An Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Risdiplam (RO7034067) in Adult and Pediatric Patients With Spinal Muscular Atrophy
Phase: PHASE2
Conditions: Spinal Muscular Atrophy
Sponsor: Hoffmann-La Roche

Official Title: An Open-Label Study to Investigate the Safety, Tolerability, and 
Pharmacokinetics/Pharmacodynamics of Risdiplam (RO7034067) in 
Adult and Pediatric Patients with Spinal Muscular Atrophy 
NCT Number: NCT03032172 
Document Date: Protocol Version 5: 08-Feb-2024 

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 (RO7034067)—F. Hoffmann-La Roche Ltd 
Protocol BP39054, Version 5 
PROTOCOL 
PROTOCOL TITLE: 
AN OPEN-LABEL STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS/PHARMACODYNAMICS OF 
RISDIPLAM (RO7034067) IN ADULT AND 
PEDIATRIC PATIENTS WITH SPINAL MUSCULAR 
ATROPHY 
PROTOCOL NUMBER: BP39054  
STUDY NAME: 
JEWELFISH 
VERSION NUMBER: 
5 
TEST PRODUCT: 
Risdiplam (RO7034067) 
STUDY PHASE: 
Phase II 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  128972 
EU CT Number:  2023-506739-14-00 
EudraCT Number:  2016-004184-39 
NCT Number:  NCT03032172 
SPONSOR’S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
APPROVAL DATE: 
See electronic signature and date stamp on the final 
page of this document. 
 

Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
2/Protocol BP39054, Version 5 
PROTOCOL HISTORY 
Protocol 
Associated Country and/or Region-Specific Protocols  
Version 
Date Final 
Country and/or 
Region 
Version 
Date Final 
5 
See electronic 
date stamp on 
final page of this 
document 
 
 
 
4 
23 June 2020 
 
 
 
3 
27 February 2019 
Germany 
Addendum 1 
5 March 2019 
2 
29 June 2018 
France 
Addendum 1 
13 December 2018 
Germany 
Addendum 1 
16 November 2018 
1 
2 November 
2016 
Rest of World 
1 
2 November 2017 
United States 
1 
26 October 2017 
Switzerland 
1 
18 August 2017 
United Kingdom 
1 
14 June 2017 
  

Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
3/Protocol BP39054, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol BP39054 has primarily been amended to remove ophthalmology monitoring.  
Additionally, digital biomarker assessments that were discontinued in 2022 have been 
removed from the protocol.  Substantive changes to the protocol, along with a rationale 
for each change, are summarized below. 
 
Background on risdiplam has been streamlined to remove outdated nonclinical and 
clinical data (Sections 1.2.1 and 1.2.2 have been deleted); more up-to-date data can 
be found in the Risdiplam Investigator’s Brochure. 
 
Given that no retinal toxicity has been observed to date and that further monitoring 
will not provide additional reassurance, ophthalmological assessments have been 
removed at all timepoints to reduce burden on patients, their families and caregivers 
and the study sites (Sections 1.3.2, 3.3.1, 4.6.1.11, 4.6.2.2, 4.7.1.1, 5.2.1, 5.2.2, 
5.2.3 [original section deleted; renumbered section amended], and 6.5; Appendices 
1A, 1B, 3A and 3B; former Appendix 5 has been deleted and subsequent 
appendices renumbered). 
 
The requirement for a safety follow-up telephone call approximately 30 days after 
the study completion/early withdrawal visit has been updated.  For patients who 
continue to receive risdiplam following this visit (receiving risdiplam investigational 
medicinal product (IMP) prior to end of study via continued access, or receiving 
risdiplam through commercial or post-trial access), the follow-up telephone call is no 
longer a requirement since these patients do not stop risdiplam treatment 
(Section 3.1.1, 3.1.3, 4.6.1, 4.6.2.4 and 5.3.1; Appendices 1B and 3B; new 
Appendix 5). 
 
The definition for the end of study (EOS) has been updated to clarify that the end of 
the study is the date of the last visit or telephone call (whichever occurs later) of the 
last patient (Section 3.1.3). 
 
Digital biomarker assessments have been removed since major hardware and 
software upgrades would have been required to continue to collect digital biomarker 
data.  Additionally, the smartphone deployed to patients to perform this assessment 
needed replacement for patients to be able to upload data and this would have 
involved significant burden for the patients and site personnel.  As such, digital 
biomarker data had already ceased to be collected from patients since July 2022 
(Sections 3.2.3, 3.3.3, 4.6.1.16, 4.6.2.2, and 6.9; Appendices 1A and 1B). 
 
Information about the two-bottle formulation of risdiplam has been removed because 
this formulation is no longer used in this study (Section 4.4.1). 
 
The text regarding treatment with risdiplam IMP after Week 260 (the final 
visit/telephone call) until EOS for patients who do not have access to commercial 
risdiplam has been clarified.  Terminology has been updated throughout the protocol 
to refer to this as ‘continued access’ or ‘treatment until EOS’.  Language has been 
added to clarify these patients are not required to attend additional study visits and 
only adverse events must continue to be reported (new Sections 4.4.4 and 4.6.2.5; 
Appendices 1B and 3B; new Appendix 5). 

Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
4/Protocol BP39054, Version 5 
 
Text has been updated to clarify that topical medications are permitted, including the 
topical form of all medications that are listed as prohibited therapies (Section 4.5.1). 
 
The list of prohibited medications has been updated to remove medications with 
retinal toxicity given the absence of ophthalmological findings and the 
discontinuation of ophthalmology monitoring.  A textual clarification has been made 
regarding the prohibition of medications with known phototoxicity liabilities 
(Section 4.5.2). 
 
The study visit occurring every 13 weeks during the open-label extension (OLE) 
phase now has the option to be performed remotely (e.g., by telephone) at the 
investigator’s discretion.  The risk of performing a remote visit is considered to be 
low and this will reduce significant burden for patients and their caregivers.  The 
Schedules of Assessments have been updated to reflect this change. 
 
The Schedules of Assessments (Appendix 1B and 3B) have been updated to 
confirm administration of study medication at the completion/early withdrawal visit 
for patients who will receive risdiplam until EOS.  The prior Schedule of 
Assessments in Protocol Version 4 did not have the daily administration of study 
medication checked as applicable for the completion/early Withdrawal visit. 
 
To comply with E.U. Clinical Trial Regulations requirements and other guidelines, 
the following changes have been made: 
– 
The Medical Monitors’ name has been removed from the protocol, and text 
regarding emergency medical contacts has been amended for clarity (front 
matter and Section 5.4.1). 
– 
The synopsis has been simplified. 
– 
A section describing duration of participation has been added (Section 3.1.4). 
– 
A comprehensive list of investigational medicinal products and auxiliary 
medicinal products has been added (Section 4.4 and Appendix 6). 
– 
It has been made explicit that expedited safety reports are notified 
to EudraVigilance (Section 5.7). 
– 
A description of the technical and organizational security measures taken to 
protect personal data has been added (Section 8.4). 
– 
Due to certain local requirements and an alignment of Sponsor process, it has 
been clarified that summaries of clinical study results may be available in health 
authority databases for public access in addition to redacted Clinical Study 
Reports.  The name of a Roche policy on data sharing has also been corrected 
(Section 9.5). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantial new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 

Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
5/Protocol BP39054, Version 5 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................. 16 
1. 
BACKGROUND AND RATIONALE ............................................... 19 
1.1 
Background on Disease ........................................................... 19 
1.2 
Background on Risdiplam ........................................................ 20 
1.3 
Study Rationale and Benefit–Risk Assessment ....................... 20 
1.3.1 
Study Rationale ....................................................................... 20 
1.3.2 
Benefit–Risk Assessment ........................................................ 21 
2. 
OBJECTIVES ................................................................................ 24 
2.1 
Primary Objectives ................................................................... 25 
2.2 
Secondary Objective ................................................................ 25 
2.3 
Exploratory Objectives ............................................................. 25 
3. 
STUDY DESIGN ........................................................................... 26 
3.1 
Description of Study ................................................................. 26 
3.1.1 
Overview of Study Design........................................................ 26 
3.1.2 
Committees .............................................................................. 27 
3.1.2.1 
Internal Monitoring Committee ................................................. 27 
3.1.2.2 
Independent Data Monitoring Committee (iDMC) .................... 27 
3.1.2.3 
Permanent Ventilation Adjudication Committee ....................... 28 
3.1.3 
End of Study ............................................................................ 28 
3.1.4 
Duration of Participation ........................................................ 29 
3.2 
Rationale for Study Design ...................................................... 29 
3.2.1 
Rationale for Dosage Selection ............................................... 29 
3.2.2 
Rationale for Study Population ................................................ 30 
3.2.3 
Rationale for Biomarker Assessments ..................................... 31 
3.3 
Outcome Measures ................................................................. 32 
3.3.1 
Safety Outcome Measures ...................................................... 32 
3.3.2 
Pharmacokinetic (PK) and Pharmacodynamic (PD) 
Outcome Measures ................................................................. 32 

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6/Protocol BP39054, Version 5 
3.3.2.1 
Pharmacokinetic Outcome Measures ...................................... 32 
3.3.2.2 
Pharmacodynamic Outcome Measures ................................... 33 
3.3.3 
Exploratory Outcome Measures .............................................. 33 
4. 
MATERIALS AND METHODS ...................................................... 33 
4.1 
Center ...................................................................................... 33 
4.2 
Study Population ...................................................................... 34 
4.2.1 
Recruitment Procedures .......................................................... 34 
4.2.2 
Inclusion Criteria ...................................................................... 34 
4.2.3 
Exclusion Criteria ..................................................................... 36 
4.3 
Method of Treatment Assignment ............................................ 38 
4.4 
Study Treatment ...................................................................... 39 
4.4.1 
Formulation, Packaging, and Handling .................................... 39 
4.4.1.1 
One-Bottle Formulation (Powder for Oral Solution) ................. 39 
4.4.1.2 
Packaging and Handling .......................................................... 39 
4.4.2 
Dosage, Administration and Compliance ................................. 40 
4.4.3 
Investigational Medicinal Product Accountability ..................... 41 
4.4.4 
Treatment with Risdiplam Until End of Study (Continued 
Access to Risdiplam)................................................................ 42 
4.4.5 
Post-Trial Access to Risdiplam ................................................ 42 
4.5 
Concomitant Therapy and Food .............................................. 43 
4.5.1 
Permitted Therapy ................................................................... 43 
4.5.2 
Prohibited Therapy .................................................................. 45 
4.6 
Study Assessments ................................................................. 45 
4.6.1 
Description of Study Assessments .......................................... 45 
4.6.1.1 
Medical History and Demographic Data .................................. 46 
4.6.1.2 
Spinal Muscular Atrophy History .............................................. 46 
4.6.1.3 
Anthropometric Measurements ................................................ 47 
4.6.1.4 
Physical Examinations ............................................................. 48 
4.6.1.5 
Neurological Examination ........................................................ 48 
4.6.1.6 
Tanner Staging ........................................................................ 49 
4.6.1.7 
Menstrual Status ...................................................................... 49 
4.6.1.8 
Vital Signs ................................................................................ 49 
4.6.1.9 
Electrocardiograms .................................................................. 50 

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7/Protocol BP39054, Version 5 
4.6.1.10 
Laboratory Assessments ......................................................... 51 
4.6.1.11 
Ophthalmological Assessments and Examination ................... 52 
4.6.1.12 
Nutritional Check ..................................................................... 55 
4.6.1.13 
Pharmacokinetic Assessments ................................................ 56 
4.6.1.14 
Plasma Protein Binding ........................................................... 56 
4.6.1.15 
Fluid Pharmacodynamic Assessments .................................... 56 
4.6.1.16 
Digital Biomarker Assessment ................................................. 57 
4.6.1.17 
Clinical Genotyping Sample ..................................................... 57 
4.6.1.18 
Functional Motor and Motor Development Assessments ......... 58 
4.6.1.19 
Six-Minute Walk Test (6MWT; ambulant patients only) ........... 62 
4.6.1.20 
Pulmonary Function Testing .................................................... 63 
4.6.1.21 
Columbia-Suicide Severity Rating Scale ................................. 64 
4.6.1.22 
SMA Independence Scale (SMAIS) ......................................... 64 
4.6.1.23 
Samples for Research Biosample Repository.......................... 65 
4.6.2 
Timing of Study Assessments .................................................. 68 
4.6.2.1 
Screening and Pretreatment Assessments .............................. 68 
4.6.2.2 
Assessments During Treatment ............................................... 69 
4.6.2.3 
Assessments at Study Completion/Early Withdrawal Visit ....... 71 
4.6.2.4 
Follow-Up................................................................................. 71 
4.6.2.5 
Assessments During Continued Access ............................................. 71 
4.6.2.6 
Assessments at Unscheduled Visits ........................................ 72 
4.6.3 
Prioritization Order for Blood Samples ..................................... 72 
4.7 
Patient, Study, and Site Discontinuation .................................. 72 
4.7.1 
Patient Discontinuation ............................................................ 72 
4.7.1.1 
Discontinuation from Study Drug ............................................. 73 
4.7.1.2 
Withdrawal from Study ............................................................. 73 
4.7.2 
Study and Site Discontinuation ................................................ 73 
5. 
ASSESSMENT OF SAFETY ......................................................... 74 
5.1 
Safety Parameters and Definitions .......................................... 74 
5.1.1 
Adverse Events ........................................................................ 74 
5.1.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 75 

Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
8/Protocol BP39054, Version 5 
5.1.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ................................ 75 
5.2 
Safety Plan .............................................................................. 76 
5.2.1 
Safety Precautions ................................................................... 76 
5.2.2 
Safety Monitoring ..................................................................... 77 
5.2.3 
Stopping Rules ........................................................................ 77 
5.3 
Methods and Timing for Capturing and Assessing Safety 
Parameters .............................................................................. 78 
5.3.1 
Adverse Event Reporting Period .............................................. 78 
5.3.2 
Eliciting Adverse Event Information ......................................... 78 
5.3.3 
Assessment of Severity of Adverse Events ............................. 79 
5.3.4 
Assessment of Causality of Adverse Events............................ 79 
5.3.5 
Procedures for Recording Adverse Events .............................. 80 
5.3.5.1 
Diagnosis versus Signs and Symptoms ................................... 80 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events ........... 80 
5.3.5.3 
Persistent or Recurrent Adverse Events .................................. 80 
5.3.5.4 
Abnormal Laboratory Values ................................................... 81 
5.3.5.5 
Abnormal Vital Sign Values ..................................................... 81 
5.3.5.6 
Abnormal Liver Function Tests ................................................ 82 
5.3.5.7 
Deaths ..................................................................................... 82 
5.3.5.8 
Preexisting Medical Conditions ................................................ 83 
5.3.5.9 
Lack of Efficacy or Worsening of Spinal Muscular Atrophy ...... 83 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ............................ 83 
5.3.5.11 
Overdoses ............................................................................... 84 
5.3.5.12 
Patient-Reported Outcome Data .............................................. 84 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 85 
5.4.1 
Emergency Medical Contacts .................................................. 85 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest ..................... 85 
5.4.3 
Reporting Requirements for Pregnancies ................................ 86 
5.4.3.1 
Pregnancies in Female Patients .............................................. 86 
5.4.3.2 
Pregnancies in Female Partners of Male Subjects .................. 86 
5.4.3.3 
Abortions.................................................................................. 86 

Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
9/Protocol BP39054, Version 5 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 87 
5.5 
Follow-Up of Patients after Adverse Events............................. 87 
5.5.1 
Investigator Follow-Up ............................................................. 87 
5.5.2 
Sponsor Follow-Up .................................................................. 87 
5.6 
Post-Study Adverse Events ..................................................... 87 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 88 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 88 
6.1 
Determination of Sample Size ................................................. 89 
6.2 
Summaries of Conduct of Study .............................................. 89 
6.3 
Analysis Populations ................................................................ 89 
6.3.1 
Safety Analysis Population ...................................................... 89 
6.3.2 
Pharmacokinetic and Pharmacodynamic Analysis 
Populations .............................................................................. 89 
6.3.3 
Intent-To-Treat/ Exploratory Efficacy Analysis Population ....... 90 
6.4 
Summaries of Treatment Group Comparability ........................ 90 
6.5 
Safety Analyses ....................................................................... 90 
6.5.1 
Adverse Events ........................................................................ 91 
6.5.2 
Clinical Laboratory Test Results .............................................. 91 
6.5.2.1 
Definition of Laboratory Abnormalities ..................................... 91 
6.5.3 
Vital Signs ................................................................................ 91 
6.5.4 
ECG Data Analysis .................................................................. 91 
6.5.5 
Concomitant Medications ........................................................ 92 
6.6 
Exploratory Efficacy Analyses .................................................. 92 
6.7 
Pharmacokinetic Analyses ....................................................... 93 
6.8 
Pharmacodynamic Analyses .................................................... 94 
6.9 
Digital Biomarker Analyses ...................................................... 94 
6.10 
Interim Analyses ...................................................................... 94 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 95 
7.1 
Data Quality Assurance ........................................................... 95 
7.2 
Electronic Case Report Forms ................................................. 95 
7.3 
Source Data Documentation .................................................... 96 
7.4 
Use of Computerized Systems ................................................ 96 

Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
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7.5 
Retention of Records ............................................................... 96 
8. 
ETHICAL CONSIDERATIONS ...................................................... 97 
8.1 
Compliance with Laws and Regulations .................................. 97 
8.2 
Informed Consent .................................................................... 97 
8.3 
Institutional Review Board or Ethics Committee ...................... 98 
8.4 
Confidentiality .......................................................................... 99 
8.5 
Financial Disclosure ................................................................. 99 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 99 
9.1 
Study Documentation .............................................................. 99 
9.2 
Protocol Deviations ................................................................ 100 
9.3 
Site Inspections ..................................................................... 100 
9.4 
Administrative Structure ......................................................... 100 
9.5 
Dissemination of Data and Protection of Trade Secrets ........ 101 
9.6 
Protocol Amendments ........................................................... 102 
10. 
REFERENCES............................................................................ 103 
 
 
LIST OF TABLES 
Table 1 
Overview of the Margins versus Key Toxicities of Risdiplam ...... 24 
Table 2 
Order and Blocks of Assessments for Patients Aged 
2 Years at Study Visits when Efficacy Measurements are 
Performed ................................................................................... 70 
Table 3 
Order of Assessments for Patients aged  2 Years at Visits 
When Efficacy Measurements Are Performed ............................ 70 
Table 4 
Prioritization Order for Blood Samples ........................................ 72 
Table 5 
Adverse Event Severity Grading Scale ....................................... 79 
 
 
LIST OF APPENDICES 
Appendix 1A  Schedule of Assessments for Patients Aged 260 Years: 
Screening through Week 52...................................................... 105 
Appendix 1B  Schedule of Assessments for Patients Aged 260 Years: 
Year 2 through End of Study ..................................................... 108 

Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
11/Protocol BP39054, Version 5 
Appendix 2 
 Detailed Schedule of Pharmacokinetic and 
Biomarker Samples: Patients Aged 260 Years ....................... 113 
Appendix 3A  Schedule of Assessments for Patients Aged 6 Months to 
 2 Years: Screening through Week 52 .................................... 116 
Appendix 3B  Schedule of Assessments for Patients Aged 6 Months to 
 2 Years: Year 2 through End of Study ................................... 118 
Appendix 4 
 Detailed Schedule of Pharmacokinetic and 
Biomarker Samples: Patients Aged 6 Months to  2 Years ...... 121 
Appendix 5 
 Treatment Flow Chart .............................................................. 123 
Appendix 6 
 Investigational Medicinal Product Designation (for Use in 
European Economic Area) ........................................................ 124 

Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
12/Protocol BP39054, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
AN OPEN-LABEL STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS/PHARMACODYNAMICS OF 
RISDIPLAM (RO7034067) IN ADULT AND 
PEDIATRIC PATIENTS WITH SPINAL MUSCULAR 
ATROPHY 
PROTOCOL NUMBER: BP39054 
STUDY NAME: 
JEWELFISH 
VERSION NUMBER: 
5 
TEST PRODUCT: 
Risdiplam (RO7034067) 
SPONSOR NAME: 
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 to 
your local study monitor. 
 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
13/Protocol BP39054, Version 5
PROTOCOL SYNOPSIS 
PROTOCOL TITLE: 
AN OPEN-LABEL STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS/ 
PHARMACODYNAMICS OF RISDIPLAM (RO7034067) IN ADULT 
AND PEDIATRIC PATIENTS WITH SPINAL MUSCULAR 
ATROPHY 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number: 128972 
EU CT Number:  2023-506739-14-00 
EudraCT Number:  2016-004184-39 
NCT Number:  NCT03032172 
 
STUDY RATIONALE 
The purpose of this study is to investigate the safety, tolerability, pharmacokinetics and 
pharmacokinetic (PK)/pharmacodynamic (PD) relationship of risdiplam in adults and children 
and infants with spinal muscular atrophy (SMA) previously enrolled in Study BP29420 
(Moonfish) with the splicing modifier RO6885247 or previously treated with nusinersen, 
AVXS-101 (adeno associated virus 9 based gene therapeutic that delivers a normal copy of the 
SMN1 gene), or olesoxime. 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Corresponding Endpoints 
 
To evaluate the safety and 
tolerability of risdiplam 
 
Incidence and severity of adverse events with 
severity determined according to National 
Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0 
 
Incidence of treatment discontinuations due to 
adverse events 
 
Incidence of abnormal laboratory values 
 
Incidence of abnormal ECG values 
 
Incidence of abnormal vital signs (body 
temperature, systolic and diastolic blood 
pressure, heart rate, respiratory rate) 
 
Physical examination. 
For patients aged 9-17 years, physical 
examination will include formal Tanner staging 
for pubertal status 
 
Incidence of clinically significant findings on 
neurological examination 
 
Anthropometric examination including height, 
weight, and head and chest circumference 
 
Incidence of emergence or worsening of 
symptoms as measured by the Columbia-Suicide 
Severity Rating Scale (adult version for adults 
and adolescents, pediatric version for patients 
aged 6-11 years) 
 
Ophthalmological assessments as appropriate for 
age 
 This objective was in place in Protocol 
Versions 1-4, inclusive.  Ophthalmological 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
14/Protocol BP39054, Version 5 
assessments have been removed starting in 
Protocol Version 5. 
 
To investigate the 
pharmacokinetics of risdiplam and 
metabolites as appropriate 
 
Concentration per timepoint listed 
 
Cmax 
 
AUC 
 
Ctrough to assess steady-state 
 
Other PK parameters as appropriate 
Secondary Objective 
Corresponding Endpoints  
 
To investigate the PK/PD 
relationship of risdiplam. 
The PD investigations will 
include analyses of SMN mRNA 
splice forms and SMN protein 
 
SMN mRNA concentration in blood 
 
SMN protein levels in blood 
AUC = area under the concentration-time curve; PD = pharmacodynamic; PK = pharmacokinetic; 
SMN = survival motor neuron. 
 
 
OVERALL DESIGN AND STUDY POPULATION
DESCRIPTION OF STUDY
This is a multi-center, exploratory, non-comparative and open-label study to investigate the 
safety, tolerability, PK and PK/PD relationship of risdiplam in adults and children and infants
with SMA previously enrolled in Study BP29420 (Moonfish) with the splicing modifier 
RO6885247 or previously treated with nusinersen, AVXS-101 (adeno-associated virus 9 based 
gene therapeutic that delivers a normal copy of the SMN1 gene), or olesoxime.
Treatment with risdiplam will initially be evaluated over a 2-year period.  After completion of the 
2-year treatment period, the patient will be given the opportunity to enter the open-label 
extension (OLE) phase of the study, which will include regular monitoring of safety, tolerability 
and efficacy.  Unless the Sponsor stops the development of risdiplam, the patient's treatment in 
the extension will continue for an additional 3 years (patients will be treated for a total duration
of at least 5 years).  After a patient has completed 3 years in the OLE, the patient may continue 
to receive risdiplam IMP until the end of study (EOS), provided that risdiplam is not 
commercially available to the patient.
The final analysis will investigate the safety, tolerability, and PK/PD relationship of risdiplam
after all patients have completed the study.
The duration of the study for patients enrolled will be divided as follows:
 
Screening: Up to 30 days prior to first dose of study drug
 
Baseline: Day -1
 
Treatment period: Up to 2 years
 
Thereafter, patients will be given the opportunity to enter the OLE phase of the study for
3 years
 
If a patient completes or withdraws early from study treatment, the patient will be requested
to attend a study completion/early withdrawal visit.
 
A follow-up telephone call, if applicable, approximately 30 days after the study
completion/early withdrawal visit.  The follow-up call will only be conducted for patients  
[a] who do not go on to receive risdiplam IMP through continued access or to receive 
risdiplam through commercial or post-trial access; or [b] who switch to another treatment 
for SMA within 30 days of stopping risdiplam.  If a patient switches to another treatment 
for SMA during the 30-day follow-up period after the study completion/early withdrawal 
visit, a telephone call should still be performed to collect information up to the time that
the patient begins the new treatment.
 

 
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Several key aspects of the study design and study population are summarized below.  
Phase: 
Phase II 
Population Type: 
Adult and pediatric patients 
Control Method: 
None 
Population Diagnosis 
or Condition: 
Spinal muscular atrophy; 
who have been previously 
enrolled in Study BP29420 
(Moonfish) or previously 
treated with nusinersen, 
AVXS-101, or olesoxime 
Interventional 
Model: 
Single group 
Population Age: 
6 months to 60 years of age 
at screening 
Test Product: 
Risdiplam 
Site Distribution: 
Multi site and multi region 
Active Comparator: Not applicable 
Study Treatment 
Assignment Method: 
All participants are 
assigned to the same 
treatment 
Number of Arms: 
One 
Number of 
Participants to Be 
Enrolled: 
Up to 180 patients (At least 
80 patients will have 
previously received 
treatment with nusinersen 
or AVXS-101) 
 
STUDY TREATMENT
For patients aged 2-60 years, the dose in this study will be 5 mg for patients with a body 
weight 20 kg and 0.25 mg/kg for patients with a body weight <20 kg, given orally once 
daily. For patients aged 6 months to < 2 years (infants), the dose will be 0.2 mg/kg.  The 
pharmacokinetics in all infants will be regularly monitored by the Clinical Pharmacologist, 
and the dose of all or individual infants may be adjusted to ensure that infants are in the 
targeted exposure range and in compliance with the exposure cap.
DURATION OF PARTICIPATION
The total duration of study participation for each individual is expected  to be approximately 
5 years (2-year treatment phase and 3-year OLE phase) and 1 month (if 30-day follow-up 
applies).
The total duration of study participation for an individual is expected to be approximately
5 years (2-year treatment phase and 3-year OLE phase) and 1 month (if 30 day follow-up 
applies).
COMMITTEES
Independent Committees: Independent Data Monitoring Committees 
Other Committees: 
Internal Monitoring Committee
Permanent Ventilation Adjudication Committee
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
6MWT 
six-minute walk test 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration–time curve 
AUC0–24 
area under the concentration–time curve from 0 to 24 hours 
AUC0-last 
area under curve from time 0 to last measurable concentration 
BCVA 
best corrected visual acuity 
BP 
blood pressure 
BSID-III 
Bayley Scales of Infant and Toddler development – Third Edition 
BW 
body weight 
CDC 
Centers for Disease Control and Prevention 
Cmax 
maximum concentration observed 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CRP 
C-reactive protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DAP 
Data Analysis Plan 
DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOS 
end of study 
ePRO 
electronic patient-reported outcome 
ERG 
electroretinogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
(U.S.) Food and Drug Administration 
FEV 
forced expiratory volume 
FMO 
flavin monooxygenase 

 
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FoxM1 
forkhead box protein M1  
FP 
fundus photography 
FVC 
forced vital capacity 
-GT 
gamma-glutamyl-transferase 
GMFM 
Gross Motor Function Measure 
HDAC 
histone deacetylase 
HFMSE 
Hammersmith Functional Motor Scale Expanded 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IEC 
independent Ethics Committee 
ILM 
inner limiting membrane 
IMC 
Internal Monitoring Committee  
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
ISCEV 
International Society for Clinical Electrophysiology of Vision 
IxRS 
interactive voice or web-based response system 
LDH 
lactate dehydrogenase 
LH 
luteinizing hormone 
LPLO 
last patient, last observation 
LPLV 
last patient, last visit 
MADD 
MAP-kinase activating death domain 
MATE 
multidrug and toxin extrusion 
MFM 
motor function measure 
MMRM 
mixed model repeated measures 
NCI 
National Cancer Institute 
NOAEL 
no-observed-adverse-effect level 
NOEL 
No-observed-effect level 
OAT 
organic anion transporter 
OCT 
organic cation transporter or Optical Coherence Tomography (in 
Ophthalmology sections) 
ONL 
outer nuclear layer 
OTC 
over-the-counter 
PCF 
peak cough flow 
PedsQL 
Pediatric Quality of Life Inventory 
PD 
pharmacodynamic 
PK 
pharmacokinetic 

 
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PRO 
patient-reported outcome 
QRS 
QRS complex 
QT 
QT interval 
QTc 
QT corrected for heart rate 
QTcB 
QT corrected for heart rate using the Bazett’s correction factor 
QTcF 
QT corrected for heart rate using the Fridericia’s correction factor 
RBC 
red blood cell 
RBR 
Research Biosample Repository  
RPE 
retinal pigment epithelium 
RR 
RR interval 
RULM 
Revised Upper Limb Module 
SAD 
single-ascending dose 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD-OCT 
spectral domain-optical coherence tomography 
SMA 
spinal muscular atrophy 
SMAIS 
SMA Independence Scale 
SMN 
survival of motor neuron 
SNIP 
sniff nasal inspiratory pressure 
SoA 
schedule of assessments 
SOC 
Scientific Oversight Committee 
TML 
Translational Medicine Leader 
TSH 
thyroidstimulating hormone 
ULN 
upper limit of normal 
U.S. 
United States 
USP/NF 
United States Pharmacopeia/National Formulary 
VA 
visual acuity 
VAS 
visual analogue scale 
VEP 
visual evoked potential 
VF 
visual field 
WGS 
whole genome sequencing 
 

 
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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND ON DISEASE 
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 et al 1996; 
Lunn et al 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 et al 1992): Type 1 SMA or Werdnig-Hoffmann disease (severe infantile type, 
onset before 6 months of age with death due to respiratory distress, usually within 
2 years), Type 2 SMA (intermediate chronic infantile type with onset before the age of 
18 months, unable to stand or walk without support), Type 3 SMA or 
Kugelberg-Welander disease (chronic juvenile type with onset after the age of 
18 months, children are able to stand and walk until the disease progresses) and Type 4 
SMA (adult onset).  A fifth type, denoted as Type 0, has been proposed for extremely 
severe SMA that manifests during fetal life and results in death within a few weeks after 
birth (Kolb et al 2011).  This clinical trial will enroll Type 1, Type 2 and Type 3 SMA 
patients. 
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 et al 2010).  Accordingly, full-length 
SMN2 mRNA is generated in only 1015% of splicing events.  Since SMA patients only 
have the SMN2 gene, their SMN protein levels are significantly decreased (Kolb 
et al 2011). 
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 super-infections are common in SMA Types 1 and 2.  Other 
common comorbidities include failure to thrive, sleep difficulties, pneumonia, osteopenia 

 
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and osteoporosis with pathological fractures, poor cough and secretion clearance, 
reduced vital capacity, gastroesophageal dysmotility, urinary incontinence, hip 
dislocation, and joint and muscle pain. 
The medical need in SMA is very high, and several drug candidates are currently under 
investigation in the nonclinical and clinical setting (Lewelt et al 2012; d’Ydewalle et al 
2015).  The SMN2-targeting antisense oligonucleotide nusinersen (SPINRAZA) has 
been approved by health authorities in the United States (U.S.), the European Union 
(E.U.), Canada, and other jurisdictions, for the treatment of SMA in pediatric and adult 
patients.  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. 
1.2 
BACKGROUND ON RISDIPLAM 
One of the promising strategies currently being pursued is to restore SMN protein levels 
in SMA patients 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 et al 2011; Nurputra et al 2013).  One such compound currently being 
developed is risdiplam (previously referred to as RO7034067), which directly targets the 
underlying molecular deficiency of the disease and promotes the inclusion of exon 7 to 
generate full-length SMN2 mRNA, which therefore increases the production of functional 
SMN protein.  SMN protein increase after treatment with risdiplam has been shown in 
fibroblasts and motor neurons derived from patients with SMA. 
Risdiplam is a follow-up compound to RO6885247, another SMN2 mRNA splicing 
modifier which in SMA patients in Study BP29420 (Moonfish) increased levels of 
full-length SMN2 mRNA and reduced levels of SMN 7 mRNA.  SMN protein in blood 
increased by up to 2-fold compared with baseline in these patients.  The study further 
showed that the compound RO6885247 was well-tolerated in 9 adolescent and adult 
SMA patients at the 10 mg dose for 12-weeks’ treatment, with no deaths, serious 
adverse events, or withdrawals due to adverse events.  The main adverse events 
reported were influenza (three patients) and diarrhea (two patients). 
See the Risdiplam Investigator’s Brochure for details on nonclinical and clinical studies. 
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.  In milder 
forms, it results in profound motor and respiratory disabilities and major orthopedic 
deformities.  One drug was recently approved in the U.S., the European Union (E.U.), 
Canada and other jurisdictions for the treatment of SMA in pediatric and adult patients 
(the antisense oligonucleotide nusinersen) but the medical need in SMA for alternative 

 
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treatment options is still very high.  There is currently no oral treatment for SMA that 
provides stabilization or improvement of motor function, which would be of immense 
value for patients and parents/caregivers. 
Small molecule SMN2 splicing modifiers such as risdiplam represent a potential 
treatment option for patients with SMA, as they increase the amount of SMN protein 
within the CNS and throughout the body.  Deficiency of SMN protein is the fundamental 
pathophysiological mechanism of SMA.  There is increasing preclinical evidence to 
suggest that SMN restoration in the CNS can result in significant improvements in 
survival, motor function and disease pathology but is insufficient to fully ameliorate the 
SMA phenotype (Porensky et al 2012; Passini et al 2011).  By restoring SMN protein 
levels in the CNS and in peripheral tissue, orally administered SMN2 splicing modifiers 
have the potential to provide improved efficacy over compounds administered to the 
CNS only (Hua et al 2011). 
Risdiplam has demonstrated effective correction of splicing of the human SMN2 gene.  
The compound shifts the balance of alternative splicing completely toward inclusion of 
SMN2 exon 7 and production of functional SMN protein in human cultured cells and in 
SMA mouse models (for details, see the Risdiplam Investigator’s Brochure).  Proof of 
mechanism for the change in SMN2 splicing in terms of SMN2 mRNA was established 
with risdiplam in a single-ascending dose study in healthy subjects.  Proof of mechanism 
in terms of an increase in SMN protein was previously demonstrated with another 
compound having a similar mechanism of action, RO6885247, with an up to 2-fold 
increase in SMN protein observed upon treatment with RO6885247. 
This exploratory, open-label study is designed to assess the safety, tolerability, PK and 
PD of risdiplam in patients with SMA (aged 6 months to 60 years) previously enrolled in 
Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previously treated 
with nusinersen, AVXS-101, or olesoxime.  Considering the different therapeutic agents 
currently approved or in development for SMA and the possibility that patients with a 
poor response to and/or lack of tolerability towards another agent may need alternative 
treatment options, it is important to evaluate the safety and PK/PD response to risdiplam 
in these patients compared to treatment-naïve patients.  The results of this study will 
allow an assessment of the safety and tolerability of risdiplam and to characterize the 
PK/PD relationship of risdiplam in these non-naïve patients in order to inform clinical 
development of risdiplam.  The PK of risdiplam will be assessed throughout the study. 
The PD characteristics of risdiplam will be measured in terms of SMN protein and SMN 
mRNA splice forms. 
1.3.2 
Benefit–Risk Assessment 
The SAD Study (BP29840) established the proof of mechanism in healthy subjects that 
risdiplam is able to modulate the splicing of SMN2 mRNA, leading to an 
exposure-dependent increase in the amount of full-length SMN2 mRNA and a 
corresponding decrease in the amount of SMN2 mRNA lacking exon 7.  In Part 1 of 

 
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Studies BP39055 and BP39056, risdiplam led to an exposure-dependent increase in 
SMN protein, confirming proof of mechanism in patients with SMA types 1, 2, and 3.  
Accordingly, available data to date suggest that risdiplam may provide significant 
benefits for patients with SMA. 
In all above mentioned studies, risdiplam was safe and well-tolerated. 
In light of the adverse findings in the animal toxicology studies, in this study, an 
exposure cap of 2000 ng  hr /mL (mean AUC0-24,ss) corresponding to the overall NOAEL 
of the 39-week toxicology study in cynomolgus monkeys and the NOAEL of the 26-week 
toxicity study in rats, along with a thorough clinical safety monitoring plan is justified, 
considering the potential benefit for the patients enrolled.  Available data suggest that a 
100% increase in SMN protein levels is expected to turn more severe SMA phenotypes 
into milder forms, while further increase is likely to provide even greater benefit.  At the 
dosing regimen selected for the study (i.e., 5 mg for patients with a BW   20 kg, 0.25 
mg/kg for patients with a BW 20 kg [for patients aged  260 years], and 0.2 mg/kg for 
patients aged 6 months to  2 years), the mean predicted exposure is 1690 nghr/mL 
[95% CI: 16001780 ng  hr/mL] for children and adults aged 225 years and 
2020 nghr/mL in infants aged  5 months.  Because the prediction for patients aged 
6 months to  2 years is based on a small number of patients from Part 1 of 
Study BP39056, in this study exposure will be monitored in all infants aged 6 months to 
 2 years and the dose may get modified, if necessary, to ensure that infants are in the 
targeted exposure range. 
This Study BP39054 will include patients up to age 60 years; no relevant difference in 
PK is expected for adults within the age range of 18-60 years.  In Part 1 of 
Study BP39055 a median SMN protein increase of 151% (range 49%251%) versus 
baseline was observed with 5 mg in the age group of 1225 years, and a 96% increase 
(range 17%150%) was noted with the 0.25 mg/kg dose in the age group of 211 years.  
In Part 1 of Study BP39056, 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 observed in 
infants with an exposure (AUC0-24)  1000 nghr/mL. 
Safety precautions are provided and a thorough safety monitoring plan focusing on the 
findings identified in the nonclinical toxicology studies will be implemented to address 
potential safety concerns for the patients enrolled in the trial (Section 5.2).  Toxicological 
findings observed in the nonclinical studies include reversible toxicity involving skin, 
pharynx/larynx, hematological changes, male fertility, and potentially irreversible retinal 
toxicity that could translate into some visual impairment at exposures above twice the 
mean cap exposure defined for this study. 
With regard to retinal effects (as detailed in the Risdiplam Investigator Brochure), it is 
essential to note that the changes found by SD-OCT scanning (and on histopathology) in 

 
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the peripheral retina in the 39-week monkey study may produce peripheral visual field 
defects that are usually asymptomatic and would normally not impact visually oriented 
behavior and quality of life.  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.  As of 18 
August 2023, almost 7000 SD-OCT assessments from 486 patients in Studies BP39055 
(SUNFISH), BP39056 (FIREFISH), BN40703 (RAINBOWFISH) and BP39054 
(JEWELFISH) have not shown any retinal toxicity in any patient exposed to risdiplam 
at any dose. 
The key elements of risk management in this study considering nonclinical findings and 
clinical experience gained from the SAD study in healthy volunteers and in SMA patients 
from Part 1 of studies BP39055 and BP39056 are summarized below: 
 
Frequent PK assessments (particularly at the beginning of the study; 
see Appendix 1A and Appendix 3A) to ensure that the average targeted exposure 
remains below the exposure cap.  For patients aged 6 months to < 2 years (infants), 
the PK data will be regularly reviewed by the Clinical Pharmacologist, and, on the 
basis of the PK monitoring, the dose of individual or all infants may be modified to 
ensure that infants are in the targeted exposure range and in compliance with the 
exposure cap. 
 
Safety monitoring throughout the treatment period, OLE phase, study 
completion/early withdrawal visit and follow-up (Section 5.2.2), including 
dermatology and clinical laboratory measures.  Ophthalmology assessments were 
conducted under Protocol Versions 1-4 inclusive, but are no longer performed 
under Protocol Version 5. 
 
Periodic review of clinical data by the safety data monitoring committees 
(Section 3.1.2). 
 
Clear definition of study and individual patient stopping rules (Section 5.2.3). 
 
Appropriate inclusion/exclusion criteria and guidance regarding prohibited therapy 
(including OCT-2 and MATE substrates; Section 4.5). 
 
Clinical experience gathered from ongoing trials with risdiplam in patients with SMA 
(BP39055 and BP39056). 
 
The strategy and rationale for dose selection is described in Section 3.2.1.  Table 1 
gives an overview of the margins versus key toxicities of risdiplam at the target exposure 
of this study and at the exposure cap.  The safety margins at the targeted exposure in 
patients aged 6 months to  2 years (infants) are similar to safety margins at the 
exposure cap, because the highest possible dose at the exposure cap has been 
selected to maximize the increase in SMN protein and hence the chance for clinical 
efficacy in infants with a severe early onset type of this disease. 

 
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Table 1 
Overview of the Margins versus Key Toxicities of Risdiplam 
Type of Toxicity 
Margin at NOAEL versus 
predicted exposure of 
1690 nghr/mL in children and 
adults 
 [mean AUC0-24,ss  
95% CI:16001780 nghr/mL] a 
Margin at NOAEL vs  
Cap Exposure of  
2000 nghr /mL 
(AUC0-24) b 
Micronucleus induction in rat 
bone marrow 
~2 
~1.5 
Testis toxicity in rats and 
monkeys 
No 
No 
Epithelial findings (skin, eyelid, 
larynx) in monkeys (with 
chronic dosing) 
  3 

 
2.5
 
Hematology changes (red 
blood cells [RBC] and 
lymphocytes) in monkeys, rats 
and mice 
  3 

 
4 
Retina changes in monkeys 
~1 
~1 
Overall NOAEL (13 weeks of 
treatment: juvenile rat) 
~4 

 3 
Overall NOAEL (39 weeks of 
treatment: monkey) 
~1 
~1 
Overall NOAEL (26 weeks of 
treatment: adult albino rat) 
~1,5 
 
NOAEL  no-observed-effect level; SMA   spinal muscular atrophy.
a The exposure of 1690 nghr/mL (95% CI: 1600-1780 nghr/mL) is the mean predicted
exposure across the SMA patient population at the dose of 5 mg for patients with a BW 
20 kg and 0.25 mg/kg for patients with a BW 20 kg (for patients aged  260 years).
b Corresponds to the targeted exposure in patients aged 6 months to  2 years.  Margins
are based on the mean exposures in animal studies in the more sensitive species/sex.
 
Overall, considering the severity of SMA and the potential for patients to benefit from 
treatment with risdiplam, Roche considers the safety margins in this study appropriate, 
and currently available data from Part 1 of Studies BP39055 and BP39056 continue to 
justify the benefitrisk of treatment with risdiplam for patients aged 6 months60 years 
with SMA, including those previously enrolled in Study BP29420 (Moonfish) with the 
splicing modifier RO6885247, or previously treated with nusinersen, AVXS-101, or 
olesoxime. 
2. 
OBJECTIVES 
This study will evaluate the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of risdiplam in adult and pediatric patients with SMA.  Specific 
objectives for the study are outlined below.  Unless otherwise specified, patient age in 
this protocol refers to age at screening. 

 
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2.1 
PRIMARY OBJECTIVES 
The primary objectives of this study are as follows: 
 
To evaluate the safety and tolerability of risdiplam 
 
To investigate the PK of risdiplam and metabolites as appropriate 
 
2.2 
SECONDARY OBJECTIVE 
The secondary objective for this study is as follows: 
 
To investigate the PK-PD relationship of risdiplam.  The PD investigations will 
include analyses of SMN mRNA splice forms and SMN protein. 
 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are defined below. 
 
To evaluate the efficacy of treatment with risdiplam in terms of the proportion of 
patients who experience a pre-specified disease-related adverse event. 
 
To evaluate the efficacy of treatment with risdiplam in terms of motor function as 
assessed through the following measures: 
– 
Motor function measure (MFM) (patients aged 260 years) 
– 
Hammersmith Functional Motor Scale Expanded (HFMSE) (patients aged 
260 years) 
– 
Revised Upper Limb Module (RULM) (patients aged 260 years) 
– 
Six-minute walk test (6MWT) of walking capacity in ambulant patients (patients 
aged 660 years) 
– 
Bayley Scales of Infant and Toddler development  Third Edition (BSID-III) 
(patients aged 6 months to  2 years) 
 
To evaluate the efficacy of treatment with risdiplam in terms of achievement of 
motor milestones as assessed through the Hammersmith Infant Neurological 
Examination (HINE) Module 2 (patients aged 6 months to  2 years). 
 
To evaluate the efficacy of treatment with risdiplam on respiratory function as 
assessed through the following measures: 
– 
Sniff nasal inspiratory pressure (SNIP) (patients aged 260 years) 
– 
Forced vital capacity (FVC) (patients aged 660 years)  
– 
Forced expiratory volume in 1 second (FEV1) (patients aged 660 years) 
– 
Peak cough flow (PCF) (patients aged 660 years) 
 
To evaluate time-matched QT profiles in patients treated with risdiplam (patients 
aged 12-60 years) 
 
To evaluate the efficacy of treatment with risdiplam in terms of patient-reported 
independence (patients aged 1260 years) and caregiver-reported independence as 
assessed through the SMA Independence Scale (SMAIS) (patients aged 
260 years) 

 
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 
To evaluate patients’ adherence to smartphone-based monitoring (patients aged 
660 years) 
 
To evaluate the collected sensor data from smartphone-based monitoring and its 
potential correlations with patients’ MFM score (patients aged 660 years) 
 
To assess time to death (patients aged 6 months to  2 years) 
 
To assess time to loss of swallowing (patients aged 6 months to  2 years) 
 
To assess time to permanent ventilation (patients aged 6 months to  2 years) 
  
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design 
This is a multi-center, exploratory, non-comparative, and open-label study to investigate 
the safety, tolerability, PK, and PK/PD relationship of risdiplam in adults, children and 
infants with SMA previously enrolled in Study BP29420 (Moonfish) with the splicing 
modifier RO6885247 or previously treated with nusinersen, AVXS-101 
(adeno-associated virus 9 based gene therapeutic that delivers a normal copy of the 
SMN1 gene), or olesoxime. 
Up to 180 patients will be enrolled to receive risdiplam.  At least 80 patients will have 
previously received treatment with nusinersen or AVXS-101. 
Treatment with risdiplam will initially be evaluated over a 2-year period.  After completion 
of the 2-year treatment period, the patients will be given the opportunity to enter the 
OLE phase of the study, which will include regular monitoring of safety, tolerability and 
efficacy.  Unless the Sponsor stops the development of risdiplam, the patient's treatment 
in the OLE will continue for an additional 3 years (patients will be treated for a total 
duration of at least 5 years).  After a patient has completed 3 years in the OLE, the 
patient may continue to receive risdiplam IMP until the end of study (EOS; as defined in 
Section 3.1.3), provided that risdiplam is not commercially available to the patient (see 
Section 4.4.4).  However, the overall study will not exceed a total of approximately 
5 years after the last patient is enrolled in the study. 
When a patient completes or withdraws early from study treatment, the patient will be 
requested to attend a study completion/early withdrawal visit as described in the 
schedules of assessments (SoAs; see Appendix 1A and Appendix 3A) and 
Section 4.6.2.3. 
A safety follow-up telephone call approximately 30 days after the study 
completion/early withdrawal visit may be conducted, if applicable (see Section 4.6.2.4). 
The patient’s route through study completion, follow-up (if applicable) and access to 
risdiplam after completion are shown in Appendix 5. 

 
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For patients aged 260 years, the dose in this study will be 5 mg for patients with a 
BW 20 kg and 0.25 mg/kg for patients with a BW  20 kg, given orally once daily. 
For patients aged 6 months to  2 years (infants), the dose will be 0.2 mg/kg.  The PK in 
all infants will be regularly monitored by the Clinical Pharmacologist, and the dose of all 
or individual infants may be adjusted to ensure that infants are in the targeted exposure 
range and in compliance with the exposure cap. 
As described above, the duration of the study for patients enrolled in this study will be 
divided as follows: 
 
Screening: Up to 30 days prior to the first dose of study drug 
 
Baseline: Day 1 
 
Treatment period: Up to 2 years 
 
Thereafter, patients will be given the opportunity to enter the OLE phase of the 
study for 3 years. 
 
3.1.2 
Committees 
3.1.2.1 
Internal Monitoring Committee 
The IMC will consist of selected Roche representatives: Clinical Pharmacologist, Clinical 
Science Leader, Safety Science Leader, Statistician, and Statistical Programmer.  The 
IMC will be responsible for monitoring safety until the external iDMC for the confirmatory 
phase of the risdiplam program takes on the responsibility for monitoring the safety of 
Type 2 and Type 3 SMA patients.  The members of the IMC for this study will be the 
same as for Study BP39055 to ensure consistency in the oversight of safety in Type 2 
and Type 3 SMA patients. 
The roles, responsibilities, membership, scope of activities, time of meetings and 
communication plan for the IMC will be documented in an appropriate charter prior to the 
initiation of the study. 
3.1.2.2 
Independent Data Monitoring Committee (iDMC) 
An external iDMC has been established to monitor patient safety during the confirmatory 
phase of the risdiplam clinical development program.  The responsibility for monitoring 
patient safety transitioned from the IMC to the iDMC when the iDMC took on the 
responsibility for monitoring the safety of Type 2 and Type 3 SMA patients within the 
program.  The iDMC will meet on a regular basis during the course of the study (once it 
is formed) and may also meet on an ad-hoc basis as required, e.g., if any unexpected 
safety concerns arise.  After meeting, the iDMC will make a recommendation to the 
Sponsor for study conduct including (but not limited to) continuation, halting or amending 
the protocol. 
The roles, responsibilities, membership, scope of activities, time of meetings and 
communication plan for the iDMC will be documented in the Charter prior to the initiation 

 
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of the study.  The 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. 
3.1.2.3 
Permanent Ventilation Adjudication Committee 
Time to permanent ventilation will be determined by a central, independent Permanent 
Ventilation Adjudication Committee.  The committee will review all pertinent data for 
patients aged 6 months to  2 years (infants) 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 
beginning 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. 
3.1.3 
End of Study 
A patient is considered to have completed the study if he or she has completed all phases 
of the study, including:  
 
The study completion or early withdrawal visit (see Section 4.6.2.3) 

 
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 
A safety follow-up telephone call, if applicable (see Section 4.6.2.4  and 
Appendix 5).  The safety follow-up telephone call is only for patients [a] who do 
not go on to receive risdiplam IMP through continued access or to receive 
risdiplam through commercial or post-trial access; or [b] who switch to another 
treatment for SMA within 30 days of stopping risdiplam 
 
The EOS is defined as the date of the last visit or telephone call (whichever occurs later) 
of the last patient in the study.  The EOS is expected to occur approximately 5 years 
and 1 month after the last patient is enrolled (completion of a 2 year treatment phase, a 
3 year OLE phase plus 30-day follow-up if applicable). 
The study will continue until the EOS, the study is terminated per local regulation, or the 
Sponsor decides to terminate the study. 
See Section 4.4.4 for conditions regarding  continued access to risdiplam until the 
EOS and Section 4.4.5 for conditions regarding post-study access to risdiplam. 
3.1.4 
Duration of Participation 
The total duration of study participation for an individual is expected to be 
approximately 5 years (2-year treatment phase and 3-year OLE phase) and 1 month (if 
30-day follow-up applies). 
3.2 
RATIONALE FOR STUDY DESIGN 
3.2.1 
Rationale for Dosage Selection 
Given the severity and the high mortality and morbidity associated with SMA, the dose 
tested in this study aims to provide therapeutic benefit to patients upon chronic dosing. 
Based on population PK modelling using available data in SMA patients from 
Study BP39055 Part 1, the selected dosing regimen of 5 mg for patients with a BW 
20 kg and 0.25 mg/kg for patients with a BW 20 kg is predicted to result in a 
steady-state AUC0-24h,ss of 1690 ng•hr/mL in SMA Type 2 and 3 patients aged 
225 years and is not expected to exceed the exposure cap (mean AUC0-24h,ss of 
2000 ngh/mL).  On the basis of currently available data from Part 1 of Study BP39056, 
the selected dose of 0.2 mg/kg in patients aged 6 months to  2 years (infants) is 
predicted to result in a steady-state AUC0-24h,ss of 2020 nghr/mL.  The predicted mean 
AUC0-24h,ss of 2020 nghr/mL is considered in compliance with the exposure cap of a 
mean AUC0-24h,ss of 2000 nghr/mL, since it is only numerically marginally greater and the 
PK will be monitored in all infants to ensure that the actual observed PK values are in 
compliance with the cap of a mean AUC0-24h,ss of 2000 nghr/mL.  The dose of individual 
or all infants may be adjusted to ensure exposure in the right target range. 
These doses and exposures are anticipated to be safe and well-tolerated based on the 
SAD data obtained in healthy subjects (single-dose administration of up to 18 mg), 
currently available data from Part 1 of Study BP39055 and BP39056 and the animal 

 
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toxicology studies.  In Part 1 of Study BP39055, this dosing regimen resulted in a 
median increase in SMN protein of 151% in the age group of 12-25 years, and 96% in 
the age group of 2-11 years.  In Part 1 of Study BP39056, 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. 
SMN protein levels in SMA patients (Sumner et al 2006; Nguyen et al 2008) and data 
obtained in animal SMA models regarding efficacy and the associated SMN protein 
increase (Risdiplam Investigator’s Brochure) suggest that a 100% increase in SMN 
protein levels could turn severe SMA phenotypes into milder forms, whereas further 
increase may provide even greater benefit.  Therefore, the selected dose levels are 
expected to lead to a substantial clinical benefit in SMA patients by turning more severe 
phenotypes into milder forms. 
The data summary from Part 1 of Study BP39055 and Study BP39056 supporting the 
rationale for the dose selection for this study can be found in the Risdiplam Investigator’s 
Brochure. 
3.2.2 
Rationale for Study Population 
This study is designed to assess the safety, tolerability, PK and PK/PD relationship of 
risdiplam following once daily oral administration in pediatric and adult patients with SMA 
who have been previously enrolled in Study BP29420 (Moonfish) with the splicing 
modifier RO6885247 or previously treated with nusinersen, AVXS-101, or olesoxime. 
Risdiplam has been shown to be safe and well-tolerated after single dose administration 
in healthy adult volunteers (BP29840) and in Part 1 of Studies BP39055 and BP39056.  
It is currently being tested in treatment-naïve pediatric and adult patients with Type 2 
and Type 3 SMA (BP39055) and infants with Type 1 SMA (BP39056).  There is a need 
to study the safety, tolerability PK and PD profile of risdiplam in patients with SMA who 
have previously received other therapy for their disorder.  Considering the different 
therapeutic agents currently approved or in development for SMA and the possibility that 
patients with a poor response to and/or lack of tolerability towards another agent may 
need alternative treatment options, it is important to evaluate the safety and PK/PD 
response to risdiplam in these patients compared to treatment-naïve patients.  This 
information would be valuable for these patients in the event that they need to switch to 
risdiplam. 
The risk-benefit of treatment with risdiplam in SMA patients previously enrolled in Study 
BP29420 (Moonfish) with the splicing modifier RO6885247 or previously treated with 
nusinersen, AVXS-101, or olesoxime is considered favorable given the potential it has to 
address the unmet medical needs of this population.  With SMA being a progressive 
disease, the Sponsor perceives an ethical obligation to provide these patients with the 
opportunity to participate in this clinical study, particularly those previously enrolled in 

BP29420 and those previously treated with olesoxime, as some of these patients may 
not have access to other treatment options.  Appropriate inclusion and exclusion criteria, 
safety monitoring and stopping rules have been established to ensure the safety of the 
patients enrolled in this study. 
3.2.3 
Rationale for Biomarker Assessments 
SMA is a heterogeneous disease presenting a spectrum of motor dysfunction (from not 
being able to sit up to not being able to walk) and variability in disease onset (from birth 
to the third decade of life).  Due to the variability in SMA phenotypes, careful 
consideration is required when enrolling patients, when following the progression of the 
disease and measuring the response to study drug treatment. 
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 a 
lack of SMN protein, changes in SMN mRNA and SMN protein levels (relating to 
changes in the spinal cord and muscle) will be measured in blood. 
As patients can have different SMN2 copy numbers, which will affect SMN protein 
production, clinical genotyping for SMN2 is important. 
The following blood samples will be collected according to the SoAs and detailed 
tables (see Appendix 1 − ........
4 for biomarker analyses: 

Clinical genotyping (Section 4.6.1.17).

Blood samples for mandatory exploratory biomarker analyses (e.g., related to SMA
disease and/or to treatment response).

Upon optional consent, samples for Research Biosample Repository (RBR) as
described in Section 4.6.1.23.
In addition, and as described in Section 4.6.1.14, the following blood samples will be 
collected according to the SoAs, in order to assess the PD effects of risdiplam as an 
SMN2 splicing modifier: 

In vivo splicing modification of SMN mRNA in blood.

SMN protein levels in blood.
For this study, a digital biomarker approach was developed.  This is a sensor-based 
assessment approach for measuring motor abilities and strength using smartphones.  
Smartphones have high quality sensors that enable the remote, non-invasive, frequent 
and precise measurement of motor and non-motor symptoms.  For this study, a 
sensor-based assessment approach using smartphones was developed, drawing on 
items assessed by the MFM (Bérard et al 2009). 
A dedicated smartphone will be provided to each patient aged 6 years and older.  The 
phone will prompt them to complete a selection of tests and surveys (Section 
4...22). 
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Patients will do a subset of these tests each day, based on their ability and an automatic 
scheduler on the phone (see Appendix 1).  Digital biomarker assessments were 
performed under Protocol Versions 1-4, inclusive, but ceased to be performed during 
2022. 
3.3 
OUTCOME MEASURES 
3.3.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) scale, Version 4.0 (see Section 5.3.3). 
 
Incidence of treatment discontinuations due to adverse events. 
 
Incidence of abnormal laboratory values. 
 
Incidence of abnormal ECG values. 
 
Incidence of abnormal vital signs (body temperature, systolic and diastolic blood 
pressure (DBP), heart rate, respiratory rate). 
 
Physical examination.  For patients aged 917 years, physical examination will 
include formal Tanner staging for pubertal status. 
 
Neurological examination. 
 
Height, weight, and head and chest circumference. 
 
Incidence of emergence or worsening of symptoms as measured by the 
Columbia-Suicide Severity Rating Scale (C-SSRS) (adult version for adults and 
adolescents, pediatric version for patients aged 611 years). 
 
Ophthalmological assessments as appropriate for age (for details, see 
Section 4.6.1.11).  This objective was in place in Protocol Versions 1-4 inclusive.  
Ophthalmological assessments have been removed starting in Protocol Version 5. 
 
Adverse events and concomitant medications will be monitored throughout the entire 
study. 
3.3.2 
Pharmacokinetic (PK) and Pharmacodynamic (PD) Outcome 
Measures 
3.3.2.1 
Pharmacokinetic Outcome Measures 
The PK evaluations for this study are as follows: 
 
Concentration per timepoint listed 
 
Cmax 
 
AUC 
 
Concentration at the end of a dosing interval (Ctrough) to assess steady-state 
 
Other PK parameters as appropriate 
 

 
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3.3.2.2 
Pharmacodynamic Outcome Measures 
The PD outcome measures for this study are as follows: 
 
SMN mRNA in blood: Blood samples will be collected at the times specified in the 
SoAs and detailed tables (see Appendices 14), to isolate mRNA and measure the 
relative amount of SMN mRNA and its splice forms.  Housekeeping genes for the 
quantitative analysis of RNA will also be measured. 
 
SMN protein levels in blood. 
 
3.3.3 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
 
Disease-related adverse events 
 
MFM (32 item version) 
 
HFMSE 
 
RULM 
 
Gross Motor Scale of the Bayley Scales of Infant and Toddler development -Third 
Edition (BSID-III) 
 
Hammersmith Infant Neurological Examination Module 2 (HINE2) 
 
Six-minute walk test (6MWT) (for ambulant patients only) 
 
SNIP 
 
Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and peak 
cough flow (PCF) 
 
SMAIS 
 
Sensor data collected using smartphone-based monitoring as part of the digital 
biomarker approach.  (This objective was in place in Protocol Versions 1-4 
inclusive; however, these assessments ceased to be performed during 2022). 
 
Ventilation-free survival (i.e., without need for permanent ventilation, defined as 
 16 hours of noninvasive ventilation per day or intubation for  21 consecutive days 
in the absence of, or following, the resolution of an acute reversible event or 
tracheostomy) 
 
Ability to swallow 
 
4. 
MATERIALS AND METHODS 
4.1 
CENTER 
This is a multi-center study to be conducted globally in several countries.  An additional 
site(s) may be included for back-up purposes and may be activated if needed. 
An administrative and contact information list for Investigators is provided separately. 

 
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4.2 
STUDY POPULATION 
This study will include both male and female patients with SMA aged 6 months to 
60 years.  Patients must meet all eligibility criteria in order to qualify for the study.  
Unless otherwise stated, inclusion and exclusion criteria refer to screening. 
4.2.1 
Recruitment Procedures 
Patients will be recruited primarily from site/country clinical databases; however, in some 
cases, potential patients may be identified prior to consenting to take part in this study 
using pre-screening enrollment logs, Independent Ethics Committee (IEC/IRB) approved 
newspaper/radio advertisements and mailing lists.  Additionally, patients previously 
enrolled in Study BP29420 or treated with olesoxime may be invited to participate in this 
study. 
4.2.2 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Males and females 6 months to 60 years of age inclusive (at screening) 
 
Confirmed diagnosis of 5q-autosomal recessive SMA, including: 
– 
Genetic confirmation of homozygous deletion or heterozygosity predictive of 
loss of function of the SMN1 gene. 
– 
Clinical history, signs, or symptoms attributable to SMA. 
 
Previous enrollment in Study BP29420 (Moonfish) with the splicing modifier 
RO6885247 or previous treatment with any of the following: 
– 
Nusinersen (defined as having received  4 doses of nusinersen, provided that 
the last dose was received  90 days prior to screening) 
– 
Olesoxime (provided that the last dose was received  18 months and  90 days 
prior to screening) 
– 
AVXS-101 (provided that the time of treatment was  12 months prior to 
screening) 
 
 
Able and willing to provide written informed consent and to comply with the study 
protocol according to International Conference on Harmonization (ICH) and local 
regulations.  Alternatively, a legally authorized representative must be able to give 
consent for the patient according to ICH and local regulations and assent must be 
given whenever possible. 
 
Adequately recovered from any acute illness at the time of screening and 
considered well enough to participate in the opinion of the Investigator. 
 
For women of childbearing potential: negative blood pregnancy test at screening, 
agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating eggs, as defined 
below: 

 
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– 
Women must remain abstinent (refrain from heterosexual intercourse) or use 
two adequate methods of contraception, including at least one method with a 
failure rate of  1% per year, during the treatment period and for at least 
28 days after the final dose of study drug.  Women must refrain from donating 
eggs during this same period. 
– 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or regulations. 
– 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, established and proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices. 
A vasectomy is a highly effective birth control method provided that the 
partner is the sole sexual partner of the woman of childbearing potential 
trial participant, and provided the vasectomized partner has received 
medical assessment of the surgical success. 
– 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below: 
– 
With a female partner of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of  1% per year during the treatment period and for at least 
4 months after the final dose of study drug.  Men must refrain from donating 
sperm during this same period.  This period is required for small molecules with 
potential for genotoxic effect and includes the spermatogenic cycle duration and 
drug elimination process. 
– 
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for at least 28 days after the final dose of study 
drug. 
– 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 

 
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 
For patients aged 2 years or younger at screening: 
– 
Receiving adequate nutrition and hydration (with or without gastrostomy) at the 
time of screening, in the opinion of the Investigator. 
– 
Medical care meets local accepted standard of care, in the opinion of the 
Investigator. 
– 
Would be able to complete all study procedures, measurements and visits, and 
the parent or caregiver of the patient has adequately supportive psychosocial 
circumstances, in the opinion of the Investigator. 
– 
Parent or caregiver of patient is willing to consider naso-gastric, naso-jejunal or 
gastrostomy tube placement, as recommended by the Investigator, during the 
study (if not already in place at the time of screening) to maintain safe 
hydration, nutrition and treatment delivery. 
– 
Parent or caregiver of patient is willing to consider the use of non-invasive 
ventilation, as recommended by the Investigator during the study (if not already 
in place at the time of screening). 
 
4.2.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Inability to meet study requirements. 
 
Concomitant participation in any investigational drug or device study. 
 
With the exception of studies of olesoxime, AVXS-101, or nusinersen:  Previous 
participation in any investigational drug or device study within 90 days prior to 
screening, or 5 half-lives of the drug, whichever is longer. 
 
Any history of gene or cell therapy, with the exception of AVXS-101. 
 
Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system 
diseases as considered to be clinically significant by the Investigator. 
 
Inadequate venous or capillary blood access for the study procedures, in the opinion 
of the Investigator. 
 
For patients aged  2 years, hospitalization for a pulmonary event within 2 months 
prior to screening and pulmonary function not fully recovered at the time of 
screening. 
 
Lactating women. 
 
Suspicion of regular consumption of drugs of abuse. 
 
For adults and adolescents only, i.e., aged  12 years, positive urine test for drugs of 
abuse or alcohol at screening or Day 1 visit. 
 
Cardiovascular, blood pressure, and heart rate: 
– 
Adults: Sustained resting systolic blood pressure (SBP)  140 mmHg 
or  80 mmHg, and/or diastolic blood pressure (DBP)  90 mmHg or  40 mmHg; 
a resting heart rate  45 bpm or  100 bpm if considered to be clinically 
significant by the Investigator. 

 
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– 
Adolescents (1217 years of age): SBP and/or DBP outside the 95th percentile 
for age; resting heart rate  50 bpm or  100 bpm if considered to be clinically 
significant by the Investigator. 
– 
Children (611 years of age): SBP and/or DBP outside the 95th percentile for 
age; resting heart rate  60 bpm or  120 bpm, if considered to be clinically 
significant by the Investigator. 
– 
Children (25 years of age): SBP and/or DBP outside the 95th percentile for 
age; resting heart rate  70 bpm or  140 bpm if considered to be clinically 
significant by the Investigator. 
– 
Children (6 months to  2 years of age): SBP and/or DBP outside the 
95th percentile for age; resting heart rate  70 bpm or  170 bpm, if considered 
to be clinically significant by the Investigator. 
 
Presence of clinically significant ECG abnormalities before study drug administration 
(e.g., second or third degree AV block, confirmed QTcF  460 msec for patients 
aged  10 years, or QTcB  460 ms for children up to age 10 years (Bazett’s 
correction is more appropriate in young children) from the average of triplicate 
measurements, or cardiovascular disease (e.g., cardiac insufficiency, coronary 
artery disease, cardiomyopathy, congestive heart failure, family history of congenital 
long QT syndrome, family history of sudden death) indicating a safety risk for the 
patient as determined by the Investigator. 
 
History of malignancy if not considered cured. 
 
For patients aged  6 years, significant risk for suicidal behavior, in the opinion of 
the Investigator as assessed by the C-SSRS. 
 
Any major illness within 1 month before the screening examination or any febrile 
illness within 1 week prior to screening and up to first dose administration. 
 
Use of any OCT-2 and MATE substrates within 2 weeks before dosing (including but 
not limited to: amantadine, cimetidine, memantine, amiloride, famotidine, metformin, 
pindolol, ranitidine, procainamide, varenicline, acyclovir, ganciclovir, oxaliplatin, 
cephalexin, cephradine, fexofenadine) including the mother, if breastfeeding the 
patient. 
 
Use of the following medications within 90 days prior to enrollment: riluzole, valproic 
acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, 
growth hormone, anabolic steroids, probenecid, agents anticipated to increase or 
decrease muscle strength, agents with known or presumed histone deacetylase 
(HDAC) inhibitory effect, and medications with known phototoxicity liabilities 
(e.g., oral retinoids including over-the-counter formulations, amiodarone, 
phenothiazines and chronic use of minocycline).  (Patients who are on inhaled 
corticosteroids, administered either through a nebulizer or an inhaler, will be allowed 
in the study.) 
 
Recently initiated treatment for SMA (within 6 weeks prior to enrollment) with oral 
salbutamol or another 2-adrenergic agonist taken orally is not allowed. Patients 
who have been on oral salbutamol (or another 2-adrenergic agonist) for  6 weeks 
before enrollment and have shown good tolerance are allowed.  The dose of 

 
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2-adrenergic agonist should remain stable as much as possible for the duration of 
the study.  Use of inhaled 2-adrenergic agonists (e.g., for the treatment of asthma) 
is allowed. 
 
Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or 
thioridazine, is not allowed.  Use of other medications known to or suspected of 
causing retinal toxicity within one year prior to enrollment is not allowed. 
 
Clinically significant abnormalities in laboratory test results, e.g., ALT values 
exceeding 1.5-fold 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) 
which is supported by elevated CK and LDH.  Out of range CK 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. 
 
Donation or loss of blood  10% of blood volume within 3 months prior to screening. 
 
Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to risdiplam 
or to the constituents of its formulation (see Risdiplam Investigator’s Brochure). 
 
Concomitant disease or condition that could interfere with, or treatment of which 
might interfere with, the conduct of the study, or that would, in the opinion of the 
Investigator, pose an unacceptable risk to the patient in this study. 
 
Recent history (less than 1 year) of ophthalmological diseases (e.g., glaucoma not 
controlled by treatment, central serous retinopathy, inflammatory/infectious retinitis 
unless clearly inactive, retinal detachment, retinal surgery, 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 at screening (e.g., retinal layer abnormalities, edema, cystic 
or atrophic changes) should be discussed with the investigator, the Ophthalmologist, 
and with the Sponsor, who will jointly make the decision if the patient may be 
enrolled in the study.  Patients in whom SD-OCT measurement of sufficient quality 
cannot be obtained at screening will not be enrolled. 
 
Any prior use of an inhibitor or inducer of FMO1 or FMO3 taken within 2 weeks (or 
within 5 elimination half-lives, whichever is longer) prior to dosing. 
 
4.3 
METHOD OF TREATMENT ASSIGNMENT 
This is an open-label study and all patients will receive risdiplam. 
An interactive voice or web-based response system (IxRS) will be used to manage 
patient screening, enrollment, and drug supply. 
Patients that are newly screened in the study will be assigned a number allocated by the 
IxRS.  Sites should call the IxRS to enter the subject into screening and to register a 
screening failure.  Patient numbers will be allocated by IxRS and will be used in the 
clinical database and for recording data in the electronic Case Report Form (eCRF).  

 
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The enrollment call to the IxRS should occur after the patient’s eligibility has been 
confirmed. The day of the enrollment call is considered as Day 1 of the trial. 
4.4 
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is risdiplam.  Appendix 6 
identifies all investigational medicinal products for this study. 
4.4.1 
Formulation, Packaging, and Handling 
4.4.1.1 
One-Bottle Formulation (Powder for Oral Solution) 
The IMP risdiplam one-bottle clinical formulation is a powder for constitution to an oral 
solution.  Each bottle contains 60 mg of risdiplam substance with excipients.  The 
powder is constituted with purified water to yield an oral solution containing 0.75 mg/mL 
of risdiplam. 
The excipients used in the one-bottle clinical formulation of risdiplam are the same as for 
the two-bottle formulation (powder and solvent for oral solution), except for isomalt 
added as an additional diluent. 
Patients that are already enrolled in the study shall continue to use the risdiplam 
two-bottle clinical formulation until availability of the one-bottle formulation.  Patients that 
are newly enrolled in the study will only receive the risdiplam one-bottle formulation 
throughout their participation in the study. 
Note:  the two-bottle formulation is no longer used in this study. 
4.4.1.2 
Packaging and Handling 
Study medication will be constituted at each site by qualified pharmaceutical personnel, 
with the exact dosing volume to be administered by an oral/enteral dispenser.  Detailed 
instructions for the constitution procedure of the respective formulations will be provided 
in a separate pharmacy manual.  The bottles containing the constituted oral solution will 
be inserted into a labeled carton provided by Roche Clinical Trials Supplies department.  
The clinical study site will provide oral/enteral dispensers to the patient/caregiver for 
administering the solution.  A diary will be provided to the patient/caregiver with 
instructions on study drug administration at home. 
For each patient and on all instances of study drug dispensing, the formulation used 
(i.e., one-bottle with 0.75 mg/mL; or two-bottle with 0.25 mg/mL or 1.5 mg/mL solution of 
risdiplam [when used earlier in the study]) must be recorded by the pharmacist or an 
authorized personnel. 
Study drug packaging will be overseen by the Roche Clinical Trial Supplies department 
and will bear a label with the identification required by local law, the protocol number, 
drug identification and dosage.  The packaging and labelling of the study medication and 
excipient will be in accordance to Roche standards and local regulations.  The qualified 

 
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individual responsible for dispensing the study drug will prepare the correct drug product 
according to the individual specific dose allocated to the individual patient.  This 
individual will also record study drug batch number received by each patient during the 
study. 
Upon arrival of investigational products at the site, site personnel should check for 
damage and verify proper identity, quantity, integrity of seals and temperature 
conditions, and report any deviations or product complaints to the Monitor upon 
discovery.  All drug supplies should be stored in a secure, temperature-controlled area 
with restricted access.  Risdiplam and the excipient blends for constitution must be 
stored according to the details on the product label. 
For further details, see the Risdiplam Investigator’s Brochure and BP39054 Pharmacy 
Manual. 
4.4.2 
Dosage, Administration and Compliance 
The qualified individual responsible for dispensing the study drug will prepare the correct 
dose.  This individual will write the date dispensed and patient number and initials on the 
study drug bottle label and on the Drug Accountability Record.  This individual will also 
record the MEDNO/study drug batch number received by each patient during the study.  
Throughout the study duration, the study medication should be taken once daily in the 
morning with the patient’s regular morning meal, except when site visits are planned and 
study medication will be administered at the clinical site (see Appendix 1A, Appendix 1B, 
Appendix 3A and Appendix 3B).  On these days, patients should have their regular 
morning meal at home before coming to the site; should there be a long time interval 
between this meal and arrival at the site, a snack will be given by the site to the patient 
prior to study medication administration.  Patients receiving the study medication orally 
should always follow this by rinsing their mouth with water and swallowing. 
Patients who are 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.  
This should always be followed by a bolus flush of water through the tube.  The study 
medication should be administered only with the supplied colored dispensers.  A patient 
diary will be required that will capture information related to drug administration for all 
doses throughout the study. 
If breastfeeding, the patient should be fed and burped prior to dosing.  For infants able to 
swallow, study drug will be administered with a syringe inserted between infant's gum 
and cheek as described in the study drug administration instructions for use (see patient 
diary).  Thereafter, water (approximately 1020 mL) should be administered with a 
baby’s bottle to prevent prolonged contact of study drug with buccal mucosa.  Similarly, 
the peribuccal area of the SMA infant should be washed with water in the event of drug 
drooling or spitting.  Breastfeeding should be avoided within 1 hour after study drug 

 
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administration.  Women breastfeeding will be advised to rinse their breasts with water if 
breastfeeding occurs shortly after (i.e.,  1 hour) study drug administration. 
If a dose is not administered by 12:00 (noon) local time, it will be considered a missed 
dose and patients, parents or caregivers will be instructed to not administer study drug 
for that day, administer the regular amount (i.e., not double the dose) at the next 
scheduled time on the subsequent day, and report the event in the medication diary. 
The first dose of study medication will be administered at the clinical site on Day 1 after 
all predose assessments have been conducted. 
All bottles and unused drug and drug supplies will be returned to the site during a study 
visit or collected during a home visit. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.2.3. 
4.4.3 
Investigational Medicinal Product Accountability 
All IMP (risdiplam) required for completion of this study will be provided by the Sponsor.  
The investigational site will acknowledge receipt of IMP, and confirm the shipment 
condition and contents.  Any damaged shipments will be replaced. 
The Investigator is responsible for the control of drugs under investigation.  Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained. 
The Drug Dispensing Log must be kept current and should contain the following 
information: 
 
The identification of the patient to whom the study drug was dispensed (for example 
patient initials and date of birth).  The date(s), quantity of the study drug dispensed 
to the patient. 
 
The date(s) and quantity of the study drug returned by the patient. 
 
All records and drug supplies must be available for inspection by the Roche Monitor at 
every monitoring visit. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed upon by the 
Sponsor.  Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons.  In these cases, it may be acceptable for investigational study 
site staff to destroy dispensed investigational product before a monitoring inspection 
provided that source document verification is performed on the remaining inventory and 
reconciled against the documentation of quantity shipped, dispensed, returned, 

 
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destroyed and provided that adequate storage and integrity of the drug has been 
confirmed. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Written documentation of IMP destruction must contain the following:  
 
Identity of investigational product[s] destroyed. 
 
Quantity of investigational product[s] destroyed. 
 
Date of destruction. 
 
Method of destruction. 
 
Name and signature of responsible person [or company] who destroyed 
investigational product[s]. 
 
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. 
4.4.4 
Treatment with Risdiplam Until End of Study (Continued 
Access to Risdiplam) 
Patients completing 5 years of study treatment (2-year treatment period and 3-year 
OLE) and with no access to commercial risdiplam are eligible to continue to receive 
risdiplam IMP until the EOS (defined as the last patient’s last visit or telephone call, 
see Section 3.1.3). 
These patients continuing to receive risdiplam IMP until the study end are not required 
to perform additional study visits.  Risdiplam IMP will be provided as per current 
study procedures.  Only adverse events must continue to be reported to maintain 
minimum study safety reporting requirements (Section 4.6.2.5). 
Once a patient gains access to commercial risdiplam or another treatment for SMA or 
post-trial access to risdiplam, the patient will leave the study. 
The patient’s route through study completion, access to risdiplam prior to EOS, and 
access to post-trial risdiplam are shown in Appendix 5. 
4.4.5 
Post-Trial Access to Risdiplam 
The Sponsor will offer continued access to risdiplam free of charge to eligible patients in 
accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, as outlined below. 

 
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A patient will be eligible to receive 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 risdiplam treatment for their well-being, and 
 
There are no appropriate alternative treatments available to the patient, and 
 
The patient and their doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A patient will not be eligible to receive risdiplam after completing the study if any of the 
following conditions are met: 
 
Risdiplam 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 would not 
otherwise create a financial hardship for the patient), or 
 
The Sponsor has discontinued development of risdiplam or data suggest that 
risdiplam is not effective for SMA, or 
 
The Sponsor has reasonable safety concerns regarding risdiplam as treatment for 
SMA, or 
 
Provision of risdiplam is not permitted under the laws and regulations of the 
patient's country, or 
 
Risdiplam has ceased to be manufactured 
 
In these situations the investigator and local health care system will transition the 
study patient to an alternative therapy, unless stated differently in the local regulation. 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
The patient’s route through study completion and access to post-trial risdiplam (as 
applicable) are shown in Appendix 5. 
4.5 
CONCOMITANT THERAPY AND FOOD 
The Medical Monitor may be consulted if there are any questions related to concomitant 
or prior therapy. 
4.5.1 
Permitted Therapy 
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter 
drugs (OTCs), approved dietary and herbal supplements, nutritional supplements and 
any non-medication interventions (e.g., individual psychotherapy, cognitive behavioral 
therapy, smoking cessation therapy, physical therapy and rehabilitative therapy) used by 
a patient within 30 days of study screening until the study completion/early withdrawal 

 
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visit.  All concomitant medications should be reported to the Investigator and recorded 
on the eCRF. 
Physiotherapy, occupational therapy and other forms of exercise therapy are 
encouraged but the frequency should remain the same during the clinical study.  All 
concomitant therapy should be reported to the Investigator and recorded in the eCRF. 
All medication administered to manage adverse events should be recorded on the 
Adverse Event eCRF. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use, which should be recorded. 
Dosing should always be used in the dose-range according to the approved local 
prescribing information. 
Unless specified differently below, for any chronic treatment (defined as a minimum of 
8 weeks of treatment), patients should be on a stable regimen for 6 weeks prior to 
screening and should remain on a stable regimen throughout the study. 
Examples of allowed medications include the following, except those that are OCT-2 or 
MATE substrates (see Section 4.5.2): 
 
Topical medications, including the topical form of all medications listed as 
prohibited therapy in Section 4.5.2 
 
Chronic treatment with oral salbutamol or another 2-adrenergic agonist taken orally 
is allowed as long as treatment has been introduced for at least 6 weeks before 
enrollment and the patient has shown good tolerance. 
 
Use of inhaled 2-adrenergic agonists (e.g., for the treatment of asthma) is also 
allowed. 
 
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. 
 
Analgesics, including opioids (e.g., hydromorphone or codeine). 
 
Antibiotics with the exceptions mentioned in Section 4.5.2. 
 
Antihistamines. 
 
Proton pump inhibitors. 
 

 
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4.5.2 
Prohibited Therapy 
All medications (prescription and OTCs) taken within 30 days of study screening will be 
recorded on the appropriate eCRF. 
The following medications are explicitly prohibited for patients and mothers of patients if 
breastfeeding the patient for 2 weeks prior to dosing and throughout the study: 
 
Any OCT-2 and MATE substrates, e.g., amantadine, cimetidine, memantine, 
amiloride, famotidine, metformin, pindolol, ranitidine, procainamide, varenicline, 
acyclovir, ganciclovir, oxaliplatin, cephalexin, cephradine, fexofenadine. 
 
Any inhibitor or inducer of FMO1 or FMO3. 
 
Use of the following therapies are prohibited during the study and for at least 90 days 
prior to enrollment: 
Medications intended for the treatment of SMA 
 
Nusinersen  
 
Riluzole 
 
Valproic acid 
 
Hydroxyurea 
 
Sodium phenylbutyrate 
 
Butyrate derivatives 
 
Creatine 
 
Carnitine 
 
Growth hormone 
 
Anabolic steroids 
 
Probenecid 
 
Chronic oral or parenteral use of corticosteroids (inhaled corticosteroid use is 
allowed) 
 
Agents anticipated to increase or decrease muscle strength or agents with known or 
presumed HDAC inhibition activity 
 
Medications with Known Phototoxicity Liabilities 
 
Amiodarone, phenothiazines, and chronic use of minocycline. 
 
4.6 
STUDY ASSESSMENTS 
4.6.1 
Description of Study Assessments 
All examinations listed below will be performed according to the SoAs outlined in 
Appendices 14. 
Prioritization of blood samples is described in Section 4.6.3. 

 
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Follow-up phone calls are planned in this study.  Patients (or caregivers of patients, as 
appropriate) will be called by the Investigator or designee to monitor safety and 
tolerability when not attending the clinic.  Assessments will include adverse events, 
concomitant medication review, and significant life events (including but not limited to 
changes in school or employment status, marriage, death of parent or spouse, if male 
becoming a parent, etc.).  A final follow-up telephone call may be made approximately 
30 days after the study completion/early withdrawal visit to collect any adverse events, if 
applicable (see Section 4.6.2.4). 
Monthly pregnancy tests are planned in this study for women of childbearing potential.  
On months without a site visit, the pregnancy test may be conducted at home either by 
the patient or by a health care provider (see Appendix 1).  Drug dispensation, return of 
used and unused study drug bottles and supplies will occur at scheduled site visits, ad 
hoc re-supply site visits, or delivery to the patient’s home if necessary.  If considered 
necessary by the investigator and delegated by him/her, a qualified health care provider 
may also visit the patient’s home.  The following could be performed during home visits: 
blood sample collection, vital signs check, weight, collection of adverse events, 
concomitant medications, and significant life events or other information, as appropriate. 
The exact timing of all study assessments (e.g., PK or PD blood sampling) may be 
shifted depending on emergent data, but the total number of assessments will not 
change, unless required to ensure the safety of a patient (e.g., after a dose change). 
Unless otherwise stated, the age at screening determines which assessments will be 
conducted throughout the entire study period (e.g., MFM, RULM and HFMSE in patients 
 2 years vs. BSID-III and HINE in patients  2 years). 
4.6.1.1 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol and drugs of abuse, all medications (e.g., prescription drugs, OTCs, 
herbal or homeopathic remedies, nutritional supplements) and 
physical/occupational/exercise therapy used by the patient within 30 days prior to the 
screening visit. 
Demographic data will include age, sex, and self/caregiver-reported race/ethnicity 
(collecting this information is essential to be able to evaluate the results of this study, 
e.g., in case of PK outliers or important between-subject differences in terms of 
treatment effect). 
4.6.1.2 
Spinal Muscular Atrophy History 
SMA history will be collected at screening as available in the patient’s medical records.  
The collected parameters will include (list is not exhaustive, please refer to the eCRF): 
 
SMA type. 

 
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 
Age of onset. 
 
SMN2 copy number (if available; it will be measured in any case during this study by 
clinical genotyping). 
 
Previous score on functional motor scale (e.g., MFM, ULM/RULM, HFSME, 
BSID-III), and/or disability scale (e.g., Brooke, Vignos). 
 
Current level of function and highest motor function achieved (i.e., sitting without 
support, rolling, crawling, standing, walking). 
 
History of previous enrollment in Study BP29420 (Moonfish) with the splicing 
modifier RO6885247 or previously treated with nusinersen, AVXS-101, or olesoxime 
(e.g., compound, duration). 
 
History of scoliosis or hip surgery (if applicable). 
 
4.6.1.3 
Anthropometric Measurements 
Anthropometric measurements will be performed at the timepoints specified in the SoAs 
as described below: 
 
For patients aged 6 months to  2 years (infants), body weight will be measured to 
the nearest 100 g using an appropriate scale.  For patients aged 211 years, body 
weight will be measured to the nearest 100 g.  For patients aged 1260 years, body 
weight will be measured to the nearest kilogram. 
 
For wheelchair-bound patients, weight of the patient and the wheelchair will be 
obtained with a wheelchair balance scale with the patient in the wheelchair.  Then, 
the wheelchair will be weighed by itself and subtracted from the total weight. For 
lighter patients, the caregiver may carry the patient and their combined weight 
measured, followed by the caregiver being weighed and subtracted from the total 
weight. 
 
Patients able to stand will be weighed directly on a standard scale. 
 
The patient’s height will be measured or derived from ulna length to the nearest 
centimeter as follows: 
 
For all patients who are able to stand, height will be measured while standing using 
a stadiometer, with at least three independent measurements, which will be 
averaged. 
 
For patients unable to stand for the duration of the measurement e.g., have too 
many contractures, height will be derived from the measurement of ulna length. 
– 
Ulna 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 to 110, palm facing 
downwards and fingers extended but together. 
 
For very young children, height will be measured with the child in lying position 
using an inflexible length board with fixed headboard and moveable footboard. 
– 
When a patient’s height can no longer be assessed by a fixed board and the 
patient is unable to stand (e.g., because the patient is longer than the fixed 

 
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board or due to scoliosis/contractures), the patient’s height will be derived from 
ulna length to the nearest centimeter as described above. 
 
The method of height measurement should be kept consistent for as long as 
possible. 
 
Body mass index (BMI) will be derived.  See the SoAs for timepoints (Appendix 1A, 
Appendix 1B, Appendix 3A and Appendix 3B). 
For patients aged  5 years only, head circumference will be measured to the nearest 
0.1 cm using a flexible, non-stretchable tape.  The head circumference (or 
occipital-frontal circumference) is measured around the widest part of the head from the 
most prominent point on the back of the head (occiput) to the most prominent part of the 
forehead between the eyebrows.  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. 
For patients aged  2 years only, chest circumference will be measured to the nearest 
0.1 cm using a flexible, non-stretchable tape 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 for children aged 
6 months to  2 years (see Section 6.6). 
4.6.1.4 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, neck and lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  
The physical examination will NOT include pelvic, rectal or breast exams except for 
Tanner staging, if needed. 
Any abnormality identified at baseline should be recorded on the General Medical 
History eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient’s notes.  New or worsened clinically significant abnormalities should 
be recorded as adverse events on the Adverse Event eCRF. 
4.6.1.5 
Neurological Examination 
A detailed neurological examination focusing on mental status, behavioral and cognitive 
assessments will be performed in all patients at the timepoints specified in the SoAs 
(Appendix 1A, Appendix 1B, Appendix 3A and Appendix 3B). 

 
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The examination will be performed by asking questions to the patient and/or the patient's 
caregiver as well as observing the behavior of the patient in general and while 
performing certain tasks.  Questions and tasks will be adapted to the age and motor 
ability of the patient and may include the following: 
 
For very young patients, according to the Investigator's discretion: observing 
reaction to a sound, speech development, shifting attention to a newly introduced 
toy, observing the patient interact with the parent/caregiver 
 
For older patients: examination of social interaction (school, friends, activities, or 
job, as appropriate), memory (e.g., with short word recall), reasoning and language, 
drawing skills, etc. 
 
4.6.1.6 
Tanner Staging 
Tanner staging will be determined at the baseline, Month 12 and subsequent yearly 
visits in all patients aged from 917 years of age at screening or following their 9th 
birthday if enrolled prior to age 9.  Once a patient reaches stage 5, Tanner staging no 
longer needs to be performed. 
Tanner staging criteria will be provided to the sites prior to study start. 
4.6.1.7 
Menstrual Status 
For female patients, menstrual status during the study will be collected as appropriate.  
Once menstruation is confirmed, the patient must undergo pregnancy testing as outlined 
in Appendix 1. 
4.6.1.8 
Vital Signs 
Blood pressure (BP), pulse rate, respiratory rate and body temperature (oral or 
tympanic) will be recorded at the timepoints specified in the SoAs. 
Vital signs will be obtained while the patient is in a semi-supine/supine position after the 
patient has been resting for approximately 5 minutes.  Vital signs should be measured 
prior to blood draw or at least 10 minutes after the last blood draw. 
BP, pulse rate and respiratory rate should be obtained in a quiet room at a comfortable 
temperature, with the patient's arm unconstrained by clothing or other material.  The 
patient should be asked to remove all clothing that covers the location of cuff placement.  
All measurements will be obtained from the same arm and, with the appropriate cuff 
size, using a well-calibrated automatic instrument with a digital readout, throughout the 
study (the “ideal” cuff should have a bladder length that is 80% and a width that is at 
least 40% of arm circumference [a length-to-width ratio of 2:1]).  The individual should be 
comfortably in a semi-supine/supine position, with the legs uncrossed. 
In pediatric patients (aged 17 years and below), at screening and at every BP 
assessment throughout the study, SBP and DBP percentiles for age should be 

 
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determined using the Centers for Disease Control and Prevention (CDC) tables, which 
require to first determine patient’s percentile for stature using the CDC growth charts. 
Both the CDC BP percentiles tables and growth charts will be provided to the sites prior 
to study start. 
4.6.1.9 
Electrocardiograms 
At each specified timepoint (see Appendices), 12-lead ECG recordings must be obtained 
in triplicate (i.e., three useful ECGs without artifacts 23 minutes apart).  The average of 
the three readings will be used to determine ECG intervals (e.g., PR, QRS, QT).  
Whenever possible, the same brand/model of a standard high-quality, high-fidelity 
electrocardiograph machine equipped with computer-based interval measurements 
should be used for each patient.  The conditions should be as close as possible to 
predose timepoints; this includes but is not limited to food intake, activity level, stressors, 
and room temperature. 
To minimize variability, it is important that patients be in a resting position for 
 10 minutes prior to each ECG evaluation.  Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate.  Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording.  ECGs should be performed prior to any 
scheduled vital sign measurements and blood draws.  The timing of 12-lead ECG 
recordings and mealtimes should be consistent throughout all study visits with multiple 
ECG recordings (e.g., Day 1 and Weeks 4 and 13).  In some cases, it may be 
appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality. 
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 laboratory. 
ECG characteristics, including heart rate, QRS duration, and PR, and QT intervals, will 
be recorded on the eCRF.  QTcB (Bazett’s correction; Phan et al 2015), QTcF 
(Fridericia’s correction) and RR will be calculated by the Sponsor in the eCRF.  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. 

 
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4.6.1.10 
Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts.  Laboratory safety tests shall be collected at timepoints specified 
in the SoAs (Appendix 1A, Appendix 1B, Appendix 3A and Appendix 3B).
At any time and as described in Section 4.6.3, safety laboratory samples
(i.e., hematology, blood chemistry, coagulation) will be given priority over any other 
sample, such that the volume of blood taken at any single timepoint will not exceed
1 mL/kg (patients aged 260 years) or 1.5 mL/kg (patients aged 6 months to  2 years), 
and the volume collected over any 8-week period throughout the study will not exceed
4 mL/kg (patients aged 260 years) or 4.5 mL/kg (patients aged 6 months to  2 years). 
For infants only, use of microcollection method to collect safety laboratory samples 
should always be favored to limit the amount of blood collected.
Additional blood or urine 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’s safety.
Where the clinical significance of abnormal laboratory results is considered uncertain, 
screening laboratory tests may be repeated before enrollment to confirm eligibility.  If 
there is an alternative explanation for a positive urine test for drugs of abuse,
e.g., previous occasional intake of a medication or food containing for example codeine, 
benzodiazepines or opiates, the test could be repeated to confirm washout.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up 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.
Samples for the following blood and urine laboratory tests will be collected as specified
in the SoAs (Appendix 1A, Appendix 1B, Appendix 3A and Appendix 3B) and sent to the 
laboratory for analysis.  Instruction manuals and supply kits will be provided for all
central laboratory assessments.  Through the duration of the study, safety laboratory 
assessments will be performed at the local laboratory for patients aged  2 years at 
screening and at the central laboratory for patients aged  2 years at screening.
 
Hematology: Hemoglobin, hematocrit, erythrocytes (RBC), platelets, leukocytes
(WBC), differentials (counts): neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, reticulocyte count.
 
Coagulation: prothrombin time (expressed as INR) and activated partial 
thromboplastin time (aPTT).  Venous blood collection is required for coagulation.
Coagulation should not be assessed for a given visit if venous blood cannot be 
drawn after two attempts.

 
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 
Blood chemistry: 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and 
conjugated bilirubin, alkaline phosphatase (ALP), gamma-glutamyl-transferase 
(-GT), creatine phosphokinase (CPK), albumin, creatinine, urea nitrogen, total 
protein, sodium, chloride, calcium, bicarbonate, phosphate, potassium, 
triglycerides, total cholesterol, glucose, C-reactive protein (CRP), amylase, 
lipase. 
 
Thyroid hormones (free T4 and thyroid stimulating hormone [TSH]; at the time of 
blood chemistry sampling at selected timepoints, see Appendix 1A and 
Appendix 1B) (for patients aged 260 years) 
 
Hormone: estradiol, follicle-stimulating hormone, luteinizing hormone in female 
patients of childbearing potential 
 
Pregnancy test 
All women of childbearing potential (including those who have had a tubal 
ligation) will have blood or urine pregnancy tests at the timepoints specified in 
the SoAs.  If a urine pregnancy test is positive, it must be confirmed by a blood 
pregnancy test. 
 
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination, if clinically significant positive results from the dipstick 
(sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria) (for patients aged 
 2 years at time of assessment). 
 
Drugs of abuse will be measured in urine: cannabinoids, amphetamines, 
methamphetamines, opiates, methadone, cocaine, benzodiazepines, phencyclidine, 
tricyclic antidepressants, and barbiturates (for patients aged 1260 years). 
 
Alcohol will be measured in urine (for patients aged 1260 years). 
 
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. 
When 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. 
4.6.1.11 
Ophthalmological Assessments and Examination 
Ophthalmological assessments are no longer performed starting with Protocol 
Version 5.  Assessments performed under Protocol Versions 1-4 inclusive are described 
below. 
Ophthalmological assessments will be performed at timepoints specified (refer to 
Appendix 5 in Protocol Version 4).  Based on the review and assessment of the 

 
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cumulative safety data of all patients in clinical trials for risdiplam, the type and 
frequency of ophthalmology assessments have been modified once the Week 52 visit 
has been completed.  Details of the changes to the ophthalmological assessments are 
described in this section.  The details of the visual tests will be included in a separate 
Central Reading Center manual.  An Ophthalmologist or other similarly trained person, 
trained and certified to perform the study-specific ophthalmological assessments will 
perform the ophthalmological assessments in all patients. 
Central Reading 
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. 
For Adults and Children Aged  10 Years 
Ophthalmological assessments include slit lamp examination for assessment of the 
anterior and posterior segment including the cornea, anterior chamber, lens and the 
fundus (indirect ophthalmoscopy with e.g., 60 and 90 diopter lenses to examine the 
macula, optic nerve, mid- and peripheral areas).  During selected visits, the intraocular 
pressure will be measured using standard techniques such as Goldmann tonometry or 
non-contact tonometry.  The frequency of intraocular pressure measurement has been 
reduced to occur only at Screening and Week 52 visits.  Once the Week 52 visit has 
been completed, measurement of intraocular pressure and fundus photography will no 
longer be performed.  The remaining ophthalmology assessments will be performed 
every 6 months following the Week 52 visit.  The method of assessment must remain 
constant for each patient throughout the study. 
Fundus Photography (up to and including Week 52) 
Seven-field or wide-field fundus photography (FP) will be performed at the study sites by 
trained and Central Reading Center-certified personnel.  Where both 7-field and 
wide-field devices are available, wide-field FP should be performed.  After a first 
unsuccessful attempt, an image of the fundus may be captured during funduscopy if 
possible. 
Visual Acuity Tests 
Best corrected visual acuity (BCVA) 
BCVA will be measured using the ETDRS or equivalent charts at a distance of 4 meters. 
The eye chart has a series of letters, with the largest at the top.  As the person being 
tested reads down the chart, the letters gradually become smaller.  The chart will be 

 
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standing, at 4 meters from the patient’s eyes.  These sheets will be considered source 
data and scores from these sheets will be transcribed on the eCRF. 
Visual Field Test - Automated Static Threshold Perimetry 
Visual fields will be measured using automated perimetry (e.g., Humphrey Field Test 
Analyzer) with the 24-2 SITA fast program.  Each visual field will be assessed centrally.  
In case of any clinically relevant abnormality, the patient should be further examined by 
an ophthalmological specialist.  Visual field data will be printed out and stored.  After a 
first unsuccessful attempt, threshold perimetry may be replaced by simple visual field 
testing such as easier perimetry protocols or, as a last resort, confrontation visual field 
testing if perimetry is not possible. 
SD-OCT 
Spectral domain-optical coherence tomography provides both qualitative (morphology 
and reflectivity) and quantitative (thickness, mapping and volume) analyses of the 
examined tissues in real time. Each SD-OCT will be graded as normal, or abnormal.  If 
abnormal, the character of the abnormality will be noted (e.g., changes in retinal 
thickness, edema, cystoid or atrophic changes, detection of fluid within the retinal layers, 
macular holes, vitreo-macular traction) and the degree of abnormality.  Additionally, 
every attempt should be made to capture additional images after up, down, left, and right 
gaze. 
For Children Aged 2 to10 Years 
Examinations will be carried out by an experienced pediatric ophthalmology specialist, a 
pediatric ophthalmologist, or neuro-ophthalmologist.  The frequency of intraocular 
pressure measurement has been reduced to occur only at Screening and Week 52 
visits.  Once the Week 52 visit has been completed, measurement of intraocular 
pressure and fundus photography (FP) will no longer performed.  The remaining 
ophthalmology assessments will be performed every 6 months following the Week 52 
visit.  Ophthalmic examinations include the following: 
 
Bruckner Test. 
 
Red reflex. 
 
Fix and follow test. 
 
Cover-uncover test. 
 
Simple visual field test.  
 
Intraocular pressure (tonometry or digital palpation of globes) (Screening and 
Week 52 only). 
 
Visual acuity (adapted based on age and neurological development). 
 
Retinal examination (dilated or not) including slit lamp examination/ophthalmoscopy 
(including anterior and posterior segment, fundus, optic nerve). 

 
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 
Imaging: SD-OCT (including up, down, left, and right gaze images whenever 
possible) and FP (after a first unsuccessful attempt, an image of the fundus may be 
captured during funduscopy if possible).  Fundus photography up to and including 
Week 52 only. 
 
For Children Aged  2 Years 
Examinations will be carried out by a pediatric ophthalmologist or neuro-ophthalmologist 
with the support of a pediatric ophthalmology imaging specialist.  Once the Week 52 visit 
has been completed, FP will no longer performed.  The remaining ophthalmology 
assessments will be performed every 6 months following the Week 52 visit.  
Ophthalmologic examination and retinal imaging include: 
 
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: including but not limited to eyelids, conjunctiva, sclera, 
cornea light reflex. 
 
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. 
 
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 (including slit lamp / ophthalmoscope of 
anterior and posterior segments including assessment (with or without dilation) of 
the retina and optic nerve). 
 
OCT imaging will be recorded with the Envisu hand-held device from Bioptigen Inc. 
(or other handheld OCT device available and 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. 
 
Color FP (up to and including Week 52 only). 
 
The details of the visual tests will be included in a separate Central Reading Center 
manual. 
4.6.1.12 
Nutritional Check 
Nutritional assessment will be performed for all patients at the timepoints indicated in 
Appendix 1A, Appendix 1B, Appendix 3A and Appendix 3B and will include: 
 
Determination of BMI, from body weight and height or head to chest circumference 
ratio from anthropometric measurements (Section 4.6.1.3). 

 
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 
Nutritional status interview of the patient or caregiver (as appropriate), including 
questions about ability to swallow, type of food swallowed, and level of solid food 
intake. 
 
Based on this assessment, specific nutritional advice may be given individually to the 
patients by the Investigator or Nutritionist.
4.6.1.13 
Pharmacokinetic Assessments
Blood for determination of plasma concentrations of risdiplam, and its metabolite(s) as 
applicable, will be collected as detailed in Appendix 2 and Appendix 4.
Plasma concentrations of risdiplam will be measured by a specific validated LC-MS/MS 
assay.  Metabolites may be measured by a specific validated LC-MS/MS assay, or other 
methods as appropriate, and PK samples may also be used for exploratory metabolite 
identification or measurement of olesoxime concentration in patients previously treated 
with olesoxime, if deemed necessary.
PK sampling must be attempted first utilizing venous blood collection.  If venous blood 
cannot be drawn after two attempts, capillary blood collection may be attempted as a 
secondary option upon agreement with the Sponsor.
PK samples will be destroyed no later than 5 years after the date of the final Clinical 
Study Report.
4.6.1.14 
Plasma Protein Binding
A venous blood sample will be collected at screening from patients aged  1 year to 
measure plasma protein binding, i.e., to measure the free fraction of the study drug. 
Results for a patient must be available and checked by the Sponsor before any study 
drug is administered to the patient.
Plasma protein binding (i.e., free fraction, fu) may also be measured from the PK 
samples collected during the study.
The measurement of plasma protein binding may be stopped during the study, if judged 
as no longer necessary on the basis of accumulated data from this and other ongoing 
studies.
4.6.1.15 
Fluid Pharmacodynamic Assessments
The following fluid PD assessments will be performed as detailed in SoAs (see 
Appendices 14).
However, should the total blood volume to be collected at any timepoint according to 
these SoAs exceed 1 mL/kg (patients aged 260 years) or 1.5 mL/kg (patients aged 
6 months to  2 years), or the volume collected over any 8-week period throughout the
study exceeds 4 mL/kg (patients aged 260 years) or 4.5 mL/kg (patients aged 6 months

 
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to  2 years) the blood sample prioritization described in Section 4.6.3 should be 
followed. 
 
In vivo splicing modification of SMN2 mRNA in blood 
Whole blood samples will be taken from every patient at the timepoints 
specified in the SoAs (see Appendices 14) to measure in vivo splicing 
modification of SMN1, SMN2 FL, and SMN7 mRNA during the course of the 
study.  In addition, housekeeping genes for the quantitative analysis of RNA will 
be measured.  Additional mRNA may be used for exploratory analysis/assay 
development related to SMA, including, but not limited to, pathways related to 
SMN function and treatment response. 
 
SMN protein levels 
Blood for SMN protein analysis will be collected from every patient. 
 
Mandatory exploratory biomarkers assessing treatment response (for patients aged 
1260 years)  
Serum for the analysis of exploratory biomarkers related to SMA or to the 
response from treatment (e.g., muscle damage or IGF system) will be collected 
from patients aged 1260 years at the timepoints specified in the SoA 
(Appendix 1). 
 
Based on continuous analysis of the data in this study and other studies, any sample 
type for PD assessments may be stopped at any time if the data from the samples 
collected does not produce useful information. 
These samples will be destroyed no later than 5 years after the date of the final clinical 
study report 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. 
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual. 
4.6.1.16 
Digital Biomarker Assessment 
Digital biomarker assessments ceased to be performed during 2022 (see amendment 
rationale).  Assessments performed under Protocol Versions 1-4 inclusive are described 
in Protocol Version 4. 
4.6.1.17 
Clinical Genotyping Sample 
A single mandatory whole blood sample will be taken for DNA extraction from every 
patient, at the timepoint indicated in the SoAs (Appendix 1A, Appendix 1B, Appendix 3A 
and Appendix 3B).  The DNA will be used to determine the copy number of SMN2 and 
may also be used to confirm the SMN1 mutation, deletion or any other modifications of 
the SMN genes. 

 
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The clinical genotyping samples may be used for additional exploratory analysis/assay 
development related to SMA including, but not limited to, mitochondrial DNA and to 
genes related to drug metabolizing pathways, SMN function, severity of the disease or 
treatment response.  These samples will be destroyed no later than 5 years after the 
date of the final clinical study report.  Data arising from clinical genotyping will be subject 
to the confidentiality standards described in Section 8.4.  For sampling procedures, 
storage conditions, and shipment instructions, see the Sample Handling and Logistics 
Manual. 
4.6.1.18 
Functional Motor and Motor Development Assessments 
Functional motor and motor development assessments will be performed as detailed in 
the SoAs (see Appendix 1A, Appendix 1B, Appendix 3A and Appendix 3B).  The MFM, 
RULM, HFMSE, BSID-III, and HINE may be video recorded for quality assessment by 
trainers.  These recordings will not be part of the clinical database.  These videos may 
be anonymized and accessible by the Sponsor and Health Authorities.  The MFM, 
RULM and HFMSE will be conducted in patients aged  2 years.  The BSID-III and HINE 
will be conducted in patients aged 6 months to  2 years. 
Patients who are unable to perform or complete one or several of the functional motor 
and motor development assessments may still participate in the study. 
Motor Function Measure 
The MFM (Bérard et al 2005) is an ordinal scale constructed for use in patients with 
neuromuscular disorders. 
The scale comprises 32 items that evaluate physical function in three dimensions: 
 
D1 (13 items) evaluates functions related to standing and transfer. 
 
D2 (12 items) evaluates axial and proximal function in supine and sitting position on 
mat and chair (3/12 items evaluate arm function with the patient seated on a chair). 
 
D3 (7 items) evaluates distal motor function. 
 
The scoring of each task uses a 4-point Likert scale based on the patient’s maximal 
abilities without assistance:  
 
0: cannot initiate the task or maintain the starting position 
 
1: performs the task partially 
 
2: performs the task incompletely or imperfectly (with compensatory/uncontrolled 
movements or slowness) 
 
3: performs the task fully and “normally.” 
 
The 32 scores are summed and then transformed onto a 0-100 scale to yield a total 
score expressed as the percentage of the maximum possible score (the one obtained 
with no physical impairment); the lower the total score, the more severe the impairment. 

 
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Strong evidence of reliability (intra-class correlation coefficients ranging from 0.96-0.99 
for the total and dimension scores for both intra-rater and inter-rater reliability) and 
validity (Spearman rank order correlation coefficients ranging from 0.85 to 0.91 with 
other functional measures including Vignos grade and Brooke grade) has previously 
been demonstrated (Bérard et al 2005). 
The MFM is free, available in several languages including English, German, Italian, 
French, and Dutch.  Users’ manual and scoring sheet will be provided to the sites prior 
to study start. 
The full MFM-32 will be administered to all patients aged  2 years.  The scale will be 
administered by a trained Physiotherapist or other suitably qualified professional who 
has received training on the administration of the MFM, following the instructions in the 
MFM users’ manual.  If possible, the same assessor should follow the patient throughout 
the study.  Scores will be recorded on the scoring sheet and on the eCRF and maximal 
score will be derived. 
Revised Upper Limb Module 
The RULM is a scale that assesses specifically the motor performance of the upper 
limbs in SMA patients.  It consists of twenty items that test proximal and distal motor 
functions of the arm in patients with SMA.  It is easy to use, measures functions related 
to everyday life and is applicable to children starting from 30 months of age. 
The first entry item is scored from 0 (no useful function of hands) to 6 (can adduct both 
arms simultaneously in a full circle until they touch above the head).  This item serves as 
a functional class identification but does not contribute to the total score.  
Eighteen of the tasks in the RULM are scored, with: 
 
0: cannot complete task independently 
 
1: modified method but can complete task independently 
 
2: completes task without any assistance 
 
The remaining task is scored as a can/ cannot score with 1 as the highest score.  The 
scores for all tasks, except the first entry item, are summed and can range from 0 (no 
tasks completed) to 37 (all tasks independently completed). 
A users’ manual and scoring sheet will be provided to the sites prior to study start.  The 
scale will be administered by a trained Physiotherapist or other suitably qualified 
professional who has received training on the administration of the RULM according to 
the users’ manual; scores will be recorded on the scoring sheet and on the eCRF and 
the total score will be derived. 

 
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The Hammersmith Functional Motor Scale Expanded 
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.  Similar to the MFM, 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 a 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), FVC (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 study start.  The 
scale will be administered by a trained Physiotherapist or other suitably qualified 
professional 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. 
Bayley Scales of Infant and Toddler DevelopmentThird Edition 
The Bayley Scales of Infant and Toddler DevelopmentThird Edition (BSID-III) is the 
current version of the most extensively used measure of infant and toddler development 
in clinical and research practice.  The BSID were first published by Nancy Bayley in The 
Bayley Scales of Infant Development (1969) and have been used extensively worldwide 
since then to assess the development of infants.  Compared to the previous version, the 
Third Edition of the BSID, published in 2006 (Bayley 2006), was improved by updating 
normative data, strengthening psychometric qualities and changing some items to make 
administration and scoring easier and more meaningful. 
BSID data reflect the U.S. population in terms of race, ethnicity, infant gender, education 
level of parents, and demographic location of the infant.  The BSID was standardized in 

 
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1,700 infants, toddlers, and preschoolers between 1 and 42 months of age.  A 
supplemental study has also demonstrated strong measurement properties for the 
BSID-III in 221 infants in the United Kingdom and Ireland.  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 scales (cognitive, motor, 
language) are administered with child interaction and 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 gross motor scale of the BSID-III will be used as an outcome measure 
to assess attainment of motor milestones; other BSID-III scales will not be used.  The 
test, which is expected to take about 25 minutes to be administered in this population, is 
assessing the following: static positioning (e.g., head control, sitting), dynamic 
movement including locomotion (e.g., crawling), quality of movement (e.g., kicking), 
balance and motor planning. 
Considering the population of this study, the test will be administered in a modified way 
compared to the standard administration of the BSID-III as described in the BSID-III 
manual, e.g., patient’s age will not be used as the starting criteria for testing and the 
order of item administration may be changed.  The standardized instrument kit will be 
used and the test will be administered by an experienced clinician specifically trained to 
the test procedures, which will be described in a separate manual. 
During the OLE phase of the study, only the following items from the BSID-III full gross 
motor scale will be assessed: 
 
Head control:  
– 
Item 9 – Controls head while upright, 15 seconds 
 
Rolling: 
– 
Item 14 – Rolls from side to back 
– 
Item 20 – Rolls from back to side 
 
Sitting: 
– 
Item 16 – Sits with support briefly 
– 
Item 19 – Sits with support 30 seconds 
– 
Item 22 – Sits without support 5 seconds 
– 
Item 26 – Sits without support 30 seconds 

 
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 
Standing  
– 
Item 33 – Supports weight 
– 
Item 40 – Stands alone 
 
Walking 
– 
Item 37 – Walks with support 
– 
Item 42 – Walks alone 
 
Hammersmith Infant Neurological Examination – Module 2 
The HINE is a neurologic examination initially designed to evaluate infants between 
2 months and 24 months of age.  Scores are assigned to 26 items assessing different 
aspects of neurological 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. 
4.6.1.19 
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 trained Physiotherapist or other 
suitably qualified professional who has received training on the administration of the 
6MWT, assisted by an additional follower to ensure patient safety during the tests. 
Patients must be aged  6 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 m in 
order to complete this test.  It will be performed with minimum verbal encouragement, 
according to the American Thoracic Society (ATS) guidelines (ATS 2002).  The 

 
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evaluator and follower keep the patient on course, let the patient know how long they 
have left to walk, and ensure the patient chooses his or her own pace for the whole 
duration of the test.  The course is a 25-m linear course in a quiet corridor at least 30-m 
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 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. 
Falls, if any, will also be recorded. 
4.6.1.20 
Pulmonary Function Testing 
Pulmonary testing will be performed as detailed in the SoA (see Appendix 1). 
Spirometry 
For patients aged  6 years, hand-held spirometry will be performed according to the 
manual of operations.  The test will be performed a minimum of three times while the 
patient is in a sitting position. 
If the patient reaches 6 years of age at any time during the 30-day screening period, the 
patient should have spirometry performed during the screening visit. 
Spirometry data will be electronically transferred from the investigational sites to Morgan 
Scientific where the data will be verified for quality.  The spirometry data, including the 
following measures, will then be electronically loaded in to the study database: 
 
FVC 
 
FEV1 
 
PCF 
 
Patients who are unable to perform or complete the pulmonary function testing 
assessments may still participate in the study. 
Sniff Nasal Inspiratory Pressure 
The SNIP is a volitional, non-invasive test of inspiratory muscle strength that has been 
successfully applied to children  2 years of age.  Advantages include the simplicity of 
the maneuver and the absence of a mouthpiece, which is particularly helpful for patients 
with SMA, who may have bulbar weakness.  SNIP also has the advantage of measuring 
inspiratory pressure during a natural maneuver that is easily performed even by young 
children with neuromuscular disorders.  Based on the shape of the normal 
pressurevolume curve, a loss of respiratory muscle strength is expected before a fall in 
volume capacity and other lung volumes.  SNIP has been shown to decline in both SMA 

 
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Type 2 and 3 patients, with an annual decline of 5.4  6.3% and 6.4  8.0%, respectively 
(Khirani et al 2013).  It is therefore plausible that SNIP measurement may detect the 
respiratory muscle strength decrease earlier in the disease or in younger children than 
would other respiratory function tests. 
The SNIP test is performed according to the manual of operations. 
At least three valid measurements must be obtained from each patient aged  2 years. 
SNIP data will be electronically transferred from the investigational sites to a third party 
vendor where the data will be verified for quality.  The SNIP data will then be 
electronically loaded in to the study database. 
4.6.1.21 
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinical-rated tool used to 
assess the lifetime suicidality of a patient (C-SSRS baseline/screening) as well as any 
new instances of suicidality (C-SSRS since last visit).  The structured interview prompts 
recollection of suicidal ideation, including the intensity of the ideation, behavior, and 
attempts with actual/potential lethality.  A modified and reduced pediatric version exists 
that has been successfully applied in children with various psychiatric disorders that do 
not involve cognitive impairment (Food and Drug Administration [FDA] 2012).  The 
suggested age range for this pediatric version is from middle childhood (typically, around 
age 7) through onset of adolescence (typically, through age 11). 
In this study, the C-SSRS will be collected at baseline and at the timepoints indicated in 
the SoA in patients aged  6 years at time of assessment, using the appropriate version 
according to the patient’s age.  It will be completed by a member of the site staff who 
has received appropriate training after an interview with the patient and additionally for 
children, with the parent attending the visit. 
4.6.1.22 
SMA Independence Scale (SMAIS) 
The SMAIS was developed specifically for SMA in order to assess function-related 
independence.  The SMAIS contains 29 items, assessing the amount of assistance 
required from another individual to perform daily activities such as eating, or transferring 
to/from their wheelchair.  Each item is scored on a 04 scale (with an additional option to 
indicate that an item is non-applicable).  Item scores are summed to create the total 
score.  Lower scores indicate greater dependence on another individual.  The SMAIS 
will be completed by patients aged  12 years. 
A parent, or caregiver, if no parent is available, should complete the caregiver-reported 
version of the SMAIS about the patient’s level of independence, where possible for 
patients aged  2 years.  This questionnaire assesses the same content as the patient-
reported version described above.  The same caregiver should complete the measure 
throughout the study. 

 
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4.6.1.23 
Samples for Research Biosample Repository 
Overview of the Research Biosample Repository 
The Roche Research Biosample Repository (RBR) is a centrally administered group of 
facilities for the long-term storage of human biologic specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage and analysis of these specimens will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may allow 
for individualized drug therapy for patients in the future. 
Specimens (blood samples) will be collected from patients who give specific consent, 
and assent if applicable, to participate in this optional RBR.  Only patients aged 
1260 years will be invited to participate.  Collected specimens will be used to achieve 
the following objectives: 
 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression. 
 
To increase knowledge and understanding of disease biology. 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition. 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays. 
 
Approval by the Institutional Review Board or Ethics Committee 
Sampling for the RBR is contingent upon the review and approval of the exploratory 
research and the RBR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for RBR sampling, this section 
of the protocol will not be applicable at that site. 
Sample Collection 
The following samples will be collected at the timepoints specified in the SoAs for 
identification of dynamic (non-inherited) biomarkers: 
 
Blood for samples plasma isolation. 
 
Blood samples will be collected for RNA analysis. 
 
The following samples will be collected for identification of genetic (inherited) 
biomarkers: 
 
Blood sample for DNA extraction for genetic biomarker (inherited) discovery and 
validation. 
 
The sample collected for DNA extraction may be used for whole genome sequencing 
(WGS) and other genetic analysis and may be sent to one or more laboratories for 
analysis. 

 
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Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents. 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RBR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the separate laboratory manual. 
RBR specimens will be stored and used until no longer needed or until they are 
exhausted.  The RBR storage period will be in accordance with the IRB/EC-approved 
Informed Consent Form and applicable laws (e.g., Health Authority requirements). 
The repository specimens will be subject to the confidentiality standards described in 
Section 8.4. 
Confidentiality 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche Monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RBR specimens is confidential and may only 
be disclosed to third parties 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. 
Data derived from RBR specimen analysis on individual patients will generally not be 
provided to study Investigators unless a request for research use is granted.  The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication. 
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers.  Patients will not be identified by 
name or any other personally identifying information.  Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or patients unless required by law. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR specimen data will become and remain the exclusive and 
unburdened property of Roche, except where agreed otherwise. 

 
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Consent to Participate in the Research Biosample Repository 
The Informed Consent and Assent Form will contain a separate section that addresses 
participation in the RBR.  The Investigator or authorized designee will explain to each 
patient, and their parent/caregiver if applicable, the objectives, methods, and potential 
hazards of participation in the RBR.  Patients will be told that they are free to refuse to 
participate and may withdraw their specimens at any time and for any reason during the 
storage period.  A separate, specific signature will be required to document a patient’s 
agreement to provide optional RBR specimens.  Patients who decline to participate will 
not provide a separate signature. 
The Investigator should document whether or not the patient, or their parent/caregiver if 
applicable, has given consent/assent to participate by completing the RBR Sample 
Informed Consent eCRF. 
In the event of death or loss of competence of a patient who is participating in the 
Research, the participant's specimens and data will continue to be used as part of the 
RBR. 
Withdrawal from the Research Biosample Repository 
Patients or their parent/caregiver if applicable, who give consent to provide specimens 
for the RBR have the right to withdraw their consent at any time for any reason.  After 
withdrawal of consent, any remaining samples will be destroyed or will no longer be 
linked to the patient.  However, if RBR samples have been tested prior to withdrawal of 
consent, results from those tests will remain as part of the overall research data.  If a 
patient or their parent/caregiver if applicable, wishes to withdraw consent to the testing 
of his or her specimens during the study, the Investigator must inform the Medical 
Monitor in writing of the patient’s wishes through the use of the appropriate RBR Subject 
Withdrawal Form and, must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the Investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from Study BP39054 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient’s withdrawal from the RBR does not 
constitute withdrawal from Study BP39054. 
Monitoring and Oversight 
Specimens collected for the Research Biosample Repository will be tracked in a manner 
consistent with Good Clinical Practice by a quality-controlled, auditable, and 
appropriately validated laboratory information management system, to ensure 
compliance with data confidentiality as well as adherence to authorized use of 
specimens as specified in this protocol and in the Informed Consent Form.  Roche 

 
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monitors and auditors will have direct access to appropriate parts of records relating to 
patient participation in Research Biosample Repository for the purposes of verifying the 
data provided to Roche.  The site will permit monitoring, audits, IRB/EC review, and 
health authority inspections by providing direct access to source data and documents 
related to the samples. 
4.6.2 
Timing of Study Assessments 
4.6.2.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that patients meet all eligibility criteria.  The Investigator will maintain a detailed 
record of all patients screened and to document eligibility or record reasons for 
screening failure, as applicable. 
An Eligibility Screening Form documenting the Investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site. 
Screening and pre-treatment assessments will be performed between 2 to 30 days prior 
to Day 1 (according to the SoAs, see Appendix 1A and Appendix 3A).  An abbreviated 
rescreening (written informed consent, medical history, physical examination, RULM 
[patients aged  2 years], HFMSE [patients aged  2 years], body weight, safety 
laboratory tests, pregnancy test [females of childbearing potential only], urine analysis 
[patients aged  2 years] and inclusion/exclusion criteria) may be allowed under 
circumstances where the patient has passed screening but could not be enrolled within 
the 30-day screening window due to a study halt, logistical, personal, or technical 
reasons.  At no time should the duration between the original screening visit and the 
abbreviated rescreening visit exceed 3 months.  An abbreviated rescreening will only be 
permitted in cases where this poses no safety risk to the patient. 
Patients cannot commence the enrollment procedure until all the entry criteria have been 
fulfilled.  Where the clinical significance of an abnormal screening test result (laboratory 
or any other tests) is considered uncertain, the test should be repeated to confirm the 
result. 
For patients aged  2 years: Due to the high number of assessments, including multiple 
12-lead ECG recordings (for patients aged 1260 years only), pulmonary testing and the 
MFM, it is important that the order of assessments be maintained on Day 1 to minimize 
variability, as follows: adverse events, previous/concomitant medications, confirmation of 
eligibility, enrollment, 1st ECG recording, 2nd ECG recording, 3rd ECG recording, 

 
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physical examination, Tanner staging, vital signs, 4th ECG recording, 
patient/caregiver-reported outcomes, pulmonary testing, MFM, 6MWT and blood 
samples.  Flexibility is given to the site whether to perform the physical examination, 
Tanner staging, vital signs, patient/caregiver-reported outcomes assessment, pulmonary 
testing, MFM, and blood samples after the 3rd or 4th ECG recording.  To minimize 
variability, it is important that patients be in a resting position for  10 minutes prior to 
each ECG evaluation.  If pulmonary testing, MFM, or blood samples are done prior to 
the 4h ECG recording, the following ECG recording should be preceded by a break of at 
least 20 minutes.  The timing of 12-lead ECG recordings and mealtimes should be 
consistent throughout all study visits with multiple ECG recordings (e.g., Day 1 and 
Weeks 4 and 13).  The pulmonary testing, the MFM and the 6MWT should be preceded 
by a break of at least 15 minutes.  Additional breaks are recommended at any other 
times as appropriate for each patient. 
4.6.2.2 
Assessments During Treatment 
Under no circumstances will patients who enroll in this study and who have completed 
treatment as specified, be permitted to re-enroll in the study. 
The study visits when efficacy assessments are performed (see SoAs for timepoints, 
Appendix 1A, Appendix 1B, Appendix 3A and Appendix 3B) will be the most extensive 
visits, including all efficacy assessments in addition to PK, PD, full physical examination, 
and safety assessments. 
For patients aged  2 years, these visits will be conducted over 2 days but can also be 
conducted over 3 days if preferred by the patient (e.g., the physical examination) may 
be conducted on the morning of the day preceding Block 1 or the day after Block 3.  For 
these visits, three blocks of assessments have been identified that must be conducted in 
the order described in Table 2, with Blocks 1 and 2 to be performed on Day 1 and Block 
3 on Day 2.  Flexibility is given to the site for the order of tests within each of these 
blocks.  It is critical that the MFM, the HFMSE, the RULM and the 6MWT are always 
preceded by a break of at least 15 minutes.  Additional breaks are recommended at any 
other time as appropriate for each patient.  
For patients aged 6 months to  2 years, these visits may be conducted either as one 
day visit or over 2 days, whichever is preferred by the parents or caregiver and possible 
for the clinical site.  Table 3 provides guidance for the order in which the assessments 
should be conducted.  Flexibility is given to the site for the order of tests.  However, it is 
critical that the BSID-III is always preceded by a break of at least 15 minutes.  Additional 
breaks, which can include nursing/feeding of the patient (if applicable), are 
recommended at any other time as appropriate for each patient. 
It is also recommended that for a single patient, assessments be conducted in the same 
order throughout the trial. 

 
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Motor function and motor milestone assessments may be delayed to another time or day 
within the visit window if, in the opinion of the investigator or physiotherapist, the patient 
is uncooperative. 
Table 2 
Order and Blocks of Assessments for Patients Aged 2 Years at 
Study Visits when Efficacy Measurements are Performed 
Day 1 
 
Block 1 
 
Collection of adverse events and concomitant therapies 
 
Pulmonary testing including SNIP 
BREAK 
 
MFM (32 item) 
BREAK 
Block 2 
 
ECGs, vital signs 
 
Physical examination 
 
C-SSRS 
Day 2 
 
Block 3 
 
Blood samples or insertion of catheter for blood sampling 
BREAK 
 
SMAIS  
BREAK 
 
HFMSE 
BREAK 
 
RULM 
BREAK 
 
Ambulant patients: 6MWT 
Note: If possible, blood samples should not be scheduled to take place during the HFMSE and 
RULM assessments.  However, if this is not possible, the blood sample should be obtained and 
the patient allowed a break if required, before resuming the assessment. 
 
Patients already enrolled in this study prior to the implementation of the 6MWT, the 
SMAIS and the digital biomarker will complete those assessments for the first time at 
their next visit with the respective assessments being scheduled. 
Table 3 
Order of Assessments for Patients aged  2 Years at Visits When 
Efficacy Measurements Are Performed 
Block 1 
 
ECG, vital signs, physical examination (including weight) 
BREAK 
 
BSID-III 
BREAK 
 
HINE-2 
BREAK 
 
Blood sample (or insertion of catheter) 
 
Dose administration 
 

 
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4.6.2.3 
Assessments at Study Completion/Early Withdrawal Visit 
Patients who complete the study or discontinue study drug early will be asked to return 
to the clinic for a study completion/early withdrawal visit as shown in the SoA 
(Appendix 1B and Appendix 3B).  For patients who reach Week 260 (Year 5), a study 
completion visit will be performed in place of the Week 260 visit. 
4.6.2.4 
Follow-Up 
A follow-up telephone call should occur approximately 30 days after the study 
completion/early withdrawal visit, to collect information on adverse events as outlined in 
Sections 5.5, 5.6, and SoAs (Appendix 1B and Appendix 3B). 
A follow-up telephone call is required for: 
– 
Patients who stop study treatment and do not receive risdiplam IMP through 
continued access (Section 4.4.4) or to receive risdiplam through commercial access 
or post-trial access; 
– 
Patients who stop study treatment and who switch to another treatment for SMA 
within 30 days of stopping risdiplam.  If a patient switches to another SMA 
treatment during the 30 day follow-up period, a telephone call should be performed 
to collect information up to the time that the patient begins the new treatment. 
 
A follow-up telephone call is not required for: 
– 
Patients who continue on risdiplam (through continued access as defined in 
Section 4.4.4, or through commercial access or post-trial access 
– 
Patients who switch to another treatment for SMA immediately after stopping 
risdiplam treatment 
 
4.6.2.5 
Assessments During Continued Access  
If risdiplam is not commercially available to the patient at the time of the Week 260 
(study completion) visit, the patient can continue to receive risdiplam in the study 
until risdiplam is commercially available to the patient or until the patient is eligible 
for post-trial access or until EOS (whichever occurs first) (Section 4.4.4; Appendix 5). 
Any patients continuing to receive risdiplam beyond their Week 260 (study completion) 
visit until the EOS are not required to perform additional study visits.  Risdiplam will 
be provided as per current study procedures.  Only adverse events must continue to be 
reported to maintain minimum study safety reporting requirements.  Therefore, 
investigators should proactively contact those patients every 13 weeks to ensure adverse 
events are reported in the eCRF and document this contact in the patient’s notes.  The 
eCRF should be updated with adverse events and any concomitant medications given 
for the adverse event only. 
Patients with a body weight <20 kg should continue to be weighed to ensure patients 
receive the correct dose for their weight.  Study sites should ensure that weight is 
measured on calibrated scales appropriate for the patient. 

 
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4.6.2.6 
Assessments at Unscheduled Visits 
Assessments as listed in Appendix 1A and Appendix 3A as deemed necessary by the 
Investigator and/or Sponsor and/or iDMC in particular for safety, will be performed at 
unscheduled visits. 
4.6.3 
Prioritization Order for Blood Samples 
Timepoints for blood samples are indicated in Appendices 14.  However, should the 
total blood volume to be collected at any timepoint according to the SoAs exceed 
1 mL/kg (patients aged 260 years) or 1.5 mL/kg (patients aged 6 months to  2 years), 
or the volume collected over any 8-week period throughout the study exceed 
4 mL/kg(patients aged 260 years) or 4.5 mL/kg (patients aged 6 months to  2 years) 
the prioritization order indicated in Table 4 below should be followed. 
Table 4 
Prioritization Order for Blood Samples 
Order 
Samples 
1 
Any safety laboratory samples (scheduled or unscheduled and 
performed at the discretion of the Investigator) 
2 
PK samples 
3 
Samples for SMN protein levels 
4 
Samples for in vivo splicing modification of SMN2 mRNA 
5 
Clinical genotyping 
6 
Samples for exploratory biomarkers (patients aged  12 years only) 
7 
RBR samples (optional, upon specific consent, patients aged 
 12 years only) 
 
4.7 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.7.1 
Patient Discontinuation 
The Investigator has the right to discontinue a patient from treatment with risdiplam or 
withdraw a patient from the study at any time.  In addition, patients have the right to 
voluntarily discontinue study drug or withdraw from the study at any time for any reason.  
Reasons for discontinuation of study drug or withdrawal from the study may include, but 
are not limited to, the following: 
 
Patient withdrawal of consent at any time. 
 
Any medical condition that the Investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study. 
 
Investigator or Sponsor determines it is in the best interest of the patient. 
 
Investigator or Sponsor determines patient non-compliance (including study drug 
administration as recorded in the patient’s diary). 
 

 
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4.7.1.1 
Discontinuation from Study Drug 
Patients must discontinue study drug if they experience any of the following: 
 
Pregnancy. 
 
Events, as described in Section 5.2.3 
 
Unable to continue to comply with study requirements. 
 
Patients discontinuing study drug prematurely will be asked to return to the clinic for a 
study completion/early withdrawal visit (Section 4.6.2.3) and will be followed with a 
telephone call from the site approximately 30 days after this last visit (Section 4.6.2.4).  
The primary reason for premature study drug discontinuation should be documented on 
the appropriate eCRF. Patients who discontinue study drug prematurely will not be 
replaced. 
During the study a patient may need to stop administration of study drug, e.g., due to 
immediate need for surgery, required treatment with a drug known to or suspected to 
have an interaction with risdiplam, etc.  The Investigator must discuss these situations 
with the Sponsor to determine if the patient should withdraw from the study or 
temporarily discontinue study drug. 
4.7.1.2 
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. 
Patients will not be followed for any reason after consent from participation in the study 
has been withdrawn. 
When a patient voluntarily withdraws from the study, or is withdrawn by the Investigator, 
samples collected until the date of withdrawal will be analyzed, unless the patient 
specifically requests for these to be discarded or local laws require their immediate 
destruction.  A patient's withdrawal from Study BP39054 does not, by itself, constitute 
withdrawal of specimens donated to the Research Biosample Repository. 
Patients who withdraw from the study, whether for safety or other reasons, will not be 
replaced. 
4.7.2 
Study and Site 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. 
 

 
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The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program. 
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the ICH guideline for Good Clinical Practice 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol‑specified safety laboratory assessments; measurement of 
protocol-specified vital signs, ECGs; and 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. 
5.1.1 
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), except as described in 
Section 5.3.5.9. 
 
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). 
 

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5.1.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 

Fatal (i.e., the adverse event actually causes or leads to death).

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).

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to
study drug.

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 (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria (e.g., NCI CTCAE criteria; 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). 
5.1.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious 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 for reporting instructions).  Adverse events of special interest for 
this study include the following: 

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or
clinical jaundice, as defined in 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 

 
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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. 
 
5.2 
SAFETY PLAN 
The Safety Plan considers observations made in nonclinical investigations, including 
Good Laboratory Practice toxicology studies in rat and cynomolgus monkey, and the 
observations made in clinical trials.  Hypothetical considerations are included in the 
interpretation of nonclinical and clinical data. 
The exposure cap of a mean AUC0-24h,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.  This exposure cap also corresponds to the NOAEL 
observed for toxicities caused in adult and juvenile rats.  Only effects on testes, i.e., on 
male fertility, were observed at exposure levels below those observed in another study in 
juvenile/young rats.  Male patients and/or their parents or caregivers will be informed 
accordingly about this potential adverse consequence of treatment with the study drug.  
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 toxicity studies and in monkey 
toxicity studies, there was no effect on female reproductive organs or female fertility.  
Any effects on meiosis and oocyte maturation will be further investigated in a 
pre-postnatal toxicity study in rats (see Risdiplam Investigator’s Brochure). 
5.2.1 
Safety Precautions 
Safety precautions and monitoring measures have been implemented to maximize the 
safeguards for the patients enrolled in this study.  The stopping rules for individuals 
detailed in Section 5.2.3 will be applied in case of specific adverse events. 
Based on observed toxicity in non-clinical studies (see Risdiplam Investigator’s Brochure 
for details), the following safety precautions should be followed for this study: 
 
Male fertility: 
Inform male patients and/or their parents or caregivers about the risk to fertility.  
In circumstances where male patients exposed to study drug desire future 
conception, they will be informed about the time required to recover from 
potential changes in semen parameters based on the duration of a 
spermatogenic cycle. 
 
Possible chromosome damage: 
Strict contraception for female patients and male patients with female partners 
of childbearing potential (Section 4.2.2). 

 
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Male patients will also be reminded of the necessity to respect a minimum 
period of 4 months before trying to conceive or before donating sperm (see also 
contraception requirements in Section 4.2.2). 
 
Effects on bone marrow/hematology:  Assessment of hematological parameters is 
part of the routine monitoring and will be performed throughout the study. 
 
Effects on the developing embryo: 
Studies in animals have shown that risdiplam is teratogenic and fetotoxic. 
Hence, strict contraception is required (Section 4.2.2; see Section 5.4.3 for 
pregnancy reporting requirements).  
 
5.2.2 
Safety Monitoring 
Based on observed toxicity in nonclinical studies (risdiplam Investigator’s Brochure for 
details), the following safety monitoring plan will be conducted in this study: 
 
The study will include frequent triplicate 12-lead ECGs.  ECGs will be time-matched 
with PK samples, on selected PK days to allow PK/QTc analyses and modelling in 
patients aged  12 years. 
 
Follow-up telephone calls (as per the timepoints in Appendix 1A and Appendix 3A): 
– 
Patients (or caregivers of patients, as appropriate) will be called by the 
Investigator or designee to monitor safety and tolerability when not attending 
the clinic.  Assessments will include adverse events, concomitant medication 
review and significant life events. 
 
5.2.3 
Stopping Rules 
While the Investigators, the Roche Clinical Science Leader, the Roche Safety Science 
Leader, the IMC and the iDMC (and any other professional(s) considered necessary to 
consult) will review available data for the individual patients on an ongoing basis, the 
following specific stopping rules for an individual patient are defined a priori: 
 
Patients with any elevated ALT or aspartate aminotransferase (AST) of  3  upper 
limit of normal (ULN), ALP  2  ULN, and associated with an increase in bilirubin 
( 2  ULN) (i.e., a suspected “Hy’s law” which indicates risk of severe/serious liver 
impairment) in the absence of a different explanation. 
 
Significant and clinically relevant changes in laboratory parameters, ECG or vital 
signs which pose an unacceptable risk for the patient. 
– 
NB: Although no cardiovascular signal emerged from safety pharmacology 
studies in animals, or in the clinical study in healthy subjects, a prolongation of 
the QTcF exceeding 500 msec with a repeat ECG within 2 hours confirming the 
QTc abnormality should be promptly reviewed by a cardiologist on the same 
day and before subsequent dosing to evaluate if treatment discontinuation is 
warranted. 
 
Other findings such as a serious adverse event or any other severe adverse event 
that indicate that dosing should be halted. 
 

 
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In addition to the above stopping rules, dosing may be stopped within a subject if safety, 
tolerability, or efficacy data suggest risdiplam is not beneficial for the patient based on 
the clinical judgment of the investigator.  The investigator should then look for the best 
standard of care option available in the country. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The Investigator is responsible for ensuring that all adverse events (see Section 5.1.1 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 to 5.5. 
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 5.1.2 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 records.  Adverse events will then be reported on the 
Adverse Event eCRF as follows: 
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 
(e.g., serious adverse events related to invasive procedures such as biopsies).  Any 
other adverse event should not be reported. 
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until the final follow-up telephone call (if applicable, per 
Section 4.6.2.4) or until final dose of IMP. 
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 felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
 

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5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used to 
assess adverse event severity.  Table 5 below will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 5 
Adverse Event Severity Grading Scale 
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 a 
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 b,c
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death-related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. Based 
on the NCI CTCAE (v4.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (Section 5.4.2 for reporting instructions), per the definition of a serious 
adverse event in Section 5..2. 
d Grade 4 and 5 events must be reported as serious adverse events (Section 5.4.2 for reporting 
instructions), per the definition of serious adverse event in Section 5.1.2. 
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 or 
not 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, considering especially the effects of dose reduction,
discontinuation of study drug, or reintroduction of study drug.

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 
For adverse events, 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 Occurring Secondary to Other Events 
In general, adverse events occurring 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.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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 subsequent fracture, all three 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 of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens.  If the event becomes serious, the Adverse Event eCRF should be updated to 
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A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately 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 
should be reported as an adverse event if it meets any of the following criteria: 
 
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. 
 
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., ALP and bilirubin 5  ULN associated with cholecystitis), only the diagnosis 
(i.e., cholecystitis) 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 if 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
 
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. 


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 BP), 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
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.  
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 a non-serious 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 5.3.1), 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. 
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 
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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, “SMA progression or complication/comorbidity” should be recorded on 
the Death Attributed to Progressive Disease eCRF. 
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 General Medical History and Baseline 
Conditions 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 Spinal Muscular Atrophy”). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.1.2), 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). 
 
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 suffered an adverse 
event. 

–
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 a serious adverse event per se.
–
Hospitalization due solely to the progression of the underlying SMA disease
(hospitalizations are expected and occur frequently in this patient population
due to the nature of the disease).
5.3.5.11 
Overdoses 
Risdiplam may have a narrow therapeutic window.  Based on exposure in animal studies 
at the limits of tolerability, there is evidence that acute or short-term toxicity of risdiplam 
is driven by exposure to free, non-protein bound risdiplam.  Calculations of the 
free-exposure concentrations compared with the exposure associated with the highest 
dose in this study allow estimating that approximately 10-fold higher free-concentrations 
may be associated with life-threatening signs. 
Therefore, administration of the precise dosage must always be ensured. 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF. 
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO or caregiver-reported outcome data 
by the Sponsor, and safety analyses will not be performed using these data.  However, if 
any PRO or caregiver-reported outcome responses suggestive of a possible adverse 
event are identified during site review of these data, the Investigator will determine 
whether the criteria for an adverse event have been met and, if so, will report the event 
on the Adverse Event eCRF. 
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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 
 
Non-serious adverse events of special interest 
 
Pregnancies 
 
The Investigator must report new significant follow-up information for these events 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 IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Investigators will be provided with contact information for the Medical Monitor.  An 
Emergency Medical Call Center will also be available 24 hours per day, 7 days per 
week.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical 
Call Center, will be distributed to investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events and non-serious adverse events of special interest 
(see Sections 5.1.2 and 5.1.3), Investigators should record all case details that can be 
gathered on the Clinical Trial Adverse Event/Special Situations Reporting Form and 
forward this form to the Serious Adverse Event Responsible (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. 

5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Studies in animals have shown that risdiplam is teratogenic and fetotoxic.  Female 
patients of childbearing potential will be instructed to immediately inform the Investigator 
if they become pregnant during the study or within 28 days after the last dose of study 
drug.  A Clinical Trial Pregnancy Reporting Form should be completed by the 
Investigator and submitted to the Sponsor within 24 hours after learning of the 
pregnancy.  Pregnancy should not be recorded on the Adverse Event eCRF.  The 
Investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy. 
5.4.3.2 
Pregnancies in Female Partners of Male Subjects 
Risdiplam is known to affect male germ cells in their development.  This is likely based 
on an interaction with cell cycle genes.  In animals, this effect with the SMN2 splicing 
modifier, risdiplam, has been demonstrated to be reversible.  Thus, male patients are 
advised to not father a child while on treatment and for up to 4 months after cessation of 
treatment.  Male patients will be instructed through the Informed Consent Form to 
immediately inform the Investigator if their partner becomes pregnant during the study or 
within 4 months after the last dose of study drug.  A Clinical Trial Pregnancy Reporting 
Form should be completed by the Investigator and submitted to the Sponsor within 
24 hours after learning of the pregnancy.  Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male patient 
exposed to study drug.  When permitted by the site, the pregnant partner would need to 
sign an Authorization for Use and Disclosure of Pregnancy Health Information to allow 
for follow-up on her pregnancy.  If the authorization has been signed, the Investigator 
should update the Clinical Trial Pregnancy Reporting Form with additional information on 
the course and outcome of the pregnancy.  An Investigator who is contacted by the male 
patient or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; 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.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
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 
POST-STUDY ADVERSE EVENTS 
The Investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 30 days after the last dose of 
study medication).  If the Investigator becomes aware of any other serious adverse 
event occurring after the end of the adverse event reporting period, if the event is 
believed to be related to prior study drug treatment, the event should be reported directly 
to the Sponsor or its designee, either by faxing or by scanning and emailing the Clinical
Trial Adverse Event/Special Situations Reporting Form using the fax number or email 
address provided to Investigators. 

 
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5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious 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. 
The Sponsor has a legal responsibility to notify regulatory authorities about the safety 
of a study treatment under clinical investigation.  The Sponsor will comply with 
regulatory requirements for expedited safety reporting to regulatory authorities (whic h 
includes the use of applicable systems, such as EudraVigilance), IRBs, ECs, and 
investigators. 
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 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to Health Authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary objective of the study is to assess the safety, tolerability, PK, and PD of 
risdiplam in patients previously enrolled in Study BP29420 (Moonfish) with the splicing 
modifier RO6885247 or previously treated with nusinersen, AVXS-101, or olesoxime.  All 
efficacy endpoints are regarded as exploratory. 
A database lock for the analyses of the 12-month safety and exploratory efficacy 
endpoints will occur once the last patient enrolled has either completed his/her 12-month 
assessments or has been withdrawn.  All available safety data will also be reported. 
An additional database lock will occur once the last patient enrolled has either completed 
his/her 24-month assessments or has been withdrawn. 
A database lock will also occur for an interim analysis to perform safety and exploratory 
efficacy analyses of the data to support initial filing and registration of risdiplam. 

 
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Additional database locks may occur in order to perform exploratory efficacy and safety 
analyses of the data in response to information that may emerge during the course of 
the study.  Data from this study will be used to complement the safety information 
contained in the regulatory dossier, and as part of a safety update if requested by Health 
Authorities. 
Final database lock will occur at the study end. 
Full details of the statistical methods will be described within the Data Analysis Plan 
(DAP). 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size was determined by practical considerations and not based on statistical 
power calculations. 
The target sample size is up to 180 SMA patients previously enrolled in Study BP29420 
(Moonfish) or previously treated with nusinersen, AVXS-101, or olesoxime.  With 
180 patients exposed to risdiplam, there is a 92% chance to detect an adverse event in 
at least one patient, assuming that the true underlying adverse event rate is 1.4%. 
Approximately 80 patients who previously received treatment with nusinersen or 
AVXS-101 will be enrolled.  This will enable an initial evaluation of whether the switch 
from nusinersen or AVXS-101 to risdiplam is well-tolerated and will generate initial 
safety, PK, and PD (SMN protein) data for the comparison between treatment-naïve 
patients and patients who previously received nusinersen or AVXS-101. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who were enrolled, discontinued, continuing treatment at the 
time of analysis or 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 POPULATIONS 
6.3.1 
Safety Analysis Population 
All patients who received at least one dose of risdiplam, whether prematurely withdrawn 
from the study or not, will be included in the safety population. 
6.3.2 
Pharmacokinetic and Pharmacodynamic Analysis Populations 
All patients with at least one timepoint with a measurable 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 or 
incomplete which may influence the PK or PD analysis.  Excluded cases will be 

 
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documented together with the reason for exclusion.  All decisions on exclusions from the 
analysis will be made prior to database closure. 
6.3.3 
Intent-To-Treat/ Exploratory Efficacy Analysis Population 
The Intent-To-Treat (ITT) population is defined as all enrolled patients, regardless of 
whether they receive risdiplam or not.  The ITT population will be the primary population 
for all exploratory efficacy analyses. 
6.4 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and other baseline characteristics will be summarized for the ITT 
population using descriptive statistics, means, standard deviations, medians, 
interquartile range and ranges for continuous variables and number and percentages for 
categorical variables, as appropriate.  Baseline will be defined as the last measurement 
prior to enrollment unless specified otherwise in the DAP.  Summaries will be presented 
overall and by previous treatment: RO6885247, nusinersen, AVXS-101, or olesoxime. 
6.5 
SAFETY ANALYSES 
The safety and tolerability 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 suicidal ideation or behavior (C-SSRS). 
 
Incidence of clinically significant findings on ophthalmological examination 
performed under Protocol Versions 1-4 inclusive. 
 
Incidence of clinically significant findings on neurological examination. 
 
Anthropometric examination including weight, height, head and chest 
circumference. 
 
All safety analyses 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 
(i.e., 12-month data for each individual patient) at the time of the 12-month analysis 
reporting event and for all available safety data collected at the time of the analysis. 
Safety data may also be summarized overall and by previous treatment: RO6885247, 
nusinersen, AVXS-101, or olesoxime, as appropriate. 

 
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Analyses required for the IMC or iDMC data review will be performed as described in the 
associated IMC or iDMC Charter. 
6.5.1 
Adverse Events 
The original terms recorded on the eCRF by the Investigator for adverse events will be 
standardized by the Sponsor.  Adverse events will be summarized by mapped term and 
appropriate thesaurus level.  The 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. 
6.5.2 
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. 
6.5.2.1 
Definition of Laboratory Abnormalities 
Laboratory values falling outside the normal range will be labeled “H” for high or “L” for 
low in patient listings of laboratory data. 
6.5.3 
Vital Signs 
Vital signs data will be listed for patients with values outside the normal ranges.  In 
addition, tabular summaries will be used, as appropriate. 
6.5.4 
ECG Data Analysis 
ECG data will be listed for patients with values outside the normal ranges.  In addition, 
tabular summaries will be used, as appropriate. 
Additionally, a time-matched QT profile assessment will be performed in patients 
aged  12 years.  
Categorical summaries by timepoint (predose, 1h, 2h, and 4h) and ‘week’ (Weeks 4 
and 13) of absolute and time-matched change from baseline in QT, QTcF, and QTcB will 
be presented, as well as, summaries for maximum post-dose absolute and 
time-matched changes from baseline in QTcF. 
For the analysis of time-matched change from baseline in QTcF, all subjects in the 
safety population with at least one non-missing value will be included in the analysis.  
The main statistical analysis is a mixed-effects ANOVA model with QTcF, the 

 
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time-matched change from baseline in QTcF, as dependent variable, the fixed effects 
‘timepoint’ (predose, 1h, 2h, and 4h) and ‘week’ (Weeks 4 and 13) and the random 
effects ‘subject’ and ‘subject  week’, the interaction between ‘subject’ and the fixed 
effect ‘week’. 
In addition, time-matched QTcF values and PK data from this study will be pooled with 
time-matched QTcF and corresponding PK values from other risdiplam studies in 
healthy volunteers (Entry-in-Human and PK ethnicity studies) and in patients treated with 
risdiplam to explore the relationship between risdiplam plasma concentrations and QTc 
interval.  This will be performed by fitting a mixed-effects model using all the data across 
the entire range of plasma concentrations to improve the precision of the estimation of 
the QTc effect. 
6.5.5 
Concomitant Medications 
The original terms recorded on the patients’ 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. 
6.6 
EXPLORATORY EFFICACY ANALYSES 
The exploratory endpoints include, but may not be limited to, the following: 
For all patients 
 
Proportion of patients who experience at least one disease-related adverse event by 
Month 12 and Month 24. 
 
Number of disease-related adverse events per patient-year at Month 12 and 
Month 24. 
 
For patients aged 1260 years  
 
Change from baseline in the total score of the patient-reported SMAIS at Month 12 
and Month 24.  
 
For patients aged 660 years old 
 
Change from baseline in FVC at Month 12 and Month 24 
 
Change from baseline in FEV1 at Month 12 and Month 24  
 
Change from baseline in PCF at Month 12 and Month 24  
 
Change from baseline in the 6MWT distance (for ambulant patients only) at 
Month 12 and Month 24 
 
Change from baseline in the percentage change in distance walked in the first 
versus the last minute of the 6MWT (for ambulant patients only) at Month 12 and 
Month 24. 
 

 
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For patients aged 260 years 
 
Change from baseline in the Total MFM score and its domain scores of D1, D2, D3 
and the total combined score of (D1  +D2) at Month12 and Month 24 
 
Proportion of patients who achieve stabilization or improvement (i.e., a change from 
the study baseline  0) on the Total MFM score by Month 12 and Month 24 
 
Change from baseline in the Total score of HFMSE at Month 12 and Month 24 
 
Change from baseline in the Total score of the RULM at Month 12 and Month 24 
 
Change from baseline in the best SNIP (expressed as a percentage of the predicted 
value) at Month 12 and Month 24 
 
Change from baseline in the total score of the caregiver-reported SMAIS at Month 
12 and Month 24. 
 
For patients aged 6 months to  2 years 
 
Proportion of infants who achieve relevant motor milestones as assessed by 
BSID-III gross motor scale at Month 12 and Month 24. 
 
Change from baseline in the total raw score of the BSID-III gross motor scale at 
Month 12 and Month 24. 
 
Proportion of infants who achieve the relevant attainment levels of the motor 
milestones as assessed by HINE-2 at Month 12 and Month 24. 
 
Proportion of motor milestone responders as assessed by HINE-2 at Month 12 and 
Month 24. 
 
Time to death (from enrollment). 
 
Time to permanent ventilation (from enrollment). 
 
Time to death or permanent ventilation (from enrollment). 
 
Proportion of infants without permanent ventilation at Month 12 and Month 24. 
 
Proportion of infants with the ability to swallow at Month 12 and Month 24. 
 
All exploratory efficacy analysis will be based on the ITT population.  Efficacy data 
collected from each of the exploratory efficacy endpoints will be summarized 
descriptively by timepoint and by previous treatment: RO6885247, nusinersen, 
AVXS-10, or olesoxime, as appropriate. 
Details of the statistical methods, definitions and analyses for all exploratory efficacy 
endpoints will be fully specified in the DAP. 
6.7 
PHARMACOKINETIC ANALYSES 
All PK parameters will be presented by listings and descriptive summary statistics, as 
appropriate.  Individual and mean plasma concentrations of risdiplam and metabolites 
(as appropriate) versus time data will be tabulated and plotted. 

 
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Non-linear mixed effects modeling (NONMEM software) 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, or previous 
treatment with nusinersen, AVXS-101, or olesoxime) on these parameters will be 
investigated in an exploratory manner.  Data may be pooled with data from other studies 
with risdiplam in order 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. 
Additional exploratory analyses on exposure and safety/efficacy relationship may be 
conducted if deemed necessary.  The details of the modelling and exploratory analyses 
may be reported in a document separate from the clinical study report. 
Additional PK analyses will be conducted as appropriate. 
6.8 
PHARMACODYNAMIC ANALYSES 
All PD parameters will be presented by listings and descriptive summary statistics 
separately. 
6.9 
DIGITAL BIOMARKER ANALYSES 
Digital biomarker assessments were in place in Protocol Versions 1-4, inclusive 
(analysis detailed below), but ceased to be performed during 2022. 
Smartphone sensor data collected as part of the digital biomarker approach will be 
analyzed.  Participant adherence will be evaluated.  After sensor data quality checks and 
pre-processing throughout the study, features will be developed for each smartphone-
based test and correlated with the MFM and other clinical endpoints.  Further exploratory 
analyses may be conducted. 
The results will be reported separately from the clinical study report.  
6.10 
INTERIM ANALYSES 
The IMC or iDMC will be requested to review all available safety data in an ongoing 
basis, in accordance with the associated IMC and iDMC Charter. 
An interim analysis of all available safety and efficacy data will be performed to support 
the initial filing and registration of risdiplam.  The interim analysis will be performed by 
the Sponsor and the results presented to the external iDMC.  The study will not be 
stopped early based on the results of the efficacy analysis. 
Given the exploratory nature of this non-comparative and open-label study, the Sponsor 
may choose to conduct additional interim efficacy or safety analyses.  The decision to 
conduct additional interim analysis and the timing of the analysis will be documented in 

 
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the Sponsor’s trial master file prior to the conduct of the interim analysis.  These interim 
analyses will also be performed by the Sponsor and results presented to the IMC or 
iDMC. 
The final analysis will occur after all patients have completed the study. 
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.  Sites will be responsible for data entry into the Electronic Data 
Capture (EDC) system. 
A comprehensive validation check program will verify the data.  Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the Investigator. 
The Sponsor will produce a Data Handling Manual and a Data Management Plan that 
describes the quality checking to be performed on the data.  Laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data. 
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an online EDC system.  The data collected in the 
source documents is entered onto the study eCRF.  An audit trail will maintain a record 
of initial entries and changes made; reasons for change; time and date of entry; and user 
name of person authorizing entry or change.  For each patient enrolled, an eCRF must 
be completed and electronically signed by the Principal Investigator or authorized 
delegate from the study staff.  If a patient withdraws from the study, the reason must be 
noted on the eCRF.  If a patient is withdrawn from the study because of a 
treatment‑limiting adverse event, thorough efforts should be made to clearly document 
the outcome. 
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor/CRO in the eCRFs and in all required reports. 
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO. 
At the end of the study, the Investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 

 
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7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification 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, patient-reported or 
caregiver-reported outcomes, evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies of transcriptions that are certified 
after verification as being accurate and complete, 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, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan. 
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, 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 investigational site must also allow 
inspection by applicable Health Authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational 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, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 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 

 
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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. 
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. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the E.U./EEA will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
or Clinical Trials Regulation (536/2014) 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 Assent or Caregiver's 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. 
In this study, caregiver specific information will be collected to evaluate caregiver burden 
requiring that a separate written informed consent be obtained from the caregiver. 
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. 

 
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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. 
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 of 1996 (HIPAA).  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 9.5).  
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. 

 
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8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
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. 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties 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. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local Health Authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
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 one year after completion of the study (i.e., last patient, last 
observation). 
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, which includes an audit trail containing a complete record of all changes 
to data. 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
100/Protocol BP39054, Version 5 
In the E.U., Roche shall also submit a Development Safety Update Report (DSUR) once 
a year to the IEC and CAs according to local regulatory requirements and timelines of 
each country participating in the study. 
In the U.S., it is the understanding of the Sponsor that this protocol (and any 
modifications) as well as appropriate consent procedures and advertisements, will be 
reviewed and approved by an Institutional Review Board (IRB).  This board must operate 
in accordance with the current Federal Regulations.  The Sponsor will be sent a letter or 
certificate of approval prior to initiation of the study, and also whenever subsequent 
amendments /modifications are made to the protocol.  Roche shall also submit an IND 
Annual Report to FDA according to local regulatory requirements and timelines. 
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 
The Sponsor of the trial is F. Hoffmann-La Roche Ltd.  The Sponsor is responsible for 
the medical oversight, data management, statistical analysis, and medical writing for the 
Clinical Study Report. 
An IMC and iDMC will be responsible for reviewing safety, PK and PD data.  The scope 
and responsibility of these committees will be detailed in a specific Charter. 
An IxRS system will be used for drug allocation. 
A CRO will be responsible for study management, monitoring, and in some cases, 
vendor oversight. 
An ophthalmological monitoring vendor will be responsible for central review of optic 
assessments, and help support activities associated with training local readers and 
procuring equipment. 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
101/Protocol BP39054, Version 5 
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/or other summaries of clinical study results may be 
available in health authority databases for public access, as required by local regulation, 
and will be made available upon request.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
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. 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
102/Protocol BP39054, Version 5 
9.6 
PROTOCOL AMENDMENTS 
Any substantial protocol amendments will be prepared by the Sponsor.  Any substantial 
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 any non-substantial changes, as defined by 
regulatory requirements. 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
103/Protocol BP39054, Version 5 
10. 
REFERENCES 
American Thoracic Society. ATS statement: Guidelines for the six-minute walk test. Am 
J Respir Crit Care Med. 2002;166:111–17. 
Bérard C, Payan C, Hodgkinson I, et al. and the MFM Collaborative Study Group. A 
motor function measure scale for neuromuscular diseases. Construction and 
validation study. Neuromuscul Disord. 2005;15:46370. 
Bérard C, Girardot F,  Payan C. Motor Function Measure in Neuromuscular Diseases: 
User’s Manual MFM-32 and MFM-20. Second Edition. 2009. 
Bussel II, Wollstein G, Schuman JS. OCT for glaucoma diagnosis, screening and 
detection of glaucoma progression. Br J Ophthalmol. 2014;98(2):ii15ii19. 
Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of 
nusinersen (ISIS-SMNRX) in children with spinal muscular atrophy. Neurology. 
2016;86:8907. 
Cho S, Dreyfuss G. A degron created by SMN2 exon 7 skipping is a principal contributor 
to spinal muscular atrophy severity. Genes Dev. 2010; 24(5):43842. 
Crawford TO, Pardo CA. The neurobiology of childhood spinal muscular atrophy. 
Neurobiol Dis. 1996;3:97110. 
d’Ydewalle C, Sumner C. Spinal muscular atrophy therapeutics: Where do we stand? 
Neurotherapeutics. 2015; 12(2):30316. 
[FDA] U.S. Food and Drug Administration. Guidance for industry: suicidal ideation and 
behavior: prospective assessment of occurrence in clinical trials [resource on the 
Internet]. 2012 [cited June 2018]. Available from: 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
ucm315156.htm. 
Glanzman AM, O’Hagen JM, McDermott MP, et al. Validation of the Expanded 
Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J 
Child Neurol. 2011;26:14991507. 
Hua Y, Sahashi K, Rigo F, et al. Peripheral SMN restoration is essential for long-term 
rescue of a severe spinal muscular atrophy mouse model. Nature. 
2011;478:1236. 
Khirani S, Colella M, Caldarelli V, et al. Longitudinal course of lung function and 
respiratory muscle strength in spinal muscular atrophy type 2 and 3. Eur J Paediatr 
Neurol. 2013;17(6):55260. 
Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 
2011;68(8):97984. 
Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal 
muscular atrophy-determining gene. Cell. 1995;80:15565. 

 
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Lewelt A, Newcomb TM, Swoboda KJ. New therapeutic approaches to spinal muscular 
atrophy. Curr Neurol Neurosci Rep. 2012;12(1):4253. 
Lorson CL, Hahnen E, Androphy E J, et al. A single nucleotide in the SMN gene 
regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad 
Sci USA. 1999;96:630711. 
Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371:212033. 
Mao J, Tay S, Khojasteh CS, et al. Evaluation of Time Dependent Inhibition Assays for 
Marketed Oncology Drugs: Comparison of Human Hepatocytes and Liver 
Microsomes in the Presence and Absence of Human Plasma. Pharm Res. 
2016;33:1204-19.   
Montes J, McDermott MP, Martens WB, et al. Six-minute walk test demonstrates motor 
fatigue in spinal muscular atrophy. Neurology. 2010;74:8338. 
Munsat TL, Davies KE. International SMA Consortium Meeting (26-28 June 1992, Bonn, 
Germany). Neuromuscul Disord. 1992;2(5-6):4238. 
Nguyen TM, Humphrey E, Lam LT, et al. A two-site ELISA can quantify upregulation of 
SMN protein by drugs for spinal muscular atrophy. Neurology. 2008; 71:175763. 
Nurputra DK, Lai PS, Haraha NIF, et al. Spinal muscular atrophy: from gene discovery to 
clinical trials. Ann Hum Genet. 2013;77:43563. 
O’Hagen JM, Glanzman AM, McDermott MP, et al. An expanded version of the 
Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul 
Disord. 2007;17:6937. 
Passini MA, Bu J, Richards AM, et al. Antisense oligonucleotides delivered to the mouse 
CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 
2011; 3(72):72ra18. 
Phan DQ, Silka MJ, Lan YT, et al. Comparison of formulas for calculation of the 
corrected QT interval in infants and young children. J Pediatr. 2015;166:9604. 
Porensky PN, Mithpant C, McGovern VL, et al. A single administration of morpholino 
antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet. 
2012;21(7):162538. 
Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal 
diagnosis for spinal muscular atrophy: clinical laboratory analysis of 
 72,400 specimens. Eur J Hum Genet. 2012;20:2732. 
Sumner CJ, Kolb SJ, Harmison GG, et al. SMN mRNA and protein levels in peripheral 
blood: biomarkers for SMA clinical trials. Neurology. 2006;66:106773. 
 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
105/Protocol BP39054, Version 5
Appendix 1A 
Schedule of Assessments for Patients Aged 260 Years: 
Screening through Week 52 
Week 
Screening a 
D 30 to D 2 Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
13 
Week  
26 a 
Week 
39 
Week  
52 a 
Day SD 1 
SD 2 
D 
1 b 
D 
1 
D 
14 
D 
28 
D 
91 
D 
182 
D  
183 
D 
273 
D 
364 
D 
365 
(Visit window, days) 
 
 
 
 
(  1) 
(  3) 
(  7) 
(  7) 
(  7) 
(  7) 
Site visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Follow-up phone call 
 
 
x c 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical history, including SMA 
history 
x 
 
 
 
 
 
 
 
 
 
 
 
Physical examination d 
x 
 
x 
 
x 
x 
x 
x 
 
x 
x 
 
Neurological examination 
x 
 
 
 
 
 
 
x 
 
 
x 
 
Vital signs 
x 
 
x 
x e 
x 
x e 
x e 
x 
 
x 
x e 
 
Plasma PK sample f, g 
 
 
 
x  
x 
x  
x  
 
x 
x  
 
x  
ECG-12 lead g 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
Substance use h 
 
x 
x 
 
 
 
 
 
 
 
 
 
Significant life events 
 
 
x 
 
x 
x 
x 
x 
 
x 
x 
 
Hematology e and blood 
chemistry e 
 
x 
 
 
x 
x 
x 
 
x 
 
 
x 
Coagulation e 
 
x 
 
 
 
x 
x 
 
x 
 
 
x 
Urinalysis e 
 
x 
 
 
 
x 
x 
 
x 
 
 
x 

Appendix 1A 
 
Schedule of Assessments for Patients Aged 260 Years:  Screening through Week 52 (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
106/Protocol BP39054, Version 5 
Week 
Screening a 
D 30 to D 2 Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
13 
Week  
26 a 
Week 
39 
Week  
52 a 
Day SD 1 
SD 2 
D 
1 b 
D 
1 
D 
14 
D 
28 
D 
91 
D 
182 
D  
183 
D 
273 
D 
364 
D 
365 
(Visit window, days) 
 
 
 
 
(  1) 
(  3) 
(  7) 
(  7) 
(  7) 
(  7) 
Hormone panel i,e 
 
x 
 
 
 
 
x 
 
 
 
 
 
Pregnancy test blood j 
 
x 
 
 
 
x 
x 
 
x 
 
 
x 
Pregnancy test urine site j 
 
 
x 
 
 
 
 
 
 
x 
 
 
Pregnancy test urine home j, k 
 
 
 
 
 
 
x k 
Ophthalmological assessments 
l 
 
Tanner staging m 
 
 
x 
 
 
 
 
 
 
 
x 
 
In vivo mRNA f 
 
 
x 
x 
 
x 
x 
 
x 
 
 
x 
SMN protein f 
 
 
x 
 
 
x 
x 
 
x 
 
 
x 
MFM n 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
Pulmonary testing o 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
6MWT (for ambulant 
patients) p, q 
 
x 
x 
 
 
 
 
 
x 
 
 
x 
RULM/HFMSE n 
 
x 
 
 
 
 
 
 
x 
 
 
x 
C-SSRS q 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
Nutritional check 
 
x 
x 
 
 
x 
x 
 
x 
x 
 
x 
Serum biomarkers e, h 
 
 
x 
 
 
 
 
 
 
 
 
x 
Digital biomarker in clinic p, r 
 
Digital biomarker remote p, r 
 
Blood sample for RBR 
(optional) e,s 
 
 
x 
 
 
 
 
 
 
 
 
 

Appendix 1A 
 
Schedule of Assessments for Patients Aged 260 Years:  Screening through Week 52 (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
107/Protocol BP39054, Version 5 
Week 
Screening a 
D 30 to D 2 Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
13 
Week  
26 a 
Week 
39 
Week  
52 a 
Day SD 1 
SD 2 
D 
1 b 
D 
1 
D 
14 
D 
28 
D 
91 
D 
182 
D  
183 
D 
273 
D 
364 
D 
365 
(Visit window, days) 
 
 
 
 
(  1) 
(  3) 
(  7) 
(  7) 
(  7) 
(  7) 
Clinical genotyping 
 
 
 
x t 
 
 
 
 
 
 
 
 
SMAIS p 
 
 
x 
 
 
 
 
 
x 
 
 
x 
Study medication 
dispensation/return  
 
 
 
x u 
Daily administration of study 
medication 
 
 
 
Daily 
Daily diary 
 
 
 
Daily 
Adverse events 
x v 
x v 
x 
Previous and concomitant 
treatments 
x 
x 
x 
 
6MWT  Six-Minute Walk Test; C-SSRS  Columbia-Suicide Severity Rating Scale; D  Day; MFM  motor function measure; PK  pharmacokinetic; 
RBR  Research Biosample Repository; RULM/HFMSE  Revised Upper limb module/ Hammersmith functional motor scale expanded; 
SD  screening day; SMA  spinal muscular atrophy; SMAIS  Spinal Muscular Atrophy Independence Scale; SMN  survival of motor neuron; 
TSH  thyroid stimulating hormone. 
For footnotes, see Appendix 1B that follows. 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
108/Protocol BP39054, Version 5
Appendix 1B 
Schedule of Assessments for Patients Aged 260 Years: 
Year 2 through End of Study 
Week 
Week 
65 
Week 78 a 
Week 91 Week 104 a 
OLE Phase a 
Comp/EW a 
Follow-Up 
Phone call z 
Day 
D 
456 
D 
546 
D 
547 
D 
637 
D 
728 
D 
729 
Every 13 
weeks y 
Every 26 weeks 
D 1 
D 2 
Comp/EW    
approx. 
30 days 
D 1 
D 2 
(Visit window, days) 
(  7) 
(  7) 
(  7) 
(  7) 
(  14) 
(  14) 
 
(  7) 
Site visit 
x 
x 
x 
x 
x 
x 
x 
 
Physical examination d 
x 
x 
 
x 
x 
 
x 
x 
 
x 
 
 
Neurological examination 
 
x 
 
 
x 
 
 
x 
 
x 
 
 
Vital signs 
x 
 
 
x e 
x 
 
 
x 
 
x 
 
 
Plasma PK sample f, g 
x 
 
 
x  
 
x 
 
 
 
 
x 
 
ECG-12 lead g 
x 
 
 
x 
x 
 
 
x 
 
x 
 
 
Substance use h 
 
 
 
 
 
 
 
 
 
 
 
 
Significant life events 
x 
x 
 
x 
x 
 
 
x 
 
x 
 
 
Hematology e and blood chemistry e 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
Coagulation e 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
Urinalysis e 
 
 
 
 
 
x 
 
 
x 
 
x 
 
Hormone panel i, e 
 
 
 
 
 
x 
 
 
 
 
 
 
Pregnancy test blood j 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
Pregnancy test urinesite j 
x 
 
 
x 
 
 
 
 
 
 
 
 
Pregnancy test urinehome j, k 
x 
 
 
 
Ophthalmological assessments l 
 
Tanner staging m 
 
 
 
 
x 
 
 
 
 
x 
 
 

Appendix 1B 
Schedule of Assessments for Patients Aged 260 Years: Year 2 through End of Study (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
109/Protocol BP39054, Version 5 
Week 
Week 
65 
Week 78 a 
Week 91 Week 104 a 
OLE Phase a 
Comp/EW a 
Follow-Up 
Phone call z 
Day 
D 
456 
D 
546 
D 
547 
D 
637 
D 
728 
D 
729 
Every 13 
weeks y 
Every 26 weeks 
D 1 
D 2 
Comp/EW    
approx. 
30 days 
D 1 
D 2 
(Visit window, days) 
(  7) 
(  7) 
(  7) 
(  7) 
(  14) 
(  14) 
 
(  7) 
In vivo mRNA f 
 
 
 
 
 
x 
 
 
 
 
x 
 
SMN protein f 
 
 
 
 
 
x 
 
 
 
 
x 
 
MFM n 
 
x 
 
 
x 
 
 
x 
 
x 
 
 
Pulmonary testing o 
 
x 
 
 
x 
 
 
x 
 
x 
 
 
6MWT (for ambulant patients) p, q 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
RULM/HFMSE n 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
C-SSRS q 
 
x 
 
 
x 
 
 
x 
 
x 
 
 
Nutritional check 
x 
 
x 
x 
 
x 
 
 
x 
 
x 
 
Serum biomarkers e, h 
 
 
 
 
 
x 
 
 
 
 
x 
 
Digital biomarkerin clinic p, r 
 
 
Digital biomarkerremote p, r 
 
 
Blood sample for RBR (optional) e, s 
 
 
 
 
 
x 
 
 
 
 
x 
 
Clinical genotyping 
 
 
 
 
 
 
 
 
 
 
 
 
SMAIS p 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
Study medication 
dispensation/return  
x u 
x w, ‡ 
 
Daily administration of study 
medication 
Daily 
x ‡ 
 
Daily diary 
Daily 
x 
 
Adverse events 
x § 
x 
Previous and concomitant 
treatments 
x 
 

Appendix 1B 
Schedule of Assessments for Patients Aged 260 Years: Year 2 through End of Study (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
110/Protocol BP39054, Version 5 
Week 
Week 
65 
Week 78 a 
Week 91 Week 104 a 
OLE Phase a 
Comp/EW a 
Follow-Up 
Phone call z 
Day 
D 
456 
D 
546 
D 
547 
D 
637 
D 
728 
D 
729 
Every 13 
weeks y 
Every 26 weeks 
D 1 
D 2 
Comp/EW    
approx. 
30 days 
D 1 
D 2 
(Visit window, days) 
(  7) 
(  7) 
(  7) 
(  7) 
(  14) 
(  14) 
 
(  7) 
6MWT  Six-Minute Walk Test; C-SSRS  Columbia-Suicide Severity Rating Scale; D  Day; Comp/EW  Completion/Early Withdrawal; 
MFM  motor function measure; OLE  open-label extension; PK  pharmacokinetic; Q13W  every 13 weeks; RBR  Research Biosample 
Repository; RULM/HFMSE  Revised Upper limb module/ Hammersmith functional motor scale expanded; SD  screening day; SMA  spinal 
muscular atrophy; SMAIS  Spinal Muscular Atrophy Independence Scale; SMN  survival of motor neuron; TSH  thyroid stimulating hormone. 
a See Section 4.6.2.2, Table 2 and Table 3 for order of assessments, it is recommended that these assessments be conducted over two days. 
b Assessments should be performed in the following order: adverse events, previous/concomitant medications, confirmation of eligibility, 
enrollment, 1st ECG recording, 2nd ECG recording, 3rd ECG recording, physical examination, Tanner staging, vital signs, 4th ECG recording, 
patient/caregiver-reported outcomes, pulmonary testing, MFM, 6MWT and blood samples.  Flexibility is given to the site whether to perform the 
physical examination, Tanner staging, vital signs, patient/caregiver-reported outcomes assessment, pulmonary testing, MFM, and blood 
samples after the third or fourth ECG recording.  The 6MWT should only be performed after the fourth ECG recording.  In case the pulmonary 
testing, the MFM or blood samples are done prior to the fourth ECG recording, the following ECG recording should be preceded by a break of 
at least 20 minutes.  The pulmonary testing, MFM and 6MWT should be preceded by a break of at least 15 minutes. 
c Mandatory follow-up phone calls on Days 4, 11, 19, 33, 49, 63 and 77.  It is at the discretion of the Investigator to perform the follow-up phone 
calls at the most appropriate time (day) between the site visits.  After Week 12, additional follow-up phone calls are per Investigator’s decision.   
d At Weeks 65, 91, and every 13 weeks during the OLE phase, only body weight will be measured.  At all other visits (including every 26 weeks 
during the OLE phase) a full physical examination needs to be done, including the head circumference in children below 5 years.  Height 
(measured or derived from ulna length) at Screening, Weeks 13, 39, 52, 78, and 104 in patients 217 years of age.  In patients 17 years of 
age, height at screening, Week 52 and Week 104 only. Body Mass Index (BMI) will be derived from the height recorded at screening in 
patients 17 years of age, and from the last known height in patients 217 years of age. 
e Predose. 
f Predose except for those outlined in Appendix 2. 
g Timing and number of samples as outlined in Appendix 2. 
h Only patients of   12 years of age. 
i Thyroid hormones (free T4 and TSH) in all patients; estradiol, follicle-stimulating hormone and luteinizing hormone in female patients of 
child-bearing potential. 
j Pregnancy tests in females of child-bearing potential only.  Pregnancy tests may be repeated at the discretion of the Investigator at any time. 
Positive urine pregnancy tests results must be confirmed with a blood pregnancy test. 

Appendix 1B 
Schedule of Assessments for Patients Aged 260 Years: Year 2 through End of Study (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
111/Protocol BP39054, Version 5 
Week 
Week 
65 
Week 78 a 
Week 91 Week 104 a 
OLE Phase a 
Comp/EW a 
Follow-Up 
Phone call z 
Day 
D 
456 
D 
546 
D 
547 
D 
637 
D 
728 
D 
729 
Every 13 
weeks y 
Every 26 weeks 
D 1 
D 2 
Comp/EW    
approx. 
30 days 
D 1 
D 2 
(Visit window, days) 
(  7) 
(  7) 
(  7) 
(  7) 
(  14) 
(  14) 
 
(  7) 
k The home pregnancy test must be performed every 4 weeks following the latest clinic visit.  The urine pregnancy test kit will be dispensed to 
patients to perform at home and the Investigator will arrange to perform a phone call to obtain the results of the pregnancy test.  Alternatively, 
a home visit at the required time will be performed to administer and obtain the results of the urine pregnancy test, unless the patient has 
agreed to return to the clinic site at the required time. 
l Ophthalmological assessments were performed under Protocol Versions 1-4, inclusive, but are no longer to be performed starting with 
Protocol Version 5. 
m Tanner staging will be determined at baseline, Month 12 and subsequent yearly visits in all patients who are 917 years of age at time of 
enrollment or following their 9th birthday, if they enrolled in the study before age 9.  Once a patient reaches stage 5, Tanner staging no longer 
needs to be performed. 
n Due to fatigue, motor function assessments should be performed over 2 days it is very important that the MFM is performed on Day 1 and the 
HFMSE is performed on Day 2 of the visit. 
o SNIP in patients 2 years of age and older; Spirometry (FVC, FEV1, and PCF) in patients 6 years of age and older. 
p For patients already enrolled in this study prior to the implementation of the 6MWT, the SMAIS and the digital biomarker:  These assessments 
will be completed for the first time at the next visit with the respective assessments being scheduled.  Digital biomarker assessments were 
performed under Protocol Versions 1-4, inclusive, but ceased to be performed during 2022. 
q Only patients of   6 years of age. 
r Digital biomarker assessments were performed under Protocol Versions 1-4, inclusive, but ceased to be performed during 2022. 
s Only in patients   12 years of age.  RBR sampling is optional, requiring additional consent.  RBR DNA samples will be collected once on 

Appendix 1B 
Schedule of Assessments for Patients Aged 260 Years: Year 2 through End of Study (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
112/Protocol BP39054, Version 5 
Week 
Week 
65 
Week 78 a 
Week 91 Week 104 a 
OLE Phase a 
Comp/EW a 
Follow-Up 
Phone call z 
Day 
D 
456 
D 
546 
D 
547 
D 
637 
D 
728 
D 
729 
Every 13 
weeks y 
Every 26 weeks 
D 1 
D 2 
Comp/EW    
approx. 
30 days 
D 1 
D 2 
(Visit window, days) 
(  7) 
(  7) 
(  7) 
(  7) 
(  14) 
(  14) 
 
(  7) 
Day 1, RBR plasma and RNA samples on Day 1 and on week 104/Early Withdrawal. 
t Blood sample for clinical genotyping may be collected once at any time after dosing (at the time of collection of other samples). 
u Starting at Week 6, drug delivery and return of unused drug and supplies at the patient’s home may be scheduled as appropriate depending 
on the formulation (two-bottle or one-bottle, respectively) the patient is receiving, unless the patient has agreed or is scheduled to visit the 
clinic at these times. 
v Only serious adverse events caused by a protocol-mandated intervention. 
w No dispensation of study medication except for patients who will continue on risdiplam IMP (Section 4.4.4) until EOS. 
y The Q13W assessments in the OLE phase may be performed remotely (e.g. by telephone) at the Investigator’s discretion. 
z Follow-up telephone call, if applicable (see Section 4.6.2.4 and Appendix 5), approximately 30 days after the study completion/early withdrawal 
visit.  The follow-up call will only be conducted for patients [a] who do not go on to receive risdiplam IMP through continued access or to 
receive risdiplam through commercial or post-trial access; or [b] who switch to another treatment for SMA within 30 days of stopping risdiplam.  
If a patient switches to another SMA treatment during the 30-day follow-up period, a telephone call should be performed to collect information 
up to the time that the patient begins the new treatment. 
‡ Study medication administration only for patients who will continue on risdiplam treatment (Section 4.4.4) until EOS. 
§ For patients receiving risdiplam IMP (Section 4.4.4) until EOS , investigators should proactively contact those patients every 13 weeks to 
ensure adverse events are reported in the eCRF and document this contact in the patient notes. 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
113/Protocol BP39054, Version 5
Appendix 2  
Detailed Schedule of Pharmacokinetic and Biomarker Samples: 
Patients Aged 260 Years 
Week 
Day 
Scheduled 
Time (hr) 
ECG-12 
Lead 
PK Sample 
In vivo 
mRNA 
SMN 
Protein 
Serum 
Biomarkers 
RBR Sample 
(optional) a 
Screening 
Day 30 to 2 
 
x 
 
 
 
 
 
Baseline 
Day 1 
0 hr 
x 
 
x b 
x b 
x b 
x b 
 1 hr 
x c 
 
 
 
 
 
 2 hr 
x c 
 
 
 
 
 
 4 hr 
x c 
 
 
 
 
 
Week 1 
Day 1 
Predose 
x 
 
 
 
 
 
 1 hr 
 
x 
 
 
 
 
 2 hr 
 
x 
 
 
 
 
 4 hr 
 
x 
x 
 
 
 
 6 hr 
 
x 
 
 
 
 
Week 2 
Day 14 
Predose 
x 
x 
 
 
 
 
Week 4 
Day 28 c 
Predose 
x 
x 
 
 
 
 
 1 hr 
x 
x 
 
 
 
 
 2 hr 
x 
x 
 
 
 
 
 4 hr 
x 
x 
x 
x 
 
 
 6 hr 
 
x 
 
 
 
 
Week 13 
Day 91 c 
Predose 
x 
x 
x 
x 
 
 
 1 hr 
x 
x 
 
 
 
 
 2 hr 
x 
x 
 
 
 
 

Appendix 2 
 
Detailed Schedule of Pharmacokinetic and Biomarker Samples: Patients Aged 260 Years (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
114/Protocol BP39054, Version 5 
Week 
Day 
Scheduled 
Time (hr) 
ECG-12 
Lead 
PK Sample 
In vivo 
mRNA 
SMN 
Protein 
Serum 
Biomarkers 
RBR Sample 
(optional) a 
 4 hr 
x 
x 
 
 
 
 
 6 hr 
 
x 
 
 
 
 
Week 26 
Day 182 
Predose 
x 
 
 
 
 
 
Day 183 
Predose 
 
x 
x 
x 
 
 
Week 39 
Day 273 
Predose 
x 
x 
 
 
 
 
Week 52 
Day 364 
Predose 
x 
 
 
 
 
 
Day 365 
Predose 
 
x 
 
 
x 
 
 1 hr 
 
x 
 
 
 
 
 2 hr 
 
x 
 
 
 
 
 4 hr 
 
x 
x 
x 
 
 
 6 hr 
 
x 
 
 
 
 
Week 65 
Day 456 
Predose 
x 
x 
 
 
 
 
Week 91 
Day 637 c 
Predose 
x 
x 
 
 
 
 
 1 hr 
 
x 
 
 
 
 
 2 hr 
 
x 
 
 
 
 
 4 hr 
 
x 
 
 
 
 
 6 hr 
 
x 
 
 
 
 
Week 104 
Day 728 
Predose 
x 
 
 
 
 
 
Day 729 
0 hr 
 
x 
x 
x 
x 
x 
OLE Phase 
 
 
x d 
 
 
 
 
 
Completion/Early 
Withdrawal 
Day 1 
 
x 
 
 
 
 
 
Day 2 
 
 
x 
x 
x 
x 
x 

Appendix 2 
 
Detailed Schedule of Pharmacokinetic and Biomarker Samples: Patients Aged 260 Years (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
115/Protocol BP39054, Version 5 
 
OLE = open-label extension; PK  pharmacokinetic; RBR  Research Biosample Repository; SMN  survival of motor neuron. 
a Only in patients  12 years of age. RBR sampling is optional, requiring additional consent.  RBR DNA samples will be collected once on 
Day 1, RBR plasma and RNA samples on Day 1 and on Week 104/Early Withdrawal. 
b Blood samples should be taken after the 12-lead ECG recordings and all other assessments scheduled on Day 1 as indicated in 
Section 4.6.2.1. 
c Matched ECG and PK samples only in patients  12 years of age.  In patients  12 years of age, only a predose ECG is to be obtained; no 
post-dose ECGs are required unless the Investigator deems them necessary for safety. 
d ECG every 26 weeks during OLE phase. 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
116/Protocol BP39054, Version 5
Appendix 3A 
Schedule of Assessments for Patients Aged 6 Months to  2 Years: 
Screening through Week 52 
Week 
Screening  
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
13 
Week 
26 
Week 
39 
Week 
52 
Day 
D   30 
to D   2 
D 
  1 a 
D 
1 
D 
14 
D 
28 
D 
91 
D 
182 
D273 
D364 
(Visit window, days) 
 
 
 
(  1) 
(  3) 
(  7) 
(  7) 
(  7) 
(  7) 
Site visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Follow-up phone call  
 
 
x b 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
 
 
Medical history, including SMA history 
x 
 
 
 
 
 
 
 
 
Physical examination c 
x 
x 
 
x 
x 
x 
x 
x 
x 
Neurological examination 
x 
x 
 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x(4 hr) d 
x 
x 
x 
x 
x 
x 
Protein binding sample e 
x 
 
 
 
 
 
 
 
 
Plasma PK sample f,g 
 
 
x  
x 
x  
x  
x  
x  
x 
ECG-12 lead g 
x 
x 
x 
x 
x 
x  
x  
x 
x 
Significant life events (including family) 
 
x 
 
x 
x 
x 
x 
x 
x 
Hematology f and blood chemistry h 
x 
 
 
x 
 
x 
x 
 
x 
Coagulation h 
x 
 
 
x 
 
x 
x 
 
x 
Urinalysis h, i 
 
 
 
x 
 
x 
x 
 
x 
Ophthalmological assessments j 
 
In vivo mRNA f 
 
 
x 
 
x (4 hr) d 
 
x 
 
x 
SMN protein f 
 
 
x 
 
x (4 hr) d 
 
x 
 
x 

Appendix 3A 
 
Schedule of Assessments for Patients Aged 6 Months to  2 Years: Screening through Week 52 (cont.)  
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
117/Protocol BP39054, Version 5 
Week 
Screening  
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
13 
Week 
26 
Week 
39 
Week 
52 
Day 
D   30 
to D   2 
D 
  1 a 
D 
1 
D 
14 
D 
28 
D 
91 
D 
182 
D273 
D364 
(Visit window, days) 
 
 
 
(  1) 
(  3) 
(  7) 
(  7) 
(  7) 
(  7) 
BSID-III-gross motor score 
 
x 
 
 
 
 
x 
 
x 
HINE2 
 
x 
 
 
 
 
x 
 
x 
Level of respiratory support 
x 
x 
 
x 
x 
x 
x 
x 
x 
Nutritional check k 
x 
x 
 
 
x 
x 
x 
x 
x 
Clinical genotyping 
 
 
 
 
 
x l 
 
 
 
Study medication dispensation/return 
 
 
x m 
Daily administration of study medication 
 
 
Daily 
Daily diary 
 
 
Daily 
Adverse events 
x n 
x n 
x 
Previous and concomitant treatments 
x 
 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
118/Protocol BP39054, Version 5
Appendix 3B 
Schedule of Assessments for Patients Aged 6 Months to  2 Years: 
Year 2 through End of Study 
Week 
Week 
65 
Week 
78 
Week 
91 
Week 
104 
OLE Phase 
Comp/EW 
Follow-up  
phone call r 
Day 
Day 
456 
Day 
546 
Day 
637 
Day 
728 
Every 13 
weeks q 
Every 26 
weeks 
 
Comp/EW  
 approx. 
30 days 
(Visit window, days) 
(  7) 
(  7) 
(  7) 
(  7) 
(  14) 
(  14) 
 
(  7) 
Site visit 
x 
x 
x 
x 
x 
x 
 
 
Physical examination c 
x 
x 
x 
x 
x o 
 
x 
 
Neurological examination 
x 
x 
x 
x 
 
x 
x 
 
Vital signs 
x 
x 
x 
x 
 
x 
x 
 
Protein binding sample e 
 
 
 
 
 
 
 
 
Plasma PK sample f,g 
x 
x 
x  
x 
 
x 
x 
 
ECG-12 lead g 
x 
x 
x 
x 
 
x 
x 
 
Significant life events (including family) 
x 
x 
x 
x 
 
x 
x 
 
Hematology h and blood chemistry h 
 
x 
 
x 
 
x 
x 
 
Coagulation h 
 
x 
 
x 
 
x 
x 
 
Urinalysis h, i 
 
 
 
x 
 
x 
x 
 
Ophthalmological assessments j 
 
In vivo mRNA f 
 
 
 
x 
 
 
x 
 
SMN protein f 
 
 
 
x 
 
 
x 
 
BSID-III-gross motor score 
 
x 
 
x 
 
x 
x 
 
HINE-2 
 
x 
 
x 
 
x 
x 
 

Appendix 3B 
 
Schedule of Assessments for Patients Aged 6 Months to  2 Years: Year 2 through End of Study (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
119/Protocol BP39054, Version 5 
Week 
Week 
65 
Week 
78 
Week 
91 
Week 
104 
OLE Phase 
Comp/EW 
Follow-up  
phone call r 
Day 
Day 
456 
Day 
546 
Day 
637 
Day 
728 
Every 13 
weeks q 
Every 26 
weeks 
 
Comp/EW  
 approx. 
30 days 
(Visit window, days) 
(  7) 
(  7) 
(  7) 
(  7) 
(  14) 
(  14) 
 
(  7) 
Level of respiratory support 
x 
x 
x 
x 
 
x 
x 
 
Nutritional check k 
x 
x 
x 
x 
 
x 
x 
 
Clinical genotyping 
 
 
 
 
 
 
 
 
Study medication dispensation/return  
x m 
x p, s 
 
Daily administration of study medication 
Daily 
x s 
 
Daily diary 
Daily 
 
Adverse events 
X t 
x 
Previous and concomitant treatments 
x 
 
 
BSID-III  Bayley Scales of Infant and Toddler development  Third Edition; Comp/EW  Completion/Early Withdrawal; HINE2  Hammersmith 
Infant Neurological Examination Module 2; OLE = open-label extension; PK  pharmacokinetic; Q13W = every 13 weeks; RBR  Research 
Biosample Repository; SMA  spinal muscular atrophy; SMN  survival of motor neuron. 
a Assessments should be performed in the following order: adverse events, previous/concomitant medications, and confirmation of eligibility, 
followed by the other scheduled assessments.  
b Mandatory follow-up phone calls on Days 4, 11, 19, 33, 49, 63, and 77.  It is at the discretion of the Investigator to perform the follow-up phone 
calls at the most appropriate time (day) between the site visits.  After Week 12, additional follow-up phone calls are per Investigator’s decision.  
If a patient withdraws from the study and if the follow-up telephone call is applicable (see Section 4.6.2.4), follow-up phone calls should occur 
every 2 weeks after the early withdrawal visit until the Follow-Up telephone call if the parent(s) guardian(s) agree to collect information on 
adverse events and use of respiratory support. 
c Physical examination will include weight, height, and head and chest circumference (until patients turn 2 years of age) at every visit. 
d Assessment to be performed 4 hours after dose administration. 
e Only required in patients aged  1 years. 
f Predose except for those outlined in Appendix 4. 
g Timing and number of samples as outlined in Appendix 4. 

Appendix 3B 
 
Schedule of Assessments for Patients Aged 6 Months to  2 Years: Year 2 through End of Study (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
120/Protocol BP39054, Version 5 
h Predose. 
i For patients aged  2 years at time of assessment only.  
j Ophthalmological assessments were performed under Protocol Versions 1-4, inclusive, but are no longer performed starting with Protocol 
Version 5. 
k A detailed interview will be performed at Day 1 and at Weeks 26, 52, 78, and 104. 
l Blood sample for clinical genotyping may be collected once at any time after dosing (at the time of collection of other samples). 
m Starting at Week 6, drug delivery and return of unused drug and supplies at the patient’s home may be scheduled as appropriate, unless the 
patient has agreed or is scheduled to visit the clinic at these times. 
n Only serious adverse events caused by a protocol-mandated intervention. 
o Collection of body weight only. 
p Study medication administration only for patients who will continue on risdiplam IMP (Section 4.4.4) until EOS. 
q The Q13W assessments in the OLE phase may be performed remotely (e.g. by telephone) at the Investigator’s discretion. 
r Follow-up telephone call, if applicable (see Section 4.6.2.4 and Appendix 5), approximately 30 days after the study completion/early 
withdrawal visit.  The follow-up call will only be conducted for patients [a] who do not go on to receive risdiplam IMP through continued 
access or to receive risdiplam through commercial or post-trial access, or [b] who switch to another treatment for SMA within 30 days of 
stopping risdiplam.  If a patient switches to another SMA treatment during the 30-day follow-up period, a telephone call should be 
performed to collect information up to the time that the patient begins the new treatment. 
s Study medication administration only for patients who will continue on risdiplam treatment (Section 4.4.4) until EOS. 
t For patients receiving risdiplam IMP (Section 4.4.4) until EOS , investigators should proactively contact those patients every 13 weeks to 
ensure adverse events are reported in the eCRF and document this contact in the patient notes. 
 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
121/Protocol BP39054, Version 5
Appendix 4  
Detailed Schedule of Pharmacokinetic and Biomarker Samples: 
Patients Aged 6 Months to  2 Years 
Week 
Day 
Scheduled 
Time (hr) 
PK 
Sample a 
ECG  
In vivo 
mRNA  
SMN 
Protein  
Screening 
Day 30 to 2 
 
 
x 
 
 
Baseline 
Day 1 
 
 
x 
 
 
Week 1 
Day 1 
Predose 
 
x 
x 
x 
 2 hr 
x 
x 
 
 
 4 hr 
x 
 
 
 
 6 hr 
x 
 
 
 
Week 2 
Day 14 
Predose 
x 
x 
 
 
Week 4 
Day 28 
Predose 
x 
x 
 
 
 2 hr 
x 
x 
 
 
 4 hr 
x 
 
x 
x 
 6 hr 
x 
 
 
 
Week 13 
Day 91 
Predose 
x 
x 
 
 
 2 hr 
x 
x 
 
 
 4 hr 
x 
 
 
 
 6 hr 
x 
 
 
 
Week 26 
Day 182 
Predose 
x 
x 
x 
x 
 2 hr 
x 
x 
 
 
 4 hr 
x 
 
 
 
 6 hr 
x 
 
 
 
Week 39 
Day 273 
Predose 
x 
x 
 
 
 2 hr 
x 
 
 
 
 4 hr 
x 
 
 
 
 6 hr 
x 
 
 
 
Week 52 
Day 364 
Predose 
x 
x 
x 
x 
Week 65 
Day 456 
Predose 
x 
x 
 
 
Week 78 
Day 546 
Predose 
x 
x 
 
 
 2 hr 
x 
 
 
 
 4 hr 
x 
 
 
 
 6 hr 
x 
 
 
 
Week 91 
Day 637 
Predose 
x 
x 
 
 
 2 hr 
x 
 
 
 
 4 hr 
x 
 
 
 

Appendix 4 
 
Detailed Schedule of Pharmacokinetic and Biomarker Samples: 
Patients Aged 6 Months to 2 Years (cont.) 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
122/Protocol BP39054, Version 5 
Week 
Day 
Scheduled 
Time (hr) 
PK 
Sample a 
ECG  
In vivo 
mRNA  
SMN 
Protein  
 6 hr 
x 
 
 
 
Week 104 
Day 728 
Predose 
x 
x 
x 
x 
OLE Phase 
 
Predose 
x a 
x 
 
 
Completion/Early 
Withdrawal 
 
 
x 
x 
x 
x 
OLE = open-label extension; PK  pharmacokinetic; RBR  Research Biosample Repository; 
SMN  survival of motor neuron. 
a Additional PK samples collected predose at additional visits every 26 weeks during the OLE 
phase. 
 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
123/Protocol BP39054, Version 5
Appendix 5  
Treatment Flow Chart 
 

 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd 
124/Protocol BP39054, Version 5 
Appendix 6  
Investigational Medicinal Product Designation (for Use in 
European Economic Area) 
Investigational Authorized Auxiliary, and Unauthorized Auxiliary Medicinal 
Product Designations for European Economic Area 
Product Name 
IMP/AxMP Designation 
Marketing Authorization 
Status in EEA  
Used within Marketing 
Authorization 
Risdiplam 
(RO7034067) 
IMP (test product)  
Authorized 
Yes 
AxMP   auxiliary medicinal product; EEA  European Economic Area; IMP   investigational 
medicinal product. 
 
 

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