Conditions: Duchenne Muscular Dystrophy
Keywords: muscular dystrophy Duchenne's Muscular Dystrophy DMD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 166
Healthy volunteers: no

Brief summary:
This is a multi-center, randomized, double-blind, placebo-controlled study to assess the efficacy, safety and tolerability of two different weekly doses of RO7239361 in ambulatory boys with Duchenne Muscular Dystrophy (DMD).

Detailed description:

Arms:
arm 1: Participants received low dose RO7239361 SC on specified days of the 48-week DB period. Following the DB period participants received low dose RO7239361 on specified days for up to 192 weeks during the open-label period followed by 24 weeks of follow-up. arm 2: Participants received high dose RO7239361 SC on specified days of the 48-week DB period. Following the DB period participants received high dose RO7239361 on specified days for up to 192 weeks during the open-label period followed by 24 weeks of follow-up. arm 3: Participants received matching placebo solution subcutaneously (SC) on specified days of the 48-week double-blind (DB) period. Following the DB period participants received low dose or high dose RO7239361 on specified days for up to 192 weeks during the open-label period followed by 24 weeks of follow-up.

Interventions: intervention 1: RO7239361 intervention 2: Placebo for RO7239361
Intervention descriptions: intervention 1: Take RO7239361 subcutaneously on specified days over a 48 week blinded period intervention 2: Take placebo subcutaneously on specified days over a 48 week blinded period

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
A Randomized, Double Blind, Placebo-Controlled, Study to Assess the 
Efficacy, Safety, and Tolerability of RO7239361 in Ambulatory Boys 
With Duchenne Muscular Dystrophy 
NCT Number: 
NCT03039686  
Document Date: 
Protocol Version 4: 16-August-2018 
 
 
 




Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
2/Protocol WN40227, Version 4 
 
1. 
DOCUMENT HISTORY 
 
Document 
Date of Issue 
Summary of Changes 
Revised Protocol 4 
(Version 4) 
See electronic date stamp. 
 
Amendment 6 
See electronic date stamp. 
• 
Deleted references to the previous 
Bristol-Myers Squibb protocol and 
product numbers throughout the 
text, except in the Introduction, 
Schedule of Assessments, and 
Treatment sections 
• 
Change the primary endpoint from 
the 4 Stair Climb velocity to the 
North Star Ambulatory Assessment 
total score 
• 
Added a new inclusion criterion 
requiring a minimum NSAA score of 
15 points at screening 
• 
Changed the 4SCV from the primary 
endpoint to a secondary endpoint 
• 
Added 95th percentile stride velocity, 
as recorded using the ActiMyo as a 
secondary endpoint 
• 
Added the caregiver video assessment 
at selected sites as a new exploratory 
endpoint 
• 
Added the Caregiver Global 
Impression of Change at selected 
sites as a new exploratory endpoint 
• 
Added the Pediatric Quality of Life 
Inventory Multidimensional Fatigue 
Scale at selected sites as an 
exploratory endpoint 
• 
Shortened the Study Rationale 
section to include a high-level 
summary of available clinical data 
and to refer to the Investigator's 
Brochure for specific details 
• 
Updated the duration of the open-
label (OL) extension phase and the 
frequency of visits during the OL 
extension phase 
• 
Added the specific sites indicated for 
subcutaneous injection 
• 
Deleted the proposed interim analysis 
• 
Updated the statistical analysis 
section to establish hierarchical 
testing of the doses 
• 
Added definitions for different 
situations of incorrect administration 
of study drug  
• 
Deleted urine biomarkers and 
miRNA biomarkers as exploratory 
endpoints 
• 
Added assessment of serum creatine 
kinase level in muscle to the 
exploratory pharmacokinetic, 
pharmacodynamic, and 
immunogenicity endpoints 
 


Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
3/Protocol WN40227, Version 4 
 
 
Document 
Date of Issue 
Summary of Changes 
Revised 
Protocol 03 
29 Jan 2018 
Incorporates Amendment 05 
Amendment 05 
29 Jan 2018. 
– 
Added assessment of CGI-C. 
– 
Reduced pulmonary function tests 
– 
Reduced anthropometry assessments 
– 
Reduced myometry assessments 
– 
Reduced TFTs and 6MWT in the 
open-label phases 
– 
Clarified signature of informed 
consent prior to Day −42 screening 
period 
– 
Clarified FVC in the exclusion 
criteria 
– 
Clarified contraception methods 
– 
Clarified GDF-11 sample timepoint 
– 
Clarified ActiMyo assessments 
– 
Clarified use of videos 
– 
Updated requirement for safety 
reporting of overdose 
– 
Clarified monitoring of ADAs during 
24-week safety follow-up phase 
– 
Updated Medical Monitor 
information 
– 
Updated for consistency with IB, 
version 6 
– 
Corrected typographical errors 
Revised Protocol 
02 
21-Aug-2017. 
Incorporates Amendment 04 
Amendment 04 
21-Aug-2017. 
– 
Changed Sponsor from Bristol-Myers Squibb 
to F. Hoffmann-La Roche Ltd 
– 
Changed study drug name from BMS-986089 
to RO7239361 
– 
Updated Medical Monitor information 


Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
4/Protocol WN40227, Version 4 
 
Revised Protocol 
01
20-Apr-2017 
Incorporates Amendment 03 
Amendment 03 
20-Apr-2017 
– 
Added text defining significant change in 
dosage for prednisone and deflazacort. 
– 
Added measurement of ulna length to baseline 
and on treatment time points. 
– 
Timing of on treatment videotaping of 
functional assessments has been clarified. 
– 
Timing of Health Care Resource 
Utilization assessments has been 
clarified. 
– 
Added clarification that DXA scanning is not 
required at early termination. 
– 
History of hypersensitivity of the components 
of the study drug added as an exclusion. 
– 
Threshold for adjusting dosing weight tier 
increased from 1 kg to 2 kg. 
– 
Text clarifying that malfunctions of pre-filled 
syringes should be reported to the sponsor in 
accordance with local regulations has been 
added. 
– 
Guidance regarding skin biopsy added. 
– 
Text describing pharmacogenomics removed. 
– 
Corrections of typographical errors. 
Original Protocol 
05-Dec-2016 
Not Applicable 


Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
5/Protocol WN40227, Version 4 
 
 
TABLE OF CONTENTS 
 
TITLE PAGE ................................................................................................................ 
1 
DOCUMENT HISTORY.............................................................................................. 
2 
TABLE OF CONTENTS............................................................................................. 
5 
PROTOCOL AMENDMENT ACCEPTANCE 
FORM........................................................................................................................... 
8 
1 SYNOPSIS................................................................................................................. 
9 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
16 
3 INTRODUCTION ..................................................................................................... 
34 
3.1 Study Rationale................................................................................................. 
35 
3.1.1 Rationale to Support Dose Selection ....................................................... 
36 
3.1.2 Rationale for Specific Inclusion/Exclusion Criteria ................................ 
40 
3.1.3 Rationale for Primary Endpoint .............................................................. 
40 
3.1.4 Research Hypothesis ................................................................................ 
40 
3.2 Background ....................................................................................................... 
40 
3.3 Benefit/Risk Assessment .................................................................................. 
42 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
44 
5 STUDY DESIGN....................................................................................................... 
46 
5.1 Overall Design .................................................................................................. 
49 
5.1.1 Independent Data Monitoring Committee and Other External  
Committees ........................................................................................................ 
49 
5.2 Number of Participants ..................................................................................... 
49 
5.3 End of Study Definition .................................................................................... 
49 
5.4 Scientific Rationale for Study Design............................................................... 
49 
5.5 Justification for Dose ........................................................................................ 
49 
6 STUDY POPULATION ............................................................................................ 
49 
6.1 Inclusion Criteria .............................................................................................. 
49 
6.2 Exclusion Criteria ............................................................................................. 
50 
6.3 Lifestyle Restrictions ........................................................................................ 
52 
6.3.1 Meals and Dietary Restrictions ............................................................... 
52 
6.3.2 Caffeine, Alcohol and Tobacco................................................................ 
52 
6.3.3 Activity ..................................................................................................... 
52 
6.4 Screen Failures.................................................................................................. 
52 
6.4.1 Rescreening and Retesting during Screening Period ........................... 
52 
7 TREATMENT ........................................................................................................... 
52 
7.1 Treatments Administered.................................................................................. 
55 
7.2 Method of Treatment Assignment .................................................................... 
56 
7.3 Blinding............................................................................................................. 
56 
7.4 Dosage Modification......................................................................................... 
57 
7.5 Preparation/Handling/Storage/Accountability.................................................. 
57 
7.5.1 Retained Samples for Bioavailability / Bioequivalence........................... 
58 
7.6 Treatment Compliance...................................................................................... 
58 
7.7 Concomitant Therapy........................................................................................ 
58 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
58 


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7.7.2 Other Restrictions and Precautions......................................................... 
59 
7.7.2.1 Management of Possible Acute Hypersensitivity Reactions to 
RO7239361........................................................................................... 
59 
7.7.2.2 Imaging Restriction and Precautions ............................................. 
59 
7.8 Treatment after the End of the Study............................................................... 
60 
8 DISCONTINUATION CRITERIA ........................................................................... 
60 
8.1 Discontinuation from Study Treatment ............................................................ 
61 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
62 
8.2 Discontinuation from the Study ........................................................................ 
62 
8.3 Lost to Follow-Up............................................................................................. 
62 
9 STUDY ASSESSMENTS AND PROCEDURES..................................................... 
63 
9.1 Efficacy Assessments........................................................................................ 
63 
9.1.1 Functional Endpoint Assessment ............................................................. 
63 
9.1.2 Myometry and Ankle Range of Motion (ROM) ........................................ 
64 
9.1.3 Imaging Assessment for the Study............................................................ 
64 
9.1.3.1 DXA................................................................................................. 
64 
9.1.3.2 Cardiac MRI (cMRI)....................................................................... 
65 
9.1.4 Exploratory Genotyping........................................................................... 
65 
9.1.5ActiMyo .................................................................................................... 
65 
9.1.6 Caregiver Video Assessment……….................................................. 
66 
9.1.7 Clinical Global Impression of Change (CGI-C) ............................... 
66 
9.1.8 Caregiver Global Impression of Change (CaGI-C) ................................. 
67 
9.1.9 Pediatric Quality of Life Inventory Multidimensional Fatigue 
Scale (PedsQL MFS) .......................................................................................... 
67 
9.2 Adverse Events ................................................................................................. 
67 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
68 
9.2.2 Method of Detecting AEs and SAEs......................................................... 
68 
9.2.3 Follow-up of AEs and SAEs..................................................................... 
69 
9.2.4 Regulatory Reporting Requirements for SAEs......................................... 
69 
9.2.5 Pregnancy ................................................................................................ 
69 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
69 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
70 
9.2.8 Other Safety Considerations .................................................................... 
70 
9.2.8.1 Injection Site Assessments............................................................... 
70 
9.2.9 Overdose or Incorrect Administration of Study Drug............................. 
71 
9.3 Safety ................................................................................................................ 
71 
9.3.1 Physical Examinations............................................................................. 
72 
9.3.2 Vital Signs................................................................................................. 
72 
9.3.3 Electrocardiograms and Echocardiograms............................................. 
72 
9.3.4 Clinical Safety Laboratory Assessments.................................................. 
73 
9.3.5 Imaging Safety Assessment ...................................................................... 
74 
9.4 Pharmacokinetics................................................................................................ 
75 
9.5 Pharmacodynamics ........................................................................................... 
75 
9.6 Pharmacogenomics ........................................................................................... 
75 
9.7 Biomarkers........................................................................................................ 
75 
9.7.1 Additional Research Collection ............................................................... 
76 
9.7.2 Immunogenicity Assessments................................................................... 
77 


Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
7/Protocol WN40227, Version 4 
 
9.7.3 RNA Transcriptome Research………………............................................. 
77 
9.7.4 RNA Expression Research of a Subset of RNA Species………………....... 
77 
9.7.5 Proteome Research………………….......................................................... 
77 
9.7.6 Metabolomic Research............................................................................. 
77 
9.7.7 Other Assessments .................................................................................... 
78 
9.8 Health Economics or Medical Resource Utilization and Health Economics… 
78 
10 STATISTICAL CONSIDERATIONS ..................................................................... 
78 
10.1 Sample Size Determination............................................................................. 
78 
10.2 Populations for Analyses ................................................................................ 
78 
10.3 Statistical Analyses ........................................................................................ .. 
79 
10.3.1 Efficacy Analyses ..................................................................................... 
80 
10.3.2 Safety Analyses.......................................................................................... 
81 
10.3.3 Other Analyses .......................................................................................... 
81 
10.3.4 Interim Analyses........................................................................................ 
81 
11 REFERENCES….............................................................................................................. 
83 
12 APPENDICES…………………........................................................................................ 
87 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................... 
88 
APPENDIX 2 STUDY GOVERANCE CONSIDERATIONS ....................................... 
94 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW UP AND 
REPORTING................................................................................................................. 
102 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS 
OF CONTRACEPTION.................................................................................................. 
106 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, DOUBLE BLIND, 
PLACEBO-CONTROLLED, STUDY TO ASSESS 
THE EFFICACY, SAFETY, AND TOLERABILITY OF 
RO7239361 IN AMBULATORY BOYS WITH 
DUCHENNE MUSCULAR DYSTROPHY 
PROTOCOL NUMBER: WN40227  
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2016-001654-18 
IND NUMBER: 
120,702 
TEST PRODUCT: 
Anti-Myostatin Adnectin (RO7239361) 
MEDICAL MONITORS: 
, M.D. 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your study monitor. 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
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1 
SYNOPSIS 
Protocol Title: A Randomized, Double Blind, Placebo-Controlled, Study to Assess the Efficacy, 
Safety, and Tolerability of RO7239361 in Ambulatory Boys with Duchenne Muscular Dystrophy 
Study Phase 2/3 Rationale 
The purpose of this study is to evaluate the efficacy, safety and tolerability of weekly subcutaneous 
(SC) doses of RO7239361 compared to placebo in ambulatory boys with Duchenne muscular 
dystrophy (DMD). 
Study Population: 
Key Inclusion Criteria: 
• Males, ≥ 6 to < 12 years of age at time of randomization 
• Diagnosis of DMD, confirmed by medical history (e.g., onset of clinical signs or symptoms 
before 5 years of age together with an elevated serum creatine kinase level observed before 
or after initial diagnosis) and by genotyping 
• Participants ≥ 15 kg 
• Ambulatory without assistance 
• Participants must be receiving corticosteroids (CS; prednisone, prednisolone, or 
deflazacort) for at least 6 months prior to the start of study drug, with no significant change 
in dosage (> 0.2 mg/kg prednisone or > 0.24 mg/kg deflazacort) or dosing regimen 
for at least 12 weeks prior to the start of study drug, with the expectation that dosage 
and dosing regimen will not change significantly for the duration of the study 
• North Star Ambulatory Assessment (NSAA) score ≥ 15 points at screening 
• 4SC ≤ 8 seconds at screening 
• Participants must agree to avoid major changes in their physical or respiratory therapy 
regimen during the double-blind phase, to the extent possible 
 
Key Exclusion Criteria: 
• Participants with cognitive impairment or behavioral issues that, in the judgement of the 
investigator, will compromise their ability to comply with study procedures 
• Participants on intermittent CS regimens with off periods of 20 days or longer (e.g.: 10 
days on, 20 days off) 
• Any change (initiation, change in drug class, dose modification unrelated to change in body 
weight, interruption or re-initiation) in prophylaxis/treatment for congestive heart failure 
(CHF) within 12 weeks prior to start of study treatment 
• Any change (initiation, change in drug class, dose modification unrelated to change in body 
weight, interruption or re-initiation) in prophylaxis/treatment for bone density within 
12 weeks prior to start of study treatment 
• Treatment with exon skipping therapies within 6 months prior to the start of study drug 
administration. 
• Treatment with ataluren currently or within 12 weeks prior to the start of study drug 
administration 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
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• Treatment with any other investigational drug (excluding deflazacort in CS dose-finding 
trials) currently or within 12 weeks prior to the start of study drug administration  
• Concomitant or previous participation at any time in a gene therapy study 
• Participants with a FVC of < 50% of predicted value (in participants able to produce a 
valid FVC, as judged by the clinical evaluator or respiratory therapist) 
• Cutaneous AEs sustained during participation in a prior clinical trial that resolved less than 
12 weeks prior to the start of study drug administration 
• Current or prior treatment within 12 weeks prior to the start of study drug administration 
with androgens or human growth hormone 
• Prior treatment with RO7239361 or any other anti-myostatin agent 
• History of lower limb fracture within 12 weeks prior to the start of study drug 
administration 
• History of upper limb fracture within 8 weeks prior to the start of study drug 
administration. 
• Any injury that may impact functional testing. Previous injuries must be fully healed 
prior to consenting. 
• Expectation of major surgical procedure, such as scoliosis surgery, during the double-blind 
phase of this study 
• Requirement of daytime ventilator assistance 
• Initiation of nighttime ventilation less than 4 weeks prior to the start of study drug 
administration 
• Expectation that daytime or nighttime ventilation may be initiated during the double-blind 
phase of this study 
• Clinical signs or symptoms of uncontrolled congestive heart failure (CHF) (American 
College of Cardiology/American Heart Associated Stage C or Stage D) 
• For participants participating in cMRI substudy: implanted ferromagnetic metal (implanted 
metal that is not ferromagnetic, such as surgical steel or titanium implants may be allowed 
if the implants will not compromise the quality of the cMRI). 
• Unwilling or unable to administer study drug at home 
 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
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Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
• 
To compare the efficacy of RO7239361 to 
placebo in ambulatory boys with Duchenne 
muscular dystrophy 
• 
The change from baseline in the North Star 
Ambulatory Assessment (NSAA) total score 
at Week 48 in RO723936-treated participants 
compared to placebo-treated participants. 
Secondary 
• To compare the efficacy of RO7239361 to placebo 
using the following tests:  
− 
4 stair climb velocity (4SCV) 
− 
Stand from supine velocity 
− 
10 M walk/run velocity 
− 
PODCI transfers and basic mobility subscale 
− 
Proximal 
lower 
extremity 
flexor 
(knee 
extension and knee flexion) strength, measured 
using manual myometry 
− 
6 Minute Walk Distance (6MWD) 
− 
Clinical Global Impression of Change 
(CGI-C) 
− 
Stride velocity recorded with ActiMyo 
 
• Change 
from 
baseline 
at 
Week 
48 
in 
RO7239361-treated 
participants 
compared 
to 
placebo- treated participants in the following  
− 
4 stair climb velocity (4SCV) 
− 
Stand from supine velocity 
− 
10 M walk/run velocity 
− 
PODCI transfers and basic mobility subscale 
− 
Proximal 
lower 
extremity 
flexor 
(knee 
extension and knee flexion) strength, measured 
using manual myometry 
− 
6-Minute Walk Distance (6MWD) 
− 
Clinical Global Impression of Change 
(CGI-C) 
− 
95th percentile stride velocity, as recorded with 
ActiMyo in a subset of the overall study 
population 
• To assess the safety and tolerability of RO7239361 in 
boys with DMD as reflected by new or worsening lab 
abnormalities (as defined by CTCAE criteria), 
serious adverse events (SAEs) and adverse events 
(AEs) leading to discontinuation.  
• Tabulations of the numbers of unique participants 
with new or worsening laboratory abnormalities, 
SAEs and AEs leading to discontinuation, in 
RO7239361 arms compared to the placebo arm.  
Tertiary/Exploratory 
• 
To assess the safety and tolerability of RO7239361 in 
boys with DMD as reflected by vital signs, 
measures of cardiac function 
 
• 
Summaries and listings of vital signs, ECG 
parameters, echocardiogram parameters. 
− 
Proportion of participants with on treatment 
adverse events in RO7239361 arms 
compared to the placebo arm 
– 
Proportion of participants with on treatment 
decrease in ejection fraction (EF), measured 
using echocardiography, in RO7239361 
arms compared to the placebo arm 
 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
12/Protocol WN40227, Version 4 
 
 
Objectives 
Endpoints 
 
 
• To compare the efficacy of RO7239361 to placebo 
using the following tests: 
- Performance of upper limb (PUL) total score 
• Change from baseline at Week 48 in RO7239361 
treated participants relative to placebo treated 
participants in: 
– Performance of upper limb (PUL) total score 
• To evaluate other measures of efficacy, quality of 
life and health care utilization 
• Change from baseline at Week 48 in RO7239361 
treated participants compared to placebo treated 
participants: 
− 
Pulmonary function tests, including FVC, 
% predicted FVC FEV1, MEP, and MIP  
− 
PODCI total score 
− 
 Caregiver Global Impression of Change  
(CaGI-C) in a subset of the overall study 
population 
− 
Pediatric Quality of Life Inventory 
Multidimensional Fatigue Scale (PedsQL 
MFS) in a subset of the overall study 
population  
− 
Cardiac magnetic resonance imaging (cMRI) 
measures of ejection fraction, fractional strain, 
and volume of fibrosis in a subset of the overall 
study population 
• Strength of elbow flexors, elbow extensors, and 
pinch, measured by manual myometry 
• Health Utilities Index III and PedsQL Family 
Impact Module scores 
• Assessments at selected timepoints during the study 
of: 
− 
Dual x-ray absorptiometry (DXA) measures 
of lean body mass, fat mass and bone mineral 
density 
− 
Activity levels in a subset of the overall study 
population, as recorded with ActiMyo 
− 
Scoring of functional assessments, as recorded 
by a subset of parents/caregivers participating 
in the caregiver video assessment 
− 
Number of falls during treatment in the 
RO7239361 arms compared with the placebo 
arm 
 
 


 
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Objectives 
Endpoints 
• To evaluate RO7239361 pharmacokinetics, 
pharmacodynamics, and immunogenicity 
• Assessments at select timepoints during the study 
of: 
− 
Serum RO7239361 concentrations 
− 
Serum free myostatin and myostatin drug 
complex concentrations 
− 
Serum ADA concentrations 
− 
Serum creatine kinase level in muscle 
• 
To explore the effect of genetic variation on target 
engagement, pharmacodynamic (PD) effects or 
functional test endpoints 
• 
Assess the impact on genetic variation in the 
DYSTROPHIN gene or in genes suspected to impact 
DMD disease expression (including but not limited 
to LTBP4, SPP1) in RO7239361 and placebo 
treated participants, on target engagement, 
pharmacodynamic (PD) and functional endpoints 
 
 
Overall Design: 
This is a multi-center, randomized, double-blind, placebo-controlled study to assess the efficacy, 
safety and tolerability of two different weekly SC doses of RO7239361 in ambulatory boys with 
Duchenne muscular dystrophy (DMD). 
Eligible participants will be randomized to receive doses of RO7239361 or placebo (1:1:1 across 
the three treatment arms). The randomization will be stratified by: 
• Age (6 through 7 and 8 through 11) 
• CS regimen: daily (prednisone, prednisolone or deflazacort) vs. intermittent (any 
non-daily dosing of prednisone, prednisolone or deflazacort) 
 
A separate randomization will be conducted for Japan (N∼15) with stratification for age only 
(6 through 7 and 8 through 11) not CS regimen. 
RO7239361 or placebo will be administered weekly. The first three doses (Days 1, 8 and 15) of 
study drug must be administered at the site. Parents/caregivers will be trained to administer SC 
injections during the first three dose administrations. Parents/caregivers can administer the 
injection at home starting at Day 22.  Site staff should ensure that the parent or caregiver is able to 
perform injections at home. Parents/caregivers will be dispensed an approximately 6- or 12-week 
supply of drug in pre-filled syringes (RO7239361 or placebo), during the double-blind phase and 
open-label (OL) extension phase, respectively, for weekly study drug/placebo administration to 
the participant. 
Study visits and endpoint measurements will occur as indicated in Table 2-1 though Table 2-4. 
After completion of this 48-week double-blind phase, participants may enter the OL phase in 
which all participants will receive active RO7239361 study drug. Participants who discontinue 


 
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the study drug at any time (i.e., early discontinuation for subjects who do not enter the OL 
extension phase or at completion of the OL extension phase) will enter a 24-week safety follow-
up phase of the study. Participants will be monitored for safety at three visits during the follow-up 
phase.  The participant will be requested to provide immunogenicity samples at all follow-up visits 
during the 24-week follow-up phase. 
Number of Participants: 
Statistical Considerations: 
Sample Size: 
Assuming the standard deviation of the NSAA is 4.4 points, with approximately 150 evaluable 
subjects, the final analysis will have 80% power to detect a between group difference of 
2.5 points. The number randomized will be increased to allow for an approximate dropout 
rate on the order of 5% at the primary analysis, so approximately 159 participants 
will be 
randomized. Approximately 15 of these participants will be randomized in Japan, and the 
remaining participants will be randomized outside of Japan. 
The final analysis will test for differences between each RO7239361 treatment and placebo in 
either direction.  The doses will be tested against placebo in a hierarchical manner, with the high 
dose (Dose 2) tested versus placebo in the first step of the hierarchy. If the null hypothesis of no 
difference between the high dose and placebo is rejected in favor of the RO7239361 dose at a two-
sided α level of 0.05, then the low dose (Dose 1) will be tested against placebo.   
The primary analysis, on the change from baseline in NSAA total score, will be conducted using 
a mixed model repeated measures (MMRM) analysis with treatment, visit, and the treatment-
by-visit interaction entered into the model as fixed effects, and participant entered as a random 
effect. The baseline value of the NSAA total score will be entered into the model as a covariate. The 
stratification factors will be entered into the model as blocks. 
Sensitivity analyses will include the following: an analysis of covariance (ANCOVA) using the 
modified intent-to-treat (mITT) data set; an ANCOVA on the mITT data set with missing data 
imputed using multiple imputations; and an MMRM analysis using the per-protocol data. 
 
 


 
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Treatment Arms and Duration: 
 
OL=open label; SC=subcutaneous. 
Study Treatment: 
Each participant will be administered weekly, SC doses of RO7239361 (previously, 
BMS-986089) or placebo for 48 weeks in a randomized, double- blind design. Participants who 
complete the 48-week double- blind phase are eligible to receive OL RO7239361 (active 
treatment) as part of an OL extension phase of this study. The OL extension phase will last up to 
192 weeks or until RO7239361 is commercially available in the subject's country, per local 
regulations, or the study is terminated by the Sponsor, whichever comes first. Please refer to Section 
7.8 for details regarding treatment after the end of study.  Doses in the OL extension phase may 
be adjusted based on emerging data. 
 
 


 
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Study Drug 
Medication 
Potency 
IP/Non-IP 
RO7239361 7.5 mg dose 
10.7 mg/mL (0.7mL/syringe) 
IP 
RO7239361 15 mg dose 
21.4 mg/mL (0.7mL/syringe) 
IP 
RO7239361 35 mg dose 
50 mg/mL (0.7mL/syringe) 
IP 
RO7239361 50 mg dose 
71.4 mg/mL (0.7mL/syringe) 
IP 
RO7239361 matching placebo 
0 mg/mL (0.7mL/syringe) 
IP 
 
 
Other medications used as support medication for preventative, diagnostic, or therapeutic reasons, 
as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. In this study, corticosteroids are considered a non-investigational 
product and will not be provided by the sponsor. 
Study drug preparation and administration instructions will be provided in a separate manual. 
 
2 
SCHEDULE OF ACTIVITIES 
Study procedures and assessments are present in Table 2-1, Table 2-2, Table 2-3, and Table 2-4. 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
17/Protocol WN40227, Version 4 
 
Table 2-1: 
Screening Procedural Outline 
 
Procedure 
Screening 
Visit 
(Day -42 to 
Day -1) 
Notes 
Eligibility Assessments 
Informed Consent 
X 
A participant is considered enrolled only when a protocol specific informed consent is signed 
Informed consent may be signed prior to Day-42. 
Register / enroll participant in IWRS 
X 
Inclusion/Exclusion Criteria 
X 
Medical History 
X 
Include disease history and any toxicities or allergies related to previous treatments. 
Concomitant Medications 
X 
Include complete history of corticosteroids. 
Physical Examination (PE) 
X 
Physical Measurements 
X 
Includes height, weight, hand circumference and ulna length; see Clinical Evaluator (CE) 
manual. 
Vital Signs 
X 
Includes body temperature (recommend using tympanic thermometer), respiratory rate, and 
seated blood pressure and heart rate. Blood pressure and heart rate should be measured after the 
participant has been resting quietly for at least 5 minutes. 
Electrocardiogram (ECG) 
X 
ECG should be recorded after the participant has been supine for at least 5 minutes. See Eli 
150c/250c User Guide 
Echocardiogram 
X 
See ECHO Manual 
Laboratory Assessments 
X 
Section 9.3.4 
Urinalysis 
X 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
18/Protocol WN40227, Version 4 
 
Table 2-1: 
Screening Procedural Outline 
 
Procedure 
Screening 
Visit 
(Day -42 to 
Day -1) 
Notes 
Cardiac MRI (At select U.S. centers only) 
X 
See Section 9.1.3.2 and the imaging procedure manual. 
Baseline cMRI should be obtained between Day -40 and Day -14. The adequacy of cMRI scan 
should be confirmed by the imaging vendor prior to randomization. 
Subjects enrolled at select U.S. centers will be required to attempt to complete the cMRI. 
DXA 
X 
See Section 9.1.3.1 and the imaging procedure manual; 
Baseline DXA should be obtained between Day -42 and Day -14. Adequacy of DXA scan 
should be confirmed by the imaging vendor prior to randomization. 
DXA is not required for subjects enrolled at sites in Germany. 
NSAA 
X 
See the Clinical Evaluator Manual.  The NSAA assessment must be performed to determine 
subject eligibility (NSAA ≥15 total score inclusion criterion), videotaped for ATOM review and 
confirmed to be adequate prior to randomization 
TFTs 
X 
Includes 4SC, 10 m walk/run, stand from supine 
At screening visit: 4SC must be ≤ 8 seconds. See CE Manual; 
A videotape of screening TFTs must be reviewed by ATOM and confirmed adequate prior to 
randomization; see Bracket Videographer Manual 
6MWD 
X 
A videotape of screening 6MWD must be reviewed by ATOM and confirmed adequate prior to 
randomization. 
PFTs 
X 
To include FVC, % predicted FVC, FEV1, MEP, and MIP. See PFT Site Manual. 
ActiMyo 
X 
Subjects at selected sites who agree to participate will wear the ActiMyo device from screening until 
Day 1.  See the ActiMyo manual. 
Adverse Event Reporting 
Monitor for Serious Adverse Events 
X 
All SAEs must be collected from the date of participant’s written consent until 50 days post 
discontinuation of dosing in the present study. If the participant enters a separate rollover 
treatment study of RO7239361, the participant’s SAEs will be reported in that study. 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
19/Protocol WN40227, Version 4 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
Physical Examination 
(PE) 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Targeted PE 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
See Section 9.3.1 
Monitor Injection Sites 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Report findings as AEs, as appropriate. 
It is strongly recommended that 
photographs of injection site reactions 
without personally identifying 
information be obtained for submission 
to the sponsor or designee 
Some subjects with injection site 
reaction or rash may be asked to 
participate in additional procedures to 
determine type of immune reaction. See 
Section 9.2.8.1. 
Weight 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See Study Procedure Manual 
Height 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See CE Manual 
Ulna Length 
X 
 
 
 
 
 
 
 
 
 
 
 
See CE Manual  
Only to be measured instead of 
standing height if height cannot be 
measured 
Hand Circumference 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See CE Manual 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See note in screening procedures. 
Con med assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Include corticosteroids 
Physical therapy and 
respiratory therapy 
assessment 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Assess current physical and respiratory 
therapy regimen 
Echocardiogram 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
See ECHO Manual 


 
 
 
 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
20/Protocol WN40227, Version 4 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
Electrocardiogram 
(ECGs) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
ECGs should be recorded after the 
participant has been supine for at least 5 
minutes. See Eli 150c/250c User Guide 
Laboratory 
Assessments 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Section 9.3.4 
Placement of an intravenous lock is 
allowed for onsite visits when multiple 
blood draws are required. 
Urinalysis 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood PK Sampling 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
See section 9.4 for the sample 
collection schedule. Must be collected 
prior to administration of study drug. 
Immunogenicity 
Sampling 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Must be collected prior to 
administration of study drug. 
In the event of a positive 
immunogenicity response, additional 
neutralizing antibody (NAB) testing 
will be conducted. 
Serum Free Myostatin 
and Myostatin-Drug 
Complex 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Myostatin-drug complex will not be 
analyzed at baseline 
Must be collected prior to 
administration of study drug. 
Serum Biomarkers 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Additional Research 
Sample 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Exploratory 
genotyping sample 
X 
 
 
 
 
 
 
 
 
 
 
 
TFTs 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual; TFT 
assessment must be videotaped for 
ATOM review at D1, Wk 24 and Wk 
48 visits 


 
 
 
 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
21/Protocol WN40227, Version 4 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
6MWD 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual; 6MWD 
assessment must be videotaped for 
ATOM review at D1, Wk 24 and Wk 
48 visits 
ActiMyo 
X 
(Scr to 
Day 1) 
 
 
 
X 
(Wk 6 
to 
Wk 12) 
 
X 
(Wk 18 
to 
Wk 24) 
 
X 
(Wk 30 to 
Wk 36) 
 
X 
(Wk 42 to 
Wk 48) 
 
Subjects at selected sites who opt in will 
wear ActiMyo device at home and 
during visits. See ActiMyo manual. 
NSAA 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual; NSAA 
assessment must be videotaped for 
ATOM review at D1, Wk 24 and Wk 
48 visits 
PFTs 
X 
 
 
 
 
 
 
X 
 
 
 
X 
To include FVC, % predicted FVC, 
FEV1, MEP, and MIP. 
See PFT Site Manual 
Upper & Lower 
Extremity Myometry 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See Clinical Evaluator Manual; 
myometry assessment must be 
videotaped for ATOM review at D1, 
Wk 24 and Wk 48 visits 
Grip & Pinch Strength 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See Clinical Evaluator Manual 
PUL 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See Clinical Evaluator Manual; PUL 
assessment must be videotaped for 
ATOM review at D1, Wk 24 and Wk 
48 visits 
Right Ankle Range of 
Motion 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See Clinical Evaluator Manual 
Caregiver video 
assessment 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Subjects at selected sites who opt in 
will record videos at selected 
timepoints of the study (as specified), 
or at any applicable visits after start 
date. The visit window is +2 weeks. 
See Section 9.1.6 and the 
parent/caregiver manual. 


 
 
 
 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
22/Protocol WN40227, Version 4 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
PODCI 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Completed by Parent/Caregiver (should 
be the same parent/caregiver at each 
visit) 
HUI-3 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Completed by Parent/Caregiver (should 
be the same parent/caregiver at each 
visit) 
Health Care Resource 
Utilization 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Protocol mandated procedures, test & 
encounters are excluded 
PedsQL Family 
Impact Module 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Completed by Parent/Caregiver (should 
be the same parent/caregiver at each 
visit) 
CaGI-C 
 
 
 
 
 
 
 
 
 
 
 
X 
Completed by parent/caregiver (who 
has been involved in the study from 
baseline) who opt in at selected sites 
CGI-C 
 
 
 
 
 
 
 
 
 
 
 
X 
Completed by Clinician 
(e.g., Principal Investigator  or other 
clinician who has interacted with 
the individual from baseline) 
CaGI-C 
 
 
 
 
 
 
 
 
 
 
 
X 
Completed by parent/caregiver (who 
has been involved in the study from 
baseline) who opt in at selected sites 
Pediatric Quality of 
Life Inventory 
Multidimensional 
Fatigue Scale (PedsQL 
MFS)  
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Completed by parent/caregiver who opt 
in at selected sites (should be the same 
parent/caregiver at each visit) 
Cardiac MRI 
 
 
 
 
 
 
 
 
 
 
 
X 
Visit window +/- 1 week. Conducted at 
early termination if ≥ 24 weeks from 
previous cMRI. 
See Section 9.1.3.2 and the imaging 
procedure manual.  cMRI will be 
completed at select U.S. sites only. 
Subjects enrolled at select U.S. centers 


 
 
 
 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
23/Protocol WN40227, Version 4 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
will be required to attempt to complete 
the cMRI. 
DXA 
 
 
 
 
 
 
 
X 
 
 
 
X 
Visit window +/- 1 week. Not required 
at early termination visit. 
See Section 9.1.3.1 and the DXA 
Scanning Guide. 
DXA is not required for subjects 
enrolled at sites in Germany or for early 
termination visits. 
Monitor for Non- 
Serious Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
All participants administered study 
drug will be closely monitored for AEs 
including possible immunogenicity-
related AEs, such as rash, fever. 
Injection sites will be evaluated at each 
visit (see above). 
Falls should be assessed at each study 
visit b. 
Monitor for Serious 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
All SAEs must be collected from the 
date of participant’s written consent 
until 50 days 
post discontinuation of dosing. 
Falls should be assessed at each study 
visit b. 
Randomize 
X 
 
 
 
 
 
 
 
 
 
 
 
Access IWRS to obtain 
study drug kit 
assignment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Access IWRS as needed to obtain 
sufficient drug. Access IWRS as 
needed to replace kits. 




 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
25/Protocol WN40227, Version 4 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
(PE) 
 
 
 
 
 
 
 
 
X 
 
 
Targeted PE 
X 
 
 
 
X 
 
X 
X 
 
 
X 
See Section 9.3.1; to be assessed every 24 weeks 
after Wk 48 of the OL phase 
Monitor Injection 
Sites 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Report findings as AEs, as appropriate. 
It is strongly recommended that photographs of 
injection site reactions without personally 
identifying information be obtained for 
submission to the sponsor or designee. 
Some subjects with injection site reaction or 
rash may be asked to participate in additional 
procedures to determine type of immune 
reaction. See Section 9.2.8.1 
Vital Signs 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
See note in screening procedures 
Con med assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Include corticosteroid assessment 
Physical therapy and 
respiratory therapy 
assessment 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Assess current physical therapy and respiratory 
therapy 
Weight 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
See Study Procedure Manual 
Height 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
See CE Manual 
Ulna Length 
X 
 
 
 
 
 
 
 
 
 
X 
See CE Manual  
Only to be measured instead of standing height if 
height cannot be measured. 
Hand Circumference 
 
 
 
 
 
 
X 
 
X 
 
X 
See CE Manual; to be assessed every 24 weeks after 
Wk 48 of the OL phase 
Echocardiogram 
 
 
 
 
 
 
X 
 
X 
 
X 
See ECHO Manual; to be assessed every 24 weeks 
after Wk 48 of the OL phase 


 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
26/Protocol WN40227, Version 4 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(ECGs) 
 
 
 
 
 
 
 
 
X 
 
X 
ECGs should be recorded after the participant has 
been supine for at least 5 minutes. See Eli 
150c/250c User Guide; to be assessed every 24 
weeks after Wk 48 of OL phase. 
Laboratory Tests 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Placement of an intravenous lock is allowed for 
onsite visits when multiple blood draws are 
required.  
Urinalysis 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Monitor for Non-
Serious Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See notes above. 
Falls should be assessed at each study visit b. 
Monitor for Serious 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See notes above. 
All SAEs must be collected from the date of 
participant’s written consent until 50 days post 
discontinuation of dosing in the present study. If 
the participant enters a separate rollover treatment 
study of RO7239361, the participant’s SAEs will 
be reported in that study. 
Falls should be assessed at each study visit b. 
Blood PK Sampling 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Must be collected prior to administration of study 
drug. See section 9.4 for the sample collection 
schedule. 
TFTs 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at Open Label Week 1 Visit must be 
obtained prior to dosing; TFT assessment must be 
videotaped for ATOM review at Wk 24 and Wk 
48 visits. To be assessed every 24 weeks after Wk 
48 of the OL phase. 


 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
27/Protocol WN40227, Version 4 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
6MWD 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual 
Functional measures at OL Week 1 visit must be 
obtained prior to dosing; 6MWD assessment must 
be videotaped for ATOM review at Wk 24 and 
Wk 48 visits. To be assessed every 24 weeks after 
Wk 48 of the OL phase. 
NSAA 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing; NSAA assessment must be 
videotaped for ATOM review at Wk 24 and Wk 
48 visits. To be assessed every 24 weeks after Wk 
48 of the OL phase. 
ActiMyo 
 
 
 
 
X 
(Wk 6 
to  
Wk 12) 
 
X  
(Wk 18 
to  
Wk 24) 
X 
(Wk 30 
to Wk 
36) 
X 
(Wk 42 
to  
Wk 48) 
 
 
Subjects at selected sites who opt in during the 
double-blind phase of the study will wear the 
ActiMyo device at home and during visits of the 
OL phase. See the ActiMyo manual. 
PUL 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at Open Label Week 1 Visit must be 
obtained prior to dosing; PUL assessment must be 
videotaped for ATOM review at Wk 24 and Wk 
48 visits. To be assessed every 24 weeks after Wk 
48 of the OL phase. 
PODCI 
 
 
 
 
 
 
X 
 
X 
 
 
Completed by parent/caregiver (should be the 
same parent/caregiver at each visit) 
CGI-C 
 
 
 
 
 
 
 
 
X 
 
 
Completed by clinician (e.g., Principal 
Investigator or other clinician who has 
interacted with the individual from baseline) 
Should be the same clinician at both visits. 


 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
28/Protocol WN40227, Version 4 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
Sampling 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Must be collected prior to administration of study 
drug. In the event of a positive immunogenicity 
response, additional NAB testing will be 
conducted. To be assessed every 24 weeks after Wk 
48 of the OL phase. 
Serum Free 
Myostatin and 
Myostatin-Drug 
Complex 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Must be collected prior to administration of 
study drug. 
Serum Biomarkers 
 
 
 
 
X 
 
X 
X 
X 
 
 
PFTs 
X 
 
 
 
 
 
X 
 
X 
 
X 
To include FVC, % predicted FVC, FEV1, MEP, 
and MIP  
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing. To be assessed every 24 weeks after 
Wk 48 of the OL phase. 
Upper & Lower 
Extremity Myometry 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing; myometry assessment must be 
videotaped for ATOM review at Wk 24 and Wk 
48 visits. To be assessed every 24 weeks after Wk 
48 of the OL phase. 
Grip & Pinch 
Strength 
X 
 
 
 
 
 
X 
 
X 
 
 
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing.  
Right Ankle Range of 
Motion 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing. To be assessed every 24 weeks after 
Wk 48 of the OL phase. 


 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
29/Protocol WN40227, Version 4 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Caregiver video 
assessment 
 
 
 
 
 
 
X 
 
X 
 
 
Subjects at selected sites who opt in to 
participate in the caregiver video assessment 
during the double-blind phase will record 
videos at the specified timepoints. Visit 
window: + 2 weeks. See Section 9.1.6 and the 
Parent/Caregiver manual. 
CaGI-C 
 
 
 
 
 
 
 
 
X 
 
 
Completed by parent/caregiver (who has been 
involved in the study from baseline) who opt in 
at selected sites. Should be the same 
parent/caregiver at each visit. 
HUI-3 
 
 
 
 
 
 
X 
 
X 
 
 
Completed by parent/caregiver (should be the 
same parent/caregiver at each visit) 
Health Care Resource 
Utilization 
X 
 
 
 
 
 
X 
 
X 
 
 
Protocol mandated procedures, tests, and 
encounters are to be excluded. 
PedsQL Family 
Impact Module 
 
 
 
 
 
 
X 
 
X 
 
 
Completed by parent/caregiver (should be the 
same parent/caregiver at each visit) 
Pediatric Quality of 
Life Inventory 
Multidimensional 
Fatigue Scale 
(PedsQL MFS) 
 
 
 
 
 
 
X 
 
X 
 
 
Completed by parent/caregiver who opt in at 
selected sites (should be the same 
parent/caregiver at each visit).  
Cardiac MRI 
(At selected sites) 
 
 
 
 
 
 
 
 
X 
 
X* 
Visit window +/- 1 week. 
Conducted at early termination if ≥ 24 weeks from 
previous cMRI. 
See the imaging procedure manual. *To be 
assessed every 48 weeks during the OL phase. 




 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
31/Protocol WN40227, Version 4 
 
a Week 1 of the open-label (OL) phase occurs one week after the end of the Week 48 double-blind visit. After Week 24 of the OL phase, visits will take place every 
12 weeks, with some assessments performed every 12, 24, or every 48 weeks as specified on the schedule of activities. The OL phase will last up to 192 weeks or 
until RO7239361 is commercially available in the subject’s country, per local regulations, or the study is terminated by the Sponsor, whichever occurs first. 
Please refer to Section 7.8 for details regarding treatment after the end of study. 
In the event of multiple procedures are required at a single timepoint, the following is a list of procedures from highest priority to low: 
1) Safety (ECG, echocardiogram) 
2) Safety (clinical labs) 
3) Pharmacokinetic Sampling 
4) Biomarker Sampling 
b 
Falls will be reported only as an adverse event if worsening (e.g., more frequent falls) compared with pre-treatment. 


  
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
32/Protocol WN40227, Version 4 
 
Table 2-4: 
Post Study Drug/Placebo Administration Follow-up Procedural Outline 
 
Procedure 
Follow-up 
Week 8 
± 1 week 
Follow-up 
Week 16 
± 1 week 
Follow up 
Week 24 
± 1 week 
Notes 
NSAA 
X 
X 
X 
For participants who discontinue study drug before Week 48 of the double-blind 
Phase, a follow-up visit will be schedule to coincide with the date at which the 
Week 48 visit of the double-blind phase would have occurred, when possible. 
Adverse Event Reporting 
 
 
 
Monitor injection site 
X 
X 
X 
Report findings as AEs, as appropriate. 
It is strongly recommended that photographs of injection site reactions without 
personally identifying information be obtained for submission to the sponsor or 
designee. 
Some subjects with injection site reaction or rash may be asked to participate in 
additional procedures to determine type of immune reaction. See Section 9.2.8.1 
Monitor for previously 
reported or new onset of non- 
serious adverse events 
X 
X 
X 
All non-serious adverse events must be collected until 50 days post discontinuation 
of dosing in the present study. If the participant enters a separate rollover treatment 
study of RO7239361, the participant’s non-serious adverse events will be reported 
in that study 
Monitor for previously 
reported or new onset of 
serious adverse events (SAEs) 
X 
X 
X 
All SAEs must be collected from the date of participant’s written consent until 
50 days post discontinuation of dosing in the present study. If the participant 
enters a separate rollover treatment study of RO7239361, the participant’s SAEs 
will be reported in that study. 
Safety Assessments 
ECG 
 
 
X 
Only required for participants who do not participate in a separate rollover study and 
who discontinue study drug due to cardiovascular concerns. 
Echocardiogram 
 
 
X 
Only required for participants who do not participate in a separate rollover study and 
who discontinued study drug due to cardiovascular concerns. 
 
 


  
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
33/Protocol WN40227, Version 4 
 
Table 2-4: 
Post Study Drug/Placebo Administration Follow-up Procedural Outline 
 
Procedure 
Follow-up 
Week 8 
± 1 week 
Follow-up 
Week 16 
± 1 week 
Follow up 
Week 24 
± 1 week 
Notes 
Laboratory Assessments 
X 
X 
X 
Only required for participants who do not participate in a separate rollover study and 
who discontinued study drug due to an abnormal laboratory result. Lab results should 
be followed until the participant’s lab values return to baseline or are considered 
stable by the investigator. 
Immunogenicity 
X 
X 
X 
Required for all patients who do not participate in a separate rollover study.   
In the event of a positive immunogenicity response, additional NAB testing will be 
conducted. 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
34/Protocol WN40227, Version 4 
 
 
3 
INTRODUCTION 
DMD is an X-linked human disease that affects 1 in 3600-6000 live male births, with an estimated 
15,000 patients with the disease in the United States. DMD results from mutations in the 
DYSTROPHIN gene (locus Xp21.2), that lead to absent or defective dystrophin production
 The 
clinical manifestation of this molecular lesion is progressive weakness and limitation in motor 
capacity, with proximal muscles affected initially followed by distal muscles. Cardiac and 
respiratory failure typically begin to develop in adolescence and lead to death in the second or 
third decade of life. Current standard of care is limited to symptomatic treatment, including 
medical and physical therapies to improve cardiac and respiratory function as well as 
corticosteroids to improve skeletal muscle strength and function. However, corticosteroids are 
associated with significant adverse side effects, including obesity, diabetes, short stature, 
osteopenia, and fracture.2 Translarna (ataluren) received a conditional marketing authorization in 
the European Union with a restricted indication for the treatment of DMD specifically resulting 
from a nonsense mutation in the DYSTROPHIN gene. Exondys51 (eteplirsen) received 
accelerated approval by the U.S. FDA for treatment of DMD resulting from mutations amenable 
to skipping exon 51. As both Translarna and Exondys51 target restricted populations with specific 
mutations, the unmet need for safe and effective treatments in DMD remains significant. 
Myostatin, also known as growth and differentiation factor-8 (GDF-8), is a member of the 
transforming growth factor-β (TGF-β) superfamily of secreted growth factors. It is a negative 
regulator of skeletal muscle growth and development that is expressed predominantly in skeletal 
muscle beginning at embryogenesis and persisting through adulthood. Nonclinical models support 
the anti-myostatin mechanism as potentially efficacious in DMD. Deletion of the Myostatin gene 
from mdx mice, the most commonly used mouse model of DMD, which carries a premature stop 
codon in exon 23 of DYSTROPHIN, resulted in attenuation of the dystrophic phenotype relative to 
mdx mice with intact Myostatin genes.3,4 Similarly, weekly administration of anti-myostatin 
monoclonal antibodies to mdx mice resulted in increases in muscle size and strength.5 
RO7239361 (previously, BMS-986089) is a bivalent human anti-myostatin adnectin, which has 
been formatted with a human IgG1 Fc tail to prolong its half-life in circulation. RO7239361 is 
being developed as a once weekly, subcutaneously administered therapeutic to increase muscle 
mass and strength. RO7239361 has a unique mechanism of action (MOA) that includes the 
competitive inhibition of Alk4/5 (signaling receptor) recruitment and binding to free myostatin or 
the myostatin-ActRIIb complex. This MOA leads to the inhibition of downstream pSMAD2/3 
intracellular signaling with physiological consequences of increased muscle volume and body 
weight. 54, 55 RO7239361 is being developed as a potential therapy to improve muscle function 
in DMD. As most ambulatory DMD patients are treated with corticosteroids (CS), in this 
study of ambulatory patients with DMD, RO7239361 will be given to subjects on stable CS 
therapy. 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
35/Protocol WN40227, Version 4 
 
3.1 
Study Rationale 
Study WN40227 is a multi-center, randomized, double-blind, placebo-controlled study to assess 
the efficacy, safety, and tolerability of two different weekly subcutaneous (SC) doses of 
RO7239361 in ambulatory boys aged ≥ 6 to < 12 years with DMD. 
DMD is caused by mutations within the DYSTROPHIN gene that result in loss of the mRNA 
reading frame, severely limiting dystrophin protein production.6  The DYSTROPHIN gene lies on 
the X chromosome and thus DMD is primarily expressed in boys. The disease manifests as 
progressive weakness of skeletal, respiratory, and cardiac muscles due to the absence of dystrophin 
in the subsarcolemmal cytoskeleton.7 Progressive weakness and contractures lead to loss of 
ambulation by age 13 and death from cardiorespiratory failure by the late 20s to early 30s.8 In the 
absence of supportive treatment, patients rarely survive beyond their teens.9 Advances in 
management, including CS use, physical therapy for contractures, ventilatory support, spinal 
surgery, and cardiac management have increased the life expectancy for patients with DMD.9,10,11 
With these advances, aggressively managed patients may ambulate beyond 14 years of age and 
survive into their early 30s.9,10 
Although advances in the management of DMD have improved survival, chronic CS treatment is 
associated with adverse side effects that contribute to morbidity in DMD.8,11 While Translarna 
(ataluren) has received a conditional marketing authorization in the EU for the treatment of DMD 
resulting from a nonsense mutation in the DYSTROPHIN gene,12 this treatment is restricted to the 
15% of patients with DMD with this type of mutation 12,13 Similarly, Exondys51 (eteplirsen) has 
received U.S. FDA approval for treatment of DMD resulting from mutations amenable to exon 
51 skipping, roughly only 13% of the DMD population. Thus, there remains a significant unmet 
medical need for novel agents to treat DMD. 
Data from prior and ongoing clinical studies suggest that RO7239361 is generally safe and well 
tolerated and has expected effects on pharmacodynamic endpoints. 
A first-in-human (FIH) assessment of RO7239361 (Study CN001001), a combined single-
ascending dose (SAD)/multiple-ascending dose (MAD) study to investigate the safety, 
tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity in healthy adult subjects, 
showed that single and multiple doses (of up to 180 mg weekly) of RO7239361 were generally safe 
and well tolerated. The most common adverse events (AEs) considered by the investigator to be 
related to study drug were mild or moderate injection site reactions, and that, in most cases, did 
not require treatment. There were no acute hypersensitivity reactions during this study. The 
presence of anti-drug antibodies (ADAs) did not appear to affect the safety or exposure of 
RO7239361 in healthy subjects. Administration of both single and multiple doses of RO7239361 
produced dose-dependent reductions in free serum myostatin and increases in myostatin-drug 
complex consistent with target engagement. Findings supporting the expected pharmacodynamic 
(PD) effects of RO7239361 include increases in whole right thigh muscle volume (measured by 
magnetic resonance imaging) and increases in the change from baseline in the percentage of lean 
body mass (as measured by dual X-ray absorptiometry [DXA]). 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
36/Protocol WN40227, Version 4 
 
 
Study WN40226 is a Phase 1b/2, multi-center, randomized, placebo-controlled, double-blind, 
multiple-ascending SC dose study in ambulatory boys ages ≥ 5 to < 11 years with DMD who 
are receiving CS. This study was designed as a dose-ranging study to characterize the safety, 
pharmaockinetics, target engagement (i.e., myostatin suppression) and the relationship between 
pharmaockinetics and target engagement over at least 3 doses in boys with DMD. As of 8 
February 2018, all 43 patients randomized had completed the 24-week double-blind phase of the 
study. In all, 42 patients completed the 48-week OL phase and 41 entered into the OL extension 
phase. Two patients withdrew from the study for non-safety reasons.  The study met its primary 
objective of showing safety and tolerability of RO7239361. The most common AEs that were 
considered by the investigators to be related to study drug were mild to moderate injection-site 
reactions that resolved without change to study treatment; there were no acute hypersensitivity 
reactions associated with study drug reported. Immunogenicity data from 43 gs showed a single 
value of low positive ADA titer in 1 patient who had received RO7239361. 
Pharmacokinetic (PK) data from Panels 1 to 3 (which included all three doses tested) show 
dose-related increases in peak and overall exposure, which appear to be dose proportional. 
Furthermore, an effect of body weight on the RO7239361 pharmacokinetics has been such 
that with increasing body weight, the clearance increases. Preliminary target engagement 
data from Panels 1 to 3 show robust dose-related increases in free serum myostatin suppression. 
As shown by the population PK/PD model, the three different dose levels achieved 77%, 92%, and 
97% reduction in serum-free myostatin. 
Further information regarding the available clinical data of RO7239361 in healthy volunteers 
and patients with DMD can be found in the Investigator's Brochure (IB). 
3.1.1 
Rationale to Support Dose Selection 
Two doses of RO7239361 were selected for this study based on interim data from 
Study WN40226; doses that are safe and were predicted to produce a moderate level of free 
myostatin suppression (≥ 70% relative to baseline) and a second dose that is safe and was predicted 
to produce a higher level of free myostatin suppression (≥ 90% relative to baseline). 
Whereas statistically significant increases in muscle volume were observed at > 80% suppression 
of free myostatin levels relative to baseline in a dose ranging study in cynomolgus monkeys, 
numerical but non statistically significant increases were observed at approximately 54% 
suppression relative to baseline following administration of RO7239361 in that study. Similarly, in 
Study CN001001, the multiple dose study in normal healthy subjects, statistically significant 
increases in muscle volume were observed for RO7239361 versus placebo at doses that sustained 
free serum myostatin suppression above 68% at the time of MRI assessment (Day 57). In that same 
study, no significant increases in muscle volume were observed at doses or regimens that 
generated a suppression of approximately 42% or lower on Day 57. The increase in muscle volume 
observed in monkeys and humans following RO7239361 administration is expected to correlate 
with an increase in thigh muscle to non-contractile tissue fraction in children with DMD. 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
37/Protocol WN40227, Version 4 
 
Given that increase in muscle mass and strength mediated by RO7239361 induced suppression 
of free myostatin is the underlying mechanism that is expected to ultimately drive the efficacy 
of RO7239361 in patients with DMD, dose selection for Study WN40227 is based on target 
engagement, i.e., free myostatin suppression. 
All available PK and free myostatin data following administration of 4 mg QW and 12.5 mg QW 
doses from Study WN40226 were analyzed in an interim analysis (Interim Analysis 1). Data were 
modeled using a population PK/PD model based on the concept of target mediated drug 
disposition (TMDD). Using the estimates of the PK/PD model parameters and the associated 
variabilities, the PK and free myostatin suppression profile following various doses in an 
ambulatory DMD population were obtained. The population of subjects in the simulations reflected 
the age (6 to 12 years) and weight (≥15 kg) of ambulatory DMD subjects in Study WN40227. 
Simulations were performed for 1000 subjects in each 5 kg weight bin. Based on the results of the 
simulations, a fixed dose by weight tier dosing strategy was chosen. Accordingly, doses for 
subjects will be based on their respective weight tier, namely Weight Tier 1: ≥ 15 to ≤ 40 kg, 
or Weight Tier 2: > 40 kg. This dosing strategy was intended to provide similarity in levels of 
exposure and target suppression for subjects within a given weight tier targeting the achievement 
of either ≥ 70% (Dose Level 1) or ≥ 90% (Dose Level 2) suppression of free myostatin at trough. 
Doses selected for Study WN40227 are as follows: 
 
Table 3.1.1-1: 
Dose Level 1, targeting moderate level of suppression: (≥ 70% 
suppression at trough) 
 
Dose Level 
Body Weight tier 
Body Weight range 
Dose 
1 
1 
≥ 15 to ≤ 40 kg 
7.5 mg QW 
1 
2 
> 40 kg 
15.0 mg QW 
 
 
Table 3.1.1-2: 
Dose Level 2, targeting high level of suppression: (≥ 90% 
suppression at trough) 
 
Dose Level 
Body Weight tier 
Body Weight range 
Dose 
2 
1 
≥ 15 to ≤ 40 kg 
35 mg QW 
2 
2 
> 40 kg 
50 mg QW 
 
The dose may be adjusted when a subject’s weight exceeds or drops below the dosing weight tier 
to which he was originally assigned by > 2 kg, confirmed by repeat. 
The population PK/PD model was further developed utilizing more observations, including the 
top dose data from Study WN40226 (see the IB). This model predicts similar reductions of free 
serum myostatin of over 90% for both doses tested. In healthy subjects, the pre-filled syringe  (PFS) 
achieved approximately 1.6-fold higher exposure than the vial formulation. If this would also be 
the case in patients with DMD, the exposure achieved in this study with the PFS at the top dose 


 
A nti -M y ost ati n A d necti n, ( R O 7 2 3 9 3 6 1) —F.  H off m a n n - L a R oc he Lt d 
3 8 /Pr ot oc ol W N 4 0 2 2 7, Versi o n 4  
 
wo ul d still be lo wer t ha n t he e x pos ure ac hie ve d wit h 1 8 0 m g i n  healt h y s u bjects. T he dr u g was 
well tolerate d u p to doses of 1 8 0 m g Q W i n healt h y vol u nteers.  Alt ho u g h t he doses ma y gi ve hi g her 
ser u m m yostati n re d uctio n as i nitiall y e x pecte d, tiss ue le vel m yostati n re d uctio n is u nk no w n. 
T here ma y be mea ni n gf ul differe nces i n tiss ue effects , a n d t herefore t he co nti n ue d use of t he selecte d 
doses is j ustifie d.  
3. 1. 2  
R ati o n al e f or S p e cifi c I n cl u si o n/ E x cl u si o n Crit eri a  
A ge R a n ge:  
A mi ni m u m  a ge of i ncl usi o n of 6 years  is pla n ne d, as c hil dre n y o u n ger t ha n 6 years  are less li kel y 
t o c o nsiste ntl y u n derst a n d a n d  be  a bl e t o c o o perat e wit h  perf or mi n g  t he f u ncti o nal e n d p oi nts, s uc h 
as t he NS A A , relia bl y. A n  u p per  a ge li mit f or i ncl usi o n of  < 1 2  years  is pla n ne d  t o e na ble  a f oc us 
o n c hil dre n w h o  are a ble t o perf or m  t he f u nctio nal e n d poi nts a n d w h ose  l o wer e xtre mities ha ve  s o me 
i ntact m uscle  tiss ue. R O 7 2 3 9 3 6 1 is e x pecte d t o preser ve  a n d i m pr o ve m uscle  stre n gt h pri maril y  
b y  i ncreasi n g t he size of e xisti n g m uscle  fi bers. T heref ore,  it is a ntici pate d t hat t he o pti mal  effect  
of R O 7 2 3 9 3 6 1 o n a m b ulat or y D M D  patie nts  will  be  bef ore  l o wer e xtre mit y m uscle  fi bers ha ve  bee n  
c o m pletel y re place d b y  fat a n d fi br osis.  A f urt her rati o nale f or li miti n g t he a ge ra n ge i n t his st u d y 
is t o mi ni mize varia bilit y wit h  res pect t o t he ti mi n g a n d e xte nt of f u ncti o nal a n d p h ysical deficits,  
a n d d u e t o t he patie nt’s  a ge, gr o wt h, mat urit y,  a n d c o nc o mita nt me dicati o ns.  B ot h  n at ural  hist or y 
a n d cli nical trial dat a  ha ve  hi g hli g hte d  t he si g nifica nt varia bilit y  i n  f u ncti o nal e n d p oi nts.1 6, 1 7, 1 8  
Ke y  a p pr o ac h es  t o mi ni mizi n g  t his varia bilit y  i ncl u de restricti n g  t he a ge ra n ge f or  i ncl usi o n, 
t here b y re d uci n g varia bilit y  ste m mi n g fr o m gr o wt h. 
N S A A M i ni m u m S core: 
It was rece ntl y re porte d  2 6 t hat i n a m b ula nt bo ys, a baseli ne total li nearize d N S A A score of 
5 0 poi nts  (∼1 6 of t he ra w scale) i m plies t hat t he bo ys are ver y u nlikel y to lose a m b ulatio n o ver t he 
co urse of a 2- year st u d y. It has also bee n o bser ve d o n t he basis of  e mer gi n g data fro m 
St u d y  W N 4 0 2 2 6 i n a m b ula nt bo ys wit h DM D  a ge d 5- 1 0 years at ra n do mizatio n t hat t here was 
a n i ncrease d rate of decli ne i n f u nctio n a n d i ncrease d rate of loss of a m b ulatio n for s u bjects wit h at 
a tot al score belo w 1 5  poi nts . A mi ni m u m N S A A score is pla n ne d  to li mit t he partici patio n to 
patie nts w ho  are not e x pecte d to lose a m b ulatio n d uri n g t he st u d y perio d  a n d w ho  will be a ble to  
co nti n ue to partici pate i n ke y f u nctio nal assess me nts. T he s pecific c utoff score of 1 5 poi nts at 
scree ni n g will allo w  a foc us o n t he i ncl usio n of patie nts w ho are a ble to p artici pate i n  ke y st u d y 
assess me nts t hro u g ho ut t he st u d y , wit ho ut bei n g too stri n ge nt. It  is i nte n de d to mi ni mize 
varia bilit y  of t he f u nctio nal  assess me nts  a n d e x pecte d disease pro gressio n , gi ve n t hat t he patie nts 
are ver y u nlikel y to lose a m b ulatio n o ver t he co urse of 2 year s. 
Use of C ortic oster oi ds:  
As  C S   ha ve de m o nstrate d  be nefit   o n m ot or  f u ncti o n i n b o ys  wit h  D M D 1 9 , b o ys   i ncl u de d i n 
t his  st u d y will   be re q uire d t o be   o n  a C S   (e. g.,  pre d nis o ne/ pre d nis ol o ne  or deflazac ort)  f or at 
least 6 m o nt hs  pri or  t o t h e start of st u d y treat me nt, wit h  n o si g nifica nt c ha n ge i n d osa ge or d osi n g 
re gi me n  f or  at  least 1 2  wee ks  pri or  t o  t he  start  of  st u d y  treat me nt.  T he  g oal of  t his i ncl usi o n 
criteri o n is t o c o ntr ol varia bilit y  i n m ot or   f u ncti o n a n d stre n gt h ste m mi n g fr o m C S  use.  


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
39/Protocol WN40227, Version 4 
 
Both prednisone/prednisolone and deflazacort have been shown to be effective in increasing and 
preserving muscle strength in DMD19,20 supporting this pharmacotherapy as an important standard 
of care. Following initiation of CS, a period of improvement in muscle strength is often observed. 
To control this potential source of variance, inclusion in this initial study will be restricted 
to patients who have been taking CS for at least 6 months, plan to continue CS for the duration 
of the double-blind phase of the clinical trial, and have not had a significant change in dose in the 
12 weeks preceding initiation of study treatment. 
Use of Translarna (Ataluren), Exon-Skipping Therapies, or Investigational Agents: 
Subjects receiving Translarna (ataluren), exon skipping therapies (e.g., Exondys51 [eteplirsen]), 
or investigational agents will not be eligible for this study. The magnitude and time course of 
treatment response to these agents in DMD is not well understood. Similarly, limited data are 
available regarding the safety and tolerability of investigational agents. These information gaps 
render controlling for potential effects of these drugs challenging and thus could complicate 
interpretation of the data emerging from this study. To avoid a potentially confounding impact of 
poorly understood effects of ataluren, patients receiving this treatment currently or within 
12 weeks prior to the start of study treatment will be excluded from participation. Patients receiving 
treatment with any (approved or investigational) exon skipping therapies within 6 months prior to 
the start of study treatment will also be excluded from participation. Treatment with deflazacort 
as part of CS dose-finding trials is allowed, as long as the patient has been on treatment 
for 6 months without significant dose changes 12 weeks prior to study start.  
Heart Failure: 
RO7239361 also binds to growth and differentiation factor-11 (GDF-11), which has been 
implicated in heart failure associated with aging in mice.41 However, this finding is controversial.42 
43 44 Although the mechanism underlying the development of aging-related re-modeling of the heart 
likely differs from that underlying the development of heart failure in DMD, potential cardiac 
effects of RO7239361 will be monitored in subjects enrolled in this study using echocardiography. 
Notably, there have been no cardiac findings in animals that received RO7239361 in completed or 
ongoing toxicology studies.  In order to clearly differentiate any potential effects of RO7239361 
on heart function from cardiac manifestations of disease progression, it is prudent to exclude 
patients with uncontrolled cardiac failure. It is requested that potential participants with ejection 
fraction < 55% at baseline be discussed with the Sponsor's Medical Monitor. 
Use of Growth Hormone or Androgens: 
Growth hormone may exert effects on cardiac morphology and function, while androgens may 
alter skeletal muscle function in boys with DMD.21,22 To avoid potential confounding effects of 
growth hormone and androgens on the endpoints being measured in this study, patients receiving 
these treatments currently or within 12 weeks or 5 half-lives (whichever is longer) prior to the start 
of study treatment will be excluded from participation. 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
40/Protocol WN40227, Version 4 
 
3.1.3 
Rationale for Primary Endpoint 
The primary endpoint for this study is the change from baseline in the NSAA total score at Week 48 
in RO7239361-treated participants compared with participants treated with placebo. The NSAA is 
a validated clinician-reported outcome instrument that has been widely used in clinical trials.  The 
instrument consists of 17 items designed to measure ambulatory function in boys with DMD. The 
instrument has a 3-point scale: 2="normal"no obvious modification of activity, 1=modified 
method but achieves goal independent of physical assistance from another, 0=unable to achieve 
independently. Therefore, higher scores represent greater functional abilities.47 
The NSAA has been demonstrated to have good inter-rater reliability and test−retest reliability.56 
The NSAA correlates with key disease progression milestones, such as losing the ability to rise 
independently from the floor (a decline in linearized score from 50 to 40 points), loss of ability to 
stand still (decline in linearized score from 21 to 11 points), and loss of ambulation.25,26 It has been 
reported that boys with DMD improve their motor function up to 7 years of age, as seen by an overall 
gain of 4 points/year in the linearized NSAA score, after which they start to decline an average of 8 
linearized units/year.25,26 However, because age alone cannot serve as a predictor of loss of 
ambulation, it has been reported that the estimated mean linearized NSAA score at 12 and 24 
months prior to loss of ambulation (i.e., at ages 12 and 11 years, respectively) is 34 and 42 units 
(approximately 9 and 13 on the raw scale, respectively).26 In addition, the NSAA has been 
demonstrated to have moderate to high construct validity based on the 6MWD, 57, 58 and it has 
been shown to detect change in an interventional setting.25 Unlike other functional tests, such as 
the 6MWD or the 4SC, NSAA is a more reliable and comprehensive scale that captures both motor 
strength and quality of movement, in addition to being less susceptible to external motivations. 
Moreover, while TFTs in DMD tend to remain stable until a point when they decline rapidly, the 
NSAA has been shown to decline more gradually. Thus, the NSAA is a reliable outcome measure 
to assess the efficacy of RO7239361 treatment in the study population. 
3.1.4 
Research Hypothesis 
The hypothesis for this study is that in ambulant patients with DMD: 
• 48 weeks of treatment with RO7239361, at either or both doses, will be generally safe and 
well tolerated and will result in improved NSAA total score relative to 48 weeks of placebo 
treatment. 
3.2 
Background 
A detailed description of the chemistry, pharmacology, efficacy, and safety of RO7239361 is 
provided in the Investigator Brochure. 
RO7239361 is expected to preserve and improve muscle strength primarily by increasing the size of 
existing muscle fibers. Several investigators have 
demonstrated 
that either genetic 
manipulation27,28,29 or pharmacologic treatments23,30,31,32,33 that reduce circulating myostatin 
produce increases in muscle mass and measures of strength and motor function in the mouse mdx 
model and the golden retriever model of DMD.34 Importantly, the relationship between myostatin 
reduction, increased muscle size, and increased muscle strength suggests that muscle volume 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
41/Protocol WN40227, Version 4 
 
increases induced by this mechanism result in increased muscle function. In contrast, the 
pseudohypertrophic increases in muscle size observed in DMD reflect increases in non-contractile 
fat and fibrotic tissue within the muscle, and do not increase muscle strength.35 
RO7239361 has potential therapeutic utility for conditions such as DMD as well as other 
muscle-wasting diseases. 
A first-in-human combined single and multiple ascending dose (SAD/MAD) study in normal 
healthy volunteers (NHVs) with RO7239361 has been completed (CN001001).36 Data from this 
study indicate that single doses up to 180 mg and multiple weekly (Q1W) doses up to 180 mg and 
every-2-week doses of 45 mg RO7239361 are generally safe and well tolerated. PK data indicate 
that plasma concentrations of total RO7239361 (serum free RO7239361 plus RO7239361-
myostatin complex) increase in a dose-related fashion. Similarly, the extent and duration of 
serum free myostatin suppression increases in a dose-related fashion. Treatment with 5 weekly 
doses of 45 mg or more of RO7239361 was associated with increases in thigh muscle volume and 
total lean body mass in NHVs.  
A Phase 1b/2, multi-site, randomized, placebo-controlled multiple ascending SC dose study to 
evaluate the safety, tolerability and PK of RO7239361 in ambulatory boys with DMD is ongoing. 
Preliminary safety data from this study, which includes ambulatory boys with DMD, age ≥ 5 to 
< 11 years on stable CS treatment, suggest that RO7239361 is generally safe and well tolerated 
in this population. 
There are no identified risks to date related to RO7239361 administration. Anti-drug antibodies 
(ADAs) and mild or moderate injection-site reactions have been observed in studies of healthy 
adults and patients with DMD. The presence of ADAs did not appear to impact the safety or 
exposure of RO7239361.  
RO7239361 also recognizes growth and differentiation factor-11 (GDF-11), which is 
hypothesized to play roles in inducing mesoderm in early development and in anterior-posterior 
patterning of axial skeleton.37,38,39,40 GDF-11 has also been implicated in heart failure associated 
with aging in mice.41 However, this finding is controversial.42 43 44 While the mechanism 
underlying the development of aging related re-modeling of the heart likely differs from that 
underlying the development of heart failure in DMD, potential cardiac effects of RO7239361 will 
be monitored in this trial using echocardiography. Notably, there have been no cardiac findings in 
animals that received RO7239361 in the completed or ongoing toxicology studies. No clinically 
significant treatment-related changes in ECG or echocardiogram parameters have been observed in 
RO7239361-treated patients with DMD to date. 
Potential risks include hypersensitivity reactions, injection-site reactions, immunogenicity, and 
findings from nonclinical studies or observations with the use of other anti-myostatin agents. These 
potential risks are described in the current Investigator Brochure.45 Appropriate clinical 
monitoring will be implemented in all clinical studies. An independent Data Monitoring 
Committee (iDMC) will review data at intervals specified in the iDMC charter. 


 
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3.3 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of RO7239361 may be found in the Investigator Brochure. 
The potential benefits of treatment with RO7239361 have not been established. 
RO7239361 has been tested in animals including rats and monkeys. Serum aminotransferase 
elevations were observed in rats given RO7239361 for 6 months. However, these elevations were 
not associated with microscopic evidence of liver or skeletal muscle damage and the animals did 
not experience muscle weakness. In monkeys that received RO7239361 for 6 months there were 
no serum transaminase elevations even though systemic exposures were approximately 4× higher 
than in rats. 
Taken together, the serum transaminase increases seen in rats in the 6-month study suggest a time- 
dependent finding that is likely rat specific. Regardless, potential hepatotoxicity will be assessed 
by monitoring of aminotransferases and bilirubin in serum and evaluations of clinical signs and 
symptoms. The hepatocyte-specific markers GGT and GLDH will also be monitored. 
In some animals treated with RO7239361 a small decrease in the IgG antibody response to 
primary immunization was observed. IgM antibody responses to primary immunization were not 
decreased in treated animals. Neither IgG nor IgM antibody responses were decreased in response 
to subsequent (booster) immunizations in those animals tested. Given the small size of the decrease 
in the IgG response to primary immunization and lack of effect of RO7239361 treatment on IgM 
response or IgG response to booster, any potential effect of RO7239361 treatment on efficacy of 
immunization in humans is expected to be minimal. Caregivers should be advised to ensure that 
their child’s immunizations are up to date prior to receiving study drug. 
Among healthy adult humans who received RO7239361 in study CN001001, the most common 
AEs were mild or moderate injection-site erythema. These AEs did not require cessation of study 
drug and were not accompanied by systemic signs or symptoms, such as fever or eosinophilia. In 
Study CN001001, 45.2% of SAD phase participants developed ADAs at some point during the 
study, while 27.8% of MAD phase participants developed ADAs. Presence of ADAs did not 
appear to impact exposure to RO7239361. Most subjects with injection-site or other skin 
reactions were ADA titer negative suggesting a lack of relationship between the presence of 
ADAs and risk for cutaneous AEs. 
A Phase 1b/2 study of RO7239361 in ambulatory boys with DMD (WN40226) is ongoing. 
Safety data from the completed double-blind and 48-week OL phases of this study suggest that 
RO7239361 is generally safe and well tolerated in this population. The most common related AEs 
were mild or moderate injection-site reactions that resolved without change to study treatment. 
Immunogenicity data from 43 patients showed a single value of low positive ADA titer in 1 patient 
who had received RO7239361. 
All participants who are administered study drug will be closely monitored for possible 
immunogenicity-related AEs, such as rash, fever, and injection-site reactions. Clinically relevant 
immune reactions (e.g., hypersensitivity reactions) will be reported as AEs and treated according to 


 
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current standard of care medical practice. If present, antibodies will be assessed for neutralizing 
activity by assessment of serum free myostatin levels and a neutralizing antibody (NAB) assay. 
Subjects completing clinical trials of RO7239361 who do not enter the Open Label Extension 
phase will enter the follow-up phase of the study. Subjects who enter the follow-up phase will 
undergo ADA monitoring during the follow-up visits, which will occur at regular intervals for 
24 weeks. Injection sites will be rotated and inspected regularly. Injection sites will be monitored 
from Day 1 through the end of the study. 
Hypersensitivity or acute allergic reactions may occur as a result of the biologic nature of 
RO7239361. As of 8 February 2018, no subject receiving RO7239361 has developed an acute 
hypersensitivity reaction associated with study drug. Although the risk of a subject developing 
an acute hypersensitivity reaction to RO7239361 is considered low, sites should be prepared to 
manage possible acute hypersensitivity reactions to initial doses of RO7239361 following accepted 
standards of medical care. Qualified personnel should administer or supervise the administration 
by the caregiver of the first 3 weekly SC doses of RO7239361, and appropriate emergency 
equipment should be available in the event of a serious anaphylactic reaction. Participants and their 
parents/caregivers will be provided with emergency contact information by the site. Participants 
and their parents/caregivers will be instructed to recognize any signs and symptoms of 
hypersensitivity reaction and for the need to seek emergency medical care in case of an extreme 
reaction.  
 
 
 


 
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4 
OBJECTIVES AND ENDPOINTS 
 
Table 4-1: 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To compare the efficacy of RO7239361 to 
placebo in ambulatory boys with Duchenne 
muscular dystrophy 
• 
The change from baseline in the North Star 
Ambulatory Assessment (NSAA) total score 
at Week 48 in RO7239361-treated 
participants compared to placebo-treated 
participants 
Secondary 
• 
To compare the efficacy of RO7239361 to placebo 
using the following tests: 
− 
4 Stair Climb Velocity 
− 
Stand from supine velocity 
− 
10 M walk/run velocity 
− 
PODCI transfers and basic mobility subscale 
− 
Proximal 
lower 
extremity 
flexor 
(knee 
extension and knee flexion) strength, measured 
using manual myometry 
− 
6 Minute Walk Distance (6MWD)  
− 
Clinical Global Impression of Change 
(CGI-C) 
− 
Stride velocity, as recorded by the 
ActiMyo device 
• To assess the safety and tolerability of RO7239361 in 
boys with DMD as reflected by new or worsening lab 
abnormalities (as defined by CTCAE criteria), 
serious adverse events (SAEs) and adverse events 
(AEs) leading to discontinuation 
• 
Change 
from 
baseline 
at 
Week 
48 
in 
RO7239361-treated 
participants 
compared 
to 
placebo-treated participants in: 
– 
4 Stair Climb Velocity 
– 
Stand from supine velocity 
– 
10 M walk/run velocity 
– 
PODCI transfers and basic mobility subscale 
– 
Proximal lower extremity flexor (knee extension 
and knee flexion) strength, measured using 
manual myometry 
– 
6 Minute Walk Distance (6MWD) 
– 
Clinical Global Impression of Change 
(CGI-C) 
– 
95th percentile stride velocity, as recorded with 
the ActiMyo device in a subset of the overall 
study population 
• 
Tabulations of the numbers of unique participants 
with new or worsening laboratory abnormalities, 
SAEs and AEs leading to discontinuation, in 
RO7239361 arms compared to the placebo arm 
 


 
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Tertiary/Exploratory 
• 
To assess the safety and tolerability of RO7239361 in 
boys with DMD as reflected by vital signs, 
measures of cardiac function. 
• 
To compare the efficacy of RO7239361 to placebo 
using the following tests: 
- Performance of upper limb (PUL) total score 
 
• 
To evaluate other measures of efficacy, quality of life, 
and health care utilization 
• 
Summaries and listings of vital signs, ECG 
parameters, echocardiogram parameters. 
− 
Proportion of participants with on treatment 
adverse events in RO7239361 arms 
compared to the placebo arm 
– 
Proportion of participants with on treatment 
decrease in ejection fraction (EF), measured 
using echocardiography, in RO7239361 
arms compared to the placebo arm 
• Change from baseline at Week 48 in RO7239361 
treated participants relative to placebo treated 
participants in: 
– Performance of upper limb (PUL) total score 
 
• 
Change from baseline at Week 48 in RO7239361 
treated participants compared to placebo treated 
participants: 
− 
Pulmonary Function Tests, including forced 
vital capacity (FVC) % predicted, forced vital 
capacity (FVC), forced expiratory volume in 
1 second (FEV1), maximal expiratory pressure 
(MEP), maximal inspiratory pressure (MIP). 
− 
PODCI total score 
− 
Caregiver Global Impression of Change  
(CaGI-C) in a subset of the overall study 
population at selected sites 
− 
Pediatric Quality of Life Inventory 
Multidimensional Fatigue Scale (PedsQL 
MFS) in a subset of the overall study 
population 
− 
Cardiac magnetic resonance imaging (cMRI) 
measures of ejection fraction, fractional strain, 
and volume of fibrosis in a subset of the 
overall study population 
− 
Strength of elbow flexors, elbow extensors, and 
pinch, measured by manual myometry 
− 
Health Utilities Index III and PedsQL Family 
Impact Module scores 
− 
Dual x-ray absorptiometry (DXA) measures 
of lean body mass, fat mass, and bone mineral 
density 
 
 


 
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Table 4-1: 
Objectives and Endpoints 
 
Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To 
evaluate 
RO7239361 
pharmacokinetics, 
pharmacodynamics, and immunogenicity 
• 
Assessments at selected timepoints during the 
study of: 
− 
Activity levels in a subset of the overall 
study population, as recorded with 
ActiMyo 
− 
Scoring of functional assessments, as recorded 
by a subset of parents/caregivers participating 
in the caregiver video assessment at selected 
sites  
− 
Number of falls while on treatment in 
RO7239361 arms compared with the placebo 
arm 
• 
Assessments at select timepoints during the study 
of: 
− 
Serum RO7239361 concentrations 
− 
Serum free myostatin and myostatin drug 
complex concentrations 
− 
Serum ADA concentrations 
− 
Serum creatine kinase level in muscle 
 
 
 


 
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Table 4-1: 
Objectives and Endpoints 
 
Objectives 
Endpoints 
• 
To explore the effect of genetic variation on target 
engagement, pharmacodynamic (PD) effects or 
functional test endpoints 
• 
Assess the impact on genetic variation in the 
DYSTROPHIN gene or in genes suspected to impact 
DMD disease expression (including but not limited 
to LTBP4, SPP1) in RO7239361- and 
placebo-treated participants, on target engagement, 
pharmacodynamic (PD) and functional endpoints 
5 
STUDY DESIGN 
5.1 
Overall Design 
This is a multi-center, randomized, double-blind, placebo-controlled study to assess the efficacy, 
safety and tolerability of two different weekly SC doses of RO7239361 in ambulatory boys with 
Duchenne muscular dystrophy (DMD). 
Eligible participants will be randomized to receive doses of RO7239361 or placebo (1:1:1 across 
the three treatment arms). The randomization will be stratified by: 
• Age (6 through 7 and 8 through 11) 
• CS regimen: daily (prednisone, prednisolone or deflazacort) vs intermittent (any non-daily 
dosing of prednisone, prednisolone or deflazacort) 
 
A separate randomization will be conducted for Japan (N∼15) with stratification for age only 
(6 through 7 and 8 through 11), not CS regimen. 
RO7239361 or placebo will be administered weekly. The first three doses (Days 1, 8 and 15) of 
study drug must be administered at the site. Parents/caregivers will be trained to administer SC 
injections during the first three dose administrations. Parents/caregivers who are comfortable with 
SC administration can administer the injection at home starting at Day 22. Parents/caregivers will 
be dispensed an approximately 6 week supply of drug in pre-filled syringes (RO7239361 or 
matching placebo) for weekly study drug/placebo administration to the participant. 
After completion of this 48-week double-blind phase, participants may enter the OL phase in 
which all participants will receive active RO7239361 study drug. Participants originally 
randomized to active drug will continue to receive the dose to which they were originally 
randomized. Participants originally randomized to placebo will be randomized to the high or low 
dose of RO7239361 on Day 1 of the OL phase. Dose assignment in the OL phase may be 
modified based upon emerging safety findings. Subjects entering the OL phase will remain 
blinded to their original dose assignment. Participants who discontinue study treatment at any 
timepoint (i.e., early discontinuation for patients who do not enter the OL phase or at termination 
of the OL phase) will enter the follow-up phase of the study. The follow-up phase of the study is 
24 weeks. Participants will be monitored for safety at three visits in the follow-up phase. 
Participants should provide immunogenicity samples at all follow-up visits. 
The study design schematic is presented in Figure 5.1-1. 


 
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Figure 5.1-1: 
Study Design Schematic 
 
OL=open label; SC=subcutaneous. 
Study visits and endpoint measurements will occur as indicated in Table 2-1 through Table 2-4. 
5.1.1 
Independent Data Monitoring Committee and Other External Committees 
There will be an iDMC for this study. The iDMC scope, frequency of review, membership, 
activities and other specifications are detailed in the iDMC charter. 
The iDMC shall have access to partially unblinded data (coded treatment assignments) including 
but not limited to the following: the frequency and spectrum of SAEs; Grades 3 to 4 laboratory 
abnormalities; occurrence of malignancies, if any; and other select AEs of interest. The iDMC 
shall also review aggregate data results from any interim analyses performed prior to the end of 
the double-blind treatment period. The iDMC shall have the right to request full unblinding of 
the data (codes will be decoded to reveal actual treatment assignments). The iDMC shall act as 
an advisor to the sponsor and have responsibility for safeguarding the subjects’ interests. The 
iDMC shall bring any safety concerns to the attention of the sponsor so that the sponsor can review 
the data and prepare appropriate communications to the Regulatory Authorities. 


 
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5.2 
Number of Participants 
A total of approximately n=159 participants randomized will provide for slightly more than 
80% power at the primary analysis. This allows for roughly a 5% dropout rate by Week 48. 
Some of the details behind sample size calculations are in Section 10.1. 
5.3 
End of Study Definition 
The start of the trial is defined as the first visit for the first participant screened. End of trial is 
defined as the last visit or scheduled procedure shown in the Schedule of Activities for the last 
participant.  
5.4 
Scientific Rationale for Study Design 
See Section 3.1 
5.5 
Justification for Dose 
See Section 3.1.1 
6 
STUDY POPULATION 
For entry into the study, the following criteria MUST be met. 
6.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
a) Prior to study participation, written informed consent from subjects, and in the case of 
minors, written permission (informed consent) also from parents, guardians, or legally 
acceptable representatives must be obtained according to local laws and regulations. 
b) Assent from minor subjects should be obtained per local laws and regulations and should 
be documented in accordance with local requirements. 
 
2) Type of Participant and Target Disease Characteristics 
a) Males, ≥ 6 to < 12 years of age at time of randomization 
b) Diagnosis of DMD, confirmed by medical history (e.g., onset of clinical signs or 
symptoms before 5 years of age together with an elevated serum creatine kinase level 
observed before or after initial diagnosis) and by genotyping 
c) Participants ≥ 15 kg 
d) Ambulatory without assistance 
e) Participants must be receiving corticosteroids (prednisone, prednisolone, or deflazacort) 
for at least 6 months prior to the start of study drug, with no significant change in dosage 
(> 0.2 mg/kg prednisone or > 0.24 mg/kg deflazacort) or dosing regimen for at least 12 
weeks prior to the start of study drug, with the expectation that dosage and dosing regimen 
will not change significantly for the duration of the study. 
f) NSAA score ≥ 15 points at screening 
g) 4SC ≤ 8 seconds at screening 
h) Subjects must agree to avoid major changes in their physical or respiratory therapy regimen 
during the double-blind phase, to the extent possible 


 
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3) Age and Reproductive Status 
a) Males, ≥ 6 to < 12 years on day of randomization 
b) Subjects who are sexually active must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study treatment(s) plus 5 half-lives of the 
study treatment [RO7239361; 50 days] plus 90 days (duration of sperm turnover) for 
a total of 140 days (5 months) post-treatment completion. 
c) Azoospermic subjects are exempt from contraceptive requirements. 
d) Subjects must be willing to refrain from sperm donation during the entire study and for 5 
half-lives of study treatment plus 90 days (duration of sperm turnover) 140 days after 
dosing has been completed. 
 
Investigators shall provide appropriate and patient-centered counseling of adolescent trial subjects 
who are sexually active with WOCBP on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. Investigators shall advise subjects who are sexually 
active with WOCBP on the use of highly effective methods of contraception in non-pregnant 
partner (Appendix 4), and on the use of condom in subjects with a pregnant partner. Highly 
effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. 
6.2 
Exclusion Criteria 
1) Medical Conditions 
a) Participants with cognitive impairment or behavioral issues that, in the judgement of the 
investigator, will compromise their ability to comply with study procedures. 
b) Participants with a FVC of < 50% of predicted value (in participants able to produce a valid 
FVC, as judged by the clinical evaluator or respiratory therapist) 
c) Cutaneous AEs sustained during participation in a prior clinical trial that resolved less than 
12 weeks prior to the start of study drug administration. 
d) History of lower limb fracture within 12 weeks prior to the start of study drug 
administration. 
e) History of upper limb fracture within 8 weeks prior to the start of study drug 
administration. 
f) Any injury that may impact functional testing. Previous injuries must be fully healed 
prior to consenting. 
g) Expectation of major surgical procedure, such as scoliosis surgery, during the double-blind 
phase of this study. 
h) Requirement of daytime ventilator assistance 
i) Initiation of nighttime ventilation less than 4 weeks prior to the start of study drug 
administration 
j) Expectation that daytime or nighttime ventilation may be initiated during the double-blind 
phase of this study. 
k) Clinical signs or symptoms of uncontrolled congestive heart failure (American College of 


 
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Cardiology/American Heart Associated Stage C or Stage D) 
l) For participants participating in cMRI substudy: implanted ferromagnetic metal (implanted 
metal that is not ferromagnetic, such as surgical steel or titanium implants may be allowed 
if the implants will not compromise the quality of the cMRI)  
2) Prior/Concomitant Therapy 
a) Any change (initiation, change in drug class, dose modification unrelated to change in body 
weight, interruption or re-initiation) in prophylaxis/treatment for CHF within 12 weeks 
prior to start of study treatment 
b) Any change (initiation, change in drug class, dose modification unrelated to change in body 
weight, interruption or re-initiation) in prophylaxis/treatment for bone density within 
12 weeks prior to start of study treatment 
c) Participants on intermittent CS regimens with off periods of 20 days or longer (e.g., 
10 days on, 20 days off) 
d) Treatment with exon skipping therapies within 6 months prior to the start of study drug 
administration. 
e) Treatment with ataluren currently or within 12 weeks prior to the start of study drug 
administration 
f) Treatment with any other investigational drug (excluding deflazacort in CS dose-finding 
trials) currently or within 12 weeks prior to the start of study drug administration 
g) Current or prior treatment within 12 weeks prior to the start of study drug administration 
with androgens or human growth hormone. 
h) Concurrent or previous participation at any time in a gene therapy study 
i) Prior treatment with RO7239361 or any other anti-myostatin agent 
3) Physical and Laboratory Test Findings 
a) Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECG or clinical laboratory determinations beyond what 
is consistent with the target population 
4) Allergies and Adverse Drug Reaction 
a) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity) 
b) History of hypersensitivity to components of the study drug (histidine, trehalose, 
diethylenetriaminepentaacetic acid, polysorbate 80) 
5) Other Exclusion Criteria 
a) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness 
b) Unwilling or unable to administer study drug at home 
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria. 


 
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6.3 
Lifestyle Restrictions 
Not applicable  
6.3.1 
Meals and Dietary Restrictions 
Not applicable 
6.3.2 
Caffeine, Alcohol and Tobacco 
Not applicable 
6.3.3 
Activity 
Not applicable 
6.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs. 
6.4.1 
Rescreening and Retesting during Screening Period 
Participant re-screening: This study permits one-time re-screening of a participant once that 
participant has discontinued the study as a screen failure (i.e., participant has not been 
randomized). Laboratory testing that is repeated because of administrative or technical issues 
(e.g., breakage of a sample vial during transit to the central laboratory or degradation of a 
sample during transportation) is not considered to be rescreening. If re-screened, the participant 
must be re-consented.  
Retesting of laboratory parameters and/or other assessments within any single screening or 
lead-in period will be permitted (in addition to any parameters that require a confirmatory value). 
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state. 
Screening Procedural Outline may be repeated in an effort to find all possible well-qualified 
participants. Consultation with the Medical Monitor may be needed to identify whether repeat 
testing of any particular parameter is clinically relevant. 
7 
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation 
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following: 
• All products, active or placebo, being tested or used as a comparator in a clinical trial 


 
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• Study required premedication 
• Other drugs administered as part of the study that are critical to claims of efficacy 
(e.g., background therapy, rescue medications) 
• Diagnostic agents: (e.g., glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection. 
 
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 
In this protocol, the investigational product is RO7239361 (previously, BMS-986089) 
solution for injection and matching placebo solution for injection, dispensed in pre-filled syringes. 
Other medications used as support medication for preventative, diagnostic, or therapeutic reasons, 
as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. In this study, CS are considered non-investigational product and will 
not be provided by the sponsor. 


 
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Table 7-1: 
Study Treatments 
Product Description 
/Class and Dosage 
Form 
Potency 
IP/Non- 
IMP 
Blinded or Open Label 
Packaging / Appearance 
Storage Conditions  
(per label) 
RO7239361 
injection 
7.5 mg/syringe 
10.7 mg/mL 
IP 
Blinded (during the 
48-week double-blind 
phase) and Open Label 
(during the  
192-week OL phase) 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect from 
light, protect from freezing 
RO7239361 
injection 
15 mg/syringe 
21.4 mg/mL 
IP 
Blinded (during the 
48-week double-blind 
phase) and Open Label 
(during the 192-week OL 
phase) 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect 
from light, protect from 
freezing 
RO7239361 
injection 
35 mg/syringe 
50 mg/mL 
IP 
Blinded (during the 
48-week double-blind 
phase) and Open Label 
(during the 192-week OL 
phase) 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect 
from light, protect from 
freezing 
RO7239361 
injection 
50 mg/syringe 
71.4 mg/mL 
IP 
Blinded (during the 
48-week double-blind 
phase) and Open Label 
(during the 192-week OL 
phase) 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect 
from light, protect from 
freezing 
Placebo for 
RO7239361 
injection 
0 mg/mL 
IP 
Blinded 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect 
from light, protect from 
freezing 
 


 
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Oral CS will be obtained by standard prescribing procedures. 
7.1 
Treatments Administered 
The selection and timing of dose for each participant is as follows: 
 
Table 7.1-1: 
Selection and Timing of Dose 
 
Study Treatment 
Unit dose 
strength(s)/Dosage 
level(s) 
Dosage formulation 
Frequency of 
Administration 
Route of Administration 
RO7239361 
injection 
7.5 mg, 15 mg, 35 mg, 
or 50 mg syringe 
Weekly 
SC 
Placebo for 
RO7239361 
injection 
0mg syringe 
Weekly 
SC 
 
 
Table 7.1-2: 
Dose Level 1, targeting moderate level of suppression: (≥ 70% 
suppression at trough) 
 
Dose Level 
Body Weight tier 
Body Weight range 
Dose 
1 
1 
≥ 15 to ≤ 40 kg 
7.5 mg QW 
1 
2 
> 40 kg 
15.0 mg QW 
 
 
Table 7.1-3: 
Dose Level 2, targeting high level of suppression: (90% suppression 
at trough) 
 
Dose Level 
Body Weight tier 
Body Weight range 
Dose 
2 
1 
≥ 15 to ≤ 40 kg 
35 mg QW 
2 
2 
> 40 kg 
50 mg QW 
 
RO7239361 or placebo will be administered as a SC injection in the abdomen, thigh, or the back of 
the upper arm. Injection sites should be rotated according to the "instruction for use" (IFU).  
Refer to the current version of the IB for PK and safety data) following single-dose administration 
across these injection sites in healthy subjects (Study WP40225) and for details on the 
recommended storage and use conditions for the PFS. 
Refer to current version of the IB for details on the recommended storage of and use conditions for 
the PFS. Do not use the PFS after the labeled expiry date. 
Subjects whose weight exceeds or drops below the dosing weight tier to which they were assigned 
by > 2 kg (confirmed by repeat) should receive the new weight-based dose in the subject’s assigned 
dose level. 


 
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7.2 
Method of Treatment Assignment 
Subjects will be randomized to receive either low or high dose of RO7239361 or placebo 
according to a computer-generated randomization scheme.  
During the screening visit the investigative site will enter into the enrollment option of the 
Interactive Web Response System (IWRS) designated by Roche for assignment of a 5-digit subject 
number that will be unique across all sites. Enrolled subjects, including those not dosed, will be 
assigned sequential subject numbers starting with 
, (e.g., 
).
 
 
 
 Once it is determined that the subject meets the eligibility criteria following 
the screening visit, the investigative site will enter into the IWRS to randomize the subject into 
the open dose panel. 
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
7.3 
Blinding 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of the 
investigational product is critical to the participant's management, the blind for that participant 
may be broken by the investigator. The participant’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unblinded. 
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, i.e., that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the participant 
is receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the participant has been made. 
In case of an emergency, the investigator(s) has unrestricted access to randomization information 
via the Interactive Web Response System (IWRS) and is capable of breaking the blind through the 
IWRS system without prior approval from sponsor. Following the unblinding the Investigator shall 
notify the medical monitor and/or study director. 
In cases of accidental unblinding, contact the medical monitor and ensure every attempt is made 
to preserve the blind. 
Any request to unblind a subject for non-emergency purposes should be discussed with the medical 
monitor. 
As this is a placebo-controlled, double-blind study, all efforts must be maintained by site staff, 
subjects and caregivers in not making any assumptions on potential treatment assignments based 
on clinical presentations. 


 
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The randomization assignments will be released to the study sites by the final study report 
generated for the study. 
7.4 
Dosage Modification 
Dose modifications are not allowed. 
7.5 
Preparation/Handling/Storage/Accountability 
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by Roche. 
If concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and contact Roche immediately. 
Study treatment not supplied by Roche will be stored in accordance with the package insert. 
Investigational product documentation (whether supplied by Roche or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets). 
Study drug will be administered in the clinical facility or off-site by the parent/caregiver. The 
parent/caregiver may administer study drug on or after the Day 22 dose and once trained and 
comfortable with SC injections of study drug/placebo. For any dose administered at the clinical 
facility, the dose and location of each SC injection must be recorded in the source record. 
For any dose administered off-site (off-site dosing allowed starting on Day 22 of double-blind 
phase and at Week 4 of the OL phase), the parents/caregivers must be trained on proper 
administration of study drug. The site staff will be provided with a pharmacy manual that includes 
parent/caregiver training guidance and a training checklist. The parents/caregivers will be provided 
with IFU on administration of study drug. The subjects and parents/caregivers will be provided 
with a dosing diary to record administration of study drug and be instructed to record the location, 
time, date, etc. of each SC injection. Parents/caregivers must be instructed to bring the used and/or 
empty syringes in a Sharps container and the dosing diary to each study visit; this will allow site 
staff to assess treatment compliance and study drug accountability. A diary will also be provided 
to the parent/caregiver to record the subject’s CS therapy, AEs, concomitant medicines, and 
falls. Study drug must be transported to and from the site in a cooler with an ice pack to maintain 
the appropriate storage temperature. If approved by the local IRB/EC, the cooler and ice pack for 
study drug transport will be provided by the Sponsor or designee. 
Parents/caregivers must be instructed by the site staff on sharps handling procedures. 
Parents/caregivers should be instructed to return the sharps container to the study site for proper 
disposal. 
• Further guidance and information for final disposition of unused study treatment are provided 


 
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in Appendix 2 and the pharmacy manual. 
7.5.1 
Retained Samples for Bioavailability/Bioequivalence 
Not applicable. 
7.6 
Treatment Compliance 
Study treatment compliance will be monitored by review of dosing diary cards. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. Sites should discuss discrepancies with the participant at each on-treatment study 
visit.   
Any overdose or incorrect administration of study drug should be reported as an adverse event and 
recorded on the Adverse Event electronic Case Report Form (eCRF), and the Medical Monitor 
should be informed.  
7.7 
Concomitant Therapy 
7.7.1 
Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration in the study are 
described below. Medications taken within 4 weeks prior to study drug administration must be 
recorded on the CRF. Prior therapies to treat DMD, including CS, should be reported on the 
CRF, regardless of when the prior therapy was administered. Routine standard of care 
immunizations should be maintained throughout the study. 
Experimental medications to treat DMD may be permitted during the OL phase. This will be 
dependent upon results from the double-blind phase. 
1) Prior exposure to RO7239361 or any other anti-myostatin agent. 
2) Treatment with ataluren within 12 weeks prior to the start of study drug administration.  
3) Treatment with any other investigational drug (excluding deflazacort in CS dose-finding 
trials) currently or within 5 half-lives prior to the start of study drug administration. If the 
half-life of the prior treatment is unknown, the investigator must consult with the Roche 
medical monitor to determine the washout duration. 
4) Treatment with exon skipping therapies within 6 months prior to the start of study drug 
administration 
5) Current or prior treatment within 12 weeks of study drug administration with androgens or 
human growth hormone. 
6) Concomitant or previous participation at any time in a gene therapy study. 
7) Use of any other drugs, including over-the-counter medications and herbal preparations, within 
1 week prior to start of study drug administration or during study participation except those 
medications cleared by the Roche medical monitor. 
Any concomitant therapies must be recorded on the CRF. 


 
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7.7.2 
Other Restrictions and Precautions 
7.7.2.1 
Management of Possible Acute Hypersensitivity Reactions to 
RO7239361 
Hypersensitivity or acute allergic reactions may occur as a result of the biologic nature of 
RO7239361. Qualified personnel should administer the first three weekly SC doses of 
RO7239361 during both the double-blind phase and during the OL phase, and appropriate 
emergency equipment should be available in the event of a serious anaphylactic reaction. For the 
first three weekly doses of both the double-blind and OL phases, subjects should remain on site for 
3 hours after drug administration for observation. Subjects and the parents/caregivers will be 
provided with emergency contact information by the site. Subjects and the parents/caregivers will 
be instructed to go to their local emergency care facility in case of an extreme reaction. 
The following information is provided to assist in the recognition of hypersensitivity reactions and 
in the management of those reactions should they occur during or after the administration of 
RO7239361. Care should be taken to treat any acute toxicity expeditiously, should it occur. When 
dosing RO7239361, equipment such as a portable tank or wall-source of oxygen, endotracheal 
intubation set, oral airway, mask, ambu-bag, syringes, injectable epinephrine, injectable 
antihistamine, and injectable glucocorticosteriods should be kept in the vicinity where the subject 
is dosed (for the first three weekly doses). 
Signs of potential acute hypersensitivity reactions include symptomatic hypotension; dyspnea; 
acute pain the chest, back or extremities/or chills, fever, urticaria; or generalized erythema. 
Clinically relevant hypersensitivity reactions will be reported as AEs and treated according to 
current standard of care medical practice. Management is as follows: 
Symptomatic Hypotension: Place subject in the Trendelenburg position and administer 
intravenous fluid. Additional medical intervention may also include the use of epinephrine, 
glucocorticosteroids, antihistamines and pressor agents. 
Dyspnea: Observe the subject for worsening of the event and for the appearance of additional 
signs and symptoms of anaphylaxis. Antihistamines, epinephrine, and glucocorticosteroids may be 
administered as indicated. 
Acute Pain in the Chest, Back or Extremities: Observe subject for worsening of the event and 
for the appearance of additional signs and symptoms of anaphylaxis. Antihistamines, epinephrine, 
and glucocorticosteroids may be administered as indicated. 
Chills, Fever, Urticaria or Generalized Erythema: Treat these possible signs and symptoms of 
an allergic reaction to biologic products with acetaminophen and antihistamines. 
The decision whether to continue the subject in the study will be made by the investigator, in 
consultation with the Roche medical monitor. 
7.7.2.2 
Imaging Restriction and Precautions 
The Principal Investigator and/or the imaging specialist at the study site imaging facility is 
responsible for determining if a subject is contraindicated from having the imaging procedures 


 
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specified in the time and events schedule (Table 2-2 and Table 2-3). Imaging contraindications 
and risks should be considered. 
The ultimate decision to perform the imaging should rest with the site radiologist, the investigator, 
and the standard set by the local Ethics Committee. 
7.8 
Treatment after the End of the Study 
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive Roche-supplied study treatment. Study treatment will be provided via an 
extension of the study, a rollover study requiring approval by responsible health authority and 
ethics committee or through another mechanism at the discretion of Roche and according to local 
legislation.  
Roche reserves the right to terminate access to Roche-supplied study treatment if any of the 
following occur: a) the study is terminated due to safety concerns; b) the development of 
RO7239361 is terminated for other reasons, including but not limited to lack of efficacy and/or 
not meeting the study objectives; c) the participant can obtain medication commercially, from a 
government-sponsored program, or from a private health program. In all cases, Roche will follow 
local regulations. 
8 
DISCONTINUATION CRITERIA 
Clinical Criteria for Dose Discontinuation: 
• Dosing may be stopped until safety information can be reviewed in the event that: 
− Two (2) or more subjects experience the same severe or very severe AE that is 
considered related to RO7239361 
• Dosing will be paused within a subject until safety information is reviewed and drug induced 
liver injury (DILI) is ruled out in the event that: 
− ALT > 5 x baseline AND no corresponding increase in CPK to indicate muscle origin as 
the reason for the increase in ALT 
OR 
 
− ALT > 10 x ULN AND ALT > 2 x baseline AND no corresponding increase in CPK to 
indicate muscle origin as the reason for the increase in ALT 
OR 
− Total bilirubin > 2 x ULN 
OR 
− Symptoms or signs of hepatic inflammation such as nausea, vomiting, right upper quadrant 
pain or tenderness with no other immediately apparent possible cause of these symptoms 
or signs, such as viral gastroenteritis or constipation. 
 
In addition to the above stopping rules, dosing may be paused or halted within a subject if a review 
of safety and tolerability data, or the clinical judgment of the investigator, suggest the emergence 
of a new potentially serious safety signal, including DILI. 


 
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The following categories and definitions of intensity as determined by a physician should be used 
for assessing the severity of AEs: 
• Mild (Grade 1) - Awareness of event but easily tolerated 
• Moderate (Grade 2) - Discomfort enough to cause some interference with usual activity 
• Severe (Grade 3) - Inability to carry out usual activity 
• Very Severe (Grade 4) - Debilitating, significantly incapacitates subject despite symptomatic 
therapy 
Dosing may not be resumed until a thorough review of safety and tolerability data has been 
completed and the Roche medical monitor, Roche pharmacovigilance representative, and the 
investigators agree that it is safe to proceed. 
Any subject meeting the above stopping criteria or otherwise removed from the study for abnormal 
laboratory, or echocardiogram will be followed until their abnormal laboratory result and/or 
echocardiogram values return to baseline. Subjects who discontinue early should enter the 
post-treatment follow-up phase of the study for this follow-up. 
8.1 
Discontinuation from Study Treatment 
Participants MUST immediately discontinue investigational product (and non-investigational 
product at the discretion of the investigator) for any of the following reasons:  
• Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information 
• Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant 
• Termination of the study by Roche 
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness 
• Unblinding a subject for any reason (emergency or non-emergency) 
• Inability to comply with protocol 
• Discretion of the investigator 
 
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed 
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness). 


 
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If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate eCRF. 
8.1.1 
Post Study Treatment Study Follow-up 
In this study, safety and the NSAA are key endpoints of the study. Post study follow-up is of 
critical importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed for collection of 
outcome and/or survival follow-up data as required and in line with Section 5 until death or the 
conclusion of the study. There will be follow-up visits up to 24 weeks after the last dose of study 
drug (Table 2-4) 
8.2 
Discontinuation from the Study 
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures (Table 2-4). The only exception to this 
is when a participant specifically withdraws consent for any further contact with him/her or 
persons previously authorized by participant to provide this information. 
• Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible. 
• The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page. 
• In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
8.3 
Lost to Follow-Up 
• All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant. 
• Lost to follow-up is defined by the inability to reach the participant after a minimum of three 
documented phone calls, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records. 
• If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death. 
• The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. 
• If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records. 


 
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9 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and timing are summarized in the Schedule of Activities (Table 2-1, 
Table 2-2, Table 2-3, and Table 2-4). 
• Protocol waivers or exemptions are not allowed. 
• All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment. 
• Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
9.1 
Efficacy Assessments 
9.1.1 
Functional Endpoint Assessment 
Measurements of function will be assessed at the timepoints specified in Table 2-1 through Table 
2-4 and include the following:  
• TFTs (4SC, 10 m walk/run, stand from supine)  
• 6 minute walk distance (6MWD)  
• NSAA scale  
• Performance of Upper Limb Scale (PUL)  
Detailed instructions for performing each of these assessments are provided in the Clinical 
Evaluator (CE) Manual. Functional endpoints will be measured by a clinical evaluator who 
has undergone study specific training on the administration of these assessments. The clinical 
evaluators who assess functional endpoints must be distinct from the clinicians who assess AEs of 
the study subjects. To ensure that clinical evaluators remain blind to study drug assignment, 
clinicians evaluating AEs should not communicate the presence, absence or severity of AEs with 
clinical evaluators at the site unless such communication is required to ensure subject safety. 
TFTs include 4SC, 10-meter walk/run and stand from supine. The 6MWD measures the distance 
a patient is able to traverse while walking for 6 minutes. TFTs, such as the 4SC and the 6MWD, 
are well validated and have been widely used in clinical trials.19, 23, 24, 46 Data delineating the 
natural history of performance of the 4SC and other TFTs in boys with DMD have been published. 
18, 25 A 2.2-second difference in 4SCV corresponds to a 30-meter difference on the 6MWD. A 30-
meter difference on the 6MWD has been shown to be associated with a significantly heightened 
risk of loss of ambulation within the ensuing 2 years.26 Unlike the 6MWD, the 4SC is less reliant 
on endurance and is most reflective of lower extremity muscle power.  The 4SC velocity (the 
number of stairs climbed per second) is calculated as the ratio of the number of stairs climbed (4) 
divided by the number of seconds taken to complete the 4-stair climb. Because children who are 


 
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or have become unable to perform this task, the time cannot be measured, conventionally a time 
equal or bigger than the worst performance in the group is subjectively given to indicate poor 
performance. In order to improve the possibility of performing statistical analysis, the results will 
be converted into velocity (distance/time) rather than the conventional time as this would allow 
conversion of all the poor or failed results from a subjectively chosen number into a meaningful 
number. 
The PUL includes 22 items with an entry item to define the starting point of testing, with 21 items 
subdivided into shoulder level, middle level, and distal level dimension. Each dimension can be 
scored separately.48 
Some of the functional endpoint assessment including the TFTs, NSAA, 6MWD and upper and 
lower extremity myometry will be video recorded at select study visits while the subject is 
completing the assessments. The videos will be uploaded by the site to a secure database, 
maintained by a separate vendor, and reviewed by master physiotherapists to assure quality or 
identify potential issues requiring re-training of clinical evaluators at the site. In addition the videos 
may be used to explore additional assessment of timing of TFTs, and to grade the quality of the 
patient’s functional abilities, which could inform the feasibility of potential new outcome measures 
focused on movement quality. 
9.1.2 
Myometry and Ankle Range of Motion (ROM) 
Muscle strength will be assessed using hand-held dynamometry at the time points specified in 
Table 2-1 through Table 2-3, following procedures outlined in the CE Manual. All measures will 
be obtained with a calibrated hand-held dynamometer.  
Detailed instructions for performing manual myometry and ankle ROM assessments will be 
provided in the CE Manual. These assessments will be performed by a clinical evaluator who has 
undergone study specific training on the administration of these assessments. 
9.1.3 
Imaging Assessment for the Study 
Images will be submitted to an imaging core lab. Sites should be trained prior to scanning the first 
study participant. Image acquisition guidelines and submission process will be outlined in the 
Imaging Manual provided by the core lab. 
9.1.3.1 
DXA 
DXA to collect measures of total lean body mass, fat mass and bone mineral density will be 
performed at the time points indicated in Table 2-1 through Table 2-3. 
DXA acquisition guidelines and submission processes will be outlined in the DXA Scanning 
Guide. 
Adequacy of DXA scans should be confirmed by the central imaging vendor prior to 
randomization. 
Screening DXA should be obtained between Day -42 and Day -14 to allow for central imaging 
vendor review. 
DXA is not required for subjects enrolled at sites in Germany. 


 
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DXA is not required at the early termination visit. 
Re-enrollment: Repeat of DXA is not required if previously obtained within 3 months of 
Day 1/randomization. 
Effective doses for whole-body DXA examinations were found to be 0.0052, 0.0048, 0.0042 and 
0.0042 mSv for a 5-, 10-, 15-year old child and adult respectively for an examination performed 
on the Hologic Discovery A device. Corresponding values for the Hologic Discovery W were 
0.0105, 0.0096, 0.0084 and 0.0084 mSv.49 
9.1.3.2 
Cardiac MRI (cMRI) 
cMRI with gadolinium enhancement will be performed in a subset of participants at select U.S. 
centers at the time points indicated in Table 2-1 through Table 2-3. Subjects enrolled at select U.S. 
centers participating in the cMRI substudy will be required to attempt to complete the cMRI. 
Subjects participating at sites where the cMRI substudy is being performed who have an allergy 
to gadolinium may undergo cMRI scanning without gadolinium. 
cMRI acquisition guidelines, protocols, contrast agent type and dose, and image submission 
processes are outlined in the imaging manual provided by the core imaging lab. 
Adequacy of cMRI scans should be confirmed by the central imaging vendor prior to 
randomization. 
Screening cMRI should be obtained between Day -42 and Day -14 to allow for central imaging 
vendor review. cMRI will be conducted at early termination visits if ≥ 24 weeks has elapsed from 
previous cMRI. 
Re-enrollment: Repeat of cMRI is not required if previously obtained within 6 months of 
Day 1/randomization. 
9.1.4 
Exploratory Genotyping 
A 2-mL whole blood 9.1.7 sample will be drawn (as indicated in Table 2-2) for potential analysis 
of genetic variation in genes suspected to impact DMD disease expression (including but not 
limited to LTBP4, SPP1). Human leukocyte antigen (HLA) genotyping may be conducted to 
better understand immunogenicity risk if ADAs are detected and it is determined that ADA 
impacts safety or efficacy. Further details of blood collection and processing will be provided to 
the site in the laboratory procedure manual. The exploratory genotyping samples will be used 
for up to 2 years after the study is closed and will be used for analyses between genotype and 
endpoints evaluated in this study. 
9.1.5 
ActiMyo 
Subjects enrolled at selected sites will be asked to wear a device called ActiMyo. The wearing of 
the ActiMyo is optional. Hence, refusal to wear ActiMyo will not affect the eligibility of a subject 
to be enrolled in the study. The purpose of the ActiMyo device is to measure the daily movement 
and activity levels of subjects with a degree of high accuracy. Unlike consumer-grade activity 
trackers and mobile phone applications, the endpoints of the ActiMyo device are clinically 
validated. Therefore, the activity data collected by ActiMyo will be analyzed to provide deep 


 
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insights into the ability of subjects to ambulate (i.e., walking distance, walking speed, ability to 
climb stairs, speed of climbing stairs, etc.) and allows for the determination of the clinical 
meaningfulness of RO7239361 in the treatment of DMD, and refusal will not exclude a subject 
from the study. The purpose of the ActiMyo device is to accurately measure the daily movement 
and activity levels of the subject. The device consists of two sensors, to be worn on each ankle. 
Subjects will wear the devices each day during specified periods of the study and during TFTs and 
6MWT at specified site visits. As the ActiMyo device battery requires recharging overnight, the 
device will not be worn at night. The subject and parent/caregiver will be trained on how to use the 
device, including correct fitting and wearing of the device, how to dock the device on the battery 
charging station, and when to return ActiMyo materials to the site. As a CE-marked device, the 
possibility of allergic reactions and skin irritation has been addressed and are thus unlikely to 
occur. Nevertheless, should any skin reaction be observed, the subject should remove the strap and 
sensor and contact the study team as soon as possible. Detailed instructions as to use of the 
ActiMyo device are provided in the ActiMyo User Manual and Quick Start Guide. 
9.1.6 
Caregiver Video Assessment 
Subjects enrolled at selected sites will be invited to participate in the caregiver video assessment. 
Participation is optional, and refusal to participate will not exclude a subject from the main study. 
The aim of the caregiver video assessment is to provide additional insight into a subject's physical 
functioning and motor strength during the study. A video application will be used to capture a 
range of standardized tasks in a real-world environment, external to the clinic. 
The video application will ask caregivers to record the subject completing selected tasks every 
12 weeks according to pre-specified instructions read aloud by the caregiver. These tasks include 
sitting up, standing up, walking, running, climbing stairs, and one additional task personally 
chosen by the caregiver. The caregiver is allowed to skip the recording of any of these tasks if not 
appropriate or applicable. In addition, the application will allow caregivers to record a new ability 
at any point during the study. 
If the subject and caregiver agree to participate, they will sign a separate Informed Consent Form at 
baseline (for newly enrolled subjects) or at a future study visit (for subjects who are already enrolled 
in the main study only). Detailed instructions regarding the caregiver video assessment are 
provided in the parent/caregiver manual. 
9.1.7 
Clinical Global Impression of Change (CGI-C)  
The CGI-C is a single item that clinicians will complete at the end of the double-blind phase (Week 
48 of the study) and at Week 48 of the OL phase (Week 96 of the study) to rate change in the 
patient’s global impression of change in DMD from the start of each phase (i.e., from baseline for 
the double-blind phase and from Week 49 for the OL phase).  There are seven response options: 
“Very much improved”, “Much improved”, “Minimally improved”, “No change”, “Minimally 
worse”, “Much worse”, and “Very much worse”.  It is a widely used endpoint in clinical trials 
across a variety of disease areas. To enhance inter-rater consistency, an instruction document 
(developed with input from clinical experts) will be provided in the user manual, which includes 
examples for each of the response options. 
The item should be completed by a clinician (e.g., Principal Investigator or study coordinator) who 


 
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has interacted with the individual since baseline. The same clinician should complete the CGI-C 
at all specified visits for an individual patient. If there is no clinician at the site who is able to 
reflect on the patient’s health status, an alternative clinician should make the rating using existing 
study notes, and sites should record this. 
9.1.8 
Caregiver Global Impression of Change (CaGI-C)  
The CaGI-C comprises six items that caregivers will complete at the end of the 
double-blind phase (Week 48 of the study) and at Week 48 of the OL phase (Week 96 of 
the study) to rate the change in a subject's symptoms, physical abilities, daily activities, 
social life, emotions and mental well-being, and overall health from the start of each phase 
(i.e., from baseline of the double-blind phase and from Week 49 of the OL phase). There are seven 
response options: “Very much improved,” “Much improved,” “Minimally improved,” 
“No change,” “Minimally worse,” “Much worse,” and “Very much worse.” It is a widely 
used endpoint in clinical trials across a variety of disease areas.  
To enhance intra- and inter-consistency, descriptions of each level of change have been 
developed and domain level global impression items have been created with input from 
patients with DMD and their caregivers. The items should be completed by the parent or 
caregiver who has been involved in the study since baseline. The same parent or caregiver 
should complete the CaGI-C for his or her child at the end of each study phase to reflect 
the subject's health status from baseline for the double-blind phase and Week 49 of the 
OL phase. The CaGI-C will be assessed at selected sites only. 
9.1.9 
Pediatric Quality of Life Inventory Multidimensional Fatigue Scale 
(PedsQL MFS) 
The PedsQL MFS parent proxy measures the severity and impact of fatigue on the subject 
from the caregiver’s perspective. The recall period is the last 4 weeks. The instrument is 
appropriate for individuals aged 2-18 years old and captures six items on general fatigue, 
six items on sleep/rest fatigue, and six items on cognitive fatigue. A total fatigue score 
can be calculated from the 18 items that ranges from 0 to 100, with higher scores 
indicating less fatigue. The PedsQL MFS takes approximately 10 minutes to complete. 
The PedsQL MFS will be assessed at selected sites only. 
9.2 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
Malfunctions of the pre-filled syringes containing study drug should be reported to the sponsor 
via designated form (electronic system) in accordance with local regulations. 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 


 
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are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
The clinical evaluators who assess functional endpoints must be distinct from the clinicians who 
assess AEs of the study subjects. Clinicians evaluating AEs should not communicate the presence, 
absence or severity of AEs with clinical evaluators at the site unless required to do so to ensure 
subject safety. 
Contacts for SAE reporting are specified in Appendix 3. 
9.2.1 
Time Period and Frequency for Collecting AE and SAE Information 
The collection of nonserious AE information should begin at initiation of study treatment until 50 
days of discontinuation of dosing.  Nonserious AE information should also be collected from 
the start of a placebo lead-in period or other observational period intended to establish a baseline 
status for the participants. 
Section 6.4 in the IB represent the Reference Safety Information to determine expectedness of 
serious AEs for expedited reporting. Following the participant’s written consent to participate in 
the study, all SAEs, whether related or not related to study drug, must be collected, including 
those thought to be associated with protocol-specified procedures. 
All SAEs must be collected that occur during the screening period and within 50 days (5 half-lives) 
of discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (e.g., a follow-up skin biopsy). 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
• Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section. 
• All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available. 
 
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor. 
The method of evaluating and assessing the seriousness, severity, and causality of AEs and the 
procedures for completing and reporting/transmitting SAE reports are provided in Appendix 3. 
Guidance for assessing severity of AEs is also provided in Section 8. 
9.2.2 
Method of Detecting AEs and SAEs 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 


 
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questioned regarding the specific occurrence of one or more AEs.) 
9.2.3 
Follow-up of AEs and SAEs 
• Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3). 
• Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate. 
• All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study. 
 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the participant is lost to follow-up (as 
defined in Section 8.3). 
Further information on follow-up procedures is given in Appendix 3. 
9.2.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met. 
• An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
 
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious 
Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements. 
9.2.5 
Pregnancy 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
9.2.6 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be reported as an AE and captured on 
the nonserious AE eCRF page or SAE Report Form electronic, as appropriate. Paper forms are 
only intended as a back-up option when the electronic system is not functioning. 


 
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• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted 
• Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
Laboratory abnormalities that are reported as AEs or SAEs should be reported utilizing the 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 
9.2.7 
Potential Drug Induced Liver Injury (DILI) 
• Dosing will be paused within a subject until safety information is reviewed and drug induced 
liver injury (DILI) is ruled out in the event that: 
− ALT > 5 x baseline AND No corresponding increase in CPK to indicate muscle origin as 
the reason for the increase in ALT 
OR 
− ALT > 10 x ULN AND ALT > 2 x baseline AND no corresponding increase in CPK to 
indicate muscle origin as the reason for the increase in ALT 
OR 
− Total bilirubin > 2 x ULN 
OR 
− Symptoms or signs of hepatic inflammation such as nausea, vomiting, right upper quadrant 
pain or tenderness with no other immediately apparent possible cause of these symptoms 
or signs, such as viral gastroenteritis or constipation. 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details). 
Criteria for initiating an evaluation for potential DILI are defined in Section 8. 
9.2.8 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
9.2.8.1 
Injection Site Assessments 
Subjects will be monitored for injection-site reactions from Day 1 through the last study visit. 
Report injection-site reactions as AEs, as appropriate. It is strongly recommended that non-subject 
identifying photographs of injection site reactions be taken for submission to the sponsor or 
designee. Some subjects with injection-site reaction or rash may be asked to participate in 
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reaction or rash. Potential subjects will be identified in consultation with the medical monitor. 
The additional procedures include a blood sample and skin biopsy to assess the type of 
immune reaction. The blood sample will be used to assess ADA titers, serum mast cell 
tryptase/histamine, and compliment activation products (e.g., C3D, C3G). The skin biopsy should 
be collected in a sterile manner in accordance with local procedures, using a 3 mm punch biopsy 
instrument and formalin fixation, and will assess mast cell, eosinophil, and neutrophil infiltration. 
The Draize Scale for erythema and edema will be used as a guide for reporting injection site 
reaction AEs50 (see Table 9.2.8.1-1). 
 
Table 9.2.8.1-1: 
Grading Injection Site Reactions 
 
Erythema 
Edema 
Description 
AE Grade 
Description 
AE Grade 
No erythema 
- 
No edema 
- 
Very slight erythema, barely 
perceptible 
Mild 
Very slight edema, barely perceptible 
Mild 
Well defined erythema 
Moderate 
Moderate edema, raised approximately 
1 milimeter (mm) 
Moderate 
Severe erythema 
Beet redness to slight eschar 
formation 
Severe 
Severe edema, raised more than 1mm 
and beyond exposure area 
Severe 
 
9.2.9 
Overdose or Incorrect Administration of Study Drug 
An overdose is defined as the accidental or intentional administration of the drug in an amount 
higher than the assigned dose. Definitions of other incorrect administration of study drug 
(including medication error, drug abuse, and drug misuse) are provided in Appendix 3.  
Any overdose or incorrect administration of study drug must be reported as an AE.  
If the associated AE fulfills seriousness criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event). Any AE 
associated with an overdose or incorrect administration of study drug should be reported as a 
separate AE as well (see Section 9.2). 
9.3 
Safety 
Planned time points for all safety assessments are listed in the Schedule of Activities. 
The data from the safety assessments required in this protocol (laboratory tests, ECGs, 
echocardiograms) will be transferred to Roche or designee from the relevant vendor. The site staff 
are not required to report these procedures in the CRF. Any findings of potential clinical relevance 
should be evaluated and managed by the investigator per standard medical/clinical judgment in 
consultation with the Roche medical monitor. Site staff are required to report to the sponsor on the 
CRF any AE that is identified during safety assessments. 


 
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9.3.1 
Physical Examinations 
Targeted physical exams to be guided by review of systems and include assessment of heart, lungs 
and abdomen. 
9.3.2 
Vital Signs 
Refer to Schedule of Activities. 
9.3.3 
Electrocardiograms and Echocardiograms 
Refer to Schedule of Activities. 
A central core lab will perform all imaging analyses. Sites will be informed of quality issues or 
needs for repeat scanning via queries from the core lab. 
Any findings of potential clinical relevance that are not directly associated with the objectives of 
the protocol should be evaluated and handled by the study investigator as per standard 
medical/clinical judgment. 
Reports (electrocardiogram and echocardiogram) from the central core lab will be provided to sites 
for inclusion in the subject’s medical record and to provide to subject caregivers. Availability of 
reports will be determined by the central core lab. 
Electrocardiograms and echocardiogram should be repeated in subjects with new cardiac 
symptoms. 
9.3.4 
Clinical Safety Laboratory Assessments 
Investigators must document their review of each laboratory safety report. 
 
 
 


 
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Table 9.3.4-1: 
Laboratory Assessments 
Screening 
On Treatment 
Follow-up 
Hematology 
Hemoglobin 
X 
X 
X 
Hematocrit 
X 
X 
X 
Total leukocyte count, including 
differential 
X 
X 
X 
Platelet count 
X 
X 
X 
Serum Chemistry 
Alanine aminotransferase (ALT) 
X 
X 
X 
Aspartate aminotransferase (AST) 
X 
X 
X 
Gamma-Glutamyl transferase (GGT) 
X 
X 
X 
Total bilirubin 
X 
X 
X 
Direct bilirubin 
X 
X 
X 
Alkaline phosphatase 
X 
X 
X 
Lactate dehydrogenase (LDH) 
X 
X 
X 
BUN 
X 
X 
X 
Creatinine 
X 
X 
X 
Creatine kinase 
X 
X 
X 
Total Protein 
X 
X 
X 
Albumin 
X 
X 
X 
Sodium 
X 
X 
X 
Potassium 
X 
X 
X 
Chloride 
X 
X 
X 
Calcium 
X 
X 
X 
Phosphorus 
X 
X 
X 
Magnesium 
X 
X 
X 
Iron 
X 
X 
X 
Plasma Chemistry 
Glutamate Dehydrogenase (GLDH) 
X (Day -1 or -2) 
X 
X 
Urine test 
Urinalysis (including protein, glucose, 
blood, leukocyte esterase, specific 
gravity) 
X 
X (only required at visits 
specified in Table 2-2 and 
Table 2-3) 
 
 


 
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Table 9.3.4-1: 
Laboratory Assessments 
Screening 
On Treatment 
Follow-up 
Other sample collections 
Serum Biomarkers 
X (see Table 2-2  
and Table 2-3) 
Immunogenicity 
X (see Table 2-2  
and Table 2-3) 
X (see Table 2-4) 
Free and myostatin drug complex 
X (see Table 2-2  
and Table 2-3) 
Exploratory genotyping 
X (see Table 2-2) 
Creatine kinase-muscle (CK-MM) 
X (Day 1, Weeks 12, 24 
 and 48 in double-blind phase) 
GDF-11 
 
X (see myostatin collection 
schedule in Table 2-2 
 and Table 2-3) 
 
9.3.5 
Imaging Safety Assessment 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.4 
Pharmacokinetics 
The PK data obtained in this study will be combined with data from other studies in the clinical 
development program to develop a population PK model. This model will be used to evaluate the 
effects of intrinsic and extrinsic covariates on the PK of RO7239361 and to determine measures 
of individual exposure (such as steady-state trough, and time-averaged concentration). Model 
determined exposures will be used for exposure-response analyses of selected efficacy and safety 
end points. Results of population PK and exposure-response analyses will be reported separately. 
Table 9.4-1 lists the sampling schedule to be followed for the assessment of pharmacokinetics. 
Further details of blood collection and processing will be provided to the site in the procedure 
manual and laboratory manual. 
Serum samples will be analyzed for RO7239361 using a validated ligand binding assay. 
Pharmacokinetic samples collected from a subject who received placebo will not be analyzed. 
 


 
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Table 9.4-1: 
Pharmacokinetic Sampling Schedule for RO7239361 
 
Study Day of Sample 
Collection 
Event 
Time (Relative To 
RO7239361 Dose)  
Hour: Min 
RO7239361 
Blood Sample for Serum 
Day 1 of the double-blind phase 
predose 
00:00 
X 
Day 8 of the double-blind phase 
predose 
00:00 
X 
Day 15 of the double-blind phase 
predose 
00:00 
X 
Day 29 of the double-blind phase 
predose 
00:00 
X 
Week 12 of the double-blind phase 
predose 
00:00 
X 
Week 24 of the double-blind phase 
predose 
00:00 
X 
Week 36 of the double-blind phase 
predose 
00:00 
X 
Week 48 of the double-blind phase 
predose 
00:00 
X 
Week 1 of the open-label phase 
predose 
00:00 
X 
Week 2 of the open-label phase 
predose 
00:00 
X 
Week 3 of the open-label phase 
predose 
00:00 
X 
Week 12 of the open-label phase 
predose 
00:00 
X 
Week 24 of the open-label phase 
predose 
00:00 
X 
Week 36 of the open-label phase 
predose 
00:00 
X 
Week 48 of the open-label phase 
predose 
00:00 
X 
 
 
9.5 
Pharmacodynamics 
Not applicable 
9.6 
Pharmacogenomics 
Not applicable. 
9.7 
Biomarkers 
Blood will be drawn at the times indicated in Table 2-1 through Table 2-3 for the measurement of 
target engagement biomarkers (free myostatin and myostatin-drug complex). 
Blood will be drawn at the times indicated in Table 2-1 through Table 2-3 for the measurement of 
exploratory biomarkers. Serum samples may be used to evaluate the levels of exploratory 
biomarkers known to be involved in muscle growth, function, and/or myostatin signaling (e.g., 
sTNI, MYL3, FABP3). 
Creatine kinase-muscle (CK-MM) will be analyzed during the double blind phase of the study to 
examine concentrations associated with muscle atrophy in boys with DMD. 
Reports of the exploratory serum biomarkers will not be provided to sites as this is a research 
measure. 


 
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9.7.1 
Additional Research Collection 
Additional research collections and retention are optional for all subjects, except where prohibited 
by local laws or regulations. 
This protocol will include both sample collection and residual sample storage for additional 
research (AR). 
This serum collection for additional research is intended to expand the translational R&D 
capability at Roche, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. For example, this sample may have potential 
in exploration of diagnostic or prognostic biomarkers contingent on scientific developments 
in the field of myostatin biology, DMD pathophysiology or unanticipated results in the study. 
This collection for additional research may also be used to support health authority requests for 
analysis, and advancement of pharmacodiagnostic development to better target drugs to the right 
patients. This may also include genetic/genomic exploration aimed at exploring disease pathways, 
progression and response to treatment etc. 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development to ensure the 
research supports appropriate and well-defined scientific research activities. 
 
• Prospective samples of serum for Additional Research will be collected at selected time points 
(see Table 9.7.1-1) 
• Residual serum from serum biomarker collections (see Table 9.7.1-2) will also be retained for 
additional research purposes 
• Residual whole blood or DNA  derived  from  the  whole  blood  sample  from  exploratory 
genotyping analysis (Table 9.7.1-2) will also be retained for additional research purposes 
Samples will be securely stored by the Roche Research Biosample Repository or at a Roche 
approved third party storage management facility. 
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual 
Additional research samples will be retained for 15 years or the maximum allowed by applicable 
law. No additional sampling is required for residual collections. 
Further details of sample collection and processing will be provided to the site in the procedure 
manual. 
 
 


 
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Table 9.7.1-1: 
Additional Research Sample Schedule 
 
Study Day 
Time 
(Event) 
Hour 
Time 
(Relative To Dosing) 
Hour: Min 
Blood Sample 
Baseline Day 1 
0 (predose) 
00:00 
X 
Week 24 
0 
00:00 
X 
Week 48 
0 
00:00 
X 
 
 
Table 9.7.1-2: 
Residual Sample Retention for Additional Research Schedule 
 
Sample Type 
Timepoints for which residual samples will be 
retained 
PK 
All 
Residual serum from serum biomarkers 
All 
Residual whole blood or DNA derived from the whole 
blood sample from exploratory genotyping 
Day 1 
Residual serum from ADA analysis 
All 
Residual serum from myostatin and myostatin-drug 
complex 
All 
 
9.7.2 
Immunogenicity Assessments  
Serum samples from all treated subjects will be analyzed by a validated immunogenicity assay. 
Individual time points are considered positive if confirmed as specific against RO7239361. The 
subject will be called positive for immunogenicity as defined in the Statistical Analysis Plan (SAP). 
The number and percentage of subjects will be listed and summarized by treatment and by time, 
and the corresponding antibody titer values will be listed. If ADAs are observed, subgroup 
analyses may be conducted to compare AEs, labs, biomarker data, and PK results across treated 
subjects with and without ADAs. In the event a subject has a positive immunogenicity response, 
additional NAB analyses may be conducted. 
9.7.3 
RNA Transcriptome Research  
Not applicable. 
9.7.4 
RNA Expression Research of a Subset of RNA Species  
Not applicable. 
9.7.5 
Proteome Research  
Not applicable. 
9.7.6 
Metabolomic Research  
Not applicable. 


 
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9.7.7 
Other Assessments 
Not applicable. 
9.8 
Health Economics or Medical Resource Utilization and Health 
Economics 
This study includes a number of patient reported outcomes, such as pediatric data collection 
instrument (PODCI), health utilities index (HUI III), and PedsQL family impact module (PedsQL 
FIM) that provide additional information to the clinician-reported outcomes. In addition, several 
questions will be included to collect presenteeism and absenteeism data, along with health care 
resource utilization. 
Health care resource utilization data associated with medical encounters, will be collected in the 
CRF by the investigator and study-site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include: 
• Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient) 
• Duration of hospitalization (total days length of stay, including duration by wards, 
e.g., intensive care unit) 
• Number and character of diagnostic and therapeutic tests and procedures 
• Outpatient medical encounters and treatments (including physician or emergency room visits, 
tests and procedures, and medications) 
10 
STATISTICAL CONSIDERATIONS 
10.1 
Sample Size Determination 
Statistical Considerations:  Sample Size 
The sample size of 159 patients (53 patients per arm) will provide 80% power for testing the null 
hypothesis of no difference between a dose of RO7239361 and placebo in the change from baseline 
in the NSAA total score at 48 weeks under the following assumptions: 
• A true treatment difference (RO7239361 minus placebo) of 2.5 points 
• A standard deviation of 4.4 points 
• A treatment discontinuation rate of 5% 
10.2 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
 


 
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Population 
Description 
Enrolled 
All participants who sign informed consent and are assigned a 
participant identification number. 
Randomized 
Enrolled participants who receive a randomization treatment 
assignment. 
Treated 
Enrolled subjects who receive at least 1 dose of study therapy. 
• If a subject received the same incorrect treatment throughout the 
study, then the participant will be analyzed based on the treatment 
received. 
• If a subject received study drug from more than one treatment 
group, and none of the administrations were consistent with the 
assigned randomized treatment group, then the participant will be 
analyzed based on the first treatment received. 
Modified Intention to Treat 
(mITT) 
Randomized subjects that received at least one dose of study 
drug. For change from baseline analyses, this includes only those 
subjects that had at least one efficacy assessment. 
Per-Protocol 
mITT subjects with no major protocol violations, as described in 
the Statistical Analysis Plan 
 
10.3 
Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the selection of 
participants to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. Below is a summary of planned statistical analyses of the primary and 
secondary endpoints. 


 
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10.3.1 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary analysis, on the change from baseline in NSAA total score, will be 
conducted using a Mixed Model Repeated Measures (MMRM) analysis with 
treatment, visit, and the treatment-by-visit interaction entered into the model as fixed 
effects, and participant entered as a random effect. The baseline NSAA total score will 
be entered into the model as a covariate. The stratification factors will be entered into 
the model as blocks. 
For each RO7239361 dose group, the null hypothesis of the no treatment difference 
between the dose group and placebo will be tested using the estimates from this 
MMRM model at the end of the 48-week double-blind treatment period. In order to 
control the overall type I error rate for the analysis, the following hierarchical testing 
of doses will be implemented:  
1. Comparison of the RO7239361 high dose (35/50 mg) to placebo at a two-sided 
α level of 0.05 is performed. 
2. If the null hypothesis for the high dose is rejected (comparison of the high dose 
to placebo in the previous step is statistically significant), then a comparison of 
the RO7239361 low dose (7.5/15 mg) to placebo at a two-sided α level of 0.05 
will be performed. If the null hypothesis for the high dose is not rejected, then 
the testing of the low dose versus placebo will not be performed. 
Sensitivity analyses will include the following: an analysis of covariance 
(ANCOVA) using the mITT data set; an ANCOVA on the mITT data set with 
missing data imputed using multiple imputations; and an MMRM analysis using the 
per-protocol data. 
Secondary Following testing of the primary endpoint, the key secondary endpoints will be 
analyzed using a hierarchical testing procedure in order to maintain the overall type 
I error rate at 0.05. This procedure will be specified in the Statistical Analysis Plan 
prior to database lock. 
Most secondary endpoints will be tested using a MMRM that is similar in structure 
to the primary analysis. Proximal lower extremity flexor strength will be tested using 
a MANOVA of the 2 component variables: knee extension and knee flexion. 
If a dose fails to reach significance against placebo in any stage of the testing 
hierarchy, any further tests will be considered as exploratory. 
Exploratory Will be described in the Statistical Analysis Plan finalized before database lock 
 


 
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10.3.2 
Safety Analyses 
All safety analyses will be performed using treated subjects. 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
Tabular summaries of SAEs, AEs leading to discontinuation and Grade 3 to 4 
laboratory abnormalities will present the number and percentage of unique 
subjects with treatment emergent events. Adverse event summaries will be 
presented by system organ class (SOC) and preferred term (PT). All SAEs 
since enrollment will be listed. Grade 3 to 4 laboratory abnormalities will be 
summarized as proportions by baseline toxicity grade. 
Endpoint 
Statistical Analysis Methods 
Exploratory 
Will be described in the Statistical Analysis Plan finalized before database lock 
 
10.3.3 
Other Analyses 
PK, PD, biomarker and exploratory analyses will be described in the SAP finalized before 
database lock. The population PK analysis and PD analyses will be presented separately from the 
main clinical study report. 
10.3.4 
Interim Analyses 
Schedule of Analyses 
In addition to the primary analysis (to be conducted when all patients have completed Week 48, the 
end of the double-blind treatment period), the following analyses may be conducted during the 
course this study: 
• When at least 20% of the total number of patients have completed 24 weeks of double-blind, 
placebo-controlled treatment 
• When at least 20% of the total number of patients has completed 48 weeks of double-blind, 
placebo-controlled treatment 
• An analysis conducted at Week 96 (at the end of the first 48 weeks of the OL phase of the study) 
• A final data analysis when the study has been completed 
The SAP will further describe the planned interim analyses.  
Interim SAPs (iSAPs) will contain detailed information about the conduct of the futility analyses, 
which will be performed by an independent data coordinating center with results reviewed by the 
iDMC. Because these futility analyses will be conducted prior to the primary efficacy analysis, the 
unblinded data will not be shared with the Sponsor in order to maintain the integrity of the study 
blind.  


 
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For the primary efficacy endpoint (the change from baseline in NSAA total score), additional 
analyses may be performed, incorporating the first 96 weeks of exposure to RO7239361 (48 weeks 
of double-blind treatment) followed by 48 weeks of OL treatment). The data will be compared with 
data from one or more control cohorts from external data sources (e.g., disease registries) that 
include at least 96 weeks of follow-up data. 


 
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11 
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2 
Manzur AY, Kuntzer T, Pike M, et al. Glucocorticoid corticosteroids for Duchenne muscular 
dystrophy. Cochrane Database Systematic Review, 2008; 1:CD003725. 
3 
Wagner KR, McPherron AC, Winik N, et al. Loss of myostatin attenuates severity of muscular 
dystrophy in mdx mice. Ann Neurol, 2002; 832-836. 
4 
Grounds MD, et al. Towards developing standard operating procedures for pre-clinical testing 
in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol Dis 2008;31(1): 1-
19. 
5 
Bogdanovich S, Krag, TO, Barton ER, et al. Functional improvement of dystrophic muscle by 
myostatin blockade. Nature, 2002; 420: 418-421. 
6 
Guiraud S, Aartsma-Rus A, Vieira NM, et al. The Pathogenesis and Therapy of Muscular 
Dystrophies. Annu Rev Genomics Hum Genet 2015;ePub ahead of print. Accessed: 23 July 
2015. 
7 
Hoffman EP, Brown RH, Kunkel LM. Dystrophin: the protein product of the Duchenne 
muscular dystrophy locus. Cell 1987:51:919-28. 
8 
Manzur AY, Kuntzer T, Pike M, Swan AV. Glucocorticoid corticosteroids for Duchenne 
muscular dystrophy. Cochrane Database Syst Rev 2008;1. 
9 
Eagle M, Baudouin SV, Chandler C, et al. Survival in Duchenne muscular dystrophy: 
improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. 
Neuromuscul Disord 2002;12:926-9. 
10 Lynn S, Aartsma-Rus A, Bushby K, et al. Measuring clinical effectiveness of medicinal 
products for the treatment of Duchenne muscular dystrophy. Neuromuscul Disord 
2015;25:96-105. 
11 Moxley RT 3rd, Pandya S, Ciafaloni E, et al. Change in natural history of Duchenne muscular 
dystrophy with long-term corticosteroid treatment: implications for management. J Child 
Neurol 2010;25:1116-29. 
12 Translarna (ataluren) Summary of Product Characteristics. Almac Pharma Services. 31 July 
2014. 
13 Dent KM, Dunn DM, von Niederhausern AC, et al. Improved molecular diagnosis of 
dystrophinopathies in an unselected clinical cohort. Am J Med Genet A 2005;134:295–8. 
14 Wright MA, Yee AS, et al. Consider Muscle Disease in Children with Elevated Transaminase. 
JABFM 2012; 25: 536-540. 
15 McMillan HJ, Kang PB, et al. Serum Transaminase Levels in Boys with Duchenne and Becker 
Muscular Dystrophy. Pediatrics 2011; 127: e132-e136. 


 
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16 Mcdonald CM, Henricson EK, Abresch RT, et al. The 6-minute walk test and other clinical 
endpoints in duchenne muscular dystrophy: Reliability, concurrent validity, and minimal 
clinically 
important differences 
from a 
multicenter study. Muscle and Nerve 
2013;48(3):357-68 
17 Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation 
dystrophinopathy. Muscle & Nerve 2014;50:477-487. 
18 Pane M, Mazzone ES, Sivo S, et al. Long term natural history data in ambulant boys with 
duchenne muscular dystrophy: 36-month changes. PLOS ONE 2014;9:e108205. 
19 Griggs RC et al. Prednisone in Duchenne muscular dystrophy: a randomized, controlled trial 
defining the time course and dose response. Archive of Neurology 1991; 48:383-388. 
20 Manzur AY, Kuntzer T, Pike M, Swan AV. Glucocorticoid corticosteroids for Duchenne 
muscular dystrophy. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. 
No.: CD003725. 
21 Cittadini A, Comi LI, Longobardi S, et al. A preliminary randomized study of growth hormone 
administration in becker and duchenne muscular dystrophies. Eur Heart J 2003;24(7):664-72. 
22 Fenichel GM, Griggs RC, Kissel J, et al. A randomized efficacy and safety trial of oxandrolone 
in the treatment of duchenne dystrophy. Neurology 2001;56(8):1075-9. 
23 Griggs, R, Moxley, R, Mendell, J, Fenchel, G, Brooke, M, Pestronk, A, Miller, J. Prednisone 
in Duchenne Dystrophy. Arch Neurol. 1991; 48:383-388. 
24 Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation 
dystrophinopathy. Muscle Nerve 2014; 50: 477-487 
25 Mayhew A, Cano S, Scott E, et al. Detecting meaningful change using the North Star 
Ambulatory Assessment in Duchenne muscular dystrophy. Dev Med Child Neurol 
2013;55:1046-52. 
26 Ricotti V, Ridout D, Pane M, et al. The North Start Ambulatory Assessment in Duchenne 
muscular dystrophy: considerations for the design of clinical trials. J Neurol Neurosurg 
Psychiatry 2016;87:149-55.   
27 McDonald C, Henricson E, Abresch R, et al. The 6-minute walk test and other endpoints in 
duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a 
multicenter study. Muscle Nerve 2013; 48: 343-356. 
28 McDonald C, Henricson E, Abresch R, et al. The 6-minute walk test and other clinical 
endpoints in Duchenne muscular dystrophy: reliability, concurrent validity, and minimal 
clinically important differences from a multicenter study. Muscle Nerve 2013; 48: 357-368. 
29 Nakatani M, Takehara Y, Sugino H, et al. Transgenic expression of a myostatin inhibitor 
derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology 
in mdx mice. FASEB J 2008;22:477-87. 
30 Morine KJ, Bish LT, Pendrak K, et al. Systemic myostatin inhibition via liver targeted gene 
transfer in normal and dystrophic mice. PLoS One 2010;5:e9176. 


 
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31 Wagner KR, McPherron AC, Winik N, Lee SJ. Loss of myostatin attenuates severity of 
muscular dystrophy in mdx mice. Ann Neurol 2002;52:832–6. 
32 Bogdanovich S, Krag TO, Barton ER, et al. Functional improvement of dystrophic muscle by 
myostatin blockade. Nature 2002;420:418-21. 
33 Morine KJ, Bish LT, Selsby JT, et al. Activin IIB receptor blockade attenuates dystrophic 
pathology in a mouse model of Duchenne muscular dystrophy. Muscle Nerve 2010;42:722-30. 
34 Murphy KT, Ryall JG, Snell SM, et al. Antibody-directed myostatin inhibition improves 
diaphragm pathology in young but not adult dystrophic mdx mice. Am J Pathol 
2010;176:2425-34. 
35 Pistilli EE, Bogdanovich S, Goncalves MD, et al. Targeting the activin type IIB receptor to 
improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy. 
Am J Pathol 2011;178:1287-97. 
36 Bish LT, Sleeper MM, Forbes SC, et al. Long-Term Systemic Myostatin Inhibition via Liver- 
Targeted Gene Transfer in Golden Retriever Muscular Dystrophy. Hum Gene Ther 
2011;22:1499-509. 
37 Kornegay JN, Childers MK, Bogan DJ, et al. The paradox of muscle hypertrophy in muscular 
dystrophy. Phys Med Rehabil Clin N Am 2012;23:149-72. 
38 Clinical Study Report for Study CN001001. A Randomized, Placebo-Controlled, Single and 
Multiple Ascending Subcutaneous Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of BMS-986089 in Healthy Adult Subjects. 
Bristol-Myers Squibb Company; 2016. Document Control No. 930103114. 
39 Gamer, LW, Wolfman NM, Celeste AJ, et al. A novel BMP expressed in developing mouse 
limb, spinal cord, and tail bud is a potent mesoderm inducer in Xenopus embryos. Dev. 
Biol 1999;208:222–232. 
40 McPherron AC, Lawler, AM, Lee S-J. Regulation of anterior/ posterior patterning of the 
axial skeleton by growth/differentiation factor 11. Nat. Genet. 22:260–264. 
41 
, BMS-986089: Scientific Report In Vitro Potency and Selectivity of 
BMS-986089 in Cell-based Luciferase Reporter Assays. Bristol-Myers Squibb Company; 
Jan 22, 2014. Document Control No. 930074468. 
42 
. BMD-986089: Scientific Report. An in Vitro Selectivity Study 
Testing BMS-989089 Blockade of GDF-8 and GDF-11 Cellular Signaling. Bristol-Myers 
Squibb Company; Jun 1, 2015. Document Control No. 930090594. 
43 Loffredo FS, et al. Growth differentiation factor 11 is a circulating factor that reverses 
age-related cardiac hypertrophy. Cell, 2013;153:828-839. 
44 Egerman MA, et al. (2015). "GDF11 Increases with Age and Inhibits Skeletal Muscle 
Regeneration." Cell Metab. 22, 164–174. 
45 Rodgers BD, and J. A. Eldridge JA. Reduced Circulating GDF11 Is Unlikely Responsible 
for Age-Dependent Changes in Mouse Heart, Muscle, and Brain. Endocrinology 
2 0 1 ; 156(11): 3885-3888. 


 
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46 Smith, S. C., et al. (2015). "GDF11 Does Not Rescue Aging-Related Pathological 
Hypertrophy." Circ Res 117(11): 926-932. 
47 Investigator Brochure: Anti-Myostatin Adnectin, RO7239361. F. Hoffmann-La Roche Ltd. 
Version 07, July 2018. 
48 Henricson E et al. The Cooperative International Neuromuscular Research Group Duchenne 
Natural History Study: Glucocorticoid treatment preserves clinically meanintful functional 
milestones and reduces rate of disease progression as measured by manual muscle testing and 
other commonly used clinical trial outcome measures. Muscle and Nerve; July 2013:55-67. 
49 Mazzone ES et al. Reliability of the North Star Ambulatory Assessment in a multicentric 
setting. Neuromuscular Disorders 2009; 19:458-461. 
50 Pane M, et al. Reliability of the Performance of Upper Limb Assessment in Duchenne 
muscular dystrophy. Neuromuscular Disorders 2014; 24: 201-206 
51 Damilakis J et al. Radiation exposure in X-ray-based imaging techniques used in osteoporosis. 
Eur Radiol 2010; 20: 2707-2714. 
52 Haschek W, Rousseaux C, Wallig M. 2010. Fundamentals of Toxicologic Pathology. 2nd 
Edition. London: Elseviers, Inc. 
53 Food and Drug Administration, FDA Briefing Document, Peripheral and Central Nervous 
System Drugs Advisory Committee Meeting, NDA 206031, Drisapersen, November 24, 2015. 
54 Rodriguez J, Vernus B, Chehl I, et al. Myostatin and the skeletal muscle atrophy and 
hypertrophy signaling pathways. Cell Mol Life Sci 2014;71:4361-71. 
55 Tando T, Hirayama A, Furukama M, Sato Y, et al.  Smad2/3 proteins are required for 
immobilization-induced skeletal muscle atrophy. J Biochem 2016;291:12184-94. doi: 
10.1074/jbc.M115.680579. 
56 Scott E, Eagle M, Mayhew A, et al. Development of a functional assessment scale for 
mbulatory boys with Duchenne muscular dystrophy and the North Star Clinical Network for 
Paediatric Neuromuscular Disease. Physio Res Int 2012;17:101-9. 
57 Mazzone E, Martinelli D, Bardinelli A, et al. North Star Ambulatory Assessment, 6-minute 
walk test and timed items in ambulant boys with Duchenne muscular dystrophy. 
Neuromuscul Disord 2010;20:712-6. 
58 Goemans NM, Tulinius M, van den Akker JT, et al. Systemic administration of PRO051 in 
Duchenne’s muscular dystrophy. N Engl J Med 2011;364:1513–22. 
 
 


 
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12. 
APPENDICES 


 
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APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS 
 
Term 
Definition 
4SC 
4 stair climb 
6MWD 
6 minute walk distance 
AE 
adverse event 
ACLS 
advanced cardiac life support 
ADA 
anti-drug antibody 
AI 
accumulation index 
AI_AUC 
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose 
AI_Cmax 
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose 
AI_Ctau 
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AT 
amino transaminases 
ATOM 
Advancing Trial Outcome Measures International, Ltd. 
AUC 
area under the concentration-time curve 
AUC(INF) 
area under the concentration-time curve from time zero extrapolated to 
infinite time 
AUC(0-T) 
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration 
AUC(TAU) 
area under the concentration-time curve in one dosing interval 
A-V 
Atrioventricular 
BID, bid 
bis in die, twice daily 
BLQ 
below limit of quantification 
BMI 
body mass index 
BMS 
Bristol-Myers Squibb 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
Celsius 
C12 
concentration at 12 hours 
24 
concentration at 24 hours 
Ca++ 
calcium 


 
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Term 
Definition 
Cavg 
average concentration 
CBC 
complete blood count 
Cexpected-tau 
expected concentration in a dosing interval 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CHF 
Congestive heart failure 
CI 
confidence interval 
C1- 
chloride 
CLcr 
creatinine clearance 
cm 
centimeter 
Cmax, CMAX 
maximum observed concentration 
Cmin, CMIN 
minimum observed concentration 
cMRI 
Cardiac magnetic resonance imaging 
CPF 
Cough peak flow 
CRC 
Clinical Research Center 
CRF 
Case Report Form, paper or electronic 
CS 
Corticosteroid 
Ct 
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (e.g., concentration at 24 hours, 
concentration at 12 hours, etc.) 
Ctau 
Concentration in a dosing interval (e.g., concentration at 24 
hours, concentration at 12 hours, etc.) 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough observed plasma concentration 
CV 
coefficient of variation 
D/C 
discontinue 
dL 
deciliter 
DMD 
Duchenne muscular dystrophy 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EF 
Ejection fraction 
e.g. 
exempli gratia (for example) 
EOSI 
events of special interest 
ESR 
Expedited Safety Report 


 
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Term 
Definition 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced Vital Capacity 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GFR 
Glomerular filtration rate 
GDF-8 
Growth and differentiation factor-8 
GLDH 
Glutamate dehydrogenase 
h 
Hour 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCO - 
3 
Bicarbonate 
HIV 
Human Immunodeficiency Virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
HUI-3 
Health Utility Index-3 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICD 
International Classification of Diseases 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
i.e. 
id est (that is) 
IEC 
Independent Ethics Committee 
IFU 
instructions for use 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IU 
International Unit 
IV 
Intravenous 
IWRS 
Interactive web response system 
K 
slope of the terminal phase of the log concentration-time curve 


 
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Term 
Definition 
K3EDTA 
potassium ethylenediaminetetraacetic acid 
K+ 
Potassium 
kg 
Kilogram 
L 
Liter 
LC 
liquid chromatography 
LDH 
lactate dehydrogenase 
ln 
natural logarithm 
LTBP4 
Latent transforming growth factor beta binding protein 4 
MAD 
Multiple ascending dose 
MEP 
Maximum expiratory pressure 
MIP 
Maximum inspiratory pressure 
mg 
Milligram 
Mg++ 
Magnesium 
min 
Minute 
mITT 
Modified intent to treat 
mL 
Milliliter 
mmHg 
millimeters of mercury 
MMRM 
Mixed model repeated measures 
MR 
medical research 
MRI 
Magnetic resonance imaging 
MRT 
mean residence time 
MS 
Mass spectrometry 
MTD 
maximum tolerated dose 
µg 
Microgram 
N 
number of subjects or observations 
Na+ 
Sodium 
NA 
not applicable 
NAB 
Neutralizing antibodies 
ng 
Nanogram 
NIMP 
non-investigational medicinal products 
NOAEL 
No observed adverse event level 
NSAA 
North Star Ambulatory Assessment Scale 
NSAID 
non-steroidal anti-inflammatory drug 
OL 
Open label 
pAUCe 
Extrapolated partial AUC from last quantifiable concentration to infinity 


 
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Term 
Definition 
Pb 
percent of bound drug 
PD 
pharmacodynamic 
PE 
Physical exam 
PedsQL FIM 
Pediatric Quality of Life Family Impact Module 
PFR 
Peak flow rate 
PFS 
pre-filled syringe 
PFTs 
Pulmonary function tests 
PK 
pharmacokinetic 
PODCI 
Pediatric Outcome Data Collection Instrument 
PO 
per os (by mouth route of administration) 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Pu 
percent of unbound drug 
PUL 
Performance of Upper Limb 
QC 
quality control 
QD, qd 
quaque die, once daily 
R2 
coefficient of determination 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SOP 
Standard Operating Procedures 
SPP1 
Secreted phosphoprotein 1 
t 
Temperature 
T 
Time 
TE 
Target engagement 
TFTs 
Timed function tests 
TGF-β 
transforming growth factor-β 
T-HALF 
Half life 
Tmax, TMAX 
time of maximum observed concentration 
Vss/F (or Vss) 
apparent volume of distribution at steady state 
W 
Washout 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 


 
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Term 
Definition 
x g 
times gravity 


 
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APPENDIX 2 
STUDY GOVERANCE CONSIDERATIONS 
The term "Participant" is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term "Subject" used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study. 
REGULATORY and ETHICAL CONSIDERATIONS 
GOOD CLINICAL PRACTICE 
This study will be conducted in accordance with: 
• Good Clinical Practice (GCP), 
• as defined by the International Council on Harmonisation (ICH) 
• in accordance with the ethical principles underlying European Union Directive 2001/20/EC 
• United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
• applicable local requirements. 
 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study. 
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(e.g., advertisements), and any other written information to be provided to subjects. The 
investigator or Roche should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures. 
 


 
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS 
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to: 
• IRB/IEC for 
• Regulatory Authority(ies), if applicable by local regulations (per national requirements) 
 
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to Roche. 
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment. 
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
FINANCIAL DISCLOSURE 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
 
INFORMED CONSENT PROCESS 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample 
informed consent form, which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki. 


 
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Investigators must: 
• Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
• Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study. 
• Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
• Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information. 
 
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant. 
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
U.S., the subjects’ signed HIPAA Authorization. 
The consent form must also include a statement that Roche and regulatory authorities have direct 
access to participant records. 
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the informed consent form approved for 
the study prior to clinical study participation. The explicit wish of a minor, who is capable of 
forming an opinion and assessing this information to refuse participation in, or to be withdrawn 
from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
 
SOURCE DOCUMENTS 
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 


 
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97/Protocol WN40227, Version 4 
 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records). 
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
 
STUDY TREATMENT RECORDS 
Records for study treatments (whether supplied by Roche, its vendors, or the site) must 
substantiate study treatment integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
Roche/designee or a Health Authority. 
 


 
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If 
Then 
Supplied by Roche (or its vendors): 
Records or logs must comply with applicable 
regulations and guidelines and should include: 
• amount received and placed in storage 
area 
• amount currently in storage area 
• label identification number or batch 
number 
• amount dispensed to and returned by each 
participant, including unique participant 
identifiers 
• amount transferred to another area/site for 
dispensing or storage 
• nonstudy disposition (e.g., lost, wasted) 
• amount destroyed at study site, if 
applicable 
• amount returned to Roche 
• retain samples for 
bioavailability/bioequivalence, if 
applicable 
• dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form. 
Sourced by site, and not supplied by Roche or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy) 
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy. 
These records should include: 
• label identification number or batch 
number 
• amount dispensed to and returned by each 
participant, including unique participant 
identifiers 
• dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form. 
Roche or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements. 


 
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CASE REPORT FORMS 
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study. 
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. 
If electronic SAE form is not available, a paper SAE form can be used. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
Roche electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections. 
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the Roche electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals. 
 
MONITORING 
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of Roche must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents such as quality of life questionnaires. 
 


 
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In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. Roche audit reports will be kept confidential. 
The investigator must notify Roche promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
 
RECORDS RETENTION 
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by Roche or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact Roche prior to destroying any records 
associated with the study. 
Roche or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed. 
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to Roche or designee. 
 
RETURN OF STUDY TREATMENT 
For this study, study treatments (those supplied by Roche, a vendor or sourced by the investigator) 
such as partially used study treatment kits, vials and syringes may be destroyed on site. 
 
If 
Then 
Study treatments supplied by Roche 
(including its vendors) 
Any unused study treatments supplied by 
Roche can only be destroyed after being 
inspected and reconciled by the responsible 
Study Monitor unless study treatments kits 
must be immediately destroyed as required 
for safety, or to meet local regulations (e.g., 
cytotoxics or biologics). 
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor. 
Study treatments sourced by site, not supplied 
by Roche (or its vendors) (examples 
include study treatments sourced from the 
sites stock or commercial supply, or a 
specialty pharmacy) 
It is the investigator’s or designee’s 
responsibility to dispose of all kits 
according to the institutional guidelines and 
procedures. 
 
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 


 
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for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to Roche upon request. 
• Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the kits. The method 
of disposal, incinerator, licensed sanitary landfill, or licensed waste disposal vendor must be 
documented. 
• Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period. 
 
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty kits. 
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by Roche (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by Roche, is solely the responsibility of the investigator 
or designee. 
 
CLINICAL STUDY REPORT AND PUBLICATIONS 
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria: 
• External Principal Investigator designated at protocol development 
• National Coordinating Investigator 
• Study Steering Committee chair or their designee 
• Participant recruitment (e.g., among the top quartile of enrollers) 
• Involvement in trial design 
• Regional representation (e.g., among top quartile of enrollers from a specified region or country) 
• Other criteria (as determined by the study team) 
 
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA. 


 
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APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING 
 
ADVERSE EVENTS 
 
Adverse Event Definition: 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug. 
 
 
SERIOUS ADVERSE EVENTS 
 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose: 
Results in death 
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
NOTE: 
The following hospitalizations are not considered SAEs in Roche clinical studies: 
o a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life- threatening 
event) 
o elective surgery, planned prior to signing consent 
o admissions as per protocol for a planned medical/surgical procedure 
o routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 
o medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases 
 


 
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o admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason) 
o admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 
is an important medical event (defined as a medical event(s) that may not be immediately life- 
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, cancer, and potential drug induced liver injury (DILI) are not always 
serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5 for 
reporting pregnancies). 
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
 
EVALUATING AEs AND SAEs 
 
Assessment of Causality 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
 
 
 


 
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Assessment of severity 
The following categories and definitions of severity as determined by a physician should be 
used for assessing severity of adverse events: 
• Mild (Grade 1):  Awareness of event but easily tolerated 
• Moderate (Grade 2):  Discomfort enough to cause some interference with usual activity 
• Severe (Grade 3):  Inability to carry out usual activity 
• Very severe (Grade 4):  Debilitating, significantly incapacitates subject despite 
symptomatic therapy 
 
 
Follow-up of AEs and SAEs 
If only limited information is initially available, follow-up reports are required.  
(Note: Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to Roche 
(or designee) using the same procedure used for transmitting the initial SAE report. 
All SAEs must be followed to resolution or stabilization. 
 
OVERDOSE, MEDICATION ERROR, DRUG MISUSE AND DRUG ABUSE 
 
Definition: 
Accidental overdose:  accidental administration of a drug in a quantity that is higher than the 
assigned dose. 
Intentional overdose:  intentional administration of a drug in a quantity that is higher than the 
assigned dose. 
Medication error:  accidental deviation in the administration of a drug (in some cases, a 
medication error may be intercepted prior to administration of the drug). 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or dependence,  
physical harm, and/or psychological harm. 
Drug misuse:  intentional deviation in the administration of a drug that does not qualify as drug 
abuse (drug misuse could involve the drug being administered to someone other than the patient). 
 
 
 
 
 
REPORTING OF SAEs TO SPONSOR OR DESIGNEE 


 
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• SAEs, whether related or not related to study drug, and pregnancies must be reported to 
Roche (or designee) within 24 hours of awareness of the event. 
• SAEs  must  be  recorded  on  the  SAE  Report  Form;  pregnancies  on  a  Pregnancy 
Surveillance Form (electronic or paper forms). 
• The preferred method for SAE data reporting collection is through the eCRF. 
• The paper SAE/pregnancy surveillance forms are only intended as a back-up option 
when the eCRF system is not functioning. 
o In this case, the paper forms are to be transmitted via email or  confirmed 
facsimile (fax) transmission to: 
SAE Email Address: Refer to Contact Information list. 
SAE Facsimile Number: Refer to Contact Information list. 
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site. 
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list 


 
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APPENDIX 4 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL. 
Appropriate patient-centered counseling of adolescent trial subjects about contraception and 
sexual health topics should be provided, including acceptable, highly effective methods as 
described below. 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. Female partners of male subjects, who are WOCBP, are expected to use one of the 
highly effective methods of contraception listed below. Male subjects must inform their female 
partners who are WOCBP of the contraceptive requirements of the protocol and are expected 
to adhere to using contraception with their partner. Contraception methods are as follows: 
1. Progestogen only hormonal contraception associated with inhibition of ovulation. 
2. Hormonal methods of contraception including oral contraceptive pills containing 
combined estrogen + progesterone, vaginal ring, injectables, implants and intrauterine 
devices (IUDs) such as Mirena® 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator. 
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study treatment(s) plus 5 half-lives of the 
study treatment [RO7239361; 50 days] plus 90 days (duration of sperm turnover) for a total of 
140 days (5 months) post-treatment completion. 
• Azoospermic males are exempt from contraceptive requirements; however, use of condom in 
male subjects (including azoospermic males) who are sexually active with a pregnant partner is 
required. 
• Male participants must be willing to refrain from sperm donation during the entire study and 
for 5 half-lives of study treatment plus 90 days (duration of sperm turnover) 140 days after 
dosing has been completed. 
 
 
2. 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting. 
 

SAP_001.pdf: 
 
Official Title: 
 
A Randomized, Double Blind, Placebo-Controlled, Study to Assess the 
Efficacy, Safety, and Tolerability of RO7239361 in Ambulatory Boys 
With Duchenne Muscular Dystrophy 
NCT Number: 
NCT03039686  
Document Date: 
SAP Version 1: 11-October-2019 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information. Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
RO7239361—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WN40227
STATISTICAL ANALYSIS PLAN
TITLE:
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO ASSESS THE EFFICACY, 
SAFETY, AND TOLERABILITY OF RO7239361 IN 
AMBULATORY BOYS WITH DUCHENNE MUSCULAR 
DYSTROPHY
PROTOCOL NUMBER:
WN40227
STUDY DRUG:
Anti-myostatin adnectin (RO7239361)
VERSION NUMBER:
1
IND NUMBER:
120,702
EUDRACT NUMBER:
2016-001654-18
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
DATE FINAL:
see electronic signature below
Date and Time(UTC)        Reason for Signing                              Name
11-Oct-2019 11:23:30
Company Signatory


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2/Statistical Analysis Plan WN40227
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 4
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 7
2.2
Endpoints................................................................................. 7
2.2.1
Primary Efficacy Endpoint........................................................ 7
2.2.2
Secondary Efficacy Endpoints................................................. 8
2.2.3
Exploratory Efficacy and Pharmacodynamic 
Endpoints................................................................................. 8
2.2.4
Safety Endpoints ..................................................................... 9
2.3
Determination of Sample Size ................................................. 9
2.4
Analysis Timing ..................................................................... 10
3.
STUDY CONDUCT..................................................................................... 10
3.1
Randomization....................................................................... 10
3.2
Data Monitoring ..................................................................... 11
4.
STATISTICAL METHODS .......................................................................... 11
4.1
Analysis Populations ............................................................. 11
4.1.1
Enrolled Population ............................................................... 11
4.1.2
Randomized Population......................................................... 11
4.1.3
Modified Intent-to-Treat Population ....................................... 11
4.1.4
Per Protocol Population......................................................... 12
4.1.5
Safety Population .................................................................. 12
4.2
Analysis of Study Conduct..................................................... 12
4.3
Analysis of Treatment Group Comparability .......................... 12
4.4
Efficacy Analysis at end of double-blind 
treatment ............................................................................... 12
4.4.1
Primary Efficacy Endpoint...................................................... 12
4.4.2
Secondary Efficacy Endpoints............................................... 13
4.4.2.1
Hypothesis Testing for Secondary Efficacy 
Endpoints............................................................................... 14
4.4.3
Exploratory Efficacy Endpoints.............................................. 14
4.4.4
Sensitivity Analyses............................................................... 14


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4.4.4.1
Additional Analyses of the Primary Endpoint......................... 15
4.4.5
Subgroup Analyses ............................................................... 16
4.5
Efficacy Analysis of open-label data...................................... 16
4.6
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 16
4.7
Safety Analyses..................................................................... 16
4.7.1
Exposure of Study Medication............................................... 17
4.7.1.1
Study Therapy Compliance ................................................... 17
4.7.1.2
Modifications of Study Therapy ............................................. 17
4.7.1.3
Corticosteroid Treatment ....................................................... 17
4.7.2
Adverse Events ..................................................................... 18
4.7.3
Laboratory Data..................................................................... 19
4.7.4
Vital Signs and Physical Measurements................................ 19
4.7.5
ECGs..................................................................................... 19
4.7.6
Echocardiograms................................................................... 19
4.7.7
Immunogenicity ..................................................................... 20
4.8
Missing Data.......................................................................... 20
4.9
Interim Analyses .................................................................... 20
LIST OF TABLES
Table 1
Terms, Definitions, and Abbreviations .......................................... 5
LIST OF APPENDICES
Appendix 1 Study WN40227 Protocol ................................................................ 21


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1.
BACKGROUND
This Statistical Analysis Plan documents the methods of summarizing and analyzing the
data to be collected in Study WN40227. The main purpose of this document is to 
describe the data handling rules and statistical analysis methods for the data that will be 
included in the clinical study reports.
This statistical analysis plan focuses on the analyses of the 48-week double-blind 
placebo controlled period. An overview of the approach to analyses of the open-label 
extension (OLE) data is described in Section 4.5.
Term definitions and abbreviations used in this SAP are defined in Table 1.


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5/Statistical Analysis Plan WN40227
Table 1
Terms, Definitions, and Abbreviations
4SCV
4 stair climb velocity
6MWD
6 minute walk distance
ADA
anti-drug antibodies
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aminotransferase
Blinded data 
data for which treatment assignment is not identified 
CaGI-C
Caregiver-reported Global Impression of Change
CGI-C
Clinical Global Impression of Change
CK
creatine kinase
Clinical cutoff date
date by which all the requirements have been achieved
CPF
cough peak flow
CS
corticosteroids
CTCAE
Common Terminology for Adverse Events
DMD
Duchenne Muscular Dystrophy
DXA
dual x-ray absorptiometry
ECG
electrocardiogram
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
iDMC 
independent Data Monitoring Committee 
ITT
intent-to-treat
IWRS
Interactive Web Response System
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
MEP
maximal expiratory pressure
MIP
maximal inspiratory pressure
mITT
modified intent-to-treat
mITT
modified intent-to-treat
NSAA
North Star Ambulatory Assessment
OLE
open-label extension
PD
pharmacodynamic
PedsQL FIM
Pediatric Quality of Life Inventory Family Impact Module
PedsQL MFS
Pediatric Quality of Life Multidimensional Fatigue Scale
PFR
peak flow rate
PFT
Pulmonary Function Test
PODCI
Pediatric Outcomes Data Collection Instrument
PP
per-protocol


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Table 1
Terms, Definitions, and Abbreviations (cont.)
PT
preferred term
PUL
Performance of Upper Limb
Roche Group 
The Roche Group includes, among others, the following entities:
F. Hoffmann−La Roche AG (Basel, Switzerland), Roche
Translational and Clinical Research Center (New York, USA),
Roche Products, Ltd. (Welwyn, United Kingdom), 
Genentech, Inc. (South San Francisco, USA), and 
Shanghai Roche Pharmaceuticals, Ltd. (Shanghai, China)
RPD
relevant protocol deviations
SAE
serious adverse event
SC
subcutaneous
SOC
System Organ Class
Sponsor 
Roche Group 
Unblinded data 
data for which treatment assignment information is specifically 
identified by treatment and dose 
2.
STUDY DESIGN
This is a multi-center, randomized, double-blind, placebo-controlled study to assess the 
efficacy, safety, and tolerability of two different weekly subcutaneous (SC) doses of 
RO7239361 in ambulatory boys with Duchenne muscular dystrophy (DMD).
Eligible subjects will be randomized to receive doses of RO7239361 or placebo (1:1:1 
across the three treatment arms). The randomization will be stratified by:

Age (6 through 7 and 8 through 11)

Corticosteroid (CS) Regimen: daily (prednisone, prednisolone, or deflazacort) vs 
intermittent (any non-daily dosing of prednisone, prednisolone, or deflazacort).
A separate randomization will be conducted for Japan (N=17) with stratification for age 
only (6 through 7 and 8 through 11), not CS regimen.
RO7239361 or placebo will be administered weekly. The first three doses (Days 1, 8,
and 15) of study medication must be administered at the site. Parents/caregivers will be 
trained to administer SC injections during the first three dose administrations. 
Parents/caregivers who are comfortable with SC administration can administer the 
injection at home starting at Day 22. Parents/caregivers will be dispensed an 
approximately 6 week supply of drug in pre-filled syringes (RO7239361 or matching 
placebo) for weekly study drug/placebo administration to the subject.
After completion of this 48-week double-blind phase, subjects may enter the open-label 
phase in which all subjects will receive active RO7239361 study drug. Subjects originally 
randomized to active drug will continue to receive the dose to which they were originally 


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randomized. Subjects originally randomized to placebo will be randomized to the high or 
low dose of RO7239361 on Day 1 of the open-label phase. Dose assignment in the 
open-label phase may be modified based upon emerging safety findings. Subjects 
entering the open-label phase will remain blinded to their original and current dose 
assignment. Any subject who discontinues the study early or who does not enter the 
open-label phase will enter the follow up phase of the study. The follow up phase of the 
study is up to 24 weeks. Subjects will be monitored for safety at three visits in the follow 
up phase. If RO7239361 anti-drug antibodies (ADAs) are present at the last on-
treatment visit, the subject should provide immunogenicity samples at all follow up visits. 
Subjects who enter the follow up phase will undergo ADA monitoring during the follow up 
visits, which will occur at regular intervals for 24 weeks. The study design schematic is 
presented below.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Section 1 of the Protocol (see Appendix 1).
2.2
ENDPOINTS
2.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint of the study is the change from baseline in the North Star 
Ambulatory Assessment (NSAA) total score at Week 48. 
Randomization  
159 Participants
24-week 
follow-up 
ENR
OLLM
ENT
RAND
O
MIZATI
ON
Dose 1 SC weekly 
(n=~27) up to 192 
weeks (~4 years) 
OL
Dose 1 (7 5 mg or  
15 mg based on weight) 
SC weekly for 48-week 
double-blind period 
(n=53) 
Dose 2 (35 mg or  
50 mg based on weight) 
SC weekly for 48-week 
double-blind period 
(n=53) 
Matching placebo SC 
weekly for 48-week 
double-blind period 
(n=53) 
Early  
Discontinuation 
Dose 2 SC weekly 
(n=~27) up to 192 
weeks (~4 years) OL
Dose 1 SC weekly 
up to 192  weeks
(~4 years) OL
Dose 2 SC weekly 
up to 192 weeks
(~4 years) OL


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2.2.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints include:

Change from baseline at Week 48 in:
•
Functional Testing:
–
4-stair climb velocity (4SCV)
–
4-stair climb time
–
Stand from supine velocity
–
10-meter walk/run velocity
–
Proximal lower extremity flexor (knee extension and knee flexion) 
strength (kg), measured using manual myometry
–
6 Minute Walk Distance (6MWD) 
–
95th percentile stride velocity recorded with ActiMyo (in a subset 
of the overall study population)
•
Observer Reported Outcome:
–
Parent-reported Pediatric Outcomes Data Collection Instrument 
(PODCI) transfers and basic mobility subscale

No change/improvement in clinical impressions as measured by Clinical Global 
Impression of Change (CGI-C) at week 48.
2.2.3
Exploratory Efficacy and Pharmacodynamic Endpoints
Exploratory efficacy endpoints include:

Change from baseline at Week 48 in:
•
Performance of Upper Limb (PUL) total score
•
Pulmonary Function Tests (PFTs), including forced vital capacity (FVC) % 
predicted, forced vital capacity (FVC), forced expiratory volume in 1 
second (FEV1), maximal expiratory pressure (MEP), maximal inspiratory 
pressure (MIP), cough peak flow (CPF), and peak flow rate (PFR)
•
Parent reported PODCI global score
•
Strength of shoulder abductors, elbow flexors, elbow extensors, hip 
abductors, grip, and pinch, measured by manual myometry
•
Health Utilities Index III utility score 
•
Parent-reported Pediatric Quality of Life Inventory Family Impact Module 
(PedsQL FIM) total score
•
Parent-reported Pediatric Quality of Life Multidimensional Fatigue Scale 
(PedsQL MFS) global score, in a subset of subjects
•
Serum concentrations of creatine kinase


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•
ActiMyo additional measures of activity level (other than 95th percentile of 
stride velocity) and falls (in the subset of the overall study population
using the ActiMyo device)
•
Cardiac MRI measures
•
Number of falls while on study treatment, as recorded in the subject’s 
diary.
•
Proportion of subjects with no change/improvement in Caregiver-
reported Global Impression of Change (CaGI-C) on DMD symptoms, 
physical ability, ability to perform daily activities, social life, emotions and 
mental well-being and overall health, in a subset of subjects
•
SPITFIRE Video Assessments of quality of movement scores

Distribution of CaGI-C responses at week 48

Percentage change from baseline at Week 48 in:
•
Serum free myostatin and myostatin-drug complex
•
Dual x-ray absorptiometry (DXA) measures of lean body mass, fat mass, 
and bone mineral density.
2.2.4
Safety Endpoints

Incidence of treatment-emergent adverse events (AEs)

Change from baseline in vital signs, electrocardiogram (ECG), and echocardiogram 
measures

Change from baseline in safety laboratory measures

Incidence of marked laboratory abnormalities, based on Roche Standard Reference 
and Marked Reference Ranges.
2.3
DETERMINATION OF SAMPLE SIZE
The sample size of 159 subjects (53 subjects per arm) will provide 80% power for testing 
the null hypothesis of no difference between a dose of RO7239361 and placebo, and 90% 
power for testing the null hypothesis of no difference between the pooled doses of 
RO7239361 and placebo, at a 2-sided α-level of 0.05 in the change from baseline in 
NSAA total score at 48 weeks, under the following assumptions:

A true treatment difference (RO7239361 minus placebo) of 2.5 points

A standard deviation of 4.4 points

A treatment discontinuation rate of 5%.
For this study design and analysis, the minimum detectable difference is approximately 
1.53 points for the comparison of the pooled dose groups to placebo, and 1.75 points for 
the comparison of an individual dose group to placebo.


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2.4
ANALYSIS TIMING
The primary analysis of efficacy and safety will be conducted when all subjects have 
completed the 48-week double-blind treatment period.
A futility analysis will be conducted when at least 30% of the total number of subjects 
have completed 48 weeks of double-blind, placebo-controlled treatment.
An additional efficacy and safety data analysis will be conducted at Week 96 (at the end 
of the first 48 weeks of the open-label phase of the study).
A final data analysis will be conducted when the study conduct (double-blind and open-
label treatment periods) is complete and the database is locked.
3.
STUDY CONDUCT
Significant protocol deviations identified by site monitor or site manager will be provided 
by the protocol manager who is responsible for study management. The following 
protocol deviations will be defined as relevant protocol deviations (RPDs) and listed. It 
should be noted, for the RPDs that occur after treatment initiation (RPDs #5 #6 #7), 
subjects are still under consideration and included in the per-protocol analysis until the 
time point that the protocol deviations started. 
1.
DMD not confirmed by medical history (e.g., onset of clinical signs or symptoms 
before 5 years of age together with an elevated serum creatine kinase level) and by 
genotyping;
2.
Subject not male or not 6 to 12 years of age at randomization;
3.
Subject not on CS for 6 months (182 days) prior to randomization;
4.
No established 4 stair climb 8 seconds prior to randomization;
5.
Treatment with prohibited medication (listed in Section 7.7.1 of Protocol) for 7 
days at any time during the study or during the 3-month period prior to initiation of 
study treatment;
6.
Dosing that deviates 20% of the intended dose for 2 weeks (2 doses). This 
addresses subjects getting the correct treatment, but not the correct dose
7.
Incorrect treatment received for 2 weeks (2 doses). This addresses incorrect 
allocation of subject to active or control and missed doses.
3.1
RANDOMIZATION 
Subjects will be randomized to receive either low or high dose of RO7239361 or placebo 
according to a computer-generated randomization scheme.
During the screening visit, the investigative site will enter into the enrollment option of 
the Interactive Web Response System (IWRS) designated by Roche for assignment of a 


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subject number that will be unique across all sites. Once it is determined that the subject 
meets the eligibility criteria following the screening visit, the investigative site will enter 
into the IWRS to randomize the subject to one of the double-blind treatment groups.
Eligible subjects will be randomized in a 1:1:1 ratio to high dose RO7239361 (35/50 mg), 
low dose RO7239361 (7.5/15 mg), or placebo. The randomization will be stratified by:

Age (6 through 7 vs 8 through 11)

CS regimen: daily (prednisone, prednisolone or deflazacort) vs intermittent (any 
non-daily dosing of prednisone, prednisolone or deflazacort).
After 48 weeks on double-blind treatment, subjects continuing on study treatment will 
enter the open-label period. Placebo subjects will be re-randomized through IWRS and 
assigned to one of the RO7239361 dose groups. 
3.2
DATA MONITORING
There will be an independent data monitoring committee (iDMC) for this study. The 
iDMC charter will document the iDMC scope, frequency of review, and membership.
The iDMC shall have access to partially unblinded data (coded treatment assignments) 
including but not limited to the following: the frequency and spectrum of serious adverse 
events (SAEs); Grades 3 to 4 laboratory abnormalities; occurrence of malignancies, if 
any; and other select AEs of interest. The iDMC shall act as an advisor to the Sponsor 
and have responsibility for safeguarding the subjects’ interests, and will make 
recommendations to the Sponsor on the conduct of the study.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
The analyses will use several populations as defined below.
4.1.1
Enrolled Population
The Enrolled Subjects Population includes all subjects who sign an informed consent 
form.
4.1.2
Randomized Population
The Randomized Subjects / Intention to Treat (ITT) Population includes all enrolled 
subjects who receive a randomization treatment assignment.
4.1.3
Modified Intent-to-Treat Population
The modified Intention to Treat (mITT) population includes all randomized subjects that 
received at least one dose of study medication. For change from baseline analyses, this 
includes only those subjects that had a baseline assessment and at least one post-
baseline efficacy assessment. This analysis population will be used for the primary and 
secondary efficacy analyses.


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4.1.4
Per Protocol Population
The per-protocol (PP) population includes all mITT subjects with no relevant protocol 
deviations through Week 48 as described in Section 2.4.
In addition, subjects with baseline NSAA total score of less than 15 points will be 
excluded from the per-protocol population, based on the August 2018 protocol 
amendment which added a screening NSAA assessment and an exclusion criterion for 
those subjects with a screening NSAA score of less than 15.
4.1.5
Safety Population
The Treated Subjects / Safety Population includes all enrolled subjects who received at 
least one dose of study therapy.
If a subject received the same incorrect treatment throughout the study, then the subject 
will be analyzed based on the treatment received.
If a subject received study drug from more than one treatment group, then the subject 
will be analyzed based on the first treatment received.
4.2
ANALYSIS OF STUDY CONDUCT
Summary tables will be provided for pre-randomization subject status, end of double-
blind phase subject status, and end of open-label phase subject status. Summary tables 
will reflect information about the number and proportion of subjects who are enrolled, 
randomized, and who have completed the double-blind and open-label extension 
periods. Reasons for not being randomized and not completing the treatment periods will 
also be summarized.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic characteristics such as gender, age, race, and ethnicity will be 
summarized for all treated subjects. Summary tables will be provided for the dosage and 
duration of prior use of CS (e.g., prednisone, prednisolone, or deflazacort). Summary 
tables will also be provided for baseline values of the NSAA total score, timed function 
tests, and pulmonary function tests.
4.4
EFFICACY ANALYSIS AT END OF DOUBLE-BLIND 
TREATMENT
4.4.1
Primary Efficacy Endpoint
The primary analysis, on the change from baseline in NSAA total score after 48 weeks of 
double-blind treatment, will be conducted using a Mixed Model Repeated Measures 
(MMRM) analysis with treatment, visit, treatment-by-visit interaction, age stratum, and 
CS stratum entered into the model as fixed effects, and subject entered as a random 
effect. The baseline value of the NSAA total score will be entered into the model as a 
covariate. The modified ITT population will be the analysis population for the primary 


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efficacy analysis. An unstructured correlation within subject will be used. In the case that 
this does not converge, a compound symmetry structure will be used.
For each RO7239361 dose group, the null hypothesis of no treatment difference 
between the dose group and placebo will be tested using the estimates from this MMRM 
model at the end of the 48-week double-blind treatment period. In order to control the 
overall Type I error rate for the analysis of the primary endpoint, the following testing 
procedure (based on the closed testing principle) will be implemented:
1. Comparison of the pooled RO7239361 doses to placebo (intersection hypothesis) 
at a 2-sided α-level of 0.05 is performed.
2. If the result from the previous step is significant, then a comparison of the 
RO7239361 high dose (35/50 mg) to placebo and a comparison of the low dose 
(7.5/15 mg) to placebo will both be performed at a 2-sided α-level of 0.05.
4.4.2
Secondary Efficacy Endpoints
The secondary efficacy analyses will compare the change from baseline to week 48 
between each RO7239361 dose group and the placebo group, for the following 
endpoints.

4SCV

6MWD

95% stride velocity (SV95C)

Stand from supine velocity

10-meter walk/run velocity

PODCI transfers and basic mobility subscale

Proximal lower extremity flexor (knee extension and knee flexion) strength 
measured using manual myometry

CGI-C
MMRM models similar in structure to that used for the primary analysis will be used for 
the continuous secondary efficacy endpoints, with the exception of proximal lower 
extremity flexor strength (which will be tested using a multivariate analysis of variance of 
the 2 component variables: knee extension and knee flexion).
The distribution of CGI-C and CaCGI-C responses at week 48 will be summarized using 
descriptive statistics. Categorical analysis of the number of subjects falling into pre-
specified categories (i.e., ‘any improvement or no change’ vs. ‘any worsening’) will be 
performed using a Cochran-Mantel-Haenszel test using age category and CS use as 
stratification factors.


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4.4.2.1
Hypothesis Testing for Secondary Efficacy Endpoints
A hierarchical testing procedure will be employed to control the overall Type I error rate 
of the analysis of the primary and secondary endpoints. For each secondary endpoint 
specified in the hierarchy, the closed testing procedure described in Section 4.4.1 will be 
applied for all endpoints up to the point where a secondary endpoint fails to reject a null 
hypothesis at either step in the procedure for a given dose arm. Results of all analyses 
performed after the incidence of a result that fails to reach statistical significance for that 
dose arm will be considered exploratory.
Hypothesis testing of the secondary endpoints will be performed using the following pre-
specified hierarchy:
1.
6MWD
2.
4-stair climb velocity
3.
Stand from supine velocity
4.
10-meter walk/run velocity
5.
CGI-C
6.
95% stride velocity from ActiMyo.
4.4.3
Exploratory Efficacy Endpoints
Analysis of the continuous exploratory efficacy endpoints will be performed (comparing 
the change from baseline to week 48 between each RO7239361 dose group and the 
placebo group) using MMRM models similar in structure to that used for the primary and 
secondary efficacy endpoints. No formal hypothesis testing will be performed for the 
exploratory efficacy endpoints.
The distribution of CaGI-C responses at week 48 will be summarized using descriptive 
statistics, as described above.
4.4.4
Sensitivity Analyses
In order to assess the impact of the presence of missing data on the results of the 
primary and secondary efficacy analyses using an MMRM analysis, additional analyses 
may be performed using methodologies such as multiple imputation methods with 
pattern mixture models. Final specifications of the methods used to handle missing data 
in these additional analyses will be finalized prior to the primary efficacy analysis, and 
will be determined based on characteristics including the proportion of subjects 
discontinuing treatment, and the reasons for discontinuation. The rate of missing data is 
expected, however, to be low. 
For selected continuous efficacy endpoints, additional analyses may be performed using:


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
an analysis of covariance (ANCOVA) model on the mITT data set using the 
observed change from baseline at week 48 as the dependent variable, treatment, 
age stratum, and CS stratum as fixed effects, and baseline value as a covariate.

ANCOVA (at week 48) and MMRM models on the mITT data set with missing data 
imputed using multiple imputations with pattern mixture models

an MMRM analysis using the per-protocol analysis population.
In this population, the treatment discontinuation and study discontinuation rates during 
the 48-week double-blind treatment period are expected to be low (as reflected in the 5% 
assumed treatment discontinuation rate incorporated into the sample size calculation). 
This expectation is based on:

the low treatment discontinuation rate, and overall safety and tolerability profile of 
RO7239361, to date from the ongoing WN40226 study

the treatment discontinuation rates in the phase III 48-week double-blind studies in 
with ataluren and drisapersen DMD ambulatory patients

the relatively short (compared to other competing clinical trials in DMD patients) 
double-blind treatment duration of 48 weeks

the inclusion of a safety follow up visit (which also includes an NSAA assessment) 
for those subjects who discontinue, which should reduce the number of missing 
assessments of the primary efficacy endpoint.
It is not expected that there will be other frequently occurring intercurrent events (i.e., 
introduction of rescue medications) that will materially affect the efficacy assessments or 
that could motivate a decision to exclude values recorded after such an event.
Based on these assumptions, it is anticipated that the results from sensitivity analyses 
will not differ appreciably from the protocol-specified primary efficacy analysis. Therefore, 
a treatment policy estimand calculated using the results from an MMRM analysis of the 
data from the modified ITT population described above (all subjects randomized, with a 
baseline and post-baseline efficacy assessment) is proposed as appropriate for the 
primary evaluation of the efficacy of RO7239361 in this study.
4.4.4.1
Additional Analyses of the Primary Endpoint
Additional analyses of the NSAA scores at week 48 may be performed using the 
following:

The proportion of subjects with a decline of 3 or more points in the NSAA total score

Change from baseline in linearized NSAA total score

Number of NSAA items transitioning from a non-zero baseline score to a zero score 
at week 48

Number of NSAA items with small improvement (one-point improvement from 
baseline) or stability (no change from baseline) at week 48


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
Proportion of subjects with loss of ambulation, based on ability to walk recorded in 
NSAA

Cumulative distribution function of the change from baseline in NSAA total score

Cumulative distribution function of the number of items with improvement from 
baseline

Cumulative distribution function of the number of items with deterioration from 
baseline.
4.4.5
Subgroup Analyses
Exploratory subgroup analyses may examine the impact of genetic variations in the 
dystrophin gene or in genes suspected to impact DMD disease expression (including but 
not limited to LTBP4, SPP1) and their impact on target engagement, pharmacodynamic 
(PD), and selected functional endpoints.
Subgroup analyses may also be performed based on the randomization strata (age 
group and baseline CS regimen) and subgroups defined based on baseline levels of 
selected functional and imaging endpoints.
4.5
EFFICACY ANALYSIS OF OPEN-LABEL DATA
For the functional efficacy endpoints, additional analyses may be performed on subjects 
continuously treated with RO7239361 for 96 weeks (48 weeks of double-blind treatment 
followed by 48 weeks of open-label treatment). These data will be compared to pre-
specified external control data from research cohorts such as disease registries and 
placebo arms from previous trials after evaluation of data quality and comparability of 
subjects in these data sources with subjects in the WN40227 trial. Specifications of this 
analysis will be documented in a separate statistical analysis plan, and will be finalized 
prior to the analysis.
4.6
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Pharmacokinetic and PK/PD analyses will be summarized in an analysis plan and report 
separate from the CSR.
4.7
SAFETY ANALYSES
Adverse events, including abnormal laboratory findings, will be defined using the 
National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE, 
version 5), and will be coded according to the most recent Medical Dictionary for 
Regulatory Activities (MedDRA) version. Adverse events will be summarized according 
to the MedDRA coded Preferred Terms (PT) by System Organ Class (SOC). Previous 
and concomitant medications will be coded using the WHO Drug Dictionary version.
The evaluation of safety is based on clinical AEs, vital signs, echocardiogram, ECG 
results, and clinical laboratory results reported during the study. Cardiac MRI measures 


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may also be included in the safety assessment. Safety analyses will be performed using 
the treated subjects. For AEs, all enrolled subjects will be listed.
Safety analysis data displays will be generated for the following:

the double-blind treatment period, with baseline defined as the last visit prior to the 
start of the double-blind treatment period

all active treatment during both the double-blind and open-label treatment periods 
(excluding data from the placebo subjects during the double-blind period); for this 
analysis, baseline will be defined as the last visit prior to the start of active treatment 
for each subject (i.e., the start of double-blind treatment period for those subjects 
randomized to active treatment from study start, or the start of the open-label 
treatment period for those subjects randomized to double-blind placebo and who are 
switching to active treatment at the start of the OLE).
4.7.1
Exposure of Study Medication
Duration of exposure will be summarized descriptively. Study drug administration, 
randomization schedule and batch numbers will be documented as per subject listings. 
Any non-study medications taken by subjects, any conducted non-study medical 
treatment procedures, and any utilized non-study diagnostic procedures will be 
summarized separately.
4.7.1.1
Study Therapy Compliance
As study drug will be administered weekly, a dose will be considered to be taken in 
compliance if it is either the first injection or is taken within 5-9 days of the previous 
injection. Compliance rate is defined as the number of doses taken in compliance,
divided by the number of expected doses. 
A subject will be considered compliant if 80% and 110% of doses are taken in 
compliance. The number and percentage of compliant subjects will be presented.
4.7.1.2
Modifications of Study Therapy
Subjects with dosing modifications due to change in weight tier will be identified in a 
subject listing.
4.7.1.3
Corticosteroid Treatment
Subjects must be receiving CS (prednisone, prednisolone, or deflazacort) for at least 6 
months prior to the start of study drug, with no significant change in dosage (0.2 mg/kg 
prednisone or 0.24 mg/kg deflazacort) or dosing regimen for at least 3 months prior to 
the start of study drug, with the expectation that dosage and dosing regimen will not 
change significantly for the duration of the study. 


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For subjects where the dosing frequency is specified, calculated daily dose of CS at 
baseline will be summarized. Baseline is defined as the last regimen period before the 
first dose of study drug. Also, a listing of subjects with absolute change in CS
([calculated daily dose]/[body weight]) from baseline 0.2 mg/kg prednisone or 0.24 
mg/kg deflazacort will be provided specifying their date and direction of change 
(increase or decrease). In case of a post-baseline change in CS drug, the following 
relationship will be used to calculate change from baseline:
1 mg prednisone = 1 mg prednisolone = 1.2 mg deflazacort
4.7.2
Adverse Events
AEs with onset on or after the first dose, and AEs with an onset date prior to first dose 
continuing into the treatment period and showing worsening (indicated by an overall 
severity higher than the initial severity) will be considered treatment-emergent for all 
analyses of the AE data. All AEs will be summarized by SOCs and PTs for each 
treatment group.
The incidence of AEs will be characterized by the proportion of subjects having an AE, 
the number of subjects experiencing the event divided by the total number of subjects 
receiving study treatment. Regardless of the presence of SOC in a summary table, a 
decreasing order of incidence rates will be used for PTs in summary tables for AEs.
Where a subject has multiple AEs within the same system organ class in a single 
analysis period, the subject will only be counted once at the system organ class level in 
AE frequency tables.
Where a subject has the same AE, based on preferred terminology, reported multiple 
times in a single analysis period, the subject will only be counted once at the preferred 
terminology level in AE frequency tables. 
Adverse event summary tables will be generated to summarize overall incidence, with 
additional tables summarizing results by intensity and by relationship to study medication.
Serious adverse events will be summarized separately. Listings will be provided for 
serious AEs, AEs leading to discontinuation, and AEs without recorded resolution.
In addition, for subjects with events of hypersensitivity reactions and injection site 
reactions, summary tables (of overall incidence and by intensity) will be provided.
MedDRA baskets based on Standardised MedDRA Queries, PT, high-level group terms, 
and high-level terms will be used as appropriate to identify the events to be included in 
these analyses. Additional baskets for summarizing AEs will be defined prior to the final 
analysis.
A by-subject listing of death will be provided for all reported deaths after a subject is 
enrolled (i.e., has signed the informed consent).


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4.7.3
Laboratory Data
Scheduled laboratory measurements and corresponding change from baseline values 
will be summarized by treatment and nominal visit for each laboratory test, in SI units.
The results of all protocol-specified clinical laboratory tests, as well as the normal range 
of laboratory results, will be listed in SI units.
The incidence of marked laboratory abnormalities (based on Roche Standard Reference 
and Marked Reference Ranges) will be summarized using descriptive statistics, for all 
parameters for which the Marked Reference Ranges are defined.
For all parameters for which NCI CTCAE grades are defined, summary tables showing 
the number of subjects with abnormal laboratory results (falling outside of the laboratory 
range of normal) based on the grading criteria will be provided.
Plots of mean lab test results over time over-plotted on a scatterplot of all subject results 
at each visit will be provided for alanine aminotransferase (ALT), aspartate
aminotransferase (AST), total bilirubin, glutamate dehydrogenase assay, gamma-
glutamyl transferase, and creatine kinase (CK).
Scatter plots of post-baseline maximum values will be provided for ALT vs. Total bilirubin 
and AST vs. Total bilirubin separately.
Double Y-axis trace plots over time will be provided for ALT and CK in the same graph.
4.7.4
Vital Signs and Physical Measurements
Summaries of observed values and changes from baseline in vital sign parameters and 
physical measurements (height, weight, body mass index) will be provided for each 
parameter for each position (standing, supine, or missing) at corresponding visits. 
Changes from baseline will be calculated based on matched postural positions.
4.7.5
ECGs
For each ECG parameter, summary statistics for observed values and change from 
baseline values (n, mean, standard deviation, median, minimum, and maximum), along 
with corresponding changes from baseline, will be presented at each time point.
Categorical analyses of observed and change from baseline values will also be 
presented.
4.7.6
Echocardiograms
Summary tables including change from baseline values will be provided for key 
echocardiogram parameters including: Left Ventricular End Diastolic Volume Index, Left 
Ventricular End Systolic Volume Index, Left Ventricular Ejection Fraction (LVEF) from 1 
and 2, Fractional Shortening, Tricuspid Regurgitation Peak Velocity, and systolic 
pulmonary artery pressure.


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A summary table will be provided for incidence rate of abnormal findings (LVEF 55%).
4.7.7
Immunogenicity
The number and percentage of subjects with an ADA-positive sample at each post-
baseline visit, and those subjects with 4-fold increase in ADA titer from baseline (if 
baseline ADA titer was positive) will be summarized. Adverse events of injection site 
reactions or hypersensitivity reactions will be summarized separately for ADA-positive 
and ADA-negative subjects.
4.8
MISSING DATA
All 17 items of the NSAA must be completed in order to calculate the NSAA total score.
No imputation for missing values of the individual NSAA items will be performed.
For each of the timed function test velocities (4-stair climb, stand from supine, 10-meter 
walk/run), if the test cannot be completed by the subject (indicated by a grade of 1) and 
there is no time recorded for that test, then a velocity value of zero will be used for 
analysis. If a subject cannot complete an assessment of ambulation due to what is 
considered by the investigator to be a transient inability to ambulate (e.g., leg fracture), 
the value for the assessment will be considered missing.
For the PODCI global and domain scores and for the PedsQL fatigue module, missing 
values will be handled as described in the scoring manual for the instrument.
For the global impression of change scales (CGI-C and CaCGI-C), no imputation of 
missing values will be performed.
4.9
INTERIM ANALYSES
No efficacy interim analyses (testing the null hypothesis of no treatment effect, with the 
possibility to reject the null hypothesis) are planned.
For each futility analysis performed, a separate interim statistical analysis plan will be 
finalized prior to the analysis describing the timing, endpoints to be included, decision 
rules for determining futility, and operating characteristics of these decision rules.
Any futility analyses performed will be conducted by an independent data coordinating 
center and reviewed by the iDMC. The Sponsor will not have access to any unblinded 
subject-level data or aggregate results generated as part of these futility analyses prior 
to the primary efficacy analysis, unless requested by the Sponsor DRB in the case that 
the iDMC communicates that the pre-specified futility threshold on the primary endpoint 
was not met.
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
charter.


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Appendix 1
Study WN40227 Protocol




Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
2/Protocol WN40227, Version 4 
 
1. 
DOCUMENT HISTORY 
 
Document 
Date of Issue 
Summary of Changes 
Revised Protocol 4 
(Version 4) 
See electronic date stamp. 
 
Amendment 6 
See electronic date stamp. 
• 
Deleted references to the previous 
Bristol-Myers Squibb protocol and 
product numbers throughout the 
text, except in the Introduction, 
Schedule of Assessments, and 
Treatment sections 
• 
Change the primary endpoint from 
the 4 Stair Climb velocity to the 
North Star Ambulatory Assessment 
total score 
• 
Added a new inclusion criterion 
requiring a minimum NSAA score of 
15 points at screening 
• 
Changed the 4SCV from the primary 
endpoint to a secondary endpoint 
• 
Added 95th percentile stride velocity, 
as recorded using the ActiMyo as a 
secondary endpoint 
• 
Added the caregiver video assessment 
at selected sites as a new exploratory 
endpoint 
• 
Added the Caregiver Global 
Impression of Change at selected 
sites as a new exploratory endpoint 
• 
Added the Pediatric Quality of Life 
Inventory Multidimensional Fatigue 
Scale at selected sites as an 
exploratory endpoint 
• 
Shortened the Study Rationale 
section to include a high-level 
summary of available clinical data 
and to refer to the Investigator's 
Brochure for specific details 
• 
Updated the duration of the open-
label (OL) extension phase and the 
frequency of visits during the OL 
extension phase 
• 
Added the specific sites indicated for 
subcutaneous injection 
• 
Deleted the proposed interim analysis 
• 
Updated the statistical analysis 
section to establish hierarchical 
testing of the doses 
• 
Added definitions for different 
situations of incorrect administration 
of study drug  
• 
Deleted urine biomarkers and 
miRNA biomarkers as exploratory 
endpoints 
• 
Added assessment of serum creatine 
kinase level in muscle to the 
exploratory pharmacokinetic, 
pharmacodynamic, and 
immunogenicity endpoints 
 


Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
3/Protocol WN40227, Version 4 
 
 
Document 
Date of Issue 
Summary of Changes 
Revised 
Protocol 03 
29 Jan 2018 
Incorporates Amendment 05 
Amendment 05 
29 Jan 2018. 
– 
Added assessment of CGI-C. 
– 
Reduced pulmonary function tests 
– 
Reduced anthropometry assessments 
– 
Reduced myometry assessments 
– 
Reduced TFTs and 6MWT in the 
open-label phases 
– 
Clarified signature of informed 
consent prior to Day −42 screening 
period 
– 
Clarified FVC in the exclusion 
criteria 
– 
Clarified contraception methods 
– 
Clarified GDF-11 sample timepoint 
– 
Clarified ActiMyo assessments 
– 
Clarified use of videos 
– 
Updated requirement for safety 
reporting of overdose 
– 
Clarified monitoring of ADAs during 
24-week safety follow-up phase 
– 
Updated Medical Monitor 
information 
– 
Updated for consistency with IB, 
version 6 
– 
Corrected typographical errors 
Revised Protocol 
02 
21-Aug-2017. 
Incorporates Amendment 04 
Amendment 04 
21-Aug-2017. 
– 
Changed Sponsor from Bristol-Myers Squibb 
to F. Hoffmann-La Roche Ltd 
– 
Changed study drug name from BMS-986089 
to RO7239361 
– 
Updated Medical Monitor information 


Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
4/Protocol WN40227, Version 4 
 
Revised Protocol 
01
20-Apr-2017 
Incorporates Amendment 03 
Amendment 03 
20-Apr-2017 
– 
Added text defining significant change in 
dosage for prednisone and deflazacort. 
– 
Added measurement of ulna length to baseline 
and on treatment time points. 
– 
Timing of on treatment videotaping of 
functional assessments has been clarified. 
– 
Timing of Health Care Resource 
Utilization assessments has been 
clarified. 
– 
Added clarification that DXA scanning is not 
required at early termination. 
– 
History of hypersensitivity of the components 
of the study drug added as an exclusion. 
– 
Threshold for adjusting dosing weight tier 
increased from 1 kg to 2 kg. 
– 
Text clarifying that malfunctions of pre-filled 
syringes should be reported to the sponsor in 
accordance with local regulations has been 
added. 
– 
Guidance regarding skin biopsy added. 
– 
Text describing pharmacogenomics removed. 
– 
Corrections of typographical errors. 
Original Protocol 
05-Dec-2016 
Not Applicable 


Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
5/Protocol WN40227, Version 4 
 
 
TABLE OF CONTENTS 
 
TITLE PAGE ................................................................................................................ 
1 
DOCUMENT HISTORY.............................................................................................. 
2 
TABLE OF CONTENTS............................................................................................. 
5 
PROTOCOL AMENDMENT ACCEPTANCE 
FORM........................................................................................................................... 
8 
1 SYNOPSIS................................................................................................................. 
9 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
16 
3 INTRODUCTION ..................................................................................................... 
34 
3.1 Study Rationale................................................................................................. 
35 
3.1.1 Rationale to Support Dose Selection ....................................................... 
36 
3.1.2 Rationale for Specific Inclusion/Exclusion Criteria ................................ 
40 
3.1.3 Rationale for Primary Endpoint .............................................................. 
40 
3.1.4 Research Hypothesis ................................................................................ 
40 
3.2 Background ....................................................................................................... 
40 
3.3 Benefit/Risk Assessment .................................................................................. 
42 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
44 
5 STUDY DESIGN....................................................................................................... 
46 
5.1 Overall Design .................................................................................................. 
49 
5.1.1 Independent Data Monitoring Committee and Other External  
Committees ........................................................................................................ 
49 
5.2 Number of Participants ..................................................................................... 
49 
5.3 End of Study Definition .................................................................................... 
49 
5.4 Scientific Rationale for Study Design............................................................... 
49 
5.5 Justification for Dose ........................................................................................ 
49 
6 STUDY POPULATION ............................................................................................ 
49 
6.1 Inclusion Criteria .............................................................................................. 
49 
6.2 Exclusion Criteria ............................................................................................. 
50 
6.3 Lifestyle Restrictions ........................................................................................ 
52 
6.3.1 Meals and Dietary Restrictions ............................................................... 
52 
6.3.2 Caffeine, Alcohol and Tobacco................................................................ 
52 
6.3.3 Activity ..................................................................................................... 
52 
6.4 Screen Failures.................................................................................................. 
52 
6.4.1 Rescreening and Retesting during Screening Period ........................... 
52 
7 TREATMENT ........................................................................................................... 
52 
7.1 Treatments Administered.................................................................................. 
55 
7.2 Method of Treatment Assignment .................................................................... 
56 
7.3 Blinding............................................................................................................. 
56 
7.4 Dosage Modification......................................................................................... 
57 
7.5 Preparation/Handling/Storage/Accountability.................................................. 
57 
7.5.1 Retained Samples for Bioavailability / Bioequivalence........................... 
58 
7.6 Treatment Compliance...................................................................................... 
58 
7.7 Concomitant Therapy........................................................................................ 
58 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
58 


Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
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7.7.2 Other Restrictions and Precautions......................................................... 
59 
7.7.2.1 Management of Possible Acute Hypersensitivity Reactions to 
RO7239361........................................................................................... 
59 
7.7.2.2 Imaging Restriction and Precautions ............................................. 
59 
7.8 Treatment after the End of the Study............................................................... 
60 
8 DISCONTINUATION CRITERIA ........................................................................... 
60 
8.1 Discontinuation from Study Treatment ............................................................ 
61 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
62 
8.2 Discontinuation from the Study ........................................................................ 
62 
8.3 Lost to Follow-Up............................................................................................. 
62 
9 STUDY ASSESSMENTS AND PROCEDURES..................................................... 
63 
9.1 Efficacy Assessments........................................................................................ 
63 
9.1.1 Functional Endpoint Assessment ............................................................. 
63 
9.1.2 Myometry and Ankle Range of Motion (ROM) ........................................ 
64 
9.1.3 Imaging Assessment for the Study............................................................ 
64 
9.1.3.1 DXA................................................................................................. 
64 
9.1.3.2 Cardiac MRI (cMRI)....................................................................... 
65 
9.1.4 Exploratory Genotyping........................................................................... 
65 
9.1.5ActiMyo .................................................................................................... 
65 
9.1.6 Caregiver Video Assessment……….................................................. 
66 
9.1.7 Clinical Global Impression of Change (CGI-C) ............................... 
66 
9.1.8 Caregiver Global Impression of Change (CaGI-C) ................................. 
67 
9.1.9 Pediatric Quality of Life Inventory Multidimensional Fatigue 
Scale (PedsQL MFS) .......................................................................................... 
67 
9.2 Adverse Events ................................................................................................. 
67 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
68 
9.2.2 Method of Detecting AEs and SAEs......................................................... 
68 
9.2.3 Follow-up of AEs and SAEs..................................................................... 
69 
9.2.4 Regulatory Reporting Requirements for SAEs......................................... 
69 
9.2.5 Pregnancy ................................................................................................ 
69 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
69 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
70 
9.2.8 Other Safety Considerations .................................................................... 
70 
9.2.8.1 Injection Site Assessments............................................................... 
70 
9.2.9 Overdose or Incorrect Administration of Study Drug............................. 
71 
9.3 Safety ................................................................................................................ 
71 
9.3.1 Physical Examinations............................................................................. 
72 
9.3.2 Vital Signs................................................................................................. 
72 
9.3.3 Electrocardiograms and Echocardiograms............................................. 
72 
9.3.4 Clinical Safety Laboratory Assessments.................................................. 
73 
9.3.5 Imaging Safety Assessment ...................................................................... 
74 
9.4 Pharmacokinetics................................................................................................ 
75 
9.5 Pharmacodynamics ........................................................................................... 
75 
9.6 Pharmacogenomics ........................................................................................... 
75 
9.7 Biomarkers........................................................................................................ 
75 
9.7.1 Additional Research Collection ............................................................... 
76 
9.7.2 Immunogenicity Assessments................................................................... 
77 


Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
7/Protocol WN40227, Version 4 
 
9.7.3 RNA Transcriptome Research………………............................................. 
77 
9.7.4 RNA Expression Research of a Subset of RNA Species………………....... 
77 
9.7.5 Proteome Research………………….......................................................... 
77 
9.7.6 Metabolomic Research............................................................................. 
77 
9.7.7 Other Assessments .................................................................................... 
78 
9.8 Health Economics or Medical Resource Utilization and Health Economics… 
78 
10 STATISTICAL CONSIDERATIONS ..................................................................... 
78 
10.1 Sample Size Determination............................................................................. 
78 
10.2 Populations for Analyses ................................................................................ 
78 
10.3 Statistical Analyses ........................................................................................ .. 
79 
10.3.1 Efficacy Analyses ..................................................................................... 
80 
10.3.2 Safety Analyses.......................................................................................... 
81 
10.3.3 Other Analyses .......................................................................................... 
81 
10.3.4 Interim Analyses........................................................................................ 
81 
11 REFERENCES….............................................................................................................. 
83 
12 APPENDICES…………………........................................................................................ 
87 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................... 
88 
APPENDIX 2 STUDY GOVERANCE CONSIDERATIONS ....................................... 
94 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW UP AND 
REPORTING................................................................................................................. 
102 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS 
OF CONTRACEPTION.................................................................................................. 
106 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
8/Protocol WN40227, Version 4 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, DOUBLE BLIND, 
PLACEBO-CONTROLLED, STUDY TO ASSESS 
THE EFFICACY, SAFETY, AND TOLERABILITY OF 
RO7239361 IN AMBULATORY BOYS WITH 
DUCHENNE MUSCULAR DYSTROPHY 
PROTOCOL NUMBER: WN40227  
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2016-001654-18 
IND NUMBER: 
120,702 
TEST PRODUCT: 
Anti-Myostatin Adnectin (RO7239361) 
MEDICAL MONITORS: 
, M.D. 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your study monitor. 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
9/Protocol WN40227, Version 4 
 
 
1 
SYNOPSIS 
Protocol Title: A Randomized, Double Blind, Placebo-Controlled, Study to Assess the Efficacy, 
Safety, and Tolerability of RO7239361 in Ambulatory Boys with Duchenne Muscular Dystrophy 
Study Phase 2/3 Rationale 
The purpose of this study is to evaluate the efficacy, safety and tolerability of weekly subcutaneous 
(SC) doses of RO7239361 compared to placebo in ambulatory boys with Duchenne muscular 
dystrophy (DMD). 
Study Population: 
Key Inclusion Criteria: 
• Males, ≥ 6 to < 12 years of age at time of randomization 
• Diagnosis of DMD, confirmed by medical history (e.g., onset of clinical signs or symptoms 
before 5 years of age together with an elevated serum creatine kinase level observed before 
or after initial diagnosis) and by genotyping 
• Participants ≥ 15 kg 
• Ambulatory without assistance 
• Participants must be receiving corticosteroids (CS; prednisone, prednisolone, or 
deflazacort) for at least 6 months prior to the start of study drug, with no significant change 
in dosage (> 0.2 mg/kg prednisone or > 0.24 mg/kg deflazacort) or dosing regimen 
for at least 12 weeks prior to the start of study drug, with the expectation that dosage 
and dosing regimen will not change significantly for the duration of the study 
• North Star Ambulatory Assessment (NSAA) score ≥ 15 points at screening 
• 4SC ≤ 8 seconds at screening 
• Participants must agree to avoid major changes in their physical or respiratory therapy 
regimen during the double-blind phase, to the extent possible 
 
Key Exclusion Criteria: 
• Participants with cognitive impairment or behavioral issues that, in the judgement of the 
investigator, will compromise their ability to comply with study procedures 
• Participants on intermittent CS regimens with off periods of 20 days or longer (e.g.: 10 
days on, 20 days off) 
• Any change (initiation, change in drug class, dose modification unrelated to change in body 
weight, interruption or re-initiation) in prophylaxis/treatment for congestive heart failure 
(CHF) within 12 weeks prior to start of study treatment 
• Any change (initiation, change in drug class, dose modification unrelated to change in body 
weight, interruption or re-initiation) in prophylaxis/treatment for bone density within 
12 weeks prior to start of study treatment 
• Treatment with exon skipping therapies within 6 months prior to the start of study drug 
administration. 
• Treatment with ataluren currently or within 12 weeks prior to the start of study drug 
administration 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
10/Protocol WN40227, Version 4 
 
• Treatment with any other investigational drug (excluding deflazacort in CS dose-finding 
trials) currently or within 12 weeks prior to the start of study drug administration  
• Concomitant or previous participation at any time in a gene therapy study 
• Participants with a FVC of < 50% of predicted value (in participants able to produce a 
valid FVC, as judged by the clinical evaluator or respiratory therapist) 
• Cutaneous AEs sustained during participation in a prior clinical trial that resolved less than 
12 weeks prior to the start of study drug administration 
• Current or prior treatment within 12 weeks prior to the start of study drug administration 
with androgens or human growth hormone 
• Prior treatment with RO7239361 or any other anti-myostatin agent 
• History of lower limb fracture within 12 weeks prior to the start of study drug 
administration 
• History of upper limb fracture within 8 weeks prior to the start of study drug 
administration. 
• Any injury that may impact functional testing. Previous injuries must be fully healed 
prior to consenting. 
• Expectation of major surgical procedure, such as scoliosis surgery, during the double-blind 
phase of this study 
• Requirement of daytime ventilator assistance 
• Initiation of nighttime ventilation less than 4 weeks prior to the start of study drug 
administration 
• Expectation that daytime or nighttime ventilation may be initiated during the double-blind 
phase of this study 
• Clinical signs or symptoms of uncontrolled congestive heart failure (CHF) (American 
College of Cardiology/American Heart Associated Stage C or Stage D) 
• For participants participating in cMRI substudy: implanted ferromagnetic metal (implanted 
metal that is not ferromagnetic, such as surgical steel or titanium implants may be allowed 
if the implants will not compromise the quality of the cMRI). 
• Unwilling or unable to administer study drug at home 
 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
11/Protocol WN40227, Version 4 
 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
• 
To compare the efficacy of RO7239361 to 
placebo in ambulatory boys with Duchenne 
muscular dystrophy 
• 
The change from baseline in the North Star 
Ambulatory Assessment (NSAA) total score 
at Week 48 in RO723936-treated participants 
compared to placebo-treated participants. 
Secondary 
• To compare the efficacy of RO7239361 to placebo 
using the following tests:  
− 
4 stair climb velocity (4SCV) 
− 
Stand from supine velocity 
− 
10 M walk/run velocity 
− 
PODCI transfers and basic mobility subscale 
− 
Proximal 
lower 
extremity 
flexor 
(knee 
extension and knee flexion) strength, measured 
using manual myometry 
− 
6 Minute Walk Distance (6MWD) 
− 
Clinical Global Impression of Change 
(CGI-C) 
− 
Stride velocity recorded with ActiMyo 
 
• Change 
from 
baseline 
at 
Week 
48 
in 
RO7239361-treated 
participants 
compared 
to 
placebo- treated participants in the following  
− 
4 stair climb velocity (4SCV) 
− 
Stand from supine velocity 
− 
10 M walk/run velocity 
− 
PODCI transfers and basic mobility subscale 
− 
Proximal 
lower 
extremity 
flexor 
(knee 
extension and knee flexion) strength, measured 
using manual myometry 
− 
6-Minute Walk Distance (6MWD) 
− 
Clinical Global Impression of Change 
(CGI-C) 
− 
95th percentile stride velocity, as recorded with 
ActiMyo in a subset of the overall study 
population 
• To assess the safety and tolerability of RO7239361 in 
boys with DMD as reflected by new or worsening lab 
abnormalities (as defined by CTCAE criteria), 
serious adverse events (SAEs) and adverse events 
(AEs) leading to discontinuation.  
• Tabulations of the numbers of unique participants 
with new or worsening laboratory abnormalities, 
SAEs and AEs leading to discontinuation, in 
RO7239361 arms compared to the placebo arm.  
Tertiary/Exploratory 
• 
To assess the safety and tolerability of RO7239361 in 
boys with DMD as reflected by vital signs, 
measures of cardiac function 
 
• 
Summaries and listings of vital signs, ECG 
parameters, echocardiogram parameters. 
− 
Proportion of participants with on treatment 
adverse events in RO7239361 arms 
compared to the placebo arm 
– 
Proportion of participants with on treatment 
decrease in ejection fraction (EF), measured 
using echocardiography, in RO7239361 
arms compared to the placebo arm 
 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
12/Protocol WN40227, Version 4 
 
 
Objectives 
Endpoints 
 
 
• To compare the efficacy of RO7239361 to placebo 
using the following tests: 
- Performance of upper limb (PUL) total score 
• Change from baseline at Week 48 in RO7239361 
treated participants relative to placebo treated 
participants in: 
– Performance of upper limb (PUL) total score 
• To evaluate other measures of efficacy, quality of 
life and health care utilization 
• Change from baseline at Week 48 in RO7239361 
treated participants compared to placebo treated 
participants: 
− 
Pulmonary function tests, including FVC, 
% predicted FVC FEV1, MEP, and MIP  
− 
PODCI total score 
− 
 Caregiver Global Impression of Change  
(CaGI-C) in a subset of the overall study 
population 
− 
Pediatric Quality of Life Inventory 
Multidimensional Fatigue Scale (PedsQL 
MFS) in a subset of the overall study 
population  
− 
Cardiac magnetic resonance imaging (cMRI) 
measures of ejection fraction, fractional strain, 
and volume of fibrosis in a subset of the overall 
study population 
• Strength of elbow flexors, elbow extensors, and 
pinch, measured by manual myometry 
• Health Utilities Index III and PedsQL Family 
Impact Module scores 
• Assessments at selected timepoints during the study 
of: 
− 
Dual x-ray absorptiometry (DXA) measures 
of lean body mass, fat mass and bone mineral 
density 
− 
Activity levels in a subset of the overall study 
population, as recorded with ActiMyo 
− 
Scoring of functional assessments, as recorded 
by a subset of parents/caregivers participating 
in the caregiver video assessment 
− 
Number of falls during treatment in the 
RO7239361 arms compared with the placebo 
arm 
 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
13/Protocol WN40227, Version 4 
 
 
Objectives 
Endpoints 
• To evaluate RO7239361 pharmacokinetics, 
pharmacodynamics, and immunogenicity 
• Assessments at select timepoints during the study 
of: 
− 
Serum RO7239361 concentrations 
− 
Serum free myostatin and myostatin drug 
complex concentrations 
− 
Serum ADA concentrations 
− 
Serum creatine kinase level in muscle 
• 
To explore the effect of genetic variation on target 
engagement, pharmacodynamic (PD) effects or 
functional test endpoints 
• 
Assess the impact on genetic variation in the 
DYSTROPHIN gene or in genes suspected to impact 
DMD disease expression (including but not limited 
to LTBP4, SPP1) in RO7239361 and placebo 
treated participants, on target engagement, 
pharmacodynamic (PD) and functional endpoints 
 
 
Overall Design: 
This is a multi-center, randomized, double-blind, placebo-controlled study to assess the efficacy, 
safety and tolerability of two different weekly SC doses of RO7239361 in ambulatory boys with 
Duchenne muscular dystrophy (DMD). 
Eligible participants will be randomized to receive doses of RO7239361 or placebo (1:1:1 across 
the three treatment arms). The randomization will be stratified by: 
• Age (6 through 7 and 8 through 11) 
• CS regimen: daily (prednisone, prednisolone or deflazacort) vs. intermittent (any 
non-daily dosing of prednisone, prednisolone or deflazacort) 
 
A separate randomization will be conducted for Japan (N∼15) with stratification for age only 
(6 through 7 and 8 through 11) not CS regimen. 
RO7239361 or placebo will be administered weekly. The first three doses (Days 1, 8 and 15) of 
study drug must be administered at the site. Parents/caregivers will be trained to administer SC 
injections during the first three dose administrations. Parents/caregivers can administer the 
injection at home starting at Day 22.  Site staff should ensure that the parent or caregiver is able to 
perform injections at home. Parents/caregivers will be dispensed an approximately 6- or 12-week 
supply of drug in pre-filled syringes (RO7239361 or placebo), during the double-blind phase and 
open-label (OL) extension phase, respectively, for weekly study drug/placebo administration to 
the participant. 
Study visits and endpoint measurements will occur as indicated in Table 2-1 though Table 2-4. 
After completion of this 48-week double-blind phase, participants may enter the OL phase in 
which all participants will receive active RO7239361 study drug. Participants who discontinue 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
14/Protocol WN40227, Version 4 
 
the study drug at any time (i.e., early discontinuation for subjects who do not enter the OL 
extension phase or at completion of the OL extension phase) will enter a 24-week safety follow-
up phase of the study. Participants will be monitored for safety at three visits during the follow-up 
phase.  The participant will be requested to provide immunogenicity samples at all follow-up visits 
during the 24-week follow-up phase. 
Number of Participants: 
Statistical Considerations: 
Sample Size: 
Assuming the standard deviation of the NSAA is 4.4 points, with approximately 150 evaluable 
subjects, the final analysis will have 80% power to detect a between group difference of 
2.5 points. The number randomized will be increased to allow for an approximate dropout 
rate on the order of 5% at the primary analysis, so approximately 159 participants 
will be 
randomized. Approximately 15 of these participants will be randomized in Japan, and the 
remaining participants will be randomized outside of Japan. 
The final analysis will test for differences between each RO7239361 treatment and placebo in 
either direction.  The doses will be tested against placebo in a hierarchical manner, with the high 
dose (Dose 2) tested versus placebo in the first step of the hierarchy. If the null hypothesis of no 
difference between the high dose and placebo is rejected in favor of the RO7239361 dose at a two-
sided α level of 0.05, then the low dose (Dose 1) will be tested against placebo.   
The primary analysis, on the change from baseline in NSAA total score, will be conducted using 
a mixed model repeated measures (MMRM) analysis with treatment, visit, and the treatment-
by-visit interaction entered into the model as fixed effects, and participant entered as a random 
effect. The baseline value of the NSAA total score will be entered into the model as a covariate. The 
stratification factors will be entered into the model as blocks. 
Sensitivity analyses will include the following: an analysis of covariance (ANCOVA) using the 
modified intent-to-treat (mITT) data set; an ANCOVA on the mITT data set with missing data 
imputed using multiple imputations; and an MMRM analysis using the per-protocol data. 
 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
15/Protocol WN40227, Version 4 
 
Treatment Arms and Duration: 
 
OL=open label; SC=subcutaneous. 
Study Treatment: 
Each participant will be administered weekly, SC doses of RO7239361 (previously, 
BMS-986089) or placebo for 48 weeks in a randomized, double- blind design. Participants who 
complete the 48-week double- blind phase are eligible to receive OL RO7239361 (active 
treatment) as part of an OL extension phase of this study. The OL extension phase will last up to 
192 weeks or until RO7239361 is commercially available in the subject's country, per local 
regulations, or the study is terminated by the Sponsor, whichever comes first. Please refer to Section 
7.8 for details regarding treatment after the end of study.  Doses in the OL extension phase may 
be adjusted based on emerging data. 
 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
16/Protocol WN40227, Version 4 
 
 
Study Drug 
Medication 
Potency 
IP/Non-IP 
RO7239361 7.5 mg dose 
10.7 mg/mL (0.7mL/syringe) 
IP 
RO7239361 15 mg dose 
21.4 mg/mL (0.7mL/syringe) 
IP 
RO7239361 35 mg dose 
50 mg/mL (0.7mL/syringe) 
IP 
RO7239361 50 mg dose 
71.4 mg/mL (0.7mL/syringe) 
IP 
RO7239361 matching placebo 
0 mg/mL (0.7mL/syringe) 
IP 
 
 
Other medications used as support medication for preventative, diagnostic, or therapeutic reasons, 
as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. In this study, corticosteroids are considered a non-investigational 
product and will not be provided by the sponsor. 
Study drug preparation and administration instructions will be provided in a separate manual. 
 
2 
SCHEDULE OF ACTIVITIES 
Study procedures and assessments are present in Table 2-1, Table 2-2, Table 2-3, and Table 2-4. 
 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
17/Protocol WN40227, Version 4 
 
Table 2-1: 
Screening Procedural Outline 
 
Procedure 
Screening 
Visit 
(Day -42 to 
Day -1) 
Notes 
Eligibility Assessments 
Informed Consent 
X 
A participant is considered enrolled only when a protocol specific informed consent is signed 
Informed consent may be signed prior to Day-42. 
Register / enroll participant in IWRS 
X 
Inclusion/Exclusion Criteria 
X 
Medical History 
X 
Include disease history and any toxicities or allergies related to previous treatments. 
Concomitant Medications 
X 
Include complete history of corticosteroids. 
Physical Examination (PE) 
X 
Physical Measurements 
X 
Includes height, weight, hand circumference and ulna length; see Clinical Evaluator (CE) 
manual. 
Vital Signs 
X 
Includes body temperature (recommend using tympanic thermometer), respiratory rate, and 
seated blood pressure and heart rate. Blood pressure and heart rate should be measured after the 
participant has been resting quietly for at least 5 minutes. 
Electrocardiogram (ECG) 
X 
ECG should be recorded after the participant has been supine for at least 5 minutes. See Eli 
150c/250c User Guide 
Echocardiogram 
X 
See ECHO Manual 
Laboratory Assessments 
X 
Section 9.3.4 
Urinalysis 
X 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
18/Protocol WN40227, Version 4 
 
Table 2-1: 
Screening Procedural Outline 
 
Procedure 
Screening 
Visit 
(Day -42 to 
Day -1) 
Notes 
Cardiac MRI (At select U.S. centers only) 
X 
See Section 9.1.3.2 and the imaging procedure manual. 
Baseline cMRI should be obtained between Day -40 and Day -14. The adequacy of cMRI scan 
should be confirmed by the imaging vendor prior to randomization. 
Subjects enrolled at select U.S. centers will be required to attempt to complete the cMRI. 
DXA 
X 
See Section 9.1.3.1 and the imaging procedure manual; 
Baseline DXA should be obtained between Day -42 and Day -14. Adequacy of DXA scan 
should be confirmed by the imaging vendor prior to randomization. 
DXA is not required for subjects enrolled at sites in Germany. 
NSAA 
X 
See the Clinical Evaluator Manual.  The NSAA assessment must be performed to determine 
subject eligibility (NSAA ≥15 total score inclusion criterion), videotaped for ATOM review and 
confirmed to be adequate prior to randomization 
TFTs 
X 
Includes 4SC, 10 m walk/run, stand from supine 
At screening visit: 4SC must be ≤ 8 seconds. See CE Manual; 
A videotape of screening TFTs must be reviewed by ATOM and confirmed adequate prior to 
randomization; see Bracket Videographer Manual 
6MWD 
X 
A videotape of screening 6MWD must be reviewed by ATOM and confirmed adequate prior to 
randomization. 
PFTs 
X 
To include FVC, % predicted FVC, FEV1, MEP, and MIP. See PFT Site Manual. 
ActiMyo 
X 
Subjects at selected sites who agree to participate will wear the ActiMyo device from screening until 
Day 1.  See the ActiMyo manual. 
Adverse Event Reporting 
Monitor for Serious Adverse Events 
X 
All SAEs must be collected from the date of participant’s written consent until 50 days post 
discontinuation of dosing in the present study. If the participant enters a separate rollover 
treatment study of RO7239361, the participant’s SAEs will be reported in that study. 


 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
19/Protocol WN40227, Version 4 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
Physical Examination 
(PE) 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Targeted PE 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
See Section 9.3.1 
Monitor Injection Sites 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Report findings as AEs, as appropriate. 
It is strongly recommended that 
photographs of injection site reactions 
without personally identifying 
information be obtained for submission 
to the sponsor or designee 
Some subjects with injection site 
reaction or rash may be asked to 
participate in additional procedures to 
determine type of immune reaction. See 
Section 9.2.8.1. 
Weight 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See Study Procedure Manual 
Height 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See CE Manual 
Ulna Length 
X 
 
 
 
 
 
 
 
 
 
 
 
See CE Manual  
Only to be measured instead of 
standing height if height cannot be 
measured 
Hand Circumference 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See CE Manual 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See note in screening procedures. 
Con med assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Include corticosteroids 
Physical therapy and 
respiratory therapy 
assessment 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Assess current physical and respiratory 
therapy regimen 
Echocardiogram 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
See ECHO Manual 


 
 
 
 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
20/Protocol WN40227, Version 4 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
Electrocardiogram 
(ECGs) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
ECGs should be recorded after the 
participant has been supine for at least 5 
minutes. See Eli 150c/250c User Guide 
Laboratory 
Assessments 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Section 9.3.4 
Placement of an intravenous lock is 
allowed for onsite visits when multiple 
blood draws are required. 
Urinalysis 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood PK Sampling 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
See section 9.4 for the sample 
collection schedule. Must be collected 
prior to administration of study drug. 
Immunogenicity 
Sampling 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Must be collected prior to 
administration of study drug. 
In the event of a positive 
immunogenicity response, additional 
neutralizing antibody (NAB) testing 
will be conducted. 
Serum Free Myostatin 
and Myostatin-Drug 
Complex 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Myostatin-drug complex will not be 
analyzed at baseline 
Must be collected prior to 
administration of study drug. 
Serum Biomarkers 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Additional Research 
Sample 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Exploratory 
genotyping sample 
X 
 
 
 
 
 
 
 
 
 
 
 
TFTs 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual; TFT 
assessment must be videotaped for 
ATOM review at D1, Wk 24 and Wk 
48 visits 


 
 
 
 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
21/Protocol WN40227, Version 4 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
6MWD 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual; 6MWD 
assessment must be videotaped for 
ATOM review at D1, Wk 24 and Wk 
48 visits 
ActiMyo 
X 
(Scr to 
Day 1) 
 
 
 
X 
(Wk 6 
to 
Wk 12) 
 
X 
(Wk 18 
to 
Wk 24) 
 
X 
(Wk 30 to 
Wk 36) 
 
X 
(Wk 42 to 
Wk 48) 
 
Subjects at selected sites who opt in will 
wear ActiMyo device at home and 
during visits. See ActiMyo manual. 
NSAA 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual; NSAA 
assessment must be videotaped for 
ATOM review at D1, Wk 24 and Wk 
48 visits 
PFTs 
X 
 
 
 
 
 
 
X 
 
 
 
X 
To include FVC, % predicted FVC, 
FEV1, MEP, and MIP. 
See PFT Site Manual 
Upper & Lower 
Extremity Myometry 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See Clinical Evaluator Manual; 
myometry assessment must be 
videotaped for ATOM review at D1, 
Wk 24 and Wk 48 visits 
Grip & Pinch Strength 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See Clinical Evaluator Manual 
PUL 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See Clinical Evaluator Manual; PUL 
assessment must be videotaped for 
ATOM review at D1, Wk 24 and Wk 
48 visits 
Right Ankle Range of 
Motion 
X 
 
 
 
 
 
 
X 
 
 
 
X 
See Clinical Evaluator Manual 
Caregiver video 
assessment 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Subjects at selected sites who opt in 
will record videos at selected 
timepoints of the study (as specified), 
or at any applicable visits after start 
date. The visit window is +2 weeks. 
See Section 9.1.6 and the 
parent/caregiver manual. 


 
 
 
 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
22/Protocol WN40227, Version 4 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
PODCI 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Completed by Parent/Caregiver (should 
be the same parent/caregiver at each 
visit) 
HUI-3 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Completed by Parent/Caregiver (should 
be the same parent/caregiver at each 
visit) 
Health Care Resource 
Utilization 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Protocol mandated procedures, test & 
encounters are excluded 
PedsQL Family 
Impact Module 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Completed by Parent/Caregiver (should 
be the same parent/caregiver at each 
visit) 
CaGI-C 
 
 
 
 
 
 
 
 
 
 
 
X 
Completed by parent/caregiver (who 
has been involved in the study from 
baseline) who opt in at selected sites 
CGI-C 
 
 
 
 
 
 
 
 
 
 
 
X 
Completed by Clinician 
(e.g., Principal Investigator  or other 
clinician who has interacted with 
the individual from baseline) 
CaGI-C 
 
 
 
 
 
 
 
 
 
 
 
X 
Completed by parent/caregiver (who 
has been involved in the study from 
baseline) who opt in at selected sites 
Pediatric Quality of 
Life Inventory 
Multidimensional 
Fatigue Scale (PedsQL 
MFS)  
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Completed by parent/caregiver who opt 
in at selected sites (should be the same 
parent/caregiver at each visit) 
Cardiac MRI 
 
 
 
 
 
 
 
 
 
 
 
X 
Visit window +/- 1 week. Conducted at 
early termination if ≥ 24 weeks from 
previous cMRI. 
See Section 9.1.3.2 and the imaging 
procedure manual.  cMRI will be 
completed at select U.S. sites only. 
Subjects enrolled at select U.S. centers 


 
 
 
 
 
Table 2-2: 
On Treatment Procedural Outline, Double-Blind Phase 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
23/Protocol WN40227, Version 4 
 
Procedure 
D1a 
D8 
± 1 day 
(Wk 1) 
D15 
± 1 day 
(Wk 2) 
D29 
± 1 day 
(Wk 4) 
Wk 6 
± 3 days 
Wk 12  
± 3 days 
Wk 18  
± 3 days 
Wk 24  
± 3 days 
Wk 30  
± 3 days 
Wk 36  
± 3 days
Wk 42  
± 3 days 
Wk 48 or 
early D/C 
± 3 days 
Notes 
will be required to attempt to complete 
the cMRI. 
DXA 
 
 
 
 
 
 
 
X 
 
 
 
X 
Visit window +/- 1 week. Not required 
at early termination visit. 
See Section 9.1.3.1 and the DXA 
Scanning Guide. 
DXA is not required for subjects 
enrolled at sites in Germany or for early 
termination visits. 
Monitor for Non- 
Serious Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
All participants administered study 
drug will be closely monitored for AEs 
including possible immunogenicity-
related AEs, such as rash, fever. 
Injection sites will be evaluated at each 
visit (see above). 
Falls should be assessed at each study 
visit b. 
Monitor for Serious 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
All SAEs must be collected from the 
date of participant’s written consent 
until 50 days 
post discontinuation of dosing. 
Falls should be assessed at each study 
visit b. 
Randomize 
X 
 
 
 
 
 
 
 
 
 
 
 
Access IWRS to obtain 
study drug kit 
assignment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Access IWRS as needed to obtain 
sufficient drug. Access IWRS as 
needed to replace kits. 




 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
25/Protocol WN40227, Version 4 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
(PE) 
 
 
 
 
 
 
 
 
X 
 
 
Targeted PE 
X 
 
 
 
X 
 
X 
X 
 
 
X 
See Section 9.3.1; to be assessed every 24 weeks 
after Wk 48 of the OL phase 
Monitor Injection 
Sites 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Report findings as AEs, as appropriate. 
It is strongly recommended that photographs of 
injection site reactions without personally 
identifying information be obtained for 
submission to the sponsor or designee. 
Some subjects with injection site reaction or 
rash may be asked to participate in additional 
procedures to determine type of immune 
reaction. See Section 9.2.8.1 
Vital Signs 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
See note in screening procedures 
Con med assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Include corticosteroid assessment 
Physical therapy and 
respiratory therapy 
assessment 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Assess current physical therapy and respiratory 
therapy 
Weight 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
See Study Procedure Manual 
Height 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
See CE Manual 
Ulna Length 
X 
 
 
 
 
 
 
 
 
 
X 
See CE Manual  
Only to be measured instead of standing height if 
height cannot be measured. 
Hand Circumference 
 
 
 
 
 
 
X 
 
X 
 
X 
See CE Manual; to be assessed every 24 weeks after 
Wk 48 of the OL phase 
Echocardiogram 
 
 
 
 
 
 
X 
 
X 
 
X 
See ECHO Manual; to be assessed every 24 weeks 
after Wk 48 of the OL phase 


 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
26/Protocol WN40227, Version 4 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(ECGs) 
 
 
 
 
 
 
 
 
X 
 
X 
ECGs should be recorded after the participant has 
been supine for at least 5 minutes. See Eli 
150c/250c User Guide; to be assessed every 24 
weeks after Wk 48 of OL phase. 
Laboratory Tests 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Placement of an intravenous lock is allowed for 
onsite visits when multiple blood draws are 
required.  
Urinalysis 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Monitor for Non-
Serious Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See notes above. 
Falls should be assessed at each study visit b. 
Monitor for Serious 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See notes above. 
All SAEs must be collected from the date of 
participant’s written consent until 50 days post 
discontinuation of dosing in the present study. If 
the participant enters a separate rollover treatment 
study of RO7239361, the participant’s SAEs will 
be reported in that study. 
Falls should be assessed at each study visit b. 
Blood PK Sampling 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Must be collected prior to administration of study 
drug. See section 9.4 for the sample collection 
schedule. 
TFTs 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at Open Label Week 1 Visit must be 
obtained prior to dosing; TFT assessment must be 
videotaped for ATOM review at Wk 24 and Wk 
48 visits. To be assessed every 24 weeks after Wk 
48 of the OL phase. 


 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
27/Protocol WN40227, Version 4 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
6MWD 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual 
Functional measures at OL Week 1 visit must be 
obtained prior to dosing; 6MWD assessment must 
be videotaped for ATOM review at Wk 24 and 
Wk 48 visits. To be assessed every 24 weeks after 
Wk 48 of the OL phase. 
NSAA 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing; NSAA assessment must be 
videotaped for ATOM review at Wk 24 and Wk 
48 visits. To be assessed every 24 weeks after Wk 
48 of the OL phase. 
ActiMyo 
 
 
 
 
X 
(Wk 6 
to  
Wk 12) 
 
X  
(Wk 18 
to  
Wk 24) 
X 
(Wk 30 
to Wk 
36) 
X 
(Wk 42 
to  
Wk 48) 
 
 
Subjects at selected sites who opt in during the 
double-blind phase of the study will wear the 
ActiMyo device at home and during visits of the 
OL phase. See the ActiMyo manual. 
PUL 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at Open Label Week 1 Visit must be 
obtained prior to dosing; PUL assessment must be 
videotaped for ATOM review at Wk 24 and Wk 
48 visits. To be assessed every 24 weeks after Wk 
48 of the OL phase. 
PODCI 
 
 
 
 
 
 
X 
 
X 
 
 
Completed by parent/caregiver (should be the 
same parent/caregiver at each visit) 
CGI-C 
 
 
 
 
 
 
 
 
X 
 
 
Completed by clinician (e.g., Principal 
Investigator or other clinician who has 
interacted with the individual from baseline) 
Should be the same clinician at both visits. 


 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
28/Protocol WN40227, Version 4 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
Sampling 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Must be collected prior to administration of study 
drug. In the event of a positive immunogenicity 
response, additional NAB testing will be 
conducted. To be assessed every 24 weeks after Wk 
48 of the OL phase. 
Serum Free 
Myostatin and 
Myostatin-Drug 
Complex 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Must be collected prior to administration of 
study drug. 
Serum Biomarkers 
 
 
 
 
X 
 
X 
X 
X 
 
 
PFTs 
X 
 
 
 
 
 
X 
 
X 
 
X 
To include FVC, % predicted FVC, FEV1, MEP, 
and MIP  
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing. To be assessed every 24 weeks after 
Wk 48 of the OL phase. 
Upper & Lower 
Extremity Myometry 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing; myometry assessment must be 
videotaped for ATOM review at Wk 24 and Wk 
48 visits. To be assessed every 24 weeks after Wk 
48 of the OL phase. 
Grip & Pinch 
Strength 
X 
 
 
 
 
 
X 
 
X 
 
 
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing.  
Right Ankle Range of 
Motion 
X 
 
 
 
 
 
X 
 
X 
 
X 
See Clinical Evaluator Manual Functional 
measures at OL Week 1 visit must be obtained 
prior to dosing. To be assessed every 24 weeks after 
Wk 48 of the OL phase. 


 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
29/Protocol WN40227, Version 4 
 
Procedure 
Wk 1a 
Wk 2  
± 1 day 
Wk 3  
± 1 day 
Wk 6  
± 3 days
Wk 12 
± 3days 
Wk 18  
± 3days 
Wk 24  
± 3days 
Wk 36  
± 3days 
Wk 48/ 
or early 
D/C 
± 3 days 
Wk 60 
±  5 days 
Wk 72 to 
Wk 192 
±  5 days 
Notes 
Week 1 of the open-label phase occurs 1 week 
after the end of the Week 48 double-blind visit 
After Week 24 visits to take place every 
12 weeks 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Caregiver video 
assessment 
 
 
 
 
 
 
X 
 
X 
 
 
Subjects at selected sites who opt in to 
participate in the caregiver video assessment 
during the double-blind phase will record 
videos at the specified timepoints. Visit 
window: + 2 weeks. See Section 9.1.6 and the 
Parent/Caregiver manual. 
CaGI-C 
 
 
 
 
 
 
 
 
X 
 
 
Completed by parent/caregiver (who has been 
involved in the study from baseline) who opt in 
at selected sites. Should be the same 
parent/caregiver at each visit. 
HUI-3 
 
 
 
 
 
 
X 
 
X 
 
 
Completed by parent/caregiver (should be the 
same parent/caregiver at each visit) 
Health Care Resource 
Utilization 
X 
 
 
 
 
 
X 
 
X 
 
 
Protocol mandated procedures, tests, and 
encounters are to be excluded. 
PedsQL Family 
Impact Module 
 
 
 
 
 
 
X 
 
X 
 
 
Completed by parent/caregiver (should be the 
same parent/caregiver at each visit) 
Pediatric Quality of 
Life Inventory 
Multidimensional 
Fatigue Scale 
(PedsQL MFS) 
 
 
 
 
 
 
X 
 
X 
 
 
Completed by parent/caregiver who opt in at 
selected sites (should be the same 
parent/caregiver at each visit).  
Cardiac MRI 
(At selected sites) 
 
 
 
 
 
 
 
 
X 
 
X* 
Visit window +/- 1 week. 
Conducted at early termination if ≥ 24 weeks from 
previous cMRI. 
See the imaging procedure manual. *To be 
assessed every 48 weeks during the OL phase. 




 
 
 
 
Table 2-3: 
Open-Label Phase Procedural Outline 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
31/Protocol WN40227, Version 4 
 
a Week 1 of the open-label (OL) phase occurs one week after the end of the Week 48 double-blind visit. After Week 24 of the OL phase, visits will take place every 
12 weeks, with some assessments performed every 12, 24, or every 48 weeks as specified on the schedule of activities. The OL phase will last up to 192 weeks or 
until RO7239361 is commercially available in the subject’s country, per local regulations, or the study is terminated by the Sponsor, whichever occurs first. 
Please refer to Section 7.8 for details regarding treatment after the end of study. 
In the event of multiple procedures are required at a single timepoint, the following is a list of procedures from highest priority to low: 
1) Safety (ECG, echocardiogram) 
2) Safety (clinical labs) 
3) Pharmacokinetic Sampling 
4) Biomarker Sampling 
b 
Falls will be reported only as an adverse event if worsening (e.g., more frequent falls) compared with pre-treatment. 


  
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
32/Protocol WN40227, Version 4 
 
Table 2-4: 
Post Study Drug/Placebo Administration Follow-up Procedural Outline 
 
Procedure 
Follow-up 
Week 8 
± 1 week 
Follow-up 
Week 16 
± 1 week 
Follow up 
Week 24 
± 1 week 
Notes 
NSAA 
X 
X 
X 
For participants who discontinue study drug before Week 48 of the double-blind 
Phase, a follow-up visit will be schedule to coincide with the date at which the 
Week 48 visit of the double-blind phase would have occurred, when possible. 
Adverse Event Reporting 
 
 
 
Monitor injection site 
X 
X 
X 
Report findings as AEs, as appropriate. 
It is strongly recommended that photographs of injection site reactions without 
personally identifying information be obtained for submission to the sponsor or 
designee. 
Some subjects with injection site reaction or rash may be asked to participate in 
additional procedures to determine type of immune reaction. See Section 9.2.8.1 
Monitor for previously 
reported or new onset of non- 
serious adverse events 
X 
X 
X 
All non-serious adverse events must be collected until 50 days post discontinuation 
of dosing in the present study. If the participant enters a separate rollover treatment 
study of RO7239361, the participant’s non-serious adverse events will be reported 
in that study 
Monitor for previously 
reported or new onset of 
serious adverse events (SAEs) 
X 
X 
X 
All SAEs must be collected from the date of participant’s written consent until 
50 days post discontinuation of dosing in the present study. If the participant 
enters a separate rollover treatment study of RO7239361, the participant’s SAEs 
will be reported in that study. 
Safety Assessments 
ECG 
 
 
X 
Only required for participants who do not participate in a separate rollover study and 
who discontinue study drug due to cardiovascular concerns. 
Echocardiogram 
 
 
X 
Only required for participants who do not participate in a separate rollover study and 
who discontinued study drug due to cardiovascular concerns. 
 
 


  
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
33/Protocol WN40227, Version 4 
 
Table 2-4: 
Post Study Drug/Placebo Administration Follow-up Procedural Outline 
 
Procedure 
Follow-up 
Week 8 
± 1 week 
Follow-up 
Week 16 
± 1 week 
Follow up 
Week 24 
± 1 week 
Notes 
Laboratory Assessments 
X 
X 
X 
Only required for participants who do not participate in a separate rollover study and 
who discontinued study drug due to an abnormal laboratory result. Lab results should 
be followed until the participant’s lab values return to baseline or are considered 
stable by the investigator. 
Immunogenicity 
X 
X 
X 
Required for all patients who do not participate in a separate rollover study.   
In the event of a positive immunogenicity response, additional NAB testing will be 
conducted. 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
34/Protocol WN40227, Version 4 
 
 
3 
INTRODUCTION 
DMD is an X-linked human disease that affects 1 in 3600-6000 live male births, with an estimated 
15,000 patients with the disease in the United States. DMD results from mutations in the 
DYSTROPHIN gene (locus Xp21.2), that lead to absent or defective dystrophin production.1 The 
clinical manifestation of this molecular lesion is progressive weakness and limitation in motor 
capacity, with proximal muscles affected initially followed by distal muscles. Cardiac and 
respiratory failure typically begin to develop in adolescence and lead to death in the second or 
third decade of life. Current standard of care is limited to symptomatic treatment, including 
medical and physical therapies to improve cardiac and respiratory function as well as 
corticosteroids to improve skeletal muscle strength and function. However, corticosteroids are 
associated with significant adverse side effects, including obesity, diabetes, short stature, 
osteopenia, and fracture.2 Translarna (ataluren) received a conditional marketing authorization in 
the European Union with a restricted indication for the treatment of DMD specifically resulting 
from a nonsense mutation in the DYSTROPHIN gene. Exondys51 (eteplirsen) received 
accelerated approval by the U.S. FDA for treatment of DMD resulting from mutations amenable 
to skipping exon 51. As both Translarna and Exondys51 target restricted populations with specific 
mutations, the unmet need for safe and effective treatments in DMD remains significant. 
Myostatin, also known as growth and differentiation factor-8 (GDF-8), is a member of the 
transforming growth factor-β (TGF-β) superfamily of secreted growth factors. It is a negative 
regulator of skeletal muscle growth and development that is expressed predominantly in skeletal 
muscle beginning at embryogenesis and persisting through adulthood. Nonclinical models support 
the anti-myostatin mechanism as potentially efficacious in DMD. Deletion of the Myostatin gene 
from mdx mice, the most commonly used mouse model of DMD, which carries a premature stop 
codon in exon 23 of DYSTROPHIN, resulted in attenuation of the dystrophic phenotype relative to 
mdx mice with intact Myostatin genes.3,4 Similarly, weekly administration of anti-myostatin 
monoclonal antibodies to mdx mice resulted in increases in muscle size and strength.5 
RO7239361 (previously, BMS-986089) is a bivalent human anti-myostatin adnectin, which has 
been formatted with a human IgG1 Fc tail to prolong its half-life in circulation. RO7239361 is 
being developed as a once weekly, subcutaneously administered therapeutic to increase muscle 
mass and strength. RO7239361 has a unique mechanism of action (MOA) that includes the 
competitive inhibition of Alk4/5 (signaling receptor) recruitment and binding to free myostatin or 
the myostatin-ActRIIb complex. This MOA leads to the inhibition of downstream pSMAD2/3 
intracellular signaling with physiological consequences of increased muscle volume and body 
weight. 54, 55 RO7239361 is being developed as a potential therapy to improve muscle function 
in DMD. As most ambulatory DMD patients are treated with corticosteroids (CS), in this 
study of ambulatory patients with DMD, RO7239361 will be given to subjects on stable CS 
therapy. 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
35/Protocol WN40227, Version 4 
 
3.1 
Study Rationale 
Study WN40227 is a multi-center, randomized, double-blind, placebo-controlled study to assess 
the efficacy, safety, and tolerability of two different weekly subcutaneous (SC) doses of 
RO7239361 in ambulatory boys aged ≥ 6 to < 12 years with DMD. 
DMD is caused by mutations within the DYSTROPHIN gene that result in loss of the mRNA 
reading frame, severely limiting dystrophin protein production.6  The DYSTROPHIN gene lies on 
the X chromosome and thus DMD is primarily expressed in boys. The disease manifests as 
progressive weakness of skeletal, respiratory, and cardiac muscles due to the absence of dystrophin 
in the subsarcolemmal cytoskeleton.7 Progressive weakness and contractures lead to loss of 
ambulation by age 13 and death from cardiorespiratory failure by the late 20s to early 30s.8 In the 
absence of supportive treatment, patients rarely survive beyond their teens.9 Advances in 
management, including CS use, physical therapy for contractures, ventilatory support, spinal 
surgery, and cardiac management have increased the life expectancy for patients with DMD.9,10,11 
With these advances, aggressively managed patients may ambulate beyond 14 years of age and 
survive into their early 30s.9,10 
Although advances in the management of DMD have improved survival, chronic CS treatment is 
associated with adverse side effects that contribute to morbidity in DMD.8,11 While Translarna 
(ataluren) has received a conditional marketing authorization in the EU for the treatment of DMD 
resulting from a nonsense mutation in the DYSTROPHIN gene,12 this treatment is restricted to the 
15% of patients with DMD with this type of mutation 12,13 Similarly, Exondys51 (eteplirsen) has 
received U.S. FDA approval for treatment of DMD resulting from mutations amenable to exon 
51 skipping, roughly only 13% of the DMD population. Thus, there remains a significant unmet 
medical need for novel agents to treat DMD. 
Data from prior and ongoing clinical studies suggest that RO7239361 is generally safe and well 
tolerated and has expected effects on pharmacodynamic endpoints. 
A first-in-human (FIH) assessment of RO7239361 (Study CN001001), a combined single-
ascending dose (SAD)/multiple-ascending dose (MAD) study to investigate the safety, 
tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity in healthy adult subjects, 
showed that single and multiple doses (of up to 180 mg weekly) of RO7239361 were generally safe 
and well tolerated. The most common adverse events (AEs) considered by the investigator to be 
related to study drug were mild or moderate injection site reactions, and that, in most cases, did 
not require treatment. There were no acute hypersensitivity reactions during this study. The 
presence of anti-drug antibodies (ADAs) did not appear to affect the safety or exposure of 
RO7239361 in healthy subjects. Administration of both single and multiple doses of RO7239361 
produced dose-dependent reductions in free serum myostatin and increases in myostatin-drug 
complex consistent with target engagement. Findings supporting the expected pharmacodynamic 
(PD) effects of RO7239361 include increases in whole right thigh muscle volume (measured by 
magnetic resonance imaging) and increases in the change from baseline in the percentage of lean 
body mass (as measured by dual X-ray absorptiometry [DXA]). 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
36/Protocol WN40227, Version 4 
 
 
Study WN40226 is a Phase 1b/2, multi-center, randomized, placebo-controlled, double-blind, 
multiple-ascending SC dose study in ambulatory boys ages ≥ 5 to < 11 years with DMD who 
are receiving CS. This study was designed as a dose-ranging study to characterize the safety, 
pharmaockinetics, target engagement (i.e., myostatin suppression) and the relationship between 
pharmaockinetics and target engagement over at least 3 doses in boys with DMD. As of 8 
February 2018, all 43 patients randomized had completed the 24-week double-blind phase of the 
study. In all, 42 patients completed the 48-week OL phase and 41 entered into the OL extension 
phase. Two patients withdrew from the study for non-safety reasons.  The study met its primary 
objective of showing safety and tolerability of RO7239361. The most common AEs that were 
considered by the investigators to be related to study drug were mild to moderate injection-site 
reactions that resolved without change to study treatment; there were no acute hypersensitivity 
reactions associated with study drug reported. Immunogenicity data from 43 gs showed a single 
value of low positive ADA titer in 1 patient who had received RO7239361. 
Pharmacokinetic (PK) data from Panels 1 to 3 (which included all three doses tested) show 
dose-related increases in peak and overall exposure, which appear to be dose proportional. 
Furthermore, an effect of body weight on the RO7239361 pharmacokinetics has been such 
that with increasing body weight, the clearance increases. Preliminary target engagement 
data from Panels 1 to 3 show robust dose-related increases in free serum myostatin suppression. 
As shown by the population PK/PD model, the three different dose levels achieved 77%, 92%, and 
97% reduction in serum-free myostatin. 
Further information regarding the available clinical data of RO7239361 in healthy volunteers 
and patients with DMD can be found in the Investigator's Brochure (IB). 
3.1.1 
Rationale to Support Dose Selection 
Two doses of RO7239361 were selected for this study based on interim data from 
Study WN40226; doses that are safe and were predicted to produce a moderate level of free 
myostatin suppression (≥ 70% relative to baseline) and a second dose that is safe and was predicted 
to produce a higher level of free myostatin suppression (≥ 90% relative to baseline). 
Whereas statistically significant increases in muscle volume were observed at > 80% suppression 
of free myostatin levels relative to baseline in a dose ranging study in cynomolgus monkeys, 
numerical but non statistically significant increases were observed at approximately 54% 
suppression relative to baseline following administration of RO7239361 in that study. Similarly, in 
Study CN001001, the multiple dose study in normal healthy subjects, statistically significant 
increases in muscle volume were observed for RO7239361 versus placebo at doses that sustained 
free serum myostatin suppression above 68% at the time of MRI assessment (Day 57). In that same 
study, no significant increases in muscle volume were observed at doses or regimens that 
generated a suppression of approximately 42% or lower on Day 57. The increase in muscle volume 
observed in monkeys and humans following RO7239361 administration is expected to correlate 
with an increase in thigh muscle to non-contractile tissue fraction in children with DMD. 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
37/Protocol WN40227, Version 4 
 
Given that increase in muscle mass and strength mediated by RO7239361 induced suppression 
of free myostatin is the underlying mechanism that is expected to ultimately drive the efficacy 
of RO7239361 in patients with DMD, dose selection for Study WN40227 is based on target 
engagement, i.e., free myostatin suppression. 
All available PK and free myostatin data following administration of 4 mg QW and 12.5 mg QW 
doses from Study WN40226 were analyzed in an interim analysis (Interim Analysis 1). Data were 
modeled using a population PK/PD model based on the concept of target mediated drug 
disposition (TMDD). Using the estimates of the PK/PD model parameters and the associated 
variabilities, the PK and free myostatin suppression profile following various doses in an 
ambulatory DMD population were obtained. The population of subjects in the simulations reflected 
the age (6 to 12 years) and weight (≥15 kg) of ambulatory DMD subjects in Study WN40227. 
Simulations were performed for 1000 subjects in each 5 kg weight bin. Based on the results of the 
simulations, a fixed dose by weight tier dosing strategy was chosen. Accordingly, doses for 
subjects will be based on their respective weight tier, namely Weight Tier 1: ≥ 15 to ≤ 40 kg, 
or Weight Tier 2: > 40 kg. This dosing strategy was intended to provide similarity in levels of 
exposure and target suppression for subjects within a given weight tier targeting the achievement 
of either ≥ 70% (Dose Level 1) or ≥ 90% (Dose Level 2) suppression of free myostatin at trough. 
Doses selected for Study WN40227 are as follows: 
 
Table 3.1.1-1: 
Dose Level 1, targeting moderate level of suppression: (≥ 70% 
suppression at trough) 
 
Dose Level 
Body Weight tier 
Body Weight range 
Dose 
1 
1 
≥ 15 to ≤ 40 kg 
7.5 mg QW 
1 
2 
> 40 kg 
15.0 mg QW 
 
 
Table 3.1.1-2: 
Dose Level 2, targeting high level of suppression: (≥ 90% 
suppression at trough) 
 
Dose Level 
Body Weight tier 
Body Weight range 
Dose 
2 
1 
≥ 15 to ≤ 40 kg 
35 mg QW 
2 
2 
> 40 kg 
50 mg QW 
 
The dose may be adjusted when a subject’s weight exceeds or drops below the dosing weight tier 
to which he was originally assigned by > 2 kg, confirmed by repeat. 
The population PK/PD model was further developed utilizing more observations, including the 
top dose data from Study WN40226 (see the IB). This model predicts similar reductions of free 
serum myostatin of over 90% for both doses tested. In healthy subjects, the pre-filled syringe  (PFS) 
achieved approximately 1.6-fold higher exposure than the vial formulation. If this would also be 
the case in patients with DMD, the exposure achieved in this study with the PFS at the top dose 


 
A nti -M y ost ati n A d necti n, ( R O 7 2 3 9 3 6 1) —F.  H off m a n n - L a R oc he Lt d 
3 8 /Pr ot oc ol W N 4 0 2 2 7, Versi o n 4  
 
wo ul d still be lo wer t ha n t he e x pos ure ac hie ve d wit h 1 8 0 m g i n  healt h y s u bjects. T he dr u g was 
well tolerate d u p to doses of 1 8 0 m g Q W i n healt h y vol u nteers.  Alt ho u g h t he doses ma y gi ve hi g her 
ser u m m yostati n re d uctio n as i nitiall y e x pecte d, tiss ue le vel m yostati n re d uctio n is u nk no w n. 
T here ma y be mea ni n gf ul differe nces i n tiss ue effects , a n d t herefore t he co nti n ue d use of t he selecte d 
doses is j ustifie d.  
3. 1. 2  
R ati o n al e f or S p e cifi c I n cl u si o n/ E x cl u si o n Crit eri a  
A ge R a n ge:  
A mi ni m u m  a ge of i ncl usi o n of 6 years  is pla n ne d, as c hil dre n y o u n ger t ha n 6 years  are less li kel y 
t o c o nsiste ntl y u n derst a n d a n d  be  a bl e t o c o o perat e wit h  perf or mi n g  t he f u ncti o nal e n d p oi nts, s uc h 
as t he NS A A , relia bl y. A n  u p per  a ge li mit f or i ncl usi o n of  < 1 2  years  is pla n ne d  t o e na ble  a f oc us 
o n c hil dre n w h o  are a ble t o perf or m  t he f u nctio nal e n d poi nts a n d w h ose  l o wer e xtre mities ha ve  s o me 
i ntact m uscle  tiss ue. R O 7 2 3 9 3 6 1 is e x pecte d t o preser ve  a n d i m pr o ve m uscle  stre n gt h pri maril y  
b y  i ncreasi n g t he size of e xisti n g m uscle  fi bers. T heref ore,  it is a ntici pate d t hat t he o pti mal  effect  
of R O 7 2 3 9 3 6 1 o n a m b ulat or y D M D  patie nts  will  be  bef ore  l o wer e xtre mit y m uscle  fi bers ha ve  bee n  
c o m pletel y re place d b y  fat a n d fi br osis.  A f urt her rati o nale f or li miti n g t he a ge ra n ge i n t his st u d y 
is t o mi ni mize varia bilit y wit h  res pect t o t he ti mi n g a n d e xte nt of f u ncti o nal a n d p h ysical deficits,  
a n d d u e t o t he patie nt’s  a ge, gr o wt h, mat urit y,  a n d c o nc o mita nt me dicati o ns.  B ot h  n at ural  hist or y 
a n d cli nical trial dat a  ha ve  hi g hli g hte d  t he si g nifica nt varia bilit y  i n  f u ncti o nal e n d p oi nts.1 6, 1 7, 1 8  
Ke y  a p pr o ac h es  t o mi ni mizi n g  t his varia bilit y  i ncl u de restricti n g  t he a ge ra n ge f or  i ncl usi o n, 
t here b y re d uci n g varia bilit y  ste m mi n g fr o m gr o wt h. 
N S A A M i ni m u m S core: 
It was rece ntl y re porte d  2 6 t hat i n a m b ula nt bo ys, a baseli ne total li nearize d N S A A score of 
5 0 poi nts  (∼1 6 of t he ra w scale) i m plies t hat t he bo ys are ver y u nlikel y to lose a m b ulatio n o ver t he 
co urse of a 2- year st u d y. It has also bee n o bser ve d o n t he basis of  e mer gi n g data fro m 
St u d y  W N 4 0 2 2 6 i n a m b ula nt bo ys wit h DM D  a ge d 5- 1 0 years at ra n do mizatio n t hat t here was 
a n i ncrease d rate of decli ne i n f u nctio n a n d i ncrease d rate of loss of a m b ulatio n for s u bjects wit h at 
a tot al score belo w 1 5  poi nts . A mi ni m u m N S A A score is pla n ne d  to li mit t he partici patio n to 
patie nts w ho  are not e x pecte d to lose a m b ulatio n d uri n g t he st u d y perio d  a n d w ho  will be a ble to  
co nti n ue to partici pate i n ke y f u nctio nal assess me nts. T he s pecific c utoff score of 1 5 poi nts at 
scree ni n g will allo w  a foc us o n t he i ncl usio n of patie nts w ho are a ble to p artici pate i n  ke y st u d y 
assess me nts t hro u g ho ut t he st u d y , wit ho ut bei n g too stri n ge nt. It  is i nte n de d to mi ni mize 
varia bilit y  of t he f u nctio nal  assess me nts  a n d e x pecte d disease pro gressio n , gi ve n t hat t he patie nts 
are ver y u nlikel y to lose a m b ulatio n o ver t he co urse of 2 year s. 
Use of C ortic oster oi ds:  
As  C S   ha ve de m o nstrate d  be nefit   o n m ot or  f u ncti o n i n b o ys  wit h  D M D 1 9 , b o ys   i ncl u de d i n 
t his  st u d y will   be re q uire d t o be   o n  a C S   (e. g.,  pre d nis o ne/ pre d nis ol o ne  or deflazac ort)  f or at 
least 6 m o nt hs  pri or  t o t h e start of st u d y treat me nt, wit h  n o si g nifica nt c ha n ge i n d osa ge or d osi n g 
re gi me n  f or  at  least 1 2  wee ks  pri or  t o  t he  start  of  st u d y  treat me nt.  T he  g oal of  t his i ncl usi o n 
criteri o n is t o c o ntr ol varia bilit y  i n m ot or   f u ncti o n a n d stre n gt h ste m mi n g fr o m C S  use.  


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
39/Protocol WN40227, Version 4 
 
Both prednisone/prednisolone and deflazacort have been shown to be effective in increasing and 
preserving muscle strength in DMD19,20 supporting this pharmacotherapy as an important standard 
of care. Following initiation of CS, a period of improvement in muscle strength is often observed. 
To control this potential source of variance, inclusion in this initial study will be restricted 
to patients who have been taking CS for at least 6 months, plan to continue CS for the duration 
of the double-blind phase of the clinical trial, and have not had a significant change in dose in the 
12 weeks preceding initiation of study treatment. 
Use of Translarna (Ataluren), Exon-Skipping Therapies, or Investigational Agents: 
Subjects receiving Translarna (ataluren), exon skipping therapies (e.g., Exondys51 [eteplirsen]), 
or investigational agents will not be eligible for this study. The magnitude and time course of 
treatment response to these agents in DMD is not well understood. Similarly, limited data are 
available regarding the safety and tolerability of investigational agents. These information gaps 
render controlling for potential effects of these drugs challenging and thus could complicate 
interpretation of the data emerging from this study. To avoid a potentially confounding impact of 
poorly understood effects of ataluren, patients receiving this treatment currently or within 
12 weeks prior to the start of study treatment will be excluded from participation. Patients receiving 
treatment with any (approved or investigational) exon skipping therapies within 6 months prior to 
the start of study treatment will also be excluded from participation. Treatment with deflazacort 
as part of CS dose-finding trials is allowed, as long as the patient has been on treatment 
for 6 months without significant dose changes 12 weeks prior to study start.  
Heart Failure: 
RO7239361 also binds to growth and differentiation factor-11 (GDF-11), which has been 
implicated in heart failure associated with aging in mice.41 However, this finding is controversial.42 
43 44 Although the mechanism underlying the development of aging-related re-modeling of the heart 
likely differs from that underlying the development of heart failure in DMD, potential cardiac 
effects of RO7239361 will be monitored in subjects enrolled in this study using echocardiography. 
Notably, there have been no cardiac findings in animals that received RO7239361 in completed or 
ongoing toxicology studies.  In order to clearly differentiate any potential effects of RO7239361 
on heart function from cardiac manifestations of disease progression, it is prudent to exclude 
patients with uncontrolled cardiac failure. It is requested that potential participants with ejection 
fraction < 55% at baseline be discussed with the Sponsor's Medical Monitor. 
Use of Growth Hormone or Androgens: 
Growth hormone may exert effects on cardiac morphology and function, while androgens may 
alter skeletal muscle function in boys with DMD.21,22 To avoid potential confounding effects of 
growth hormone and androgens on the endpoints being measured in this study, patients receiving 
these treatments currently or within 12 weeks or 5 half-lives (whichever is longer) prior to the start 
of study treatment will be excluded from participation. 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
40/Protocol WN40227, Version 4 
 
3.1.3 
Rationale for Primary Endpoint 
The primary endpoint for this study is the change from baseline in the NSAA total score at Week 48 
in RO7239361-treated participants compared with participants treated with placebo. The NSAA is 
a validated clinician-reported outcome instrument that has been widely used in clinical trials.  The 
instrument consists of 17 items designed to measure ambulatory function in boys with DMD. The 
instrument has a 3-point scale: 2="normal"no obvious modification of activity, 1=modified 
method but achieves goal independent of physical assistance from another, 0=unable to achieve 
independently. Therefore, higher scores represent greater functional abilities.47 
The NSAA has been demonstrated to have good inter-rater reliability and test−retest reliability.56 
The NSAA correlates with key disease progression milestones, such as losing the ability to rise 
independently from the floor (a decline in linearized score from 50 to 40 points), loss of ability to 
stand still (decline in linearized score from 21 to 11 points), and loss of ambulation.25,26 It has been 
reported that boys with DMD improve their motor function up to 7 years of age, as seen by an overall 
gain of 4 points/year in the linearized NSAA score, after which they start to decline an average of 8 
linearized units/year.25,26 However, because age alone cannot serve as a predictor of loss of 
ambulation, it has been reported that the estimated mean linearized NSAA score at 12 and 24 
months prior to loss of ambulation (i.e., at ages 12 and 11 years, respectively) is 34 and 42 units 
(approximately 9 and 13 on the raw scale, respectively).26 In addition, the NSAA has been 
demonstrated to have moderate to high construct validity based on the 6MWD, 57, 58 and it has 
been shown to detect change in an interventional setting.25 Unlike other functional tests, such as 
the 6MWD or the 4SC, NSAA is a more reliable and comprehensive scale that captures both motor 
strength and quality of movement, in addition to being less susceptible to external motivations. 
Moreover, while TFTs in DMD tend to remain stable until a point when they decline rapidly, the 
NSAA has been shown to decline more gradually. Thus, the NSAA is a reliable outcome measure 
to assess the efficacy of RO7239361 treatment in the study population. 
3.1.4 
Research Hypothesis 
The hypothesis for this study is that in ambulant patients with DMD: 
• 48 weeks of treatment with RO7239361, at either or both doses, will be generally safe and 
well tolerated and will result in improved NSAA total score relative to 48 weeks of placebo 
treatment. 
3.2 
Background 
A detailed description of the chemistry, pharmacology, efficacy, and safety of RO7239361 is 
provided in the Investigator Brochure. 
RO7239361 is expected to preserve and improve muscle strength primarily by increasing the size of 
existing muscle fibers. Several investigators have 
demonstrated 
that either genetic 
manipulation27,28,29 or pharmacologic treatments23,30,31,32,33 that reduce circulating myostatin 
produce increases in muscle mass and measures of strength and motor function in the mouse mdx 
model and the golden retriever model of DMD.34 Importantly, the relationship between myostatin 
reduction, increased muscle size, and increased muscle strength suggests that muscle volume 


 
Anti-Myostatin Adnectin, (RO7239361) —F. Hoffmann-La Roche Ltd 
41/Protocol WN40227, Version 4 
 
increases induced by this mechanism result in increased muscle function. In contrast, the 
pseudohypertrophic increases in muscle size observed in DMD reflect increases in non-contractile 
fat and fibrotic tissue within the muscle, and do not increase muscle strength.35 
RO7239361 has potential therapeutic utility for conditions such as DMD as well as other 
muscle-wasting diseases. 
A first-in-human combined single and multiple ascending dose (SAD/MAD) study in normal 
healthy volunteers (NHVs) with RO7239361 has been completed (CN001001).36 Data from this 
study indicate that single doses up to 180 mg and multiple weekly (Q1W) doses up to 180 mg and 
every-2-week doses of 45 mg RO7239361 are generally safe and well tolerated. PK data indicate 
that plasma concentrations of total RO7239361 (serum free RO7239361 plus RO7239361-
myostatin complex) increase in a dose-related fashion. Similarly, the extent and duration of 
serum free myostatin suppression increases in a dose-related fashion. Treatment with 5 weekly 
doses of 45 mg or more of RO7239361 was associated with increases in thigh muscle volume and 
total lean body mass in NHVs.  
A Phase 1b/2, multi-site, randomized, placebo-controlled multiple ascending SC dose study to 
evaluate the safety, tolerability and PK of RO7239361 in ambulatory boys with DMD is ongoing. 
Preliminary safety data from this study, which includes ambulatory boys with DMD, age ≥ 5 to 
< 11 years on stable CS treatment, suggest that RO7239361 is generally safe and well tolerated 
in this population. 
There are no identified risks to date related to RO7239361 administration. Anti-drug antibodies 
(ADAs) and mild or moderate injection-site reactions have been observed in studies of healthy 
adults and patients with DMD. The presence of ADAs did not appear to impact the safety or 
exposure of RO7239361.  
RO7239361 also recognizes growth and differentiation factor-11 (GDF-11), which is 
hypothesized to play roles in inducing mesoderm in early development and in anterior-posterior 
patterning of axial skeleton.37,38,39,40 GDF-11 has also been implicated in heart failure associated 
with aging in mice.41 However, this finding is controversial.42 43 44 While the mechanism 
underlying the development of aging related re-modeling of the heart likely differs from that 
underlying the development of heart failure in DMD, potential cardiac effects of RO7239361 will 
be monitored in this trial using echocardiography. Notably, there have been no cardiac findings in 
animals that received RO7239361 in the completed or ongoing toxicology studies. No clinically 
significant treatment-related changes in ECG or echocardiogram parameters have been observed in 
RO7239361-treated patients with DMD to date. 
Potential risks include hypersensitivity reactions, injection-site reactions, immunogenicity, and 
findings from nonclinical studies or observations with the use of other anti-myostatin agents. These 
potential risks are described in the current Investigator Brochure.45 Appropriate clinical 
monitoring will be implemented in all clinical studies. An independent Data Monitoring 
Committee (iDMC) will review data at intervals specified in the iDMC charter. 


 
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3.3 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of RO7239361 may be found in the Investigator Brochure. 
The potential benefits of treatment with RO7239361 have not been established. 
RO7239361 has been tested in animals including rats and monkeys. Serum aminotransferase 
elevations were observed in rats given RO7239361 for 6 months. However, these elevations were 
not associated with microscopic evidence of liver or skeletal muscle damage and the animals did 
not experience muscle weakness. In monkeys that received RO7239361 for 6 months there were 
no serum transaminase elevations even though systemic exposures were approximately 4× higher 
than in rats. 
Taken together, the serum transaminase increases seen in rats in the 6-month study suggest a time- 
dependent finding that is likely rat specific. Regardless, potential hepatotoxicity will be assessed 
by monitoring of aminotransferases and bilirubin in serum and evaluations of clinical signs and 
symptoms. The hepatocyte-specific markers GGT and GLDH will also be monitored. 
In some animals treated with RO7239361 a small decrease in the IgG antibody response to 
primary immunization was observed. IgM antibody responses to primary immunization were not 
decreased in treated animals. Neither IgG nor IgM antibody responses were decreased in response 
to subsequent (booster) immunizations in those animals tested. Given the small size of the decrease 
in the IgG response to primary immunization and lack of effect of RO7239361 treatment on IgM 
response or IgG response to booster, any potential effect of RO7239361 treatment on efficacy of 
immunization in humans is expected to be minimal. Caregivers should be advised to ensure that 
their child’s immunizations are up to date prior to receiving study drug. 
Among healthy adult humans who received RO7239361 in study CN001001, the most common 
AEs were mild or moderate injection-site erythema. These AEs did not require cessation of study 
drug and were not accompanied by systemic signs or symptoms, such as fever or eosinophilia. In 
Study CN001001, 45.2% of SAD phase participants developed ADAs at some point during the 
study, while 27.8% of MAD phase participants developed ADAs. Presence of ADAs did not 
appear to impact exposure to RO7239361. Most subjects with injection-site or other skin 
reactions were ADA titer negative suggesting a lack of relationship between the presence of 
ADAs and risk for cutaneous AEs. 
A Phase 1b/2 study of RO7239361 in ambulatory boys with DMD (WN40226) is ongoing. 
Safety data from the completed double-blind and 48-week OL phases of this study suggest that 
RO7239361 is generally safe and well tolerated in this population. The most common related AEs 
were mild or moderate injection-site reactions that resolved without change to study treatment. 
Immunogenicity data from 43 patients showed a single value of low positive ADA titer in 1 patient 
who had received RO7239361. 
All participants who are administered study drug will be closely monitored for possible 
immunogenicity-related AEs, such as rash, fever, and injection-site reactions. Clinically relevant 
immune reactions (e.g., hypersensitivity reactions) will be reported as AEs and treated according to 


 
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current standard of care medical practice. If present, antibodies will be assessed for neutralizing 
activity by assessment of serum free myostatin levels and a neutralizing antibody (NAB) assay. 
Subjects completing clinical trials of RO7239361 who do not enter the Open Label Extension 
phase will enter the follow-up phase of the study. Subjects who enter the follow-up phase will 
undergo ADA monitoring during the follow-up visits, which will occur at regular intervals for 
24 weeks. Injection sites will be rotated and inspected regularly. Injection sites will be monitored 
from Day 1 through the end of the study. 
Hypersensitivity or acute allergic reactions may occur as a result of the biologic nature of 
RO7239361. As of 8 February 2018, no subject receiving RO7239361 has developed an acute 
hypersensitivity reaction associated with study drug. Although the risk of a subject developing 
an acute hypersensitivity reaction to RO7239361 is considered low, sites should be prepared to 
manage possible acute hypersensitivity reactions to initial doses of RO7239361 following accepted 
standards of medical care. Qualified personnel should administer or supervise the administration 
by the caregiver of the first 3 weekly SC doses of RO7239361, and appropriate emergency 
equipment should be available in the event of a serious anaphylactic reaction. Participants and their 
parents/caregivers will be provided with emergency contact information by the site. Participants 
and their parents/caregivers will be instructed to recognize any signs and symptoms of 
hypersensitivity reaction and for the need to seek emergency medical care in case of an extreme 
reaction.  
 
 
 


 
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4 
OBJECTIVES AND ENDPOINTS 
 
Table 4-1: 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To compare the efficacy of RO7239361 to 
placebo in ambulatory boys with Duchenne 
muscular dystrophy 
• 
The change from baseline in the North Star 
Ambulatory Assessment (NSAA) total score 
at Week 48 in RO7239361-treated 
participants compared to placebo-treated 
participants 
Secondary 
• 
To compare the efficacy of RO7239361 to placebo 
using the following tests: 
− 
4 Stair Climb Velocity 
− 
Stand from supine velocity 
− 
10 M walk/run velocity 
− 
PODCI transfers and basic mobility subscale 
− 
Proximal 
lower 
extremity 
flexor 
(knee 
extension and knee flexion) strength, measured 
using manual myometry 
− 
6 Minute Walk Distance (6MWD)  
− 
Clinical Global Impression of Change 
(CGI-C) 
− 
Stride velocity, as recorded by the 
ActiMyo device 
• To assess the safety and tolerability of RO7239361 in 
boys with DMD as reflected by new or worsening lab 
abnormalities (as defined by CTCAE criteria), 
serious adverse events (SAEs) and adverse events 
(AEs) leading to discontinuation 
• 
Change 
from 
baseline 
at 
Week 
48 
in 
RO7239361-treated 
participants 
compared 
to 
placebo-treated participants in: 
– 
4 Stair Climb Velocity 
– 
Stand from supine velocity 
– 
10 M walk/run velocity 
– 
PODCI transfers and basic mobility subscale 
– 
Proximal lower extremity flexor (knee extension 
and knee flexion) strength, measured using 
manual myometry 
– 
6 Minute Walk Distance (6MWD) 
– 
Clinical Global Impression of Change 
(CGI-C) 
– 
95th percentile stride velocity, as recorded with 
the ActiMyo device in a subset of the overall 
study population 
• 
Tabulations of the numbers of unique participants 
with new or worsening laboratory abnormalities, 
SAEs and AEs leading to discontinuation, in 
RO7239361 arms compared to the placebo arm 
 


 
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Tertiary/Exploratory 
• 
To assess the safety and tolerability of RO7239361 in 
boys with DMD as reflected by vital signs, 
measures of cardiac function. 
• 
To compare the efficacy of RO7239361 to placebo 
using the following tests: 
- Performance of upper limb (PUL) total score 
 
• 
To evaluate other measures of efficacy, quality of life, 
and health care utilization 
• 
Summaries and listings of vital signs, ECG 
parameters, echocardiogram parameters. 
− 
Proportion of participants with on treatment 
adverse events in RO7239361 arms 
compared to the placebo arm 
– 
Proportion of participants with on treatment 
decrease in ejection fraction (EF), measured 
using echocardiography, in RO7239361 
arms compared to the placebo arm 
• Change from baseline at Week 48 in RO7239361 
treated participants relative to placebo treated 
participants in: 
– Performance of upper limb (PUL) total score 
 
• 
Change from baseline at Week 48 in RO7239361 
treated participants compared to placebo treated 
participants: 
− 
Pulmonary Function Tests, including forced 
vital capacity (FVC) % predicted, forced vital 
capacity (FVC), forced expiratory volume in 
1 second (FEV1), maximal expiratory pressure 
(MEP), maximal inspiratory pressure (MIP). 
− 
PODCI total score 
− 
Caregiver Global Impression of Change  
(CaGI-C) in a subset of the overall study 
population at selected sites 
− 
Pediatric Quality of Life Inventory 
Multidimensional Fatigue Scale (PedsQL 
MFS) in a subset of the overall study 
population 
− 
Cardiac magnetic resonance imaging (cMRI) 
measures of ejection fraction, fractional strain, 
and volume of fibrosis in a subset of the 
overall study population 
− 
Strength of elbow flexors, elbow extensors, and 
pinch, measured by manual myometry 
− 
Health Utilities Index III and PedsQL Family 
Impact Module scores 
− 
Dual x-ray absorptiometry (DXA) measures 
of lean body mass, fat mass, and bone mineral 
density 
 
 


 
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Table 4-1: 
Objectives and Endpoints 
 
Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To 
evaluate 
RO7239361 
pharmacokinetics, 
pharmacodynamics, and immunogenicity 
• 
Assessments at selected timepoints during the 
study of: 
− 
Activity levels in a subset of the overall 
study population, as recorded with 
ActiMyo 
− 
Scoring of functional assessments, as recorded 
by a subset of parents/caregivers participating 
in the caregiver video assessment at selected 
sites  
− 
Number of falls while on treatment in 
RO7239361 arms compared with the placebo 
arm 
• 
Assessments at select timepoints during the study 
of: 
− 
Serum RO7239361 concentrations 
− 
Serum free myostatin and myostatin drug 
complex concentrations 
− 
Serum ADA concentrations 
− 
Serum creatine kinase level in muscle 
 
 
 


 
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Table 4-1: 
Objectives and Endpoints 
 
Objectives 
Endpoints 
• 
To explore the effect of genetic variation on target 
engagement, pharmacodynamic (PD) effects or 
functional test endpoints 
• 
Assess the impact on genetic variation in the 
DYSTROPHIN gene or in genes suspected to impact 
DMD disease expression (including but not limited 
to LTBP4, SPP1) in RO7239361- and 
placebo-treated participants, on target engagement, 
pharmacodynamic (PD) and functional endpoints 
5 
STUDY DESIGN 
5.1 
Overall Design 
This is a multi-center, randomized, double-blind, placebo-controlled study to assess the efficacy, 
safety and tolerability of two different weekly SC doses of RO7239361 in ambulatory boys with 
Duchenne muscular dystrophy (DMD). 
Eligible participants will be randomized to receive doses of RO7239361 or placebo (1:1:1 across 
the three treatment arms). The randomization will be stratified by: 
• Age (6 through 7 and 8 through 11) 
• CS regimen: daily (prednisone, prednisolone or deflazacort) vs intermittent (any non-daily 
dosing of prednisone, prednisolone or deflazacort) 
 
A separate randomization will be conducted for Japan (N∼15) with stratification for age only 
(6 through 7 and 8 through 11), not CS regimen. 
RO7239361 or placebo will be administered weekly. The first three doses (Days 1, 8 and 15) of 
study drug must be administered at the site. Parents/caregivers will be trained to administer SC 
injections during the first three dose administrations. Parents/caregivers who are comfortable with 
SC administration can administer the injection at home starting at Day 22. Parents/caregivers will 
be dispensed an approximately 6 week supply of drug in pre-filled syringes (RO7239361 or 
matching placebo) for weekly study drug/placebo administration to the participant. 
After completion of this 48-week double-blind phase, participants may enter the OL phase in 
which all participants will receive active RO7239361 study drug. Participants originally 
randomized to active drug will continue to receive the dose to which they were originally 
randomized. Participants originally randomized to placebo will be randomized to the high or low 
dose of RO7239361 on Day 1 of the OL phase. Dose assignment in the OL phase may be 
modified based upon emerging safety findings. Subjects entering the OL phase will remain 
blinded to their original dose assignment. Participants who discontinue study treatment at any 
timepoint (i.e., early discontinuation for patients who do not enter the OL phase or at termination 
of the OL phase) will enter the follow-up phase of the study. The follow-up phase of the study is 
24 weeks. Participants will be monitored for safety at three visits in the follow-up phase. 
Participants should provide immunogenicity samples at all follow-up visits. 
The study design schematic is presented in Figure 5.1-1. 


 
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Figure 5.1-1: 
Study Design Schematic 
 
OL=open label; SC=subcutaneous. 
Study visits and endpoint measurements will occur as indicated in Table 2-1 through Table 2-4. 
5.1.1 
Independent Data Monitoring Committee and Other External Committees 
There will be an iDMC for this study. The iDMC scope, frequency of review, membership, 
activities and other specifications are detailed in the iDMC charter. 
The iDMC shall have access to partially unblinded data (coded treatment assignments) including 
but not limited to the following: the frequency and spectrum of SAEs; Grades 3 to 4 laboratory 
abnormalities; occurrence of malignancies, if any; and other select AEs of interest. The iDMC 
shall also review aggregate data results from any interim analyses performed prior to the end of 
the double-blind treatment period. The iDMC shall have the right to request full unblinding of 
the data (codes will be decoded to reveal actual treatment assignments). The iDMC shall act as 
an advisor to the sponsor and have responsibility for safeguarding the subjects’ interests. The 
iDMC shall bring any safety concerns to the attention of the sponsor so that the sponsor can review 
the data and prepare appropriate communications to the Regulatory Authorities. 


 
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5.2 
Number of Participants 
A total of approximately n=159 participants randomized will provide for slightly more than 
80% power at the primary analysis. This allows for roughly a 5% dropout rate by Week 48. 
Some of the details behind sample size calculations are in Section 10.1. 
5.3 
End of Study Definition 
The start of the trial is defined as the first visit for the first participant screened. End of trial is 
defined as the last visit or scheduled procedure shown in the Schedule of Activities for the last 
participant.  
5.4 
Scientific Rationale for Study Design 
See Section 3.1 
5.5 
Justification for Dose 
See Section 3.1.1 
6 
STUDY POPULATION 
For entry into the study, the following criteria MUST be met. 
6.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
a) Prior to study participation, written informed consent from subjects, and in the case of 
minors, written permission (informed consent) also from parents, guardians, or legally 
acceptable representatives must be obtained according to local laws and regulations. 
b) Assent from minor subjects should be obtained per local laws and regulations and should 
be documented in accordance with local requirements. 
 
2) Type of Participant and Target Disease Characteristics 
a) Males, ≥ 6 to < 12 years of age at time of randomization 
b) Diagnosis of DMD, confirmed by medical history (e.g., onset of clinical signs or 
symptoms before 5 years of age together with an elevated serum creatine kinase level 
observed before or after initial diagnosis) and by genotyping 
c) Participants ≥ 15 kg 
d) Ambulatory without assistance 
e) Participants must be receiving corticosteroids (prednisone, prednisolone, or deflazacort) 
for at least 6 months prior to the start of study drug, with no significant change in dosage 
(> 0.2 mg/kg prednisone or > 0.24 mg/kg deflazacort) or dosing regimen for at least 12 
weeks prior to the start of study drug, with the expectation that dosage and dosing regimen 
will not change significantly for the duration of the study. 
f) NSAA score ≥ 15 points at screening 
g) 4SC ≤ 8 seconds at screening 
h) Subjects must agree to avoid major changes in their physical or respiratory therapy regimen 
during the double-blind phase, to the extent possible 


 
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3) Age and Reproductive Status 
a) Males, ≥ 6 to < 12 years on day of randomization 
b) Subjects who are sexually active must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study treatment(s) plus 5 half-lives of the 
study treatment [RO7239361; 50 days] plus 90 days (duration of sperm turnover) for 
a total of 140 days (5 months) post-treatment completion. 
c) Azoospermic subjects are exempt from contraceptive requirements. 
d) Subjects must be willing to refrain from sperm donation during the entire study and for 5 
half-lives of study treatment plus 90 days (duration of sperm turnover) 140 days after 
dosing has been completed. 
 
Investigators shall provide appropriate and patient-centered counseling of adolescent trial subjects 
who are sexually active with WOCBP on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. Investigators shall advise subjects who are sexually 
active with WOCBP on the use of highly effective methods of contraception in non-pregnant 
partner (Appendix 4), and on the use of condom in subjects with a pregnant partner. Highly 
effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. 
6.2 
Exclusion Criteria 
1) Medical Conditions 
a) Participants with cognitive impairment or behavioral issues that, in the judgement of the 
investigator, will compromise their ability to comply with study procedures. 
b) Participants with a FVC of < 50% of predicted value (in participants able to produce a valid 
FVC, as judged by the clinical evaluator or respiratory therapist) 
c) Cutaneous AEs sustained during participation in a prior clinical trial that resolved less than 
12 weeks prior to the start of study drug administration. 
d) History of lower limb fracture within 12 weeks prior to the start of study drug 
administration. 
e) History of upper limb fracture within 8 weeks prior to the start of study drug 
administration. 
f) Any injury that may impact functional testing. Previous injuries must be fully healed 
prior to consenting. 
g) Expectation of major surgical procedure, such as scoliosis surgery, during the double-blind 
phase of this study. 
h) Requirement of daytime ventilator assistance 
i) Initiation of nighttime ventilation less than 4 weeks prior to the start of study drug 
administration 
j) Expectation that daytime or nighttime ventilation may be initiated during the double-blind 
phase of this study. 
k) Clinical signs or symptoms of uncontrolled congestive heart failure (American College of 


 
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Cardiology/American Heart Associated Stage C or Stage D) 
l) For participants participating in cMRI substudy: implanted ferromagnetic metal (implanted 
metal that is not ferromagnetic, such as surgical steel or titanium implants may be allowed 
if the implants will not compromise the quality of the cMRI)  
2) Prior/Concomitant Therapy 
a) Any change (initiation, change in drug class, dose modification unrelated to change in body 
weight, interruption or re-initiation) in prophylaxis/treatment for CHF within 12 weeks 
prior to start of study treatment 
b) Any change (initiation, change in drug class, dose modification unrelated to change in body 
weight, interruption or re-initiation) in prophylaxis/treatment for bone density within 
12 weeks prior to start of study treatment 
c) Participants on intermittent CS regimens with off periods of 20 days or longer (e.g., 
10 days on, 20 days off) 
d) Treatment with exon skipping therapies within 6 months prior to the start of study drug 
administration. 
e) Treatment with ataluren currently or within 12 weeks prior to the start of study drug 
administration 
f) Treatment with any other investigational drug (excluding deflazacort in CS dose-finding 
trials) currently or within 12 weeks prior to the start of study drug administration 
g) Current or prior treatment within 12 weeks prior to the start of study drug administration 
with androgens or human growth hormone. 
h) Concurrent or previous participation at any time in a gene therapy study 
i) Prior treatment with RO7239361 or any other anti-myostatin agent 
3) Physical and Laboratory Test Findings 
a) Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECG or clinical laboratory determinations beyond what 
is consistent with the target population 
4) Allergies and Adverse Drug Reaction 
a) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity) 
b) History of hypersensitivity to components of the study drug (histidine, trehalose, 
diethylenetriaminepentaacetic acid, polysorbate 80) 
5) Other Exclusion Criteria 
a) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness 
b) Unwilling or unable to administer study drug at home 
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria. 


 
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6.3 
Lifestyle Restrictions 
Not applicable  
6.3.1 
Meals and Dietary Restrictions 
Not applicable 
6.3.2 
Caffeine, Alcohol and Tobacco 
Not applicable 
6.3.3 
Activity 
Not applicable 
6.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs. 
6.4.1 
Rescreening and Retesting during Screening Period 
Participant re-screening: This study permits one-time re-screening of a participant once that 
participant has discontinued the study as a screen failure (i.e., participant has not been 
randomized). Laboratory testing that is repeated because of administrative or technical issues 
(e.g., breakage of a sample vial during transit to the central laboratory or degradation of a 
sample during transportation) is not considered to be rescreening. If re-screened, the participant 
must be re-consented.  
Retesting of laboratory parameters and/or other assessments within any single screening or 
lead-in period will be permitted (in addition to any parameters that require a confirmatory value). 
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state. 
Screening Procedural Outline may be repeated in an effort to find all possible well-qualified 
participants. Consultation with the Medical Monitor may be needed to identify whether repeat 
testing of any particular parameter is clinically relevant. 
7 
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation 
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following: 
• All products, active or placebo, being tested or used as a comparator in a clinical trial 


 
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• Study required premedication 
• Other drugs administered as part of the study that are critical to claims of efficacy 
(e.g., background therapy, rescue medications) 
• Diagnostic agents: (e.g., glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection. 
 
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 
In this protocol, the investigational product is RO7239361 (previously, BMS-986089) 
solution for injection and matching placebo solution for injection, dispensed in pre-filled syringes. 
Other medications used as support medication for preventative, diagnostic, or therapeutic reasons, 
as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. In this study, CS are considered non-investigational product and will 
not be provided by the sponsor. 


 
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Table 7-1: 
Study Treatments 
Product Description 
/Class and Dosage 
Form 
Potency 
IP/Non- 
IMP 
Blinded or Open Label 
Packaging / Appearance 
Storage Conditions  
(per label) 
RO7239361 
injection 
7.5 mg/syringe 
10.7 mg/mL 
IP 
Blinded (during the 
48-week double-blind 
phase) and Open Label 
(during the  
192-week OL phase) 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect from 
light, protect from freezing 
RO7239361 
injection 
15 mg/syringe 
21.4 mg/mL 
IP 
Blinded (during the 
48-week double-blind 
phase) and Open Label 
(during the 192-week OL 
phase) 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect 
from light, protect from 
freezing 
RO7239361 
injection 
35 mg/syringe 
50 mg/mL 
IP 
Blinded (during the 
48-week double-blind 
phase) and Open Label 
(during the 192-week OL 
phase) 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect 
from light, protect from 
freezing 
RO7239361 
injection 
50 mg/syringe 
71.4 mg/mL 
IP 
Blinded (during the 
48-week double-blind 
phase) and Open Label 
(during the 192-week OL 
phase) 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect 
from light, protect from 
freezing 
Placebo for 
RO7239361 
injection 
0 mg/mL 
IP 
Blinded 
Solution packaged in a 1 cc glass 
syringe equipped with a safety syringe 
device 
Secondary packaging is either a  
1 syringe carton or 4 syringe carton 
2-8° C (36-46° F), protect 
from light, protect from 
freezing 
 


 
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Oral CS will be obtained by standard prescribing procedures. 
7.1 
Treatments Administered 
The selection and timing of dose for each participant is as follows: 
 
Table 7.1-1: 
Selection and Timing of Dose 
 
Study Treatment 
Unit dose 
strength(s)/Dosage 
level(s) 
Dosage formulation 
Frequency of 
Administration 
Route of Administration 
RO7239361 
injection 
7.5 mg, 15 mg, 35 mg, 
or 50 mg syringe 
Weekly 
SC 
Placebo for 
RO7239361 
injection 
0mg syringe 
Weekly 
SC 
 
 
Table 7.1-2: 
Dose Level 1, targeting moderate level of suppression: (≥ 70% 
suppression at trough) 
 
Dose Level 
Body Weight tier 
Body Weight range 
Dose 
1 
1 
≥ 15 to ≤ 40 kg 
7.5 mg QW 
1 
2 
> 40 kg 
15.0 mg QW 
 
 
Table 7.1-3: 
Dose Level 2, targeting high level of suppression: (90% suppression 
at trough) 
 
Dose Level 
Body Weight tier 
Body Weight range 
Dose 
2 
1 
≥ 15 to ≤ 40 kg 
35 mg QW 
2 
2 
> 40 kg 
50 mg QW 
 
RO7239361 or placebo will be administered as a SC injection in the abdomen, thigh, or the back of 
the upper arm. Injection sites should be rotated according to the "instruction for use" (IFU).  
Refer to the current version of the IB for PK and safety data) following single-dose administration 
across these injection sites in healthy subjects (Study WP40225) and for details on the 
recommended storage and use conditions for the PFS. 
Refer to current version of the IB for details on the recommended storage of and use conditions for 
the PFS. Do not use the PFS after the labeled expiry date. 
Subjects whose weight exceeds or drops below the dosing weight tier to which they were assigned 
by > 2 kg (confirmed by repeat) should receive the new weight-based dose in the subject’s assigned 
dose level. 


 
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7.2 
Method of Treatment Assignment 
Subjects will be randomized to receive either low or high dose of RO7239361 or placebo 
according to a computer-generated randomization scheme.  
During the screening visit the investigative site will enter into the enrollment option of the 
Interactive Web Response System (IWRS) designated by Roche for assignment of a 5-digit subject 
number that will be unique across all sites. Enrolled subjects, including those not dosed, will be 
assigned sequential subject numbers starting with 
 (e.g., 
).
 
 
 
 Once it is determined that the subject meets the eligibility criteria following 
the screening visit, the investigative site will enter into the IWRS to randomize the subject into 
the open dose panel. 
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
7.3 
Blinding 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of the 
investigational product is critical to the participant's management, the blind for that participant 
may be broken by the investigator. The participant’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unblinded. 
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, i.e., that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the participant 
is receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the participant has been made. 
In case of an emergency, the investigator(s) has unrestricted access to randomization information 
via the Interactive Web Response System (IWRS) and is capable of breaking the blind through the 
IWRS system without prior approval from sponsor. Following the unblinding the Investigator shall 
notify the medical monitor and/or study director. 
In cases of accidental unblinding, contact the medical monitor and ensure every attempt is made 
to preserve the blind. 
Any request to unblind a subject for non-emergency purposes should be discussed with the medical 
monitor. 
As this is a placebo-controlled, double-blind study, all efforts must be maintained by site staff, 
subjects and caregivers in not making any assumptions on potential treatment assignments based 
on clinical presentations. 


 
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The randomization assignments will be released to the study sites by the final study report 
generated for the study. 
7.4 
Dosage Modification 
Dose modifications are not allowed. 
7.5 
Preparation/Handling/Storage/Accountability 
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by Roche. 
If concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and contact Roche immediately. 
Study treatment not supplied by Roche will be stored in accordance with the package insert. 
Investigational product documentation (whether supplied by Roche or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets). 
Study drug will be administered in the clinical facility or off-site by the parent/caregiver. The 
parent/caregiver may administer study drug on or after the Day 22 dose and once trained and 
comfortable with SC injections of study drug/placebo. For any dose administered at the clinical 
facility, the dose and location of each SC injection must be recorded in the source record. 
For any dose administered off-site (off-site dosing allowed starting on Day 22 of double-blind 
phase and at Week 4 of the OL phase), the parents/caregivers must be trained on proper 
administration of study drug. The site staff will be provided with a pharmacy manual that includes 
parent/caregiver training guidance and a training checklist. The parents/caregivers will be provided 
with IFU on administration of study drug. The subjects and parents/caregivers will be provided 
with a dosing diary to record administration of study drug and be instructed to record the location, 
time, date, etc. of each SC injection. Parents/caregivers must be instructed to bring the used and/or 
empty syringes in a Sharps container and the dosing diary to each study visit; this will allow site 
staff to assess treatment compliance and study drug accountability. A diary will also be provided 
to the parent/caregiver to record the subject’s CS therapy, AEs, concomitant medicines, and 
falls. Study drug must be transported to and from the site in a cooler with an ice pack to maintain 
the appropriate storage temperature. If approved by the local IRB/EC, the cooler and ice pack for 
study drug transport will be provided by the Sponsor or designee. 
Parents/caregivers must be instructed by the site staff on sharps handling procedures. 
Parents/caregivers should be instructed to return the sharps container to the study site for proper 
disposal. 
• Further guidance and information for final disposition of unused study treatment are provided 


 
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in Appendix 2 and the pharmacy manual. 
7.5.1 
Retained Samples for Bioavailability/Bioequivalence 
Not applicable. 
7.6 
Treatment Compliance 
Study treatment compliance will be monitored by review of dosing diary cards. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. Sites should discuss discrepancies with the participant at each on-treatment study 
visit.   
Any overdose or incorrect administration of study drug should be reported as an adverse event and 
recorded on the Adverse Event electronic Case Report Form (eCRF), and the Medical Monitor 
should be informed.  
7.7 
Concomitant Therapy 
7.7.1 
Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration in the study are 
described below. Medications taken within 4 weeks prior to study drug administration must be 
recorded on the CRF. Prior therapies to treat DMD, including CS, should be reported on the 
CRF, regardless of when the prior therapy was administered. Routine standard of care 
immunizations should be maintained throughout the study. 
Experimental medications to treat DMD may be permitted during the OL phase. This will be 
dependent upon results from the double-blind phase. 
1) Prior exposure to RO7239361 or any other anti-myostatin agent. 
2) Treatment with ataluren within 12 weeks prior to the start of study drug administration.  
3) Treatment with any other investigational drug (excluding deflazacort in CS dose-finding 
trials) currently or within 5 half-lives prior to the start of study drug administration. If the 
half-life of the prior treatment is unknown, the investigator must consult with the Roche 
medical monitor to determine the washout duration. 
4) Treatment with exon skipping therapies within 6 months prior to the start of study drug 
administration 
5) Current or prior treatment within 12 weeks of study drug administration with androgens or 
human growth hormone. 
6) Concomitant or previous participation at any time in a gene therapy study. 
7) Use of any other drugs, including over-the-counter medications and herbal preparations, within 
1 week prior to start of study drug administration or during study participation except those 
medications cleared by the Roche medical monitor. 
Any concomitant therapies must be recorded on the CRF. 


 
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7.7.2 
Other Restrictions and Precautions 
7.7.2.1 
Management of Possible Acute Hypersensitivity Reactions to 
RO7239361 
Hypersensitivity or acute allergic reactions may occur as a result of the biologic nature of 
RO7239361. Qualified personnel should administer the first three weekly SC doses of 
RO7239361 during both the double-blind phase and during the OL phase, and appropriate 
emergency equipment should be available in the event of a serious anaphylactic reaction. For the 
first three weekly doses of both the double-blind and OL phases, subjects should remain on site for 
3 hours after drug administration for observation. Subjects and the parents/caregivers will be 
provided with emergency contact information by the site. Subjects and the parents/caregivers will 
be instructed to go to their local emergency care facility in case of an extreme reaction. 
The following information is provided to assist in the recognition of hypersensitivity reactions and 
in the management of those reactions should they occur during or after the administration of 
RO7239361. Care should be taken to treat any acute toxicity expeditiously, should it occur. When 
dosing RO7239361, equipment such as a portable tank or wall-source of oxygen, endotracheal 
intubation set, oral airway, mask, ambu-bag, syringes, injectable epinephrine, injectable 
antihistamine, and injectable glucocorticosteriods should be kept in the vicinity where the subject 
is dosed (for the first three weekly doses). 
Signs of potential acute hypersensitivity reactions include symptomatic hypotension; dyspnea; 
acute pain the chest, back or extremities/or chills, fever, urticaria; or generalized erythema. 
Clinically relevant hypersensitivity reactions will be reported as AEs and treated according to 
current standard of care medical practice. Management is as follows: 
Symptomatic Hypotension: Place subject in the Trendelenburg position and administer 
intravenous fluid. Additional medical intervention may also include the use of epinephrine, 
glucocorticosteroids, antihistamines and pressor agents. 
Dyspnea: Observe the subject for worsening of the event and for the appearance of additional 
signs and symptoms of anaphylaxis. Antihistamines, epinephrine, and glucocorticosteroids may be 
administered as indicated. 
Acute Pain in the Chest, Back or Extremities: Observe subject for worsening of the event and 
for the appearance of additional signs and symptoms of anaphylaxis. Antihistamines, epinephrine, 
and glucocorticosteroids may be administered as indicated. 
Chills, Fever, Urticaria or Generalized Erythema: Treat these possible signs and symptoms of 
an allergic reaction to biologic products with acetaminophen and antihistamines. 
The decision whether to continue the subject in the study will be made by the investigator, in 
consultation with the Roche medical monitor. 
7.7.2.2 
Imaging Restriction and Precautions 
The Principal Investigator and/or the imaging specialist at the study site imaging facility is 
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specified in the time and events schedule (Table 2-2 and Table 2-3). Imaging contraindications 
and risks should be considered. 
The ultimate decision to perform the imaging should rest with the site radiologist, the investigator, 
and the standard set by the local Ethics Committee. 
7.8 
Treatment after the End of the Study 
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive Roche-supplied study treatment. Study treatment will be provided via an 
extension of the study, a rollover study requiring approval by responsible health authority and 
ethics committee or through another mechanism at the discretion of Roche and according to local 
legislation.  
Roche reserves the right to terminate access to Roche-supplied study treatment if any of the 
following occur: a) the study is terminated due to safety concerns; b) the development of 
RO7239361 is terminated for other reasons, including but not limited to lack of efficacy and/or 
not meeting the study objectives; c) the participant can obtain medication commercially, from a 
government-sponsored program, or from a private health program. In all cases, Roche will follow 
local regulations. 
8 
DISCONTINUATION CRITERIA 
Clinical Criteria for Dose Discontinuation: 
• Dosing may be stopped until safety information can be reviewed in the event that: 
− Two (2) or more subjects experience the same severe or very severe AE that is 
considered related to RO7239361 
• Dosing will be paused within a subject until safety information is reviewed and drug induced 
liver injury (DILI) is ruled out in the event that: 
− ALT > 5 x baseline AND no corresponding increase in CPK to indicate muscle origin as 
the reason for the increase in ALT 
OR 
 
− ALT > 10 x ULN AND ALT > 2 x baseline AND no corresponding increase in CPK to 
indicate muscle origin as the reason for the increase in ALT 
OR 
− Total bilirubin > 2 x ULN 
OR 
− Symptoms or signs of hepatic inflammation such as nausea, vomiting, right upper quadrant 
pain or tenderness with no other immediately apparent possible cause of these symptoms 
or signs, such as viral gastroenteritis or constipation. 
 
In addition to the above stopping rules, dosing may be paused or halted within a subject if a review 
of safety and tolerability data, or the clinical judgment of the investigator, suggest the emergence 
of a new potentially serious safety signal, including DILI. 


 
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The following categories and definitions of intensity as determined by a physician should be used 
for assessing the severity of AEs: 
• Mild (Grade 1) - Awareness of event but easily tolerated 
• Moderate (Grade 2) - Discomfort enough to cause some interference with usual activity 
• Severe (Grade 3) - Inability to carry out usual activity 
• Very Severe (Grade 4) - Debilitating, significantly incapacitates subject despite symptomatic 
therapy 
Dosing may not be resumed until a thorough review of safety and tolerability data has been 
completed and the Roche medical monitor, Roche pharmacovigilance representative, and the 
investigators agree that it is safe to proceed. 
Any subject meeting the above stopping criteria or otherwise removed from the study for abnormal 
laboratory, or echocardiogram will be followed until their abnormal laboratory result and/or 
echocardiogram values return to baseline. Subjects who discontinue early should enter the 
post-treatment follow-up phase of the study for this follow-up. 
8.1 
Discontinuation from Study Treatment 
Participants MUST immediately discontinue investigational product (and non-investigational 
product at the discretion of the investigator) for any of the following reasons:  
• Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information 
• Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant 
• Termination of the study by Roche 
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness 
• Unblinding a subject for any reason (emergency or non-emergency) 
• Inability to comply with protocol 
• Discretion of the investigator 
 
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed 
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either 
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If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate eCRF. 
8.1.1 
Post Study Treatment Study Follow-up 
In this study, safety and the NSAA are key endpoints of the study. Post study follow-up is of 
critical importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed for collection of 
outcome and/or survival follow-up data as required and in line with Section 5 until death or the 
conclusion of the study. There will be follow-up visits up to 24 weeks after the last dose of study 
drug (Table 2-4) 
8.2 
Discontinuation from the Study 
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures (Table 2-4). The only exception to this 
is when a participant specifically withdraws consent for any further contact with him/her or 
persons previously authorized by participant to provide this information. 
• Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible. 
• The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page. 
• In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
8.3 
Lost to Follow-Up 
• All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant. 
• Lost to follow-up is defined by the inability to reach the participant after a minimum of three 
documented phone calls, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records. 
• If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death. 
• The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. 
• If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records. 


 
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9 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and timing are summarized in the Schedule of Activities (Table 2-1, 
Table 2-2, Table 2-3, and Table 2-4). 
• Protocol waivers or exemptions are not allowed. 
• All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment. 
• Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
9.1 
Efficacy Assessments 
9.1.1 
Functional Endpoint Assessment 
Measurements of function will be assessed at the timepoints specified in Table 2-1 through Table 
2-4 and include the following:  
• TFTs (4SC, 10 m walk/run, stand from supine)  
• 6 minute walk distance (6MWD)  
• NSAA scale  
• Performance of Upper Limb Scale (PUL)  
Detailed instructions for performing each of these assessments are provided in the Clinical 
Evaluator (CE) Manual. Functional endpoints will be measured by a clinical evaluator who 
has undergone study specific training on the administration of these assessments. The clinical 
evaluators who assess functional endpoints must be distinct from the clinicians who assess AEs of 
the study subjects. To ensure that clinical evaluators remain blind to study drug assignment, 
clinicians evaluating AEs should not communicate the presence, absence or severity of AEs with 
clinical evaluators at the site unless such communication is required to ensure subject safety. 
TFTs include 4SC, 10-meter walk/run and stand from supine. The 6MWD measures the distance 
a patient is able to traverse while walking for 6 minutes. TFTs, such as the 4SC and the 6MWD, 
are well validated and have been widely used in clinical trials.19, 23, 24, 46 Data delineating the 
natural history of performance of the 4SC and other TFTs in boys with DMD have been published. 
18, 25 A 2.2-second difference in 4SCV corresponds to a 30-meter difference on the 6MWD. A 30-
meter difference on the 6MWD has been shown to be associated with a significantly heightened 
risk of loss of ambulation within the ensuing 2 years.26 Unlike the 6MWD, the 4SC is less reliant 
on endurance and is most reflective of lower extremity muscle power.  The 4SC velocity (the 
number of stairs climbed per second) is calculated as the ratio of the number of stairs climbed (4) 
divided by the number of seconds taken to complete the 4-stair climb. Because children who are 


 
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or have become unable to perform this task, the time cannot be measured, conventionally a time 
equal or bigger than the worst performance in the group is subjectively given to indicate poor 
performance. In order to improve the possibility of performing statistical analysis, the results will 
be converted into velocity (distance/time) rather than the conventional time as this would allow 
conversion of all the poor or failed results from a subjectively chosen number into a meaningful 
number. 
The PUL includes 22 items with an entry item to define the starting point of testing, with 21 items 
subdivided into shoulder level, middle level, and distal level dimension. Each dimension can be 
scored separately.48 
Some of the functional endpoint assessment including the TFTs, NSAA, 6MWD and upper and 
lower extremity myometry will be video recorded at select study visits while the subject is 
completing the assessments. The videos will be uploaded by the site to a secure database, 
maintained by a separate vendor, and reviewed by master physiotherapists to assure quality or 
identify potential issues requiring re-training of clinical evaluators at the site. In addition the videos 
may be used to explore additional assessment of timing of TFTs, and to grade the quality of the 
patient’s functional abilities, which could inform the feasibility of potential new outcome measures 
focused on movement quality. 
9.1.2 
Myometry and Ankle Range of Motion (ROM) 
Muscle strength will be assessed using hand-held dynamometry at the time points specified in 
Table 2-1 through Table 2-3, following procedures outlined in the CE Manual. All measures will 
be obtained with a calibrated hand-held dynamometer.  
Detailed instructions for performing manual myometry and ankle ROM assessments will be 
provided in the CE Manual. These assessments will be performed by a clinical evaluator who has 
undergone study specific training on the administration of these assessments. 
9.1.3 
Imaging Assessment for the Study 
Images will be submitted to an imaging core lab. Sites should be trained prior to scanning the first 
study participant. Image acquisition guidelines and submission process will be outlined in the 
Imaging Manual provided by the core lab. 
9.1.3.1 
DXA 
DXA to collect measures of total lean body mass, fat mass and bone mineral density will be 
performed at the time points indicated in Table 2-1 through Table 2-3. 
DXA acquisition guidelines and submission processes will be outlined in the DXA Scanning 
Guide. 
Adequacy of DXA scans should be confirmed by the central imaging vendor prior to 
randomization. 
Screening DXA should be obtained between Day -42 and Day -14 to allow for central imaging 
vendor review. 
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DXA is not required at the early termination visit. 
Re-enrollment: Repeat of DXA is not required if previously obtained within 3 months of 
Day 1/randomization. 
Effective doses for whole-body DXA examinations were found to be 0.0052, 0.0048, 0.0042 and 
0.0042 mSv for a 5-, 10-, 15-year old child and adult respectively for an examination performed 
on the Hologic Discovery A device. Corresponding values for the Hologic Discovery W were 
0.0105, 0.0096, 0.0084 and 0.0084 mSv.49 
9.1.3.2 
Cardiac MRI (cMRI) 
cMRI with gadolinium enhancement will be performed in a subset of participants at select U.S. 
centers at the time points indicated in Table 2-1 through Table 2-3. Subjects enrolled at select U.S. 
centers participating in the cMRI substudy will be required to attempt to complete the cMRI. 
Subjects participating at sites where the cMRI substudy is being performed who have an allergy 
to gadolinium may undergo cMRI scanning without gadolinium. 
cMRI acquisition guidelines, protocols, contrast agent type and dose, and image submission 
processes are outlined in the imaging manual provided by the core imaging lab. 
Adequacy of cMRI scans should be confirmed by the central imaging vendor prior to 
randomization. 
Screening cMRI should be obtained between Day -42 and Day -14 to allow for central imaging 
vendor review. cMRI will be conducted at early termination visits if ≥ 24 weeks has elapsed from 
previous cMRI. 
Re-enrollment: Repeat of cMRI is not required if previously obtained within 6 months of 
Day 1/randomization. 
9.1.4 
Exploratory Genotyping 
A 2-mL whole blood 9.1.7 sample will be drawn (as indicated in Table 2-2) for potential analysis 
of genetic variation in genes suspected to impact DMD disease expression (including but not 
limited to LTBP4, SPP1). Human leukocyte antigen (HLA) genotyping may be conducted to 
better understand immunogenicity risk if ADAs are detected and it is determined that ADA 
impacts safety or efficacy. Further details of blood collection and processing will be provided to 
the site in the laboratory procedure manual. The exploratory genotyping samples will be used 
for up to 2 years after the study is closed and will be used for analyses between genotype and 
endpoints evaluated in this study. 
9.1.5 
ActiMyo 
Subjects enrolled at selected sites will be asked to wear a device called ActiMyo. The wearing of 
the ActiMyo is optional. Hence, refusal to wear ActiMyo will not affect the eligibility of a subject 
to be enrolled in the study. The purpose of the ActiMyo device is to measure the daily movement 
and activity levels of subjects with a degree of high accuracy. Unlike consumer-grade activity 
trackers and mobile phone applications, the endpoints of the ActiMyo device are clinically 
validated. Therefore, the activity data collected by ActiMyo will be analyzed to provide deep 


 
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insights into the ability of subjects to ambulate (i.e., walking distance, walking speed, ability to 
climb stairs, speed of climbing stairs, etc.) and allows for the determination of the clinical 
meaningfulness of RO7239361 in the treatment of DMD, and refusal will not exclude a subject 
from the study. The purpose of the ActiMyo device is to accurately measure the daily movement 
and activity levels of the subject. The device consists of two sensors, to be worn on each ankle. 
Subjects will wear the devices each day during specified periods of the study and during TFTs and 
6MWT at specified site visits. As the ActiMyo device battery requires recharging overnight, the 
device will not be worn at night. The subject and parent/caregiver will be trained on how to use the 
device, including correct fitting and wearing of the device, how to dock the device on the battery 
charging station, and when to return ActiMyo materials to the site. As a CE-marked device, the 
possibility of allergic reactions and skin irritation has been addressed and are thus unlikely to 
occur. Nevertheless, should any skin reaction be observed, the subject should remove the strap and 
sensor and contact the study team as soon as possible. Detailed instructions as to use of the 
ActiMyo device are provided in the ActiMyo User Manual and Quick Start Guide. 
9.1.6 
Caregiver Video Assessment 
Subjects enrolled at selected sites will be invited to participate in the caregiver video assessment. 
Participation is optional, and refusal to participate will not exclude a subject from the main study. 
The aim of the caregiver video assessment is to provide additional insight into a subject's physical 
functioning and motor strength during the study. A video application will be used to capture a 
range of standardized tasks in a real-world environment, external to the clinic. 
The video application will ask caregivers to record the subject completing selected tasks every 
12 weeks according to pre-specified instructions read aloud by the caregiver. These tasks include 
sitting up, standing up, walking, running, climbing stairs, and one additional task personally 
chosen by the caregiver. The caregiver is allowed to skip the recording of any of these tasks if not 
appropriate or applicable. In addition, the application will allow caregivers to record a new ability 
at any point during the study. 
If the subject and caregiver agree to participate, they will sign a separate Informed Consent Form at 
baseline (for newly enrolled subjects) or at a future study visit (for subjects who are already enrolled 
in the main study only). Detailed instructions regarding the caregiver video assessment are 
provided in the parent/caregiver manual. 
9.1.7 
Clinical Global Impression of Change (CGI-C)  
The CGI-C is a single item that clinicians will complete at the end of the double-blind phase (Week 
48 of the study) and at Week 48 of the OL phase (Week 96 of the study) to rate change in the 
patient’s global impression of change in DMD from the start of each phase (i.e., from baseline for 
the double-blind phase and from Week 49 for the OL phase).  There are seven response options: 
“Very much improved”, “Much improved”, “Minimally improved”, “No change”, “Minimally 
worse”, “Much worse”, and “Very much worse”.  It is a widely used endpoint in clinical trials 
across a variety of disease areas. To enhance inter-rater consistency, an instruction document 
(developed with input from clinical experts) will be provided in the user manual, which includes 
examples for each of the response options. 
The item should be completed by a clinician (e.g., Principal Investigator or study coordinator) who 


 
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has interacted with the individual since baseline. The same clinician should complete the CGI-C 
at all specified visits for an individual patient. If there is no clinician at the site who is able to 
reflect on the patient’s health status, an alternative clinician should make the rating using existing 
study notes, and sites should record this. 
9.1.8 
Caregiver Global Impression of Change (CaGI-C)  
The CaGI-C comprises six items that caregivers will complete at the end of the 
double-blind phase (Week 48 of the study) and at Week 48 of the OL phase (Week 96 of 
the study) to rate the change in a subject's symptoms, physical abilities, daily activities, 
social life, emotions and mental well-being, and overall health from the start of each phase 
(i.e., from baseline of the double-blind phase and from Week 49 of the OL phase). There are seven 
response options: “Very much improved,” “Much improved,” “Minimally improved,” 
“No change,” “Minimally worse,” “Much worse,” and “Very much worse.” It is a widely 
used endpoint in clinical trials across a variety of disease areas.  
To enhance intra- and inter-consistency, descriptions of each level of change have been 
developed and domain level global impression items have been created with input from 
patients with DMD and their caregivers. The items should be completed by the parent or 
caregiver who has been involved in the study since baseline. The same parent or caregiver 
should complete the CaGI-C for his or her child at the end of each study phase to reflect 
the subject's health status from baseline for the double-blind phase and Week 49 of the 
OL phase. The CaGI-C will be assessed at selected sites only. 
9.1.9 
Pediatric Quality of Life Inventory Multidimensional Fatigue Scale 
(PedsQL MFS) 
The PedsQL MFS parent proxy measures the severity and impact of fatigue on the subject 
from the caregiver’s perspective. The recall period is the last 4 weeks. The instrument is 
appropriate for individuals aged 2-18 years old and captures six items on general fatigue, 
six items on sleep/rest fatigue, and six items on cognitive fatigue. A total fatigue score 
can be calculated from the 18 items that ranges from 0 to 100, with higher scores 
indicating less fatigue. The PedsQL MFS takes approximately 10 minutes to complete. 
The PedsQL MFS will be assessed at selected sites only. 
9.2 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
Malfunctions of the pre-filled syringes containing study drug should be reported to the sponsor 
via designated form (electronic system) in accordance with local regulations. 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 


 
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are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
The clinical evaluators who assess functional endpoints must be distinct from the clinicians who 
assess AEs of the study subjects. Clinicians evaluating AEs should not communicate the presence, 
absence or severity of AEs with clinical evaluators at the site unless required to do so to ensure 
subject safety. 
Contacts for SAE reporting are specified in Appendix 3. 
9.2.1 
Time Period and Frequency for Collecting AE and SAE Information 
The collection of nonserious AE information should begin at initiation of study treatment until 50 
days of discontinuation of dosing.  Nonserious AE information should also be collected from 
the start of a placebo lead-in period or other observational period intended to establish a baseline 
status for the participants. 
Section 6.4 in the IB represent the Reference Safety Information to determine expectedness of 
serious AEs for expedited reporting. Following the participant’s written consent to participate in 
the study, all SAEs, whether related or not related to study drug, must be collected, including 
those thought to be associated with protocol-specified procedures. 
All SAEs must be collected that occur during the screening period and within 50 days (5 half-lives) 
of discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (e.g., a follow-up skin biopsy). 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
• Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section. 
• All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available. 
 
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor. 
The method of evaluating and assessing the seriousness, severity, and causality of AEs and the 
procedures for completing and reporting/transmitting SAE reports are provided in Appendix 3. 
Guidance for assessing severity of AEs is also provided in Section 8. 
9.2.2 
Method of Detecting AEs and SAEs 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 


 
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questioned regarding the specific occurrence of one or more AEs.) 
9.2.3 
Follow-up of AEs and SAEs 
• Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3). 
• Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate. 
• All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study. 
 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the participant is lost to follow-up (as 
defined in Section 8.3). 
Further information on follow-up procedures is given in Appendix 3. 
9.2.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met. 
• An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
 
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious 
Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements. 
9.2.5 
Pregnancy 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
9.2.6 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be reported as an AE and captured on 
the nonserious AE eCRF page or SAE Report Form electronic, as appropriate. Paper forms are 
only intended as a back-up option when the electronic system is not functioning. 


 
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• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted 
• Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
Laboratory abnormalities that are reported as AEs or SAEs should be reported utilizing the 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 
9.2.7 
Potential Drug Induced Liver Injury (DILI) 
• Dosing will be paused within a subject until safety information is reviewed and drug induced 
liver injury (DILI) is ruled out in the event that: 
− ALT > 5 x baseline AND No corresponding increase in CPK to indicate muscle origin as 
the reason for the increase in ALT 
OR 
− ALT > 10 x ULN AND ALT > 2 x baseline AND no corresponding increase in CPK to 
indicate muscle origin as the reason for the increase in ALT 
OR 
− Total bilirubin > 2 x ULN 
OR 
− Symptoms or signs of hepatic inflammation such as nausea, vomiting, right upper quadrant 
pain or tenderness with no other immediately apparent possible cause of these symptoms 
or signs, such as viral gastroenteritis or constipation. 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details). 
Criteria for initiating an evaluation for potential DILI are defined in Section 8. 
9.2.8 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
9.2.8.1 
Injection Site Assessments 
Subjects will be monitored for injection-site reactions from Day 1 through the last study visit. 
Report injection-site reactions as AEs, as appropriate. It is strongly recommended that non-subject 
identifying photographs of injection site reactions be taken for submission to the sponsor or 
designee. Some subjects with injection-site reaction or rash may be asked to participate in 
additional procedures to determine the type of immune reaction associated with the injection-site 


 
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reaction or rash. Potential subjects will be identified in consultation with the medical monitor. 
The additional procedures include a blood sample and skin biopsy to assess the type of 
immune reaction. The blood sample will be used to assess ADA titers, serum mast cell 
tryptase/histamine, and compliment activation products (e.g., C3D, C3G). The skin biopsy should 
be collected in a sterile manner in accordance with local procedures, using a 3 mm punch biopsy 
instrument and formalin fixation, and will assess mast cell, eosinophil, and neutrophil infiltration. 
The Draize Scale for erythema and edema will be used as a guide for reporting injection site 
reaction AEs50 (see Table 9.2.8.1-1). 
 
Table 9.2.8.1-1: 
Grading Injection Site Reactions 
 
Erythema 
Edema 
Description 
AE Grade 
Description 
AE Grade 
No erythema 
- 
No edema 
- 
Very slight erythema, barely 
perceptible 
Mild 
Very slight edema, barely perceptible 
Mild 
Well defined erythema 
Moderate 
Moderate edema, raised approximately 
1 milimeter (mm) 
Moderate 
Severe erythema 
Beet redness to slight eschar 
formation 
Severe 
Severe edema, raised more than 1mm 
and beyond exposure area 
Severe 
 
9.2.9 
Overdose or Incorrect Administration of Study Drug 
An overdose is defined as the accidental or intentional administration of the drug in an amount 
higher than the assigned dose. Definitions of other incorrect administration of study drug 
(including medication error, drug abuse, and drug misuse) are provided in Appendix 3.  
Any overdose or incorrect administration of study drug must be reported as an AE.  
If the associated AE fulfills seriousness criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event). Any AE 
associated with an overdose or incorrect administration of study drug should be reported as a 
separate AE as well (see Section 9.2). 
9.3 
Safety 
Planned time points for all safety assessments are listed in the Schedule of Activities. 
The data from the safety assessments required in this protocol (laboratory tests, ECGs, 
echocardiograms) will be transferred to Roche or designee from the relevant vendor. The site staff 
are not required to report these procedures in the CRF. Any findings of potential clinical relevance 
should be evaluated and managed by the investigator per standard medical/clinical judgment in 
consultation with the Roche medical monitor. Site staff are required to report to the sponsor on the 
CRF any AE that is identified during safety assessments. 


 
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9.3.1 
Physical Examinations 
Targeted physical exams to be guided by review of systems and include assessment of heart, lungs 
and abdomen. 
9.3.2 
Vital Signs 
Refer to Schedule of Activities. 
9.3.3 
Electrocardiograms and Echocardiograms 
Refer to Schedule of Activities. 
A central core lab will perform all imaging analyses. Sites will be informed of quality issues or 
needs for repeat scanning via queries from the core lab. 
Any findings of potential clinical relevance that are not directly associated with the objectives of 
the protocol should be evaluated and handled by the study investigator as per standard 
medical/clinical judgment. 
Reports (electrocardiogram and echocardiogram) from the central core lab will be provided to sites 
for inclusion in the subject’s medical record and to provide to subject caregivers. Availability of 
reports will be determined by the central core lab. 
Electrocardiograms and echocardiogram should be repeated in subjects with new cardiac 
symptoms. 
9.3.4 
Clinical Safety Laboratory Assessments 
Investigators must document their review of each laboratory safety report. 
 
 
 


 
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Table 9.3.4-1: 
Laboratory Assessments 
Screening 
On Treatment 
Follow-up 
Hematology 
Hemoglobin 
X 
X 
X 
Hematocrit 
X 
X 
X 
Total leukocyte count, including 
differential 
X 
X 
X 
Platelet count 
X 
X 
X 
Serum Chemistry 
Alanine aminotransferase (ALT) 
X 
X 
X 
Aspartate aminotransferase (AST) 
X 
X 
X 
Gamma-Glutamyl transferase (GGT) 
X 
X 
X 
Total bilirubin 
X 
X 
X 
Direct bilirubin 
X 
X 
X 
Alkaline phosphatase 
X 
X 
X 
Lactate dehydrogenase (LDH) 
X 
X 
X 
BUN 
X 
X 
X 
Creatinine 
X 
X 
X 
Creatine kinase 
X 
X 
X 
Total Protein 
X 
X 
X 
Albumin 
X 
X 
X 
Sodium 
X 
X 
X 
Potassium 
X 
X 
X 
Chloride 
X 
X 
X 
Calcium 
X 
X 
X 
Phosphorus 
X 
X 
X 
Magnesium 
X 
X 
X 
Iron 
X 
X 
X 
Plasma Chemistry 
Glutamate Dehydrogenase (GLDH) 
X (Day -1 or -2) 
X 
X 
Urine test 
Urinalysis (including protein, glucose, 
blood, leukocyte esterase, specific 
gravity) 
X 
X (only required at visits 
specified in Table 2-2 and 
Table 2-3) 
 
 


 
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Table 9.3.4-1: 
Laboratory Assessments 
Screening 
On Treatment 
Follow-up 
Other sample collections 
Serum Biomarkers 
X (see Table 2-2  
and Table 2-3) 
Immunogenicity 
X (see Table 2-2  
and Table 2-3) 
X (see Table 2-4) 
Free and myostatin drug complex 
X (see Table 2-2  
and Table 2-3) 
Exploratory genotyping 
X (see Table 2-2) 
Creatine kinase-muscle (CK-MM) 
X (Day 1, Weeks 12, 24 
 and 48 in double-blind phase) 
GDF-11 
 
X (see myostatin collection 
schedule in Table 2-2 
 and Table 2-3) 
 
9.3.5 
Imaging Safety Assessment 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.4 
Pharmacokinetics 
The PK data obtained in this study will be combined with data from other studies in the clinical 
development program to develop a population PK model. This model will be used to evaluate the 
effects of intrinsic and extrinsic covariates on the PK of RO7239361 and to determine measures 
of individual exposure (such as steady-state trough, and time-averaged concentration). Model 
determined exposures will be used for exposure-response analyses of selected efficacy and safety 
end points. Results of population PK and exposure-response analyses will be reported separately. 
Table 9.4-1 lists the sampling schedule to be followed for the assessment of pharmacokinetics. 
Further details of blood collection and processing will be provided to the site in the procedure 
manual and laboratory manual. 
Serum samples will be analyzed for RO7239361 using a validated ligand binding assay. 
Pharmacokinetic samples collected from a subject who received placebo will not be analyzed. 
 


 
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Table 9.4-1: 
Pharmacokinetic Sampling Schedule for RO7239361 
 
Study Day of Sample 
Collection 
Event 
Time (Relative To 
RO7239361 Dose)  
Hour: Min 
RO7239361 
Blood Sample for Serum 
Day 1 of the double-blind phase 
predose 
00:00 
X 
Day 8 of the double-blind phase 
predose 
00:00 
X 
Day 15 of the double-blind phase 
predose 
00:00 
X 
Day 29 of the double-blind phase 
predose 
00:00 
X 
Week 12 of the double-blind phase 
predose 
00:00 
X 
Week 24 of the double-blind phase 
predose 
00:00 
X 
Week 36 of the double-blind phase 
predose 
00:00 
X 
Week 48 of the double-blind phase 
predose 
00:00 
X 
Week 1 of the open-label phase 
predose 
00:00 
X 
Week 2 of the open-label phase 
predose 
00:00 
X 
Week 3 of the open-label phase 
predose 
00:00 
X 
Week 12 of the open-label phase 
predose 
00:00 
X 
Week 24 of the open-label phase 
predose 
00:00 
X 
Week 36 of the open-label phase 
predose 
00:00 
X 
Week 48 of the open-label phase 
predose 
00:00 
X 
 
 
9.5 
Pharmacodynamics 
Not applicable 
9.6 
Pharmacogenomics 
Not applicable. 
9.7 
Biomarkers 
Blood will be drawn at the times indicated in Table 2-1 through Table 2-3 for the measurement of 
target engagement biomarkers (free myostatin and myostatin-drug complex). 
Blood will be drawn at the times indicated in Table 2-1 through Table 2-3 for the measurement of 
exploratory biomarkers. Serum samples may be used to evaluate the levels of exploratory 
biomarkers known to be involved in muscle growth, function, and/or myostatin signaling (e.g., 
sTNI, MYL3, FABP3). 
Creatine kinase-muscle (CK-MM) will be analyzed during the double blind phase of the study to 
examine concentrations associated with muscle atrophy in boys with DMD. 
Reports of the exploratory serum biomarkers will not be provided to sites as this is a research 
measure. 


 
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9.7.1 
Additional Research Collection 
Additional research collections and retention are optional for all subjects, except where prohibited 
by local laws or regulations. 
This protocol will include both sample collection and residual sample storage for additional 
research (AR). 
This serum collection for additional research is intended to expand the translational R&D 
capability at Roche, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. For example, this sample may have potential 
in exploration of diagnostic or prognostic biomarkers contingent on scientific developments 
in the field of myostatin biology, DMD pathophysiology or unanticipated results in the study. 
This collection for additional research may also be used to support health authority requests for 
analysis, and advancement of pharmacodiagnostic development to better target drugs to the right 
patients. This may also include genetic/genomic exploration aimed at exploring disease pathways, 
progression and response to treatment etc. 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development to ensure the 
research supports appropriate and well-defined scientific research activities. 
 
• Prospective samples of serum for Additional Research will be collected at selected time points 
(see Table 9.7.1-1) 
• Residual serum from serum biomarker collections (see Table 9.7.1-2) will also be retained for 
additional research purposes 
• Residual whole blood or DNA  derived  from  the  whole  blood  sample  from  exploratory 
genotyping analysis (Table 9.7.1-2) will also be retained for additional research purposes 
Samples will be securely stored by the Roche Research Biosample Repository or at a Roche 
approved third party storage management facility. 
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual 
Additional research samples will be retained for 15 years or the maximum allowed by applicable 
law. No additional sampling is required for residual collections. 
Further details of sample collection and processing will be provided to the site in the procedure 
manual. 
 
 


 
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Table 9.7.1-1: 
Additional Research Sample Schedule 
 
Study Day 
Time 
(Event) 
Hour 
Time 
(Relative To Dosing) 
Hour: Min 
Blood Sample 
Baseline Day 1 
0 (predose) 
00:00 
X 
Week 24 
0 
00:00 
X 
Week 48 
0 
00:00 
X 
 
 
Table 9.7.1-2: 
Residual Sample Retention for Additional Research Schedule 
 
Sample Type 
Timepoints for which residual samples will be 
retained 
PK 
All 
Residual serum from serum biomarkers 
All 
Residual whole blood or DNA derived from the whole 
blood sample from exploratory genotyping 
Day 1 
Residual serum from ADA analysis 
All 
Residual serum from myostatin and myostatin-drug 
complex 
All 
 
9.7.2 
Immunogenicity Assessments  
Serum samples from all treated subjects will be analyzed by a validated immunogenicity assay. 
Individual time points are considered positive if confirmed as specific against RO7239361. The 
subject will be called positive for immunogenicity as defined in the Statistical Analysis Plan (SAP). 
The number and percentage of subjects will be listed and summarized by treatment and by time, 
and the corresponding antibody titer values will be listed. If ADAs are observed, subgroup 
analyses may be conducted to compare AEs, labs, biomarker data, and PK results across treated 
subjects with and without ADAs. In the event a subject has a positive immunogenicity response, 
additional NAB analyses may be conducted. 
9.7.3 
RNA Transcriptome Research  
Not applicable. 
9.7.4 
RNA Expression Research of a Subset of RNA Species  
Not applicable. 
9.7.5 
Proteome Research  
Not applicable. 
9.7.6 
Metabolomic Research  
Not applicable. 


 
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9.7.7 
Other Assessments 
Not applicable. 
9.8 
Health Economics or Medical Resource Utilization and Health 
Economics 
This study includes a number of patient reported outcomes, such as pediatric data collection 
instrument (PODCI), health utilities index (HUI III), and PedsQL family impact module (PedsQL 
FIM) that provide additional information to the clinician-reported outcomes. In addition, several 
questions will be included to collect presenteeism and absenteeism data, along with health care 
resource utilization. 
Health care resource utilization data associated with medical encounters, will be collected in the 
CRF by the investigator and study-site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include: 
• Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient) 
• Duration of hospitalization (total days length of stay, including duration by wards, 
e.g., intensive care unit) 
• Number and character of diagnostic and therapeutic tests and procedures 
• Outpatient medical encounters and treatments (including physician or emergency room visits, 
tests and procedures, and medications) 
10 
STATISTICAL CONSIDERATIONS 
10.1 
Sample Size Determination 
Statistical Considerations:  Sample Size 
The sample size of 159 patients (53 patients per arm) will provide 80% power for testing the null 
hypothesis of no difference between a dose of RO7239361 and placebo in the change from baseline 
in the NSAA total score at 48 weeks under the following assumptions: 
• A true treatment difference (RO7239361 minus placebo) of 2.5 points 
• A standard deviation of 4.4 points 
• A treatment discontinuation rate of 5% 
10.2 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
 


 
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Population 
Description 
Enrolled 
All participants who sign informed consent and are assigned a 
participant identification number. 
Randomized 
Enrolled participants who receive a randomization treatment 
assignment. 
Treated 
Enrolled subjects who receive at least 1 dose of study therapy. 
• If a subject received the same incorrect treatment throughout the 
study, then the participant will be analyzed based on the treatment 
received. 
• If a subject received study drug from more than one treatment 
group, and none of the administrations were consistent with the 
assigned randomized treatment group, then the participant will be 
analyzed based on the first treatment received. 
Modified Intention to Treat 
(mITT) 
Randomized subjects that received at least one dose of study 
drug. For change from baseline analyses, this includes only those 
subjects that had at least one efficacy assessment. 
Per-Protocol 
mITT subjects with no major protocol violations, as described in 
the Statistical Analysis Plan 
 
10.3 
Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the selection of 
participants to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. Below is a summary of planned statistical analyses of the primary and 
secondary endpoints. 


 
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10.3.1 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary analysis, on the change from baseline in NSAA total score, will be 
conducted using a Mixed Model Repeated Measures (MMRM) analysis with 
treatment, visit, and the treatment-by-visit interaction entered into the model as fixed 
effects, and participant entered as a random effect. The baseline NSAA total score will 
be entered into the model as a covariate. The stratification factors will be entered into 
the model as blocks. 
For each RO7239361 dose group, the null hypothesis of the no treatment difference 
between the dose group and placebo will be tested using the estimates from this 
MMRM model at the end of the 48-week double-blind treatment period. In order to 
control the overall type I error rate for the analysis, the following hierarchical testing 
of doses will be implemented:  
1. Comparison of the RO7239361 high dose (35/50 mg) to placebo at a two-sided 
α level of 0.05 is performed. 
2. If the null hypothesis for the high dose is rejected (comparison of the high dose 
to placebo in the previous step is statistically significant), then a comparison of 
the RO7239361 low dose (7.5/15 mg) to placebo at a two-sided α level of 0.05 
will be performed. If the null hypothesis for the high dose is not rejected, then 
the testing of the low dose versus placebo will not be performed. 
Sensitivity analyses will include the following: an analysis of covariance 
(ANCOVA) using the mITT data set; an ANCOVA on the mITT data set with 
missing data imputed using multiple imputations; and an MMRM analysis using the 
per-protocol data. 
Secondary Following testing of the primary endpoint, the key secondary endpoints will be 
analyzed using a hierarchical testing procedure in order to maintain the overall type 
I error rate at 0.05. This procedure will be specified in the Statistical Analysis Plan 
prior to database lock. 
Most secondary endpoints will be tested using a MMRM that is similar in structure 
to the primary analysis. Proximal lower extremity flexor strength will be tested using 
a MANOVA of the 2 component variables: knee extension and knee flexion. 
If a dose fails to reach significance against placebo in any stage of the testing 
hierarchy, any further tests will be considered as exploratory. 
Exploratory Will be described in the Statistical Analysis Plan finalized before database lock 
 


 
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10.3.2 
Safety Analyses 
All safety analyses will be performed using treated subjects. 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
Tabular summaries of SAEs, AEs leading to discontinuation and Grade 3 to 4 
laboratory abnormalities will present the number and percentage of unique 
subjects with treatment emergent events. Adverse event summaries will be 
presented by system organ class (SOC) and preferred term (PT). All SAEs 
since enrollment will be listed. Grade 3 to 4 laboratory abnormalities will be 
summarized as proportions by baseline toxicity grade. 
Endpoint 
Statistical Analysis Methods 
Exploratory 
Will be described in the Statistical Analysis Plan finalized before database lock 
 
10.3.3 
Other Analyses 
PK, PD, biomarker and exploratory analyses will be described in the SAP finalized before 
database lock. The population PK analysis and PD analyses will be presented separately from the 
main clinical study report. 
10.3.4 
Interim Analyses 
Schedule of Analyses 
In addition to the primary analysis (to be conducted when all patients have completed Week 48, the 
end of the double-blind treatment period), the following analyses may be conducted during the 
course this study: 
• When at least 20% of the total number of patients have completed 24 weeks of double-blind, 
placebo-controlled treatment 
• When at least 20% of the total number of patients has completed 48 weeks of double-blind, 
placebo-controlled treatment 
• An analysis conducted at Week 96 (at the end of the first 48 weeks of the OL phase of the study) 
• A final data analysis when the study has been completed 
The SAP will further describe the planned interim analyses.  
Interim SAPs (iSAPs) will contain detailed information about the conduct of the futility analyses, 
which will be performed by an independent data coordinating center with results reviewed by the 
iDMC. Because these futility analyses will be conducted prior to the primary efficacy analysis, the 
unblinded data will not be shared with the Sponsor in order to maintain the integrity of the study 
blind.  


 
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82/Protocol WN40227, Version 4 
 
For the primary efficacy endpoint (the change from baseline in NSAA total score), additional 
analyses may be performed, incorporating the first 96 weeks of exposure to RO7239361 (48 weeks 
of double-blind treatment) followed by 48 weeks of OL treatment). The data will be compared with 
data from one or more control cohorts from external data sources (e.g., disease registries) that 
include at least 96 weeks of follow-up data. 


 
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11 
REFERENCES 
 
1 
Emery AE. Population frequencies of inherited neuromuscular disease - a world survey. 
Neuromuscular Disord, 1991; 1:19-29. 
2 
Manzur AY, Kuntzer T, Pike M, et al. Glucocorticoid corticosteroids for Duchenne muscular 
dystrophy. Cochrane Database Systematic Review, 2008; 1:CD003725. 
3 
Wagner KR, McPherron AC, Winik N, et al. Loss of myostatin attenuates severity of muscular 
dystrophy in mdx mice. Ann Neurol, 2002; 832-836. 
4 
Grounds MD, et al. Towards developing standard operating procedures for pre-clinical testing 
in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol Dis 2008;31(1): 1-
19. 
5 
Bogdanovich S, Krag, TO, Barton ER, et al. Functional improvement of dystrophic muscle by 
myostatin blockade. Nature, 2002; 420: 418-421. 
6 
Guiraud S, Aartsma-Rus A, Vieira NM, et al. The Pathogenesis and Therapy of Muscular 
Dystrophies. Annu Rev Genomics Hum Genet 2015;ePub ahead of print. Accessed: 23 July 
2015. 
7 
Hoffman EP, Brown RH, Kunkel LM. Dystrophin: the protein product of the Duchenne 
muscular dystrophy locus. Cell 1987:51:919-28. 
8 
Manzur AY, Kuntzer T, Pike M, Swan AV. Glucocorticoid corticosteroids for Duchenne 
muscular dystrophy. Cochrane Database Syst Rev 2008;1. 
9 
Eagle M, Baudouin SV, Chandler C, et al. Survival in Duchenne muscular dystrophy: 
improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. 
Neuromuscul Disord 2002;12:926-9. 
10 Lynn S, Aartsma-Rus A, Bushby K, et al. Measuring clinical effectiveness of medicinal 
products for the treatment of Duchenne muscular dystrophy. Neuromuscul Disord 
2015;25:96-105. 
11 Moxley RT 3rd, Pandya S, Ciafaloni E, et al. Change in natural history of Duchenne muscular 
dystrophy with long-term corticosteroid treatment: implications for management. J Child 
Neurol 2010;25:1116-29. 
12 Translarna (ataluren) Summary of Product Characteristics. Almac Pharma Services. 31 July 
2014. 
13 Dent KM, Dunn DM, von Niederhausern AC, et al. Improved molecular diagnosis of 
dystrophinopathies in an unselected clinical cohort. Am J Med Genet A 2005;134:295–8. 
14 Wright MA, Yee AS, et al. Consider Muscle Disease in Children with Elevated Transaminase. 
JABFM 2012; 25: 536-540. 
15 McMillan HJ, Kang PB, et al. Serum Transaminase Levels in Boys with Duchenne and Becker 
Muscular Dystrophy. Pediatrics 2011; 127: e132-e136. 


 
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16 Mcdonald CM, Henricson EK, Abresch RT, et al. The 6-minute walk test and other clinical 
endpoints in duchenne muscular dystrophy: Reliability, concurrent validity, and minimal 
clinically 
important differences 
from a 
multicenter study. Muscle and Nerve 
2013;48(3):357-68 
17 Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation 
dystrophinopathy. Muscle & Nerve 2014;50:477-487. 
18 Pane M, Mazzone ES, Sivo S, et al. Long term natural history data in ambulant boys with 
duchenne muscular dystrophy: 36-month changes. PLOS ONE 2014;9:e108205. 
19 Griggs RC et al. Prednisone in Duchenne muscular dystrophy: a randomized, controlled trial 
defining the time course and dose response. Archive of Neurology 1991; 48:383-388. 
20 Manzur AY, Kuntzer T, Pike M, Swan AV. Glucocorticoid corticosteroids for Duchenne 
muscular dystrophy. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. 
No.: CD003725. 
21 Cittadini A, Comi LI, Longobardi S, et al. A preliminary randomized study of growth hormone 
administration in becker and duchenne muscular dystrophies. Eur Heart J 2003;24(7):664-72. 
22 Fenichel GM, Griggs RC, Kissel J, et al. A randomized efficacy and safety trial of oxandrolone 
in the treatment of duchenne dystrophy. Neurology 2001;56(8):1075-9. 
23 Griggs, R, Moxley, R, Mendell, J, Fenchel, G, Brooke, M, Pestronk, A, Miller, J. Prednisone 
in Duchenne Dystrophy. Arch Neurol. 1991; 48:383-388. 
24 Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation 
dystrophinopathy. Muscle Nerve 2014; 50: 477-487 
25 Mayhew A, Cano S, Scott E, et al. Detecting meaningful change using the North Star 
Ambulatory Assessment in Duchenne muscular dystrophy. Dev Med Child Neurol 
2013;55:1046-52. 
26 Ricotti V, Ridout D, Pane M, et al. The North Start Ambulatory Assessment in Duchenne 
muscular dystrophy: considerations for the design of clinical trials. J Neurol Neurosurg 
Psychiatry 2016;87:149-55.   
27 McDonald C, Henricson E, Abresch R, et al. The 6-minute walk test and other endpoints in 
duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a 
multicenter study. Muscle Nerve 2013; 48: 343-356. 
28 McDonald C, Henricson E, Abresch R, et al. The 6-minute walk test and other clinical 
endpoints in Duchenne muscular dystrophy: reliability, concurrent validity, and minimal 
clinically important differences from a multicenter study. Muscle Nerve 2013; 48: 357-368. 
29 Nakatani M, Takehara Y, Sugino H, et al. Transgenic expression of a myostatin inhibitor 
derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology 
in mdx mice. FASEB J 2008;22:477-87. 
30 Morine KJ, Bish LT, Pendrak K, et al. Systemic myostatin inhibition via liver targeted gene 
transfer in normal and dystrophic mice. PLoS One 2010;5:e9176. 


 
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31 Wagner KR, McPherron AC, Winik N, Lee SJ. Loss of myostatin attenuates severity of 
muscular dystrophy in mdx mice. Ann Neurol 2002;52:832–6. 
32 Bogdanovich S, Krag TO, Barton ER, et al. Functional improvement of dystrophic muscle by 
myostatin blockade. Nature 2002;420:418-21. 
33 Morine KJ, Bish LT, Selsby JT, et al. Activin IIB receptor blockade attenuates dystrophic 
pathology in a mouse model of Duchenne muscular dystrophy. Muscle Nerve 2010;42:722-30. 
34 Murphy KT, Ryall JG, Snell SM, et al. Antibody-directed myostatin inhibition improves 
diaphragm pathology in young but not adult dystrophic mdx mice. Am J Pathol 
2010;176:2425-34. 
35 Pistilli EE, Bogdanovich S, Goncalves MD, et al. Targeting the activin type IIB receptor to 
improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy. 
Am J Pathol 2011;178:1287-97. 
36 Bish LT, Sleeper MM, Forbes SC, et al. Long-Term Systemic Myostatin Inhibition via Liver- 
Targeted Gene Transfer in Golden Retriever Muscular Dystrophy. Hum Gene Ther 
2011;22:1499-509. 
37 Kornegay JN, Childers MK, Bogan DJ, et al. The paradox of muscle hypertrophy in muscular 
dystrophy. Phys Med Rehabil Clin N Am 2012;23:149-72. 
38 Clinical Study Report for Study CN001001. A Randomized, Placebo-Controlled, Single and 
Multiple Ascending Subcutaneous Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of BMS-986089 in Healthy Adult Subjects. 
Bristol-Myers Squibb Company; 2016. Document Control No. 930103114. 
39 Gamer, LW, Wolfman NM, Celeste AJ, et al. A novel BMP expressed in developing mouse 
limb, spinal cord, and tail bud is a potent mesoderm inducer in Xenopus embryos. Dev. 
Biol 1999;208:222–232. 
40 McPherron AC, Lawler, AM, Lee S-J. Regulation of anterior/ posterior patterning of the 
axial skeleton by growth/differentiation factor 11. Nat. Genet. 22:260–264. 
41 
, BMS-986089: Scientific Report In Vitro Potency and Selectivity of 
BMS-986089 in Cell-based Luciferase Reporter Assays. Bristol-Myers Squibb Company; 
Jan 22, 2014. Document Control No. 930074468. 
42 
. BMD-986089: Scientific Report. An in Vitro Selectivity Study 
Testing BMS-989089 Blockade of GDF-8 and GDF-11 Cellular Signaling. Bristol-Myers 
Squibb Company; Jun 1, 2015. Document Control No. 930090594. 
43 Loffredo FS, et al. Growth differentiation factor 11 is a circulating factor that reverses 
age-related cardiac hypertrophy. Cell, 2013;153:828-839. 
44 Egerman MA, et al. (2015). "GDF11 Increases with Age and Inhibits Skeletal Muscle 
Regeneration." Cell Metab. 22, 164–174. 
45 Rodgers BD, and J. A. Eldridge JA. Reduced Circulating GDF11 Is Unlikely Responsible 
for Age-Dependent Changes in Mouse Heart, Muscle, and Brain. Endocrinology 
2 0 1 ; 156(11): 3885-3888. 


 
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46 Smith, S. C., et al. (2015). "GDF11 Does Not Rescue Aging-Related Pathological 
Hypertrophy." Circ Res 117(11): 926-932. 
47 Investigator Brochure: Anti-Myostatin Adnectin, RO7239361. F. Hoffmann-La Roche Ltd. 
Version 07, July 2018. 
48 Henricson E et al. The Cooperative International Neuromuscular Research Group Duchenne 
Natural History Study: Glucocorticoid treatment preserves clinically meanintful functional 
milestones and reduces rate of disease progression as measured by manual muscle testing and 
other commonly used clinical trial outcome measures. Muscle and Nerve; July 2013:55-67. 
49 Mazzone ES et al. Reliability of the North Star Ambulatory Assessment in a multicentric 
setting. Neuromuscular Disorders 2009; 19:458-461. 
50 Pane M, et al. Reliability of the Performance of Upper Limb Assessment in Duchenne 
muscular dystrophy. Neuromuscular Disorders 2014; 24: 201-206 
51 Damilakis J et al. Radiation exposure in X-ray-based imaging techniques used in osteoporosis. 
Eur Radiol 2010; 20: 2707-2714. 
52 Haschek W, Rousseaux C, Wallig M. 2010. Fundamentals of Toxicologic Pathology. 2nd 
Edition. London: Elseviers, Inc. 
53 Food and Drug Administration, FDA Briefing Document, Peripheral and Central Nervous 
System Drugs Advisory Committee Meeting, NDA 206031, Drisapersen, November 24, 2015. 
54 Rodriguez J, Vernus B, Chehl I, et al. Myostatin and the skeletal muscle atrophy and 
hypertrophy signaling pathways. Cell Mol Life Sci 2014;71:4361-71. 
55 Tando T, Hirayama A, Furukama M, Sato Y, et al.  Smad2/3 proteins are required for 
immobilization-induced skeletal muscle atrophy. J Biochem 2016;291:12184-94. doi: 
10.1074/jbc.M115.680579. 
56 Scott E, Eagle M, Mayhew A, et al. Development of a functional assessment scale for 
mbulatory boys with Duchenne muscular dystrophy and the North Star Clinical Network for 
Paediatric Neuromuscular Disease. Physio Res Int 2012;17:101-9. 
57 Mazzone E, Martinelli D, Bardinelli A, et al. North Star Ambulatory Assessment, 6-minute 
walk test and timed items in ambulant boys with Duchenne muscular dystrophy. 
Neuromuscul Disord 2010;20:712-6. 
58 Goemans NM, Tulinius M, van den Akker JT, et al. Systemic administration of PRO051 in 
Duchenne’s muscular dystrophy. N Engl J Med 2011;364:1513–22. 
 
 


 
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12. 
APPENDICES 


 
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APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS 
 
Term 
Definition 
4SC 
4 stair climb 
6MWD 
6 minute walk distance 
AE 
adverse event 
ACLS 
advanced cardiac life support 
ADA 
anti-drug antibody 
AI 
accumulation index 
AI_AUC 
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose 
AI_Cmax 
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose 
AI_Ctau 
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AT 
amino transaminases 
ATOM 
Advancing Trial Outcome Measures International, Ltd. 
AUC 
area under the concentration-time curve 
AUC(INF) 
area under the concentration-time curve from time zero extrapolated to 
infinite time 
AUC(0-T) 
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration 
AUC(TAU) 
area under the concentration-time curve in one dosing interval 
A-V 
Atrioventricular 
BID, bid 
bis in die, twice daily 
BLQ 
below limit of quantification 
BMI 
body mass index 
BMS 
Bristol-Myers Squibb 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
Celsius 
C12 
concentration at 12 hours 
24 
concentration at 24 hours 
Ca++ 
calcium 


 
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Term 
Definition 
Cavg 
average concentration 
CBC 
complete blood count 
Cexpected-tau 
expected concentration in a dosing interval 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CHF 
Congestive heart failure 
CI 
confidence interval 
C1- 
chloride 
CLcr 
creatinine clearance 
cm 
centimeter 
Cmax, CMAX 
maximum observed concentration 
Cmin, CMIN 
minimum observed concentration 
cMRI 
Cardiac magnetic resonance imaging 
CPF 
Cough peak flow 
CRC 
Clinical Research Center 
CRF 
Case Report Form, paper or electronic 
CS 
Corticosteroid 
Ct 
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (e.g., concentration at 24 hours, 
concentration at 12 hours, etc.) 
Ctau 
Concentration in a dosing interval (e.g., concentration at 24 
hours, concentration at 12 hours, etc.) 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough observed plasma concentration 
CV 
coefficient of variation 
D/C 
discontinue 
dL 
deciliter 
DMD 
Duchenne muscular dystrophy 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EF 
Ejection fraction 
e.g. 
exempli gratia (for example) 
EOSI 
events of special interest 
ESR 
Expedited Safety Report 


 
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Term 
Definition 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced Vital Capacity 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GFR 
Glomerular filtration rate 
GDF-8 
Growth and differentiation factor-8 
GLDH 
Glutamate dehydrogenase 
h 
Hour 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCO - 
3 
Bicarbonate 
HIV 
Human Immunodeficiency Virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
HUI-3 
Health Utility Index-3 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICD 
International Classification of Diseases 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
i.e. 
id est (that is) 
IEC 
Independent Ethics Committee 
IFU 
instructions for use 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IU 
International Unit 
IV 
Intravenous 
IWRS 
Interactive web response system 
K 
slope of the terminal phase of the log concentration-time curve 


 
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Term 
Definition 
K3EDTA 
potassium ethylenediaminetetraacetic acid 
K+ 
Potassium 
kg 
Kilogram 
L 
Liter 
LC 
liquid chromatography 
LDH 
lactate dehydrogenase 
ln 
natural logarithm 
LTBP4 
Latent transforming growth factor beta binding protein 4 
MAD 
Multiple ascending dose 
MEP 
Maximum expiratory pressure 
MIP 
Maximum inspiratory pressure 
mg 
Milligram 
Mg++ 
Magnesium 
min 
Minute 
mITT 
Modified intent to treat 
mL 
Milliliter 
mmHg 
millimeters of mercury 
MMRM 
Mixed model repeated measures 
MR 
medical research 
MRI 
Magnetic resonance imaging 
MRT 
mean residence time 
MS 
Mass spectrometry 
MTD 
maximum tolerated dose 
µg 
Microgram 
N 
number of subjects or observations 
Na+ 
Sodium 
NA 
not applicable 
NAB 
Neutralizing antibodies 
ng 
Nanogram 
NIMP 
non-investigational medicinal products 
NOAEL 
No observed adverse event level 
NSAA 
North Star Ambulatory Assessment Scale 
NSAID 
non-steroidal anti-inflammatory drug 
OL 
Open label 
pAUCe 
Extrapolated partial AUC from last quantifiable concentration to infinity 


 
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Term 
Definition 
Pb 
percent of bound drug 
PD 
pharmacodynamic 
PE 
Physical exam 
PedsQL FIM 
Pediatric Quality of Life Family Impact Module 
PFR 
Peak flow rate 
PFS 
pre-filled syringe 
PFTs 
Pulmonary function tests 
PK 
pharmacokinetic 
PODCI 
Pediatric Outcome Data Collection Instrument 
PO 
per os (by mouth route of administration) 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Pu 
percent of unbound drug 
PUL 
Performance of Upper Limb 
QC 
quality control 
QD, qd 
quaque die, once daily 
R2 
coefficient of determination 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SOP 
Standard Operating Procedures 
SPP1 
Secreted phosphoprotein 1 
t 
Temperature 
T 
Time 
TE 
Target engagement 
TFTs 
Timed function tests 
TGF-β 
transforming growth factor-β 
T-HALF 
Half life 
Tmax, TMAX 
time of maximum observed concentration 
Vss/F (or Vss) 
apparent volume of distribution at steady state 
W 
Washout 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 


 
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Term 
Definition 
x g 
times gravity 


 
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APPENDIX 2 
STUDY GOVERANCE CONSIDERATIONS 
The term "Participant" is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term "Subject" used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study. 
REGULATORY and ETHICAL CONSIDERATIONS 
GOOD CLINICAL PRACTICE 
This study will be conducted in accordance with: 
• Good Clinical Practice (GCP), 
• as defined by the International Council on Harmonisation (ICH) 
• in accordance with the ethical principles underlying European Union Directive 2001/20/EC 
• United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
• applicable local requirements. 
 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study. 
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(e.g., advertisements), and any other written information to be provided to subjects. The 
investigator or Roche should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures. 
 


 
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS 
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to: 
• IRB/IEC for 
• Regulatory Authority(ies), if applicable by local regulations (per national requirements) 
 
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to Roche. 
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment. 
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
FINANCIAL DISCLOSURE 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
 
INFORMED CONSENT PROCESS 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample 
informed consent form, which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki. 


 
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Investigators must: 
• Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
• Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study. 
• Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
• Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information. 
 
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant. 
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
U.S., the subjects’ signed HIPAA Authorization. 
The consent form must also include a statement that Roche and regulatory authorities have direct 
access to participant records. 
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the informed consent form approved for 
the study prior to clinical study participation. The explicit wish of a minor, who is capable of 
forming an opinion and assessing this information to refuse participation in, or to be withdrawn 
from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
 
SOURCE DOCUMENTS 
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 


 
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or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records). 
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
 
STUDY TREATMENT RECORDS 
Records for study treatments (whether supplied by Roche, its vendors, or the site) must 
substantiate study treatment integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
Roche/designee or a Health Authority. 
 


 
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If 
Then 
Supplied by Roche (or its vendors): 
Records or logs must comply with applicable 
regulations and guidelines and should include: 
• amount received and placed in storage 
area 
• amount currently in storage area 
• label identification number or batch 
number 
• amount dispensed to and returned by each 
participant, including unique participant 
identifiers 
• amount transferred to another area/site for 
dispensing or storage 
• nonstudy disposition (e.g., lost, wasted) 
• amount destroyed at study site, if 
applicable 
• amount returned to Roche 
• retain samples for 
bioavailability/bioequivalence, if 
applicable 
• dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form. 
Sourced by site, and not supplied by Roche or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy) 
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy. 
These records should include: 
• label identification number or batch 
number 
• amount dispensed to and returned by each 
participant, including unique participant 
identifiers 
• dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form. 
Roche or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements. 


 
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CASE REPORT FORMS 
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study. 
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. 
If electronic SAE form is not available, a paper SAE form can be used. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
Roche electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections. 
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the Roche electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals. 
 
MONITORING 
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of Roche must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents such as quality of life questionnaires. 
 


 
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In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. Roche audit reports will be kept confidential. 
The investigator must notify Roche promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
 
RECORDS RETENTION 
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by Roche or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact Roche prior to destroying any records 
associated with the study. 
Roche or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed. 
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to Roche or designee. 
 
RETURN OF STUDY TREATMENT 
For this study, study treatments (those supplied by Roche, a vendor or sourced by the investigator) 
such as partially used study treatment kits, vials and syringes may be destroyed on site. 
 
If 
Then 
Study treatments supplied by Roche 
(including its vendors) 
Any unused study treatments supplied by 
Roche can only be destroyed after being 
inspected and reconciled by the responsible 
Study Monitor unless study treatments kits 
must be immediately destroyed as required 
for safety, or to meet local regulations (e.g., 
cytotoxics or biologics). 
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor. 
Study treatments sourced by site, not supplied 
by Roche (or its vendors) (examples 
include study treatments sourced from the 
sites stock or commercial supply, or a 
specialty pharmacy) 
It is the investigator’s or designee’s 
responsibility to dispose of all kits 
according to the institutional guidelines and 
procedures. 
 
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for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to Roche upon request. 
• Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the kits. The method 
of disposal, incinerator, licensed sanitary landfill, or licensed waste disposal vendor must be 
documented. 
• Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period. 
 
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty kits. 
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by Roche (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by Roche, is solely the responsibility of the investigator 
or designee. 
 
CLINICAL STUDY REPORT AND PUBLICATIONS 
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria: 
• External Principal Investigator designated at protocol development 
• National Coordinating Investigator 
• Study Steering Committee chair or their designee 
• Participant recruitment (e.g., among the top quartile of enrollers) 
• Involvement in trial design 
• Regional representation (e.g., among top quartile of enrollers from a specified region or country) 
• Other criteria (as determined by the study team) 
 
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA. 


 
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APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING 
 
ADVERSE EVENTS 
 
Adverse Event Definition: 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug. 
 
 
SERIOUS ADVERSE EVENTS 
 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose: 
Results in death 
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
NOTE: 
The following hospitalizations are not considered SAEs in Roche clinical studies: 
o a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life- threatening 
event) 
o elective surgery, planned prior to signing consent 
o admissions as per protocol for a planned medical/surgical procedure 
o routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 
o medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases 
 


 
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o admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason) 
o admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 
is an important medical event (defined as a medical event(s) that may not be immediately life- 
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, cancer, and potential drug induced liver injury (DILI) are not always 
serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5 for 
reporting pregnancies). 
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
 
EVALUATING AEs AND SAEs 
 
Assessment of Causality 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
 
 
 


 
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Assessment of severity 
The following categories and definitions of severity as determined by a physician should be 
used for assessing severity of adverse events: 
• Mild (Grade 1):  Awareness of event but easily tolerated 
• Moderate (Grade 2):  Discomfort enough to cause some interference with usual activity 
• Severe (Grade 3):  Inability to carry out usual activity 
• Very severe (Grade 4):  Debilitating, significantly incapacitates subject despite 
symptomatic therapy 
 
 
Follow-up of AEs and SAEs 
If only limited information is initially available, follow-up reports are required.  
(Note: Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to Roche 
(or designee) using the same procedure used for transmitting the initial SAE report. 
All SAEs must be followed to resolution or stabilization. 
 
OVERDOSE, MEDICATION ERROR, DRUG MISUSE AND DRUG ABUSE 
 
Definition: 
Accidental overdose:  accidental administration of a drug in a quantity that is higher than the 
assigned dose. 
Intentional overdose:  intentional administration of a drug in a quantity that is higher than the 
assigned dose. 
Medication error:  accidental deviation in the administration of a drug (in some cases, a 
medication error may be intercepted prior to administration of the drug). 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or dependence,  
physical harm, and/or psychological harm. 
Drug misuse:  intentional deviation in the administration of a drug that does not qualify as drug 
abuse (drug misuse could involve the drug being administered to someone other than the patient). 
 
 
 
 
 
REPORTING OF SAEs TO SPONSOR OR DESIGNEE 


 
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• SAEs, whether related or not related to study drug, and pregnancies must be reported to 
Roche (or designee) within 24 hours of awareness of the event. 
• SAEs  must  be  recorded  on  the  SAE  Report  Form;  pregnancies  on  a  Pregnancy 
Surveillance Form (electronic or paper forms). 
• The preferred method for SAE data reporting collection is through the eCRF. 
• The paper SAE/pregnancy surveillance forms are only intended as a back-up option 
when the eCRF system is not functioning. 
o In this case, the paper forms are to be transmitted via email or  confirmed 
facsimile (fax) transmission to: 
SAE Email Address: Refer to Contact Information list. 
SAE Facsimile Number: Refer to Contact Information list. 
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site. 
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list 


 
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APPENDIX 4 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL. 
Appropriate patient-centered counseling of adolescent trial subjects about contraception and 
sexual health topics should be provided, including acceptable, highly effective methods as 
described below. 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. Female partners of male subjects, who are WOCBP, are expected to use one of the 
highly effective methods of contraception listed below. Male subjects must inform their female 
partners who are WOCBP of the contraceptive requirements of the protocol and are expected 
to adhere to using contraception with their partner. Contraception methods are as follows: 
1. Progestogen only hormonal contraception associated with inhibition of ovulation. 
2. Hormonal methods of contraception including oral contraceptive pills containing 
combined estrogen + progesterone, vaginal ring, injectables, implants and intrauterine 
devices (IUDs) such as Mirena® 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator. 
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study treatment(s) plus 5 half-lives of the 
study treatment [RO7239361; 50 days] plus 90 days (duration of sperm turnover) for a total of 
140 days (5 months) post-treatment completion. 
• Azoospermic males are exempt from contraceptive requirements; however, use of condom in 
male subjects (including azoospermic males) who are sexually active with a pregnant partner is 
required. 
• Male participants must be willing to refrain from sperm donation during the entire study and 
for 5 half-lives of study treatment plus 90 days (duration of sperm turnover) 140 days after 
dosing has been completed. 
 
 
2. 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.