects on the oocyte are not expected because premature 
infants will not be included.  In juvenile and adult rat toxicology studies and in monkey 
toxicology studies, there was no effect on female reproductive organs or female fertility.  

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Any effects on meiosis and oocyte maturation will be further investigated in a 
prepostnatal toxicity study in rats (see Risdiplam Investigator’s Brochure).
Several measures will be taken to ensure the safety of patients participating in this 
study.  Patients will undergo safety monitoring during the study, including assessment of 
the nature, frequency, and severity of adverse events.  In addition, guidelines for 
managing adverse events, including criteria for treatment interruption or discontinuation, 
are provided below. The pharmacokinetics will be monitored in each individual patient to 
ensure that each infant is in the targeted exposure range and in compliance with the 
exposure cap. Free fraction will be measured from a sample taken at screening, and the 
dose adjusted if the free fraction is different for a particular infant.
The stopping rules detailed in Section 5.1.3 will be applied in case of specific adverse 
events.
5.1.1
Risks Associated with Risdiplam
Based on observed toxicity in nonclinical studies (see Risdiplam Investigator’s Brochure 
for details), the following safety precautions should be followed for this study. For effects 
on the skin, oral and larynx mucosa, hematology, conjunctival mucous membranes, and 
retinal toxicity no safety data are available in the age group of 2 months and younger. 
5.1.1.1
Skin Toxicity
Patients treated with risdiplam may be at risk for developing skin redness, dry or peeling 
skin, or cracking in the corner of the mouth. Aggressive skin treatments, on body or
face, should be avoided as well as scented lotions, soaps, and deodorants. Parents 
(or caregivers) will be instructed to apply alcohol-free hypoallergenic moisturizing 
cream early in case of dry skin and to quickly contact the investigator.
5.1.1.2
Oral and Larynx Mucous Membranes
Patients treated with risdiplam are at risk of developing effects on oral and larynx 
mucous membranes.  Parents (or caregivers) who will administer the study medication 
orally will be instructed to rinse the patient’s mouth with water (that should be swallowed) 
after administration and to generally ensure that oral mucosa is well-lubricated with 
fluids. Similarly, the peribuccal area of the patient will be washed with water in case of 
drug drooling or spitting. Parents (or caregivers) will be instructed to promptly consult 
the study investigator in case of symptoms of laryngitis for a specialized examination.
5.1.1.3
Effects on Hematology Parameters
Patients treated with risdiplam are at risk of developing hematological effects with 
decreased cellularity in bone marrow and peripheral blood. Regular monitoring of 
hematological parameters will be performed.

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5.1.1.4
Conjunctival Mucous Membranes
Patients treated with risdiplam are at risk of developing adverse effects affecting 
conjunctival mucous membranes. Use of ocular lubricants (artificial tears) will be 
advised in patients who exhibit signs of dry eye (paradoxical tearing, ocular discomfort, 
conjunctival injection).
5.1.1.5
Visual Impairments
Patients treated with risdiplam are at risk of developing retinal toxicities (irreversible loss 
of photoreceptor cells in the peripheral retina and potentially reversible microcystic 
macular degeneration). Ophthalmology monitoring including SD-OCT will be performed 
throughout the study. Parents or caregivers will be informed that in case of visual 
impairments, young children could present with, for example, strabismus or behavioral 
changes (e.g., fixation losses, not reaching/grabbing objects, rubbing of the eyes).
Parents or caregivers will be instructed by the investigators to comply with concomitant 
medications restriction (i.e., use of drugs with known human retinal toxicity, see 
Section 4.4.2). 
5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Dose Modifications
Dose modifications are not permitted, unless based on weight changes (weight must be 
measured at the site or, in exceptional circumstances, at home or local clinic upon 
discussion with the Sponsor (see Section 3.3.1) or requested by the Sponsor based on 
the PK monitoring.
5.1.3
Stopping Rules
5.1.3.1
Individual Patient Stopping Rules
While the investigators, the Roche Clinical Science Leader (CSL), the Roche Safety 
Science Leader, and the external iDMC (and any other professional considered 
necessary to consult) will review the benefitrisk profile for the individual patients on an 
ongoing basis, the following specific safety stopping rules for an individual subject are 
defined a priori:

Skin or subcutaneous reaction, pharyngeal/laryngeal or mucosal reaction 
(Grade2, CTCAE, v5) considered to be clearly related to study drug as confirmed 
by a dermatologist/ear, nose, and throat specialist, making the benefitrisk ratio 
non-favorable

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
Functional or structural eye abnormalities
Clinically relevant abnormalities on SD-OCT considered to be related to study 
drug as assessed by an ophthalmologist (i.e., changes in retinal thickness, 
presence of edema, cystoid or atrophic changes). In case of equivocal 
observations, retinal imaging can be repeated to confirm or refute the initial 
results. In case of retinal findings, each individual case will be discussed 
between the investigator, the ophthalmologist examining the patient, and the 
Sponsor to decide discontinuation of study drug administration.
Clinically relevant impairment of vision detected by the ophthalmological 
examination.

Significant and clinically relevant changes in laboratory parameters, ECG, or vital 
signs that pose an unacceptable risk for the patient

Patients with any elevated ALT or AST of3ULN, ALP2ULN, and associated 
with an increase in bilirubin (2upper limit of normal) (i.e., a suspected “Hy’s law” 
which indicates risk of severe/serious liver impairment) in the absence of a different 
explanation

Other findings such as a serious adverse event or any other severe adverse event 
that, at the joint discretion of Roche CSL, Roche Safety Science Leader, and the 
investigator, indicate that dosing should be halted.
In addition to the above stopping rules, dosing may be stopped if safety, tolerability, or
efficacy data suggest risdiplam is not beneficial for the patient, in the investigator's 
judgment. The investigator should then look for the best standard of care option 
available in the country.

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5.1.3.2
Management Guidelines
Specific adverse events related to pharyngeal/laryngeal, skin, and ophthalmological 
adverse events should be managed as described in Table 2.
Table 2
Guidelines for Management of Patients Who Experience Adverse 
Events
Event
Action to take
Symptoms or signs of oropharyngitis
Examine, treat symptomatically, and document resolution 
and outcome.
Consult otolaryngology specialist in case of unusual 
findings.
Grade2 skin toxicity reaction
Grade2 larynx toxicity reaction
Consult a dermatologist.  Discontinue study treatment if 
determined to be study-drug related.
Promptly contact the study investigator, consult as 
quickly as possible a dermatologist/otolaryngology 
specialist.  Discontinue study treatment immediately if 
determined to be study-drug related.
Ophthalmological event
Consult a study trained ophthalmologist as quickly as 
possible for ophthalmic examination and contact promptly 
the study investigator. If findings are consistent with 
preclinical findings, discontinue study treatment until the 
study-trained ophthalmologist at study site and the study 
investigator have been consulted and the results of a full 
ophthalmic examination have been reviewed.
5.1.4
Safety Monitoring
Based on observed toxicity in nonclinical studies (see Risdiplam Investigator’s Brochure 
for details), the following safety monitoring plan has been compiled:

Physical examinations (see Section 4.5.4), with specialty medical doctors 
(ophthalmologist, dermatologist, and otolaryngology specialist) identified who will be 
trained in risdiplam observed nonclinical toxicological findings prior to study start to 
follow-up quickly in case of any suspicious or actual adverse toxicity event. 
Photographs may be taken of any skin, mouth, or pharynx lesions for 
documentation, at the discretion of the investigator or specialty medical doctors. 
These photographs may be shared with the Sponsor to allow for safety monitoring 
and will be stored in a computer system with restricted access (the sites will be 
instructed not to submit photographs that identify the patient, e.g., photos of a cheek 
skin lesion in which the entire face is captured).

Ophthalmological assessments (see Section 4.5.7)

Stopping rules for individual patients have been defined that include criteria for 
treatment discontinuation in case of skin, pharynx/larynx, or ophthalmic events 
(see Section 5.1.3.1).

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
Follow-up phone calls (as per the timepoints in the schedule of activities; 
Appendix 1): parents (or caregivers) will be called by the investigator or designee to 
monitor safety and tolerability when not attending the clinic. Assessments will 
include review of adverse events, concomitant medications, and significant life 
events.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8
and 5.3.5.9 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

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
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.  
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events, regardless of relationship to study drug, 
will be reported until 30 days after the study completion/early withdrawal visit (i.e., at 
least 30 days after the final dose of study drug).
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you/your child felt since your last clinic visit?"
"Have you/your child had any new or changed health problems since you were last 
here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.

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Table 3
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living a
4
Life-threatening consequences or urgent intervention indicated b
5
Death related to adverse event b
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
b Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event

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5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 

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more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).

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5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.2), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of SMA.

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Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed to progression of SMA disease and/or associated complications 
or comorbidities, the Death Attributed to Progressive Disease eCRF should be 
completed.
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the Medical History eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Spinal Muscular Atrophy
Medical occurrences or symptoms of deterioration that are anticipated as part of 
SMA should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study. When recording an unanticipated worsening of SMA on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated worsening of Spinal Muscular Atrophy").
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration)

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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available.

Admission to emergency room that does not result in hospitalization will not 
constitute per se a serious adverse event.

Hospitalization due solely to the progression of the underlying SMA disease, as 
particularly in this patient population, hospitalizations are expected and frequently 
occurring due to the nature of the disease.
5.3.5.11
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be administered by the parent (or caregiver), drug 
misuse could involve the drug being administered to someone other than the 
patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
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risdiplam, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with risdiplam, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

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
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require two
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.12
Patient/Caregiver-Reported Outcome Data
Adverse event reports will not be derived from parent (or caregiver)-reported outcome 
data by the Sponsor, and safety analyses will not be performed using these data. Sites 
are not expected to review these data for adverse events.
5.3.5.13
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Medical device complaints (see Sections 5.4.2 and 5.4.3 for details on reporting 
requirements).

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For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/Ethics 
Committee (EC).
5.4.1
Emergency Medical Contacts
To ensure the safety of study patients, access to the Medical Monitors is available 
24 hours a day 7 days a week. Country-specific toll-free numbers of the Emergency 
Medical Call Center are filed in the investigator site file.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 30 days after the study completion/early withdrawal visit.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the appropriate Adverse Event eCRF and submit 
the report via the electronic data capture (EDC) system.  A report will be generated and 
sent to Roche Safety Risk Management department.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 

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EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur more than 30 days after the 
study completion/early withdrawal visit are provided in Section 5.6.
5.4.3
Reporting Requirements for Medical Device Complaints
In this study, dispenser for oral drug administration is considered a medical device.  The 
investigator must report all medical device complaints to the Sponsor.  The investigator 
should document as much information as possible on the IMP Deviation Form, including 
the product batch number, and forward the form to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event) (refer to the pharmacy manual for further 
details).  If the medical device results in an adverse event to the study patient, the event 
must be reported on the Adverse Event eCRF and submitted through the EDC system.  
If the event is serious, the Adverse Event eCRF must be completed immediately (i.e., no 
more than 24 hours after learning of the event), as outlined in Section 5.4.2.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
5.5.2
Sponsor Follow-Up
For serious adverse events and adverse events of special interest, the Sponsor or a 
designee may follow up by telephone, fax, email, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (as defined 
in Section 5.3.1), if the event is believed to be related to prior study drug treatment.  
These events should be reported through use of the Adverse Event eCRF.  However, if 
the EDC system is not available, the investigator should report these events directly to 

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the Sponsor or its designee, either by faxing or by scanning and emailing the paper 
Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Risdiplam Investigator's Brochure
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary objective of the study is to evaluate the efficacy, safety, pharmacokinetics, 
and pharmacodynamics of risdiplam in infants genetically diagnosed with SMA but not 
yet presenting with symptoms. 
A database lock will occur for the purpose of the primary analysis and analyses of the 
12-month secondary and exploratory endpoints once the last infant enrolled has either 
completed his/her 12-month assessment or has been withdrawn. At the time of the 
primary analysis, all available efficacy data after Month 12 and all available safety data 
will also be reported. Following the primary analysis, another database lock will occur 
for the analyses of the 24-month secondary and exploratory endpoints once the last 
patient enrolled has completed his/her 24-month assessment or has been withdrawn. 
All available safety data and efficacy data after Month 24 will also be reported.
Subsequent locks of the database may occur to perform exploratory efficacy and safety 
analyses of the data at further timepoints in response to information that may emerge 
during the course of the study. Final database lock will occur at the end of the study.  
Full details of the statistical methods will be described in the Data Analysis Plan (DAP).
6.1
DETERMINATION OF SAMPLE SIZE
The purpose of the study is to estimate the proportion of infants with two SMN2 copies 
(excluding the known SMN2 gene modifier mutation c.859GC) and a baseline CMAP 
amplitude 1.5 mV who are sitting without support after 12 months of treatment and to 
test whether this proportion is higher than a performance criterion set at 5%. The 5% 

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threshold was chosen based on the natural history of the disease (typically patients with 
Type 1 SMA never achieve sitting without support by definition) and based on the 
assumption that there is a 97% chance that a presymptomatic infant with two SMN2
copies develops Type 1 SMA (Feldkotter et al. 2002). 
The target sample size to be enrolled in the study is 10 patients with two SMN2 copies 
and a baseline CMAP amplitude 1.5 mV. The sample size of 10 patients provides 83% 
power to test the null hypothesis Ho: p5% versus alternative hypothesis Ha: p5%, 
if the true proportion of infants who would sit after 12 months on treatment is 40%. This 
is based on an exact binomial test with a one-sided 5% significance level. The minimum 
number of infants needed to be observed sitting without support is 3 out of 10 for a 
statistically significant result. If 3 out of 10 infants sit without support, the lower limit of 
the two-sided 90% Clopper-Pearson (Exact) confidence interval would be above 5%.
If recruitment is completed prior to enrolling 10 patients with two SMN2 copies and a 
baseline CMAP amplitude 1.5 mV, the number of patients needed to be observed 
sitting without support for a statistically significant result may differ. Table 4 shows 
the minimum number of patients that would need to achieve the primary endpoint
(based on the number enrolled), in order for the endpoint to meet statistical significance
(the critical value). In each case, the lower limit of the two-sided 90% Clopper-Pearson 
(Exact) confidence interval would be above 5%. 
Table 4:
Number of Patients in the Primary Analysis Population Needed 
to Achieve the Primary Endpoint  
Number of Patients 
in the Primary 
Population
Critical Value
Power (%)
5
2
66.3
6
2
76.7
7
2
84.1
8
3
68.5
9
3
76.8
10
3
83.3
  

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6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who are enrolled, discontinued, continuing treatment at the time 
of analysis, or have completed the study will be summarized. Reasons for premature 
study withdrawal will be listed and summarized. Enrollment and major protocol 
deviations will be listed and evaluated for their potential effects on the interpretation of 
study results.
6.3
ANALYSIS POPULATION
6.3.1
Safety Analysis Population
All patients who receive at least one dose of risdiplam, whether prematurely 
withdrawn from the study or not, will be included in the safety population. Selected 
key safety outputs will be produced for All Patients and separately for the subgroups 
CMAP amplitude 1.5 mV and CMAP amplitude 1.5 mV.
6.3.2
Pharmacokinetic and Pharmacodynamic Analysis Population
All patients with at least one timepoint with a measureable drug concentration or PD 
marker will be included in the respective analysis data sets. Patients will only be 
excluded from the analysis population if they significantly violate the inclusion or 
exclusion criteria, deviate significantly from the protocol, or if data are unavailable, not 
plausible, or incomplete that may influence the PK or PD analysis. Excluded cases will 
be documented together with the reason for exclusion.
6.3.3
Intent-to-Treat and Primary Efficacy Analysis Population
The intend-to-treat (ITT) population is defined as all enrolled patients, regardless of 
whether they receive risdiplam or not. The primary efficacy analysis population is 
defined as all infants in the ITT population with two SMN2 copies (excluding the known 
SMN2 gene modifier mutation c.859GC) and a baseline CMAP amplitude 1.5 mV.
The primary efficacy analysis population will be the population for the primary efficacy 
analysis (see Section 6.5.1). The ITT population will be used for all secondary and
exploratory efficacy summaries; however, any hypothesis testing if performed will be 
limited to the primary efficacy analysis population.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and other baseline characteristics will be summarized by overall 
population, by SMN2 copy number for the ITT population and for the primary efficacy 
analysis population using descriptive statistics, means, standard deviations, medians, 
interquartile ranges and ranges for continuous variables and number, and percentages 
for categorical variables, as appropriate. Baseline will be defined as the last 
measurement prior to the first dose of risdiplam unless specified otherwise in the DAP.

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6.5
EFFICACY ANALYSES
6.5.1
Primary Efficacy Endpoint
All enrolled infants with two SMN2 copies (excluding the known SMN2 gene modifier 
mutation c.859GC) and a baseline CMAP amplitude 1.5 mV will be included in the 
primary efficacy analysis. The primary endpoint of the study is the proportion of infants
who are sitting without support after 12 months of treatment.  Infants who do not achieve 
sitting, or have not maintained sitting achieved earlier, have been withdrawn, or died, will 
be classified as non-responders (i.e., non-sitters) for the primary analysis.  Sitting is 
defined as “sits without support for 5 seconds” as assessed in Item 22 of the BSID-III 
Gross Motor Scale. The assessment of the independent central readers will be used for 
the primary analysis.
The proportion of infants who are alive and sitting after 12 months of treatment will be 
presented with a two-sided 90% Clopper-Pearson (Exact) confidence interval.  An exact 
binomial test will be performed. The hypothesis to be tested will be that the proportion of 
infants who sit on treatment (p) is:
Ho: p5% (null) versus Ha: p5% (alternative).
If the one-sided p-value is 5% (Type 1 error rate), then the null hypothesis will be 
rejected. If the lower limit of the two-sided 90% confidence interval is above the 5% 
threshold, the primary objective of the study will be considered achieved.  The number 
and percentage of infants sitting at each timepoint will also be presented, using the 
same responder/non-responder definition described above.
As this is an open-label study, once at least 3 out of 10 infants (if 10 patients in the 
primary analysis population are enrolled) have met the primary endpoint of sitting 
without support at Month 12 (as assessed by the independent central readers), the 
minimum number of infants needed for a statistically significant result will have been 
achieved and the primary objective of the study will be considered achieved at this 
earlier timepoint.  The primary analysis will be conducted once the last patient enrolled 
(irrespective of SMN2 copy number) has reached 12 months of treatment, in order to 
assess the primary endpoint, and to allow the assessment of the 12 month secondary 
and exploratory endpoints in all patients. The study will not be stopped early if the 
primary objective has been reached, and all infants enrolled will continue to receive 
12 months of treatment to provide an unbiased estimate of the proportion of infants
sitting at Month 12.
If recruitment is completed prior to enrolling 10 patients with two SMN2 copies and a 
baseline CMAP amplitude 1.5 mV, the number of patients needed to meet the primary 
endpoint for a statistically significant result may differ (see Table 4).

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6.5.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:
Development of clinically manifested SMA

Proportion of patients developing clinically manifested SMA at Month 12 of 
treatment

Proportion of patients developing clinically manifested SMA at Month 24 of 
treatment
Survival and ventilation-free survival

Time to death (from enrollment)

Time to permanent ventilation (from enrollment)
Permanent ventilation is defined as 16 hours of non-invasive ventilation per day or 
intubation for 21 consecutive days in the absence of, or following the resolution of, 
an acute reversible event or tracheostomy

Time to death or permanent ventilation (from enrollment)

Proportion of patients who are alive without permanent ventilation at Month 12 of 
treatment

Proportion of patients who are alive without permanent ventilation at Month 24 of 
treatment

Proportion of patients who are alive at Month 12 of treatment

Proportion of patients who are alive at Month 24 of treatment
Motor function and development milestones

Proportion of patients who achieve the attainment levels of the motor milestones as 
assessed in the HINE-2 (head control, sitting, voluntary grasp, ability to kick, rolling,
crawling, standing, and walking) at Month 12 of treatment

Proportion of patients who achieve the attainment levels of motor milestones as 
assessed in the HINE-2 (head control, sitting, voluntary grasp, ability to kick, rolling, 
crawling, standing, and walking) at Month 24 of treatment

Proportion of patients with two copies of the SMN2 gene sitting without support (at 
Month 12 of treatment [as assessed in Item 22 of BSID-III Gross Motor Scale]) for 
5 seconds (independent of the CMAP value at baseline)

Proportion of patients sitting without support at Month 24 of treatment (as assessed 
in Item 22 of BSID-III Gross Motor Scale) for 5 seconds

Proportion of patients sitting without support at Month 12 of treatment (as assessed 
in Item 26 of BSID-III Gross Motor Scale) for 30 seconds

Proportion of patients sitting without support at Month 24 of treatment (as assessed 
in Item 26 of BSID-III Gross Motor Scale) for 30 seconds

Proportion of patients standing at Month 24 of treatment (defined as “Stands Alone”
for at least 3 seconds as assessed in Item 40 of the BSID-III Gross Motor Scale)

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
Proportion of patients walking at Month 24 of treatment (defined as “Walks Alone”
takes at least 3 steps as assessed in Item 42 of the BSID-III Gross Motor Scale)

Proportion of patients demonstrating the ability to achieve a scaled score within 
1.5 standard deviations of chronological reference standard at Months 24 and 42 of 
treatment (as assessed through the use of the BSIDIII Gross Motor Scale)

Change from baseline score in the CHOP INTEND motor function scale at Month 12
of treatment

Proportion of patients who achieve a score of 40 or higher in the CHOP INTEND 
motor function scale at Month 12 of treatment

Proportion of patients who achieve a score of 50 or higher in the CHOP INTEND
motor function scale at Month 12 of treatment

Proportion of patients who achieve a score of 60 or higher in the CHOP INTEND
motor function scale at Month 12 of treatment

Proportion of patients who meet CHOP INTEND stopping criteria at any point up to 
Month 24

Change from baseline (Month 24) in the HFMSE at Month 60 of treatment
Growth measures

Number and proportion of patients within 3rd percentile of normal range for 
weight-for-age, length/height-for-age, weight-for-length/height, and head
circumference-for-age at Month 12 of treatment, based on the WHO Child Growth 
Standards (WHO 2019)

Number and proportion of patients within 3rd percentile of normal range for 
weight-for-age, length/height-for-age, weight-for-length/height, and head 
circumference-for-age at Month 24 of treatment, based on the WHO Child Growth 
Standards (WHO 2019)

Number and proportion of patients within 3rd percentile of normal range for 
weight-for-age, length/height-for-age and weight-for-length/height at Month 36 of 
treatment, based on the WHO Child Growth Standards (WHO 2019)

Number and proportion of patients within 3rd percentile of normal range for 
weight-for-age, length/height-for-age and weight-for-length/height at Month 48 of 
treatment, based on the WHO Child Growth Standards (WHO 2019)

Number and proportion of patients within 3rd percentile of normal range for 
weight-for-age, length/height-for-age and weight-for-length/height at Month 60 of 
treatment, based on the WHO Child Growth Standards (WHO 2019)

Change from baseline percentiles for weight-for-age, length/height-for-age, 
weight-for-length/height, and head circumference-for-age at Month 12 of treatment

Change from baseline percentiles for weight-for-age, length/height-for-age and
weight-for-length/height, and head circumference-for-age at Month 24 of treatment

Change from baseline percentiles for weight-for-age, length/height-for-age and
weight-for-length/height at Month 36 of treatment

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
Change from baseline percentiles for weight-for-age, length/height-for-age and
weight-for-length/height at Month 48 of treatment

Change from baseline percentiles for weight-for-age, length/height-for-age and
weight-for-length/height at Month 60 of treatment

Change from baseline in chest circumference at Month 12 of treatment

Change from baseline in chest circumference at Month 24 of treatment

Ratio between chest and head circumferences at Month 12 of treatment
Head circumference will be the denominator of the ratio.

Ratio between chest and head circumferences at Month 24 of treatment
Head circumference will be the denominator of the ratio.
Nutrition

Proportion of patients with the ability to swallow at Month 12 of treatment

Proportion of patients with the ability to swallow at Month 24 of treatment

Proportion of patients with the ability to swallow at Month 36 of treatment

Proportion of patients with the ability to swallow at Month 48 of treatment

Proportion of patients with the ability to swallow at Month 60 of treatment

Proportion of patients with the ability to feed orally at Month 12 of treatment

Proportion of patients with the ability to feed orally at Month 24 of treatment

Proportion of patients with the ability to feed orally at Month 36 of treatment

Proportion of patients with the ability to feed orally at Month 48 of treatment

Proportion of patients with the ability to feed orally at Month 60 of treatment
Muscle electrophysiology

Change from baseline in CMAP amplitude at Month 12 of treatment

Change from baseline in CMAP amplitude at Month 24 of treatment
Analyses of the secondary efficacy endpoints will be performed using all data available 
at the time of the 12-month, 24-month, and further analysis reporting events. All 
secondary endpoints will be summarized by timepoint (except for the time-to-event 
endpoints) by overall population, by SMN2 copy number for the ITT population and the 
primary efficacy analysis population using descriptive statistics. The two-sided 90% 
confidence intervals will also be presented as appropriate.
Time-to-death or permanent ventilation and its individual components will be presented
graphically using Kaplan-Meier curves. The median time to ventilation-free survival and
the proportion of patients who are surviving ventilation-free at Months 12 and 24 of 
treatment will be estimated using Kaplan-Meier methodology, when possible. 
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enrollment in the study until the date of death from any cause or date of permanent 
ventilation, whichever event occurs first. Patients with no event reported prior to the 
analysis cutoff date will be censored at the latest date before the cutoff in which they 
were known to be alive and ventilation free.
The number and percentage of patients within each attainment response category of the 
HINE-2 motor milestones at Month 12 and Month 24 of treatment will be presented.
For the primary efficacy population only, the proportion of infants who at 12 months of 
treatment are alive and sitting without support for 30 seconds (as assessed in item 26 of 
the BSID-III Gross Motor Scale), and the proportion of patients who at 24 months of 
treatment are alive and 1) sitting without support for 5 seconds (as assessed in Item 22 
of the BSID-III Gross Motor Scale), 2) sitting without support for 30 seconds (as 
assessed in Item 26 of the BSID-III Gross Motor Scale), 3) standing (as assessed in 
Item 40 of the BSID-III Gross Motor Scale), and 4) walking (as assessed in Item 42 of 
the BSID-III Gross Motor Scale) will be analyzed as for the primary endpoint (using the 
same performance criterion of 5%) testing the null hypothesis that the proportion of 
patients who are alive and have achieved the motor milestone 5% (null) versus p5% 
(alternative).  
Further details of the statistical methods, definitions, and analyses for all the secondary 
endpoints will be provided in the DAP.
6.5.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints will include, but may not be limited to, the following:

Cognition as measured by the BSID-III Cognitive Scale at Months 12, 24, and 42 of 
treatment

Proportion of patients demonstrating the ability to achieve a scaled score within 
1.5 standard deviations of chronological reference standard at Months 24 and 42 of 
treatment (as assessed through the use of the BSIDIII Cognitive Scale)

Fine motor function assessed through the use of the BSIDIII Fine Motor Scale at 
Months 12, 24, and 42 of treatment

Proportion of patients demonstrating the ability to achieve a scaled score within 
1.5 standard deviations of chronological reference standard at Months 24 and 42 of 
treatment (as assessed through the use of the BSIDIII Fine Motor Scale)

Total walk distance as assessed by the 6MWT (ambulant patients only) at Month 60
of treatment

Proportion of patients who attain motor milestones as assessed by WHO criteria at 
Month 48 of treatment

Proportion of patients who attain motor milestones as assessed by WHO criteria at 
Month 60 of treatment

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
Speech development as assessed by neurological examination at Months 12, 24, 
36, 48, and 60 of treatment

Change from baseline in ITQOL questionnaire at Month 12 of treatment

Change from baseline in ITQOL questionnaire at Month 24 of treatment

Number of hospitalizations (for any reason, except if for study purpose only [e.g., to 
facilitate study assessments]) per patient-year and number of nights admitted to 
hospital per patient at Months 12, 24, 36, 48, and 60 of treatment

Proportion of patients with no hospitalizations at Months 12, 24, 36, 48, and 60 of 
treatment

Proportion of patients who experience at least one disease-related adverse event by 
Month 12 of treatment

Proportion of patients who experience at least one disease-related adverse event by 
Month 24 of treatment

Number of disease-related adverse events per patient-year at Month 12 of treatment

Number of disease-related adverse events per patient-year at Month 24 of treatment
Disease-related adverse events will be collected through the adverse event 
reporting of the study and events will be identified by applying baskets of Medical 
Dictionary for Regulatory Activities (MedDRA) lowest level/preferred terms to the 
adverse event dataset.  The baskets will be defined in the DAP.
Further details of the statistical methods, definitions, and analyses for all exploratory 
endpoints will be specified in the DAP.
6.5.4
Subgroup Analyses
Subgroup analyses may be performed. Further details of the statistical methods, 
definitions and analyses will be specified in the DAP.
6.6
SAFETY ANALYSES
The safety endpoints include, but may not be limited to, the following:

Incidence of adverse events (overall, by severity and by relationship to study 
medication)

Incidence of serious adverse events

Incidence of treatment discontinuations due to adverse events

Incidence of laboratory abnormalities

Incidence of ECG abnormalities

Incidence of vital sign abnormalities

Incidence of clinically significant findings on ophthalmological examination
All safety analysis will be based on the safety analysis population. Safety data collected 
from each of the endpoints will be summarized descriptively for the first 12-month period 

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(i.e., 12-month data for each individual infant) at the time of the 12-month analysis 
reporting event and for all available safety data collected at the time of analysis. Similar 
summaries for the first 24-month period will be presented at the time of the 24-month 
analysis reporting event.
Analyses required for the iDMC data review will be performed as described in the 
associated iDMC Charter.
6.6.1
Adverse Events
The original terms recorded on the eCRF by the investigator for adverse events will be 
standardized by the Sponsor (mapped by MedDRA ([latest version]). Adverse Events 
will be summarized by mapped term and appropriate thesaurus level. Adverse Events 
will also be summarized by severity and relationship to the study drug. Serious adverse 
events and adverse events leading to treatment discontinuation will be summarized 
separately.
6.6.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Data will be presented using the International System of Units (SI units;
Système International d’Unités). Laboratory data not reported in SI units will be 
converted to SI units before processing.
Laboratory data will be listed for patients with laboratory abnormalities or values outside 
the normal ranges. In addition, tabular summaries including shift tables to compare the 
status at baseline to each timepoint post-baseline and overall will be used, as 
appropriate.
6.6.3
Vital Signs
Vital sign data will be listed for patients with values outside the normal ranges.  
In addition, tabular summaries will be used, as appropriate.
6.6.4
Electrocardiogram Data Analysis
ECG data will be listed for patients with values outside the normal ranges. In addition, 
tabular summaries will be used, as appropriate.
6.6.5
Concomitant Medications
The original terms recorded on the patient’s eCRF by the investigator for concomitant 
medications will be standardized by the Sponsor by assigning preferred terms. 
Concomitant medications will be presented in summary tables.
6.7
PHARMACODYNAMIC ANALYSES
All PD parameters will be presented by listings and descriptive summary statistics, as 
appropriate. Further details will be in the DAP.

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6.8
PHARMACOKINETIC ANALYSES
All PK parameters will be presented by listings and descriptive summary statistics. 
Individual and mean plasma concentrations of risdiplam (and metabolites, as 
appropriate) versus time data will be tabulated.
Non-linear mixed effects modeling (software NONMEM) will be used to analyze the 
sparse samples of concentration-time data of risdiplam (and its metabolites if deemed 
necessary). Population and individual PK parameters will be estimated, and the 
influence of various covariates (such as age, gender and body weight) on these 
parameters will be investigated in an exploratory manner. Data may be pooled with data
from other studies with risdiplam to improve the parameter estimates from the model. 
Secondary PK parameters (such as Cmax and AUC) may be derived from the model for 
each individual included in the PK analysis and will be presented descriptively.
Additionally, exploratory analyses on exposure and safety/efficacy relationship may be 
conducted if deemed necessary. The details of the modeling and exploratory analyses 
may be reported in a document separate from the clinical study report.
Assessment of protein binding will be performed on predose samples (and also may be 
performed on PK samples throughout the study, as required) and reported.
Additional PK analyses will be conducted as appropriate.
6.9
INTERIM ANALYSIS 
As this study is open-label, once at least 3 of the 10 infants (if 10 of these patients have 
been enrolled) have met the primary endpoint of sitting without support at Month 12 
(as assessed by the independent central readers), the minimum number of infants
needed for a statistically significant result will have been achieved and the primary 
objective of the study will be considered achieved at this earlier timepoint.  The study will 
not be stopped and all infants enrolled will continue to receive 12 months of treatment in 
order to provide an unbiased estimate of the proportion of infants sitting at Month 12. An 
interim analysis may also be performed to summarize descriptively the safety and 
efficacy data to support the initial filing and registration of risdiplam in pre-symptomatic 
patients and patients below the age of 2 months.  
Interim analyses for efficacy will be performed by the Sponsor and the results presented 
to the iDMC. The iDMC will be requested to review all available safety data and asked 
to provide an independent assessment of the benefit–risk profile of risdiplam in the 
pre-symptomatic SMA population at this earlier timepoint.

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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Local laboratory data and other electronic 
data will be sent directly to the Sponsor, using the Sponsor’s standard procedures to 
handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
Patient-reported outcome (PRO) data will be collected on paper questionnaires. The 
data from the questionnaires will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 

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microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.

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8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.

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Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.

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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  
In addition, redacted clinical study reports and other summary reports will be provided 
upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct
of the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will 
receive the patient data, including an audit trail containing a complete record of all 
changes to data.

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9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 1215 sites globally will participate to enroll approximately 25 patients.  
Enrollment will occur through an IxRS.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
An iDMC will be employed to monitor and evaluate patient safety until the last patient 
enrolled in this study has completed 12 months of treatment or until the last patient in 
Studies BP39055 and BP39056 completes 2 years of treatment, whichever occurs later.
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 

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met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).

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10.
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2006;119:422–8.

Appendix 1:
Schedule of Activities (cont.)
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6MWT six-minute walk test; BSID-III Bayley Scales of Infant and Toddler Development, Third Edition; CHOP INTEND Children’s Hospital 
of Philadelphia Infant Test of Neuromuscular Disorders; CMAP compound muscle action potential; D day; EW early withdrawal; 
FU follow-up; HINE-2 Hammersmith Infant Neurological ExaminationModule 2; HFMSE Hammersmith Functional Motor Scale Expanded; 
OLE open-label extension; PD pharmacodynamic; PK pharmacokinetic; SC study completion; Screen. screening; 
SD-OCT spectral-domain optical coherence tomography; SMA spinal muscular atrophy; SMN survival motor neuron (protein); Wk week.
a Visits every 26 weeks after the Week 104 visit until the completion of the OLE.
b If a patient withdraws within 4 weeks of an OLE visit , only the following assessments need to be repeated at the study completion/early 
withdrawal visit: study drug return, diary return, adverse event, and concomitant medication.  EOS is when the last patient completes five
years in the study. All patients should attend an SC/EW visit. If risdiplam is approved in the country of the site before the Week 260 (Year 5) 
visit, then the final visit for the patient will be at 260 weeks – in this case the SC/EW visit be performed in place of the Week 260 visit. If 
risdiplam is not approved in the country of the site at the time of the Week 260 visit, the patient should attend the Week 260 visit, and all OLE 
visits beyond Week 260 until risdiplam is approved or until EOS (whichever occurs first), ensuring that the final site visit is the SC/EW visit.
c Assessments should be performed in the following order:  adverse events, previous/concomitant medication, confirmation of eligibility, IxRS
enrollment call, all required assessments according to the order of assessments specified in Appendix 4.
d Follow-up telephone calls should be done at Days 4, 11, 19, 25, 33, 42, 63, and 77.  The investigator must agree with the parent (or caregiver) 
when to perform the follow-up telephone calls at the most appropriate time (day) between study visits.  After Week 11, additional follow-up 
telephone calls are per investigator decision.
e See Section 4.5.4 for details on physical and neurologic examinations.  Photographs may be taken to document the nature of skin findings (or 
other adverse events). 
f
See Section 4.5.3 for details on anthropometric measurements.  Only weight needs to be measured at Week 2 and Week 4.  Measuring of the 
patient’s weight during an unscheduled visit is allowed at the discretion of the investigator, i.e., if weight change is 10% according to 
parent/caregiver reporting or a dose adjustment has been requested.  During OLE, as visits are 26 weeks apart, unscheduled visits to assess 
weight may be expected.  If patients are attending site for any other reason during OLE, it is advisable to also take the opportunity to measure 
weight.  During OLE, head circumference and chest circumference will not be measured.
g Vital signs will include measurements of blood pressure, pulse rate, respiratory rate, and body temperature (oral or tympanic).  Measurements 
should be taken 4 hours post dose on Day 1.  See Section 4.5.5 for details.
h ECG recordings must be performed after the patient has been resting in a relaxed (e.g., semi-supine/supine) position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws). 
Measurements should be taken 4 hours post dose on Day 1.  See Section 4.5.6 for details.
i
Oral dosing should be performed during site visits.  Oral dosing once daily in the morning when at home.  See Section 4.3.2 for details. At 
study completion/early withdrawal visit, no study drug will be dispensed and used and unused study drug bottles are to be returned.

Appendix 1:
Schedule of Activities (cont.)
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t
World Health Organisation milestones to be assessed during OLE visits, starting from Week 208 (Month 48) onwards 
u Includes head-to-chest circumference ratio from anthropometric measurements and nutritional status interview of the parent (or caregiver), 
including ability to swallow and level of solid food intake.  A swallowing assessment will be performed at Day 1 and on Weeks 28, 52, 78, 
104; and the OLE visits (see Section 4.5.8).
v This includes SMA related surgeries and procedures.
w Only serious adverse events.

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Appendix 2
Blood Samples
Week/Visit
Day
Scheduled 
Time (hr)
PK 
Blood 
Sample
Safety
Laboratory 
(Hematology 
and Blood 
Chemistry)
Fluid PD 
Markers a
Plasma 
Protein 
Binding
Clinical 
Genotyping
Screening
x
x
x
Week 1
Day 1
Predose
x
2 hr
x
4 hr
x
6 hr
x
Day 2
Predose (24 hr) b
x
Week 2
Day 14
Predose
x
x
Week 4
Day 28
Predose
x
2 hr
x
4 hr
x
6 hr
x
Week 8
Day 56
Predose
x
x
2 hr
x
x
4 hr
x
6 hr
x
Week 16
Day 
112
Predose
x
x
Week 28
Day 
196
Predose
x
x
x
2 hr
x
4 hr
x
6 hr
x
Week 40
Day 
280
Predose
x
x
Week 52
Day 
364
Predose
x
x
x
2 hr
x
4 hr
x
6 hr
x

Appendix 2:
Blood Samples (cont.)
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Week/Visit
Day
Scheduled 
Time (hr)
PK 
Blood 
Sample
Safety
Laboratory 
(Hematology 
and Blood 
Chemistry)
Fluid PD 
Markers a
Plasma 
Protein 
Binding
Clinical 
Genotyping
Week 64
Day 
448
Predose
x
x
Week 78
Day 
546
Predose
x
x
2 hr
x
4 hr
x
6 hr
x
Week 92
Day 
644
Predose
x
x
Week 104
Day 
728
Predose
x
x
x
2 hr
x
4 hr
x
6 hr
x
OLE
Predose
x
x
Study 
Completion
/Early 
Withdrawal
x
x
x
OLEopen-label extension; PDpharmacodynamic; PKpharmacokinetic.
a Fluid PD markers will only be collected if the limit on total blood volume allows:  Total blood 
volume to be collected at any timepoint should not exceed 0.8 mL/kg or 2.4 mL/kg over any 
4-week period.
b Patients will have a PK sample taken 24 hours after the first dose and prior to receiving the 
second dose of risdiplam.

Risdiplam—F. Hoffmann-La Roche Ltd
120/Protocol BN40703, Version 4
Appendix 3
Ophthalmology Assessments
Week
Screening
8
28
52
104
OLE
Study 
Completion/EW a
Day
56
196
364
728
Examination b, c
x
x
x
x
x
x b
x
SD-OCT
x d
x
x
x
x
x b
x
Color fundus photography e
x
x
x
EW early withdrawal; OLE open-label extension; SD-OCTspectral-domain optical coherence tomography.
a  Ophthalmology assessments are not required at the Study Completion/Early Withdrawal Visits if the assessments have occurred within the prior 6 months.
b Ophthalmologic examination and SD-OCT are required once per year from Week 52, including during OLE (the first ophthalmologic 
assessment in OLE will be performed at Week 156, then at alternating OLE visits thereafter).  
c The ophthalmology examination as appropriate for age of patient includes: visual development, red reflex, external ocular examination, pupillary 
response, cover/uncover, fix and follow test, and ocular examination under magnification.
d Screening ophthalmologic assessments are to be performed between Day 42 and Day 14.  
e   Fundus photography should be attempted at least once at each scheduled visit up to Week 52. After Week 52, fundus photography will no 
longer be required.

Risdiplam—F. Hoffmann-La Roche Ltd
121/Protocol BN40703, Version 4
Appendix 4
Order and Blocks of Assessments at Visits When Efficacy 
Measurements Are Performed up to and Including Week 104 a
Block 1

ECG, vital signs, physical examination (including weight)
(Note: At Visit 1 only, should be performed 4 hours after dosing.)
BREAK

BSID-III (Sitting, Standing Walking; Gross; Fine Motor;
Cognition)
BREAK

CHOP INTEND
BREAK

HINE-2
BREAK

Blood sample (or insertion of catheter)

Dose administration
BREAK
Block 2

Infant Toddler Quality of Life Questionnaire
BREAK

CMAP
BREAK
Block 3

Ophthalmological examination
BSID-IIIBayley Scales of Infant and Toddler Development, Third Edition; CMAPcompound 
muscle action potential; HINE-2Hammersmith Infant Neurological ExaminationModule 2.
a The Week 104 visit will be the first HFMSE assessment for all patients and the last 
CHOP-INTEND assessment (for patients who did not already meet the CHOP-INTEND 
stopping criteria prior to Week 104). At Week 104, if CHOP-INTEND is required, then the 
order of assessments should be BSID-III, CHOP-INTEND, HINE-2, HFMSE, If 
CHOP-INTEND is not required, then the HFMSE can replace the CHOP-INTEND so that the 
order is BSID-III, HFMSE, HINE-2.
After Week 104, continue to use the Block 1 order as a recommendation, with the motor 
function and milestone assessments being completed prior to the blood sample and dose 
administration. The order of priority for motor function and milestone assessments is: 
BSID-III (up to and including Week 182, Month 42), HFMSE, HINE-2 (until the max score is 
reached at two consecutive visits), WHO milestones (starting at Week 208, Month 48) and 
6MWT (starting at Week 182, Month 42).
Please ensure that motor function and milestone assessments are each preceded by a 
break of at least 15 minutes, with the exception of between the HINE-2 and WHO 
milestones (if they occur at the same visit) where no break is required.