A Multi-Site, Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Subcutaneous Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7239361 (BMS-986089) in Ambulatory Boys With Duchenne Muscular Dystrophy
Phase: PHASE1
Conditions: Muscular Dystrophy (DMD)
Sponsor: Hoffmann-La Roche

Official Title:  
A Multi-Site, Randomized, Placebo-Controlled, Double-Blind, Multiple 
Ascending Subcutaneous Dose Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of RO7239361 (BMS-986089) in Ambulatory Boys with 
Duchenne Muscular Dystrophy 
 
NCT Number:   
NCT02515669 
 
Document Dates:  
Protocol Amendment/Version 6: 14-Oct-18 

FINAL PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
Protocol WN40226, Version 6
PROTOCOL
TITLE:
A MULTI-SITE, RANDOMIZED, 
PLACEBO-CONTROLLED, DOUBLE-BLIND, 
MULTIPLE ASCENDING SUBCUTANEOUS DOSE 
STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF 
RO7239361 IN AMBULATORY BOYS WITH 
DUCHENNE MUSCULAR DYSTROPHY
PROTOCOL NUMBER:
WN40226 
VERSION NUMBER:
6
EUDRACT NUMBER:
2015-005455-28
IND NUMBER:
120,702
TEST PRODUCT:
Anti-Myostatin Adnectin (RO7239361)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
 
14-Oct-2018 20:17:19
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
2/Protocol WN40226, Version 6
DOCUMENT HISTORY
Document
Date of Issue
Summary of Changes
Protocol 06
See electronic
(Version 6)
date stamp.
Incorporates Amendment 06
Amendment 06
See electronic
- Changed IMP dose in the open-label extension (OLE) phase
date stamp.
- Changed IMP from vial to prefilled syringes (PFS) in the OLE
- Changed the study assessments and procedures to add a new 
                                                                 clinic visits, PK/PD and safety assessments after the switch to PFS
                                                              - Updated Medical Monitor information
                                                              - Product Development Background and Overall Risk/Benefit sections   
                                                                 have been updated
                                                              - Updated monitoring of anti-drug antibodies (ADAs) during 24-week 
follow-up period
                                                              - Deleted references to BMS study and drug number
Revised
Protocol 05
(Version 5)
21 Aug 2017
Incorporated Amendment 05
Amendment 05
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
Revised
Protocol 04
21-Feb-2017
Incorporated Amendment 04
- Added OLE phase to the study
Amendment 04
21-Feb-2017
Revised
- Updated plan for clinical study reports
- Incorporated administrative corrections which were included in
Administrative Letters 03 and 04
Protocol 03
21-Apr-2016
Incorporated Amendment 03
- Clarification added after the withdrawal of study drug into an
appropriate-sized syringe, the product should be administered SC within
4 hours to align with our current investigational brochure.
-Updated CN001-001 safety information
-Removed the exclusion criteria: baseline 4SC 9 Day -1) more than a
20% or 0.5 second reduction, whichever is greater, from the valid
screening 4SC 9 Day -45 to Day -7) used to determine eligibility.
Amendment 03
21-Apr-2016
Revised
- The wash out period of prior investigational drug exclusion criteria is
clarified to 5 half-lives, removing the 3 month criteria.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
3/Protocol WN40226, Version 6
- The addition of vital signs in the 
open label phase at week 2 & 3.
- The addition of the 
PODCI measurement in 
the open-label phase at Weeks 12, 24 and 36.
- Administrative corrections which were included in the administrative
letter 01 and 02
- Administrative changes and clarifications
Protocol 02
09-Dec-2015
Incorporates Amendment 02
- Removed ACTIVE assessment from study procedures
- Clarified inclusion/exclusion criteria (4SC, use of bisphosphonates,
Amendment 02
09-Dec-2015
subject travel distance to site, etc.)
- Updated number of planned interim analyses
- Administrative changes and clarifications
Document
Date of Issue
Summary of Change
Revised
Protocol 01
18-Sep-2015
Incorporated Amendment 01
- Updated schedule and clarified data to be included in the interim
analyses
- Added additional laboratory assessments for additional safety
monitoring and added storage of residual plasma sample remaining after
GLDH analysis for up to five years after the last subject’s last study visit
Amendment 01
18-Sep-2015
- Clarified the secondary and exploratory endpoints associated with MRI
and MRS procedures and clarified that MRS will be conducted at selected
sites as training is completed
- Added video recording of some of the exploratory functional
assessments to ensure quality of assessments or identify potential issues
requiring re-training of clinical evaluators
- Administrative changes and clarifications
Original
Protocol
08-Jul-2015
Not applicable

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
4/Protocol WN40226, Version 6
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTI-SITE, RANDOMIZED, PLACEBO-
CONTROLLED, DOUBLE-BLIND, MULTIPLE 
ASCENDING SUBCUTANEOUS DOSE STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF RO7239361 IN 
AMBULATORY BOYS WITH DUCHENNE MUSCULAR 
DYSTROPHY
PROTOCOL NUMBER:
WN40226 
VERSION NUMBER:
6
EUDRACT NUMBER:
2015-005455-28
IND NUMBER:
120,702
TEST PRODUCT:
Anti-Myostatin Adnectin (RO7239361)
MEDICAL MONITOR:
 M.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
5/Protocol WN40226, Version 6
SYNOPSIS
Protocol Title: A Multi-Site, Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Subcutaneous
Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of RO7239361 in Ambulatory Boys with
Duchenne Muscular Dystrophy
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational
Product(s): Each subject will be administered weekly subcutaneous (SC) doses of RO7239361 or placebo for
24 weeks. Subjects will be assigned to one of three dose panels. The initial 24-week double-blind phase will be
followed by a 48-week open-label (OL) phase. During the OL phase, all subjects will receive weekly SC doses of
RO7239361 for 48 weeks at the active dose corresponding to the dose in their originally assigned panel. In the OL
extension (OLE) phase, all subjects will continue to receive weekly unblinded SC doses of RO7239361 for up to
228 weeks, or until RO7239361 is commercially available, whichever comes first. Doses may be adjusted based
on emerging data.
Study Phase: Ib/II
Research Hypothesis: The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, free
myostatin suppression, and immunogenicity of multiple SC doses of RO7239361 in boys with Duchenne muscular
dystrophy (DMD).
Objectives:
Primary Objective:

To assess the safety and tolerability of multiple SC doses of RO7239361 in boys with DMD
Secondary Objectives:

To evaluate the pharmacokinetics of multiple SC doses of RO7239361 in boys with DMD

To evaluate the immunogenicity of multiple SC doses of RO7239361 in boys with DMD

To evaluate the effects of RO7239361 on free myostatin and myostatin-drug complex levels in boys with
DMD

To evaluate magnetic resonance imaging (MRI) measures of right thigh maximal cross-sectional area (CSAmax)
and contractile versus non-contractile content
Exploratory Objectives:

To explore the pharmacodynamic (PD) effects of multiple doses of RO7239361 in boys with DMD on:
o
Measures of function, including timed function tests (TFTs): 4-stair climb (4SC), 4-stair descend (4SD), 
10- m walk/run,
standing
from supine),
6-minute
walk
distance (6MWD),
and
the
North
Star
Ambulatory Assessment Scale (NSAA)
o
Serum analytes that include but are not limited to:

miR-206, miR-133a, miR-1, miR-6 (control miR), miR-21, miR-39, and other miRNAs

Transforming growth factor(TGF-) concentrations, which are associated with fibrosis of muscle seen
in DMD

Serum creatine kinase concentrations and creatine kinase-muscle (CK-MM), which are associated with
muscle atrophy in DMD
o
Urine analytes that include but are not limited to:

Titin protein amino-terminal fragment concentrations that are associated with muscle damage
o
Manual myometry measures of upper and lower extremity strength
o
Ankle range of motion in degrees
o
Dual-energy X-ray absorptiometry (DXA) scanning measures of total lean body mass, fat mass, and bone
mineral density
o
Magnetic resonance spectroscopy (MRS) measures of right thigh lipid fraction
o
Health-related quality of life as measured by the Pediatric Outcome Data Collection Instrument (PODCI)
o
Pulmonary function tests (PFTs), including forced vital capacity (FVC), forced expiratory volume in

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
6/Protocol WN40226, Version 6
1 second (FEV1), maximal expiratory pressure (MEP), maximal inspiratory pressure (MIP), cough peak
flow (CPF), and peak flow rate (PFR)
o
Upper extremity motor ability measured using the Performance of Upper Limb Scale (PUL)

To explore the effect of genetic variation in genes suspected to impact DMD disease expression (including but
not limited to LTBP4, SPP1) on target engagement, PD, or function test endpoints 13, 14, 15
Study Design: This is a multi-site, randomized, placebo-controlled, double-blind, multiple-ascending SC dose study
to assess the safety and tolerability of RO7239361 in ambulatory boys with DMD. The initial 24-week double-blind
phase will be followed by a 48-week OL phase. The initial phase will have two parts: Part A and Part B. Following
the 48-week OL phase, subjects will have the option to continue treatment in an OLE phase.
Part A will include 3 dose panels of 5 to < 11 year old (the age of the subject is the age at randomization)
ambulatory subjects with DMD and will consist of 4 weeks of double- blind dosing. Panels 13 will randomize
approximately 8 subjects each (randomized 3:1 to RO7239361 or placebo). If, after all subjects in a Panel have
been randomized, and it is determined that older or younger ages are underrepresented, the Panel may be opened to
additional subjects of specific ages, even if 8 subjects have already been randomized. Opening Panels 13 to more
than 8 subjects may provide more robust safety and tolerability data in certain age ranges. Roche will inform sites if
and when dose panels are opened to additional subjects. All subjects will receive weekly (Day 1, Day 8, etc.)
SC doses of RO7239361 or placebo.
In Panels 1 and 2, up to 4 subjects can be randomized on 1 day. Once the third subject randomized reaches Day 8,
the remaining 4 subjects in that dose panel may be randomized. The rationale for this sentinel dosing is to observe
safety and tolerability for 7 days post dose, in at least 1 subject randomized to RO7239361 before continuing to
dose the remaining subjects within a panel. In addition, dose initiation in Panels 2 and 3 will begin only after Day 14
has been completed by at least 6 of 8 subjects participating in the preceding panel and all available safety and
tolerability data have been reviewed and deemed safe to proceed by the study investigators (Principal Investigator or
designee) and the Roche Medical Monitor. Prior to dose escalation the Roche Medical Monitor and the
investigators must agree that it is safe to proceed with dose escalation to the next panel.
A body weighttiered (for Panels 2 and 3), fixed- dose strategy targeting the approximate achievement of
moderate (> 50% suppression), high (> 85%) and near complete (> 95%) suppression of serum free myostatin
levels for Panels 1, 2, and 3, respectively, was used to select the three doses for the study. The body weighttiered
(for Panels 2 and 3) doses are presented in Tables 1, 2, and 3 below:
Table 1:
Panel 1 Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
15 kg
4.0 mg/0.08 mL
Table 2:
Panel 2 Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
15 kg to 45 kg
45 kg
12.5 mg/0.25 mL
20.0 mg/0.4 mL

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
7/Protocol WN40226, Version 6
Table 3:
Panel 3 Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
15 kg to 45 kg
45 kg
35 mg/0.7 mL
50.0 mg/1 mL
Table 4:
Expansion Panel Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
15 kg to 45 kg
45 kg
35 mg/0.7 mL
       50.0 mg/1 mL
Following the PK and PD assessment in this study, if the PD targets were not achieved (e.g., myostatin
inhibition was much higher than 40% in all dose groups OR if none of the dose groups achieved >90%
inhibition), dose modification may be performed and additional dose cohorts may be enrolled to confirm
exposures and myostatin inhibition at the modified dose. Modified doses will be selected so that the estimated
exposures in pediatric subjects will not exceed those observed in adults.
The dose selected for the Expansion Panel will be a safe and well tolerated dose that is less than or equal to the
highest dose tested in the panels. The Expansion Panel will provide additional safety, tolerability, PD, and functional
data at a dose anticipated to be efficacious. As such, a dose that produces > 90% suppression in serum levels of
free myostatin is expected to be efficacious. A review of safety data from Panels 13 supports the selection of the 
Panel 3 dose (35 mg for subjects 15 kg to 45 kg; 50 mg for subjects > 45 kg).
Part B will include 20 weeks of continued double-blind dosing in Panels 13 and an Expansion Panel of 24-week
double-blind dosing. The Expansion Panel will randomize approximately 16 subjects (randomized 3:1 to
RO7239361 or placebo). The Expansion Panel will be initiated only after at least 2 weeks of dosing has been
completed by at least 6 subjects participating in Panel 3 and all available safety and tolerability data, including but
not limited to, injection-site reactions, reported adverse events (AEs), clinical laboratory results and vital signs have
been reviewed and deemed safe to proceed by the study investigators and the Roche Medical Monitor. The Expansion
Panel may be opened to additional subjects to either explore another dose that may be safe and efficacious or to
provide additional safety and tolerability data.
Upon completion of 24 weeks of double-blind dosing, all subjects will be eligible to enter the OL phase. In this
phase, all subjects will receive unblinded RO7239361 SC doses, weekly for 48 weeks. Subjects in the OL phase
will receive the active dose corresponding to the dose in their originally assigned Panel. Dosing in the OL phase
may be adjusted based upon emerging safety and tolerability data and/or upon the results of the interim analysis (IA)
of the double-blind data. The schedule of events in the OL phase is described in Table 5.1-3.
Upon completion of the 48- week OL phase, all subjects will have the option to continue treatment in the
OLE phase. Dosing in the OLE phase may be adjusted based on emerging safety and tolerability data and/or upon
the results of IAs. During the OLE phase, all subjects will switch from the vial formulation to a prefilled syringe 
(PFS) dosage formulation corresponding to the same dose from Panel 3 (i.e., the 35-mg dose if a subject's body weight 
is15 kg to 45 kg and the 50-mg dose if the subject's body weight is >45 kg). The schedule of events in the OLE 
phase is described in Table 5.1-4.
Any subject who discontinues from the study early or who does not enroll in a rollover protocol should enter the
follow- up phase of the study. The follow-up phase of the study is up to 24 weeks in length.
Subjects should
provide immunogenicity samples at all follow-up visits.
Up to five IAs are planned. The content and timing of the IAs are described in Section 8.5 of the protocol.
Measures of function, including TFTs (4SC, 4SD, 10-m walk/run, stand from supine), 6MWD, the NSAA, manual
myometry measures of upper and lower extremity strength, ankle range of motion, PFTs, and PUL measures of
upper extremity motor ability, echocardiograms, laboratory assessments, MRI and MRS scanning of the right thigh

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
9/Protocol WN40226, Version 6

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 3 months 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 3 months prior to start of study treatment.

Treatment with ataluren, or any investigational drug (excluding deflazacort) currently or within 5 half-lives
(whichever is longer) 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 washout duration.

Treatment with exon skipping therapies within 6 months prior to the start of study drug administration

History of major surgical procedure within 6 weeks prior to the start of study drug administration.

Any injury, which may impact functional testing. Previous injuries, including fractures, must be fully healed
prior to consenting.

Expectation of major surgical procedure, such as scoliosis surgery, during the treatment period of this study.

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 MRI, MRS or DXA scans) or
unable to complete right thigh MRI scan or DXA scan

Ongoing immunosuppressive therapy (other than corticosteroids)

Current or prior treatment within 3 months prior to the start of study drug administration with androgens, human
growth hormone

Requirement of daytime ventilator assistance

Uncontrolled
clinical
signs
and
symptoms
of
CHF
(American
College
of
Cardiology/American 
Heartassociated Stage C or Stage D).
Study Drug: Includes both investigational (medicinal) product (IP) and non-investigational (medicinal) product
(non-IP) as listed:
Study Drug
Medication
Potency
IP/Non-IP
RO7239361 vial
RO7239361 matching placebo vial
RO7239361 35-mg prefilled syringe
RO7239361 50-mg prefilled syringe
50 mg/mL
0 mg/mL
50 mg/mL
71.4 mg/mL
IP
IP
IP
IP
Study drug preparation and administration instructions will be provided in a separate manual.
Study Assessments:

Safety Outcome Measures: All subjects who received treatment (RO7239361 or placebo) will be evaluated
for safety. Safety assessments will be based on medical review of adverse event reports (including injection-site
reactions) and the results of vital sign measurements, ECGs, echocardiograms, physical examinations,
immunogenicity, and clinical laboratory tests. The incidence of observed adverse events will be tabulated and
reviewed for potential significance and clinical importance. Cardiac safety assessments (e.g., echocardiogram)
will be used to evaluate baseline ejection fraction and to assess for any impact of RO7239361 on this endpoint.

PK Measures: The pharmacokinetics of RO7239361 following multiple doses will be assessed by measuring
serum concentrations of RO7239361 at selected timepoints.

Target Engagement Measures: Effects of multiple doses of RO7239361 on free myostatin and drug myostatin 
complex will be assessed by measuring these markers in serum at selected timepoints.

Immunogenicity Measures: Detection of anti-RO7239361 antibodies (anti-drug antibodies [ADAs]) will be
assessed at selected timepoints. Additional characterization of immunogenicity samples for any detected
antibodies may also be performed.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
10/Protocol WN40226, Version 6

Imaging Measures: MRI measures of right thigh maximal cross-sectional area (CSAmax), and contractile
versus non-contractile content and MRS measures of right thigh lipid fraction (MRS procedures will be
completed at selected sites, based on completed training).

Exploratory PD Measures: Effects of multiple doses of RO7239361 on the following:
o
Measures of function, including TFTs, 6MWD, and the NSAA scale
o
Serum analytes that may include but are not limited to:

miR-206, miR-133a, miR-1, miR-6 (control miR), miR-21, and miR-39

TGF-concentrations, which are associated with fibrosis of muscle seen in DMD

Follistatin

Serum creatine kinase concentrations and creatine kinase-muscle (CK-MM) which are associated with
muscle atrophy in DMD
o
Urine analytes that include but are not limited to:

Titin protein amino-terminal fragment concentrations that are associated with muscle damage
o
Upper and lower extremity strength obtained via hand held myometry assessments of strength
o
Measures of ankle range of motion
o
DXA scanning measures of total lean body mass, fat mass, and bone mineral density
o
MRS measure of right thigh lipid fraction
o
Pulmonary function tests, including FVC, FEV1, MEP, MIP, CPF, and PFR
o
Health-related quality of life (will be obtained using the PODCI)
o
Upper extremity motor ability as measured using the PUL

Genetic variation: Explore the effect of genetic variation in genes suspected to impact DMD disease expression
(including but not limited to LTBP4, SPP1) on target engagement, PD or function test endpoints13,14,15
Statistical Considerations:
Sample Size: Overall, approximately 40 subjects will be randomized in this study. Panels 13 will each have
approximately 8 subjects and the Expansion Panel will have approximately 16 subjects. In all panels, the age range is
between 5 and < 11. The panels may be opened to additional subjects if certain ages are underrepresented in
the panels. Further details are included in Section 8.1.
Endpoints:
Primary Endpoint:
The primary endpoints of the study are safety and tolerability endpoints, including incidence of AEs, serious AEs,
AEs leading to discontinuation and death, as well as marked treatment emergent abnormalities in clinical laboratory
tests, vital sign measurements, ECGs, echocardiograms, and physical examinations across treatment conditions
during 24 weeks of double-blind treatment.
Secondary Endpoints:
The secondary endpoints include Cmax and Ctrough of serum RO7239361 concentrations, serum concentration of free
myostatin and drug-myostatin complex, percent
inhibition of free
myostatin
at
trough,
anti-RO7239361
antibodies, and MRI measurements of changes from baseline in right thigh CSAmax and fold number changes in
contractile versus non-contractile content during the 24-week double-blind treatment period, compared to placebo.
Additional characterization of immunogenicity samples for any detected antibodies will also be performed. All 
timepoints are specified in Table 5.1-1 through Table 5.1-3.
Exploratory Endpoints:

Measures of function, including TFTs, 6MWD, and the NSAA

Serum analytes that may include but are not limited to:
o
miR-206, miR-133a, miR-1, miR-6 (control miR), miR-21, miR-39, and other miRNAs
o
TGF-concentrations which are associated with fibrosis of muscle seen in DMD
o
Follistatin

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
11/Protocol WN40226, Version 6
o
Serum creatine kinase concentrations and creatine kinase-muscle (CK-MM) which are associated with
muscle atrophy in DMD

Urine analytes that include but are not limited to:
o
Titin protein amino-terminal fragment concentrations that are associated with muscle damage

Upper and lower extremity strength obtained by hand held myometry

Ankle range of motion

DXA measures of total lean body mass, fat mass and bone mineral density

MRS measures of right thigh lipid fraction

Measures of pulmonary function, including FVC, FEV1, MEP, MIP, CPF and PFR

Health related quality of life as measured by the PODCI

Upper extremity motor ability as measured using the PUL

Genetic variation status of in genes suspected to impact DMD disease expression (including but not limited to
LTBP4, SPP1)
Analyses:
Primary Endpoint:
Safety: All recorded AEs will be listed and tabulated by system organ class, preferred term and treatment.
Any physical examination findings will be listed. ECG, echocardiogram, vital signs and clinical laboratory test
results and corresponding change from baseline values will be listed and summarized by treatment panel. Values
for ECG, vital signs and clinical laboratory test results outside the pre-specified criteria will also be listed and 
summarized. The placebo data will be pooled as one group.
Summary statistics will be presented for each echocardiogram, ECG, vital sign parameters, and the corresponding 
changes from baseline by treatment panel and timepoint. Plots of the mean change from baseline value for each 
parameters versus time since dosing will be presented by treatment panel. The last pre-dose value is defined as 
baseline value.
Secondary Endpoints:
Pharmacokinetics: RO7239361 serum concentrations will be summarized by treatment group, study day and 
times postdose. To assess the attainment of steady state, geometric mean Ctrough values will be plotted versus study
day. Cmax and Ctrough will be summarized by treatment group, study day and times postdose.
Dose Proportionality: Dose proportionality of RO7239361 will be assessed by estimating the slope of the
linear regression of the natural log of the PK parameter (Cmax and Ctrough) on the natural log of dose (by tiered
weight) using the power model described by Gough et al.27
Target Engagement: Free myostatin and myostatin-drug complex will be tabulated by dose and study day,
and the corresponding changes from baseline and percent change from baseline will be calculated and summarized.
Profile plots may be provided.
A dose-response (exposure-response) analysis may be applied to characterize the relationship between dose levels
(PK parameters) of RO7239361 and free myostatin and/or myostatin drug complex
Immunogenicity: Immunogenicity test results will be listed and summarized by treatment. 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, if sizes of the subgroups warrant such.
MRI measures: A dose-response (exposure-response) analysis may be applied to characterize the
relationship between dose levels (PK parameters) of RO7239361 and MRI measures of right thigh maximal
cross-sectional area (CSAmax) and contractile versus non-contractile content.
Exploratory Analysis:
PK and target engagement data collected in this study may be used to develop a population PK/PD model to
estimate model-derived population and individual PK/PD parameters (e.g., CL/F, Vc/F, Ka, etc) and may be reported
separately from the clinical study report.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
12/Protocol WN40226, Version 6
All the exploratory endpoints such as miRNA 206, urine titin fragment concentration, exploratory blood biomarkers,
measures of function, DXA measures of total lean body mass, fat mass, and bone mineral density, MRS measures of
right thigh lipid fraction, and PFTs will be tabulated by dose and study day; and the corresponding changes from
baseline and percent change from baseline will be calculated and summarized. Profile plots may be provided.
Key primary, secondary or exploratory endpoints may be characterized for subject subgroups with specific genetic
variations (including. but not limited to, LTBP4, SPP1). When sample size permit, dose/exposure response model
will be used to quantify dose-dependent treatment effects.
Interim Analyses:
Up to five IAs are planned until all subjects have completed Week 72 of the study, after which additional IAs may be 
conducted. The first IA may be conducted when 4-week data of Panels 1 and 2 are available. The timing of the
second and third IAs may be based on when the 4-week data of Panel 3 are available and when the 24-week data of 
Panels 1 and 2 are available, the timing to be based on the milestone. A fourth IA will be conducted when all subjects
have completed the (24-week) double-blind phase. A fifth IA will be conducted to support regulatory submissions
for marketing approval. The first three IAs will include available safety and tolerability data but not PD or
functional data from the Expansion Panel.

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TABLE OF CONTENTS
TITLE PAGE................................................................................................................
1
DOCUMENT HISTORY..............................................................................................
2
PROTOCOL AMENDMENT ACCEPTANCE FORM…………………..................
4
SYNOPSIS....................................................................................................................
5
TABLE OF CONTENTS..............................................................................................
13
1 INTRODUCTION AND STUDY RATIONALE .....................................................
16
1.1 Study Rationale.................................................................................................
16
1.2 Rationale for Change to Prefilled Syringe..........................................................
20
1.3 Rationale for Specific Inclusion/Exclusion Criteria........................................
20
1.4 Research Hypothesis.........................................................................................
21
1.5 Objectives(s).....................................................................................................
22
1.5.1 Primary Objectives ..................................................................................
22
1.5.2 Secondary Objectives...............................................................................
22
1.5.3 Exploratory Objectives ............................................................................
22
1.6 Product Development Background...................................................................
23
1.6.1 Pharmacology..........................................................................................
23
1.6.2 Toxicity.....................................................................................................
23
1.6.3 Preclinical Metabolism and Pharmacokinetics.......................................
24
1.6.4 Clinical Pharmacology and Safety ..........................................................
25
1.6.4.1 Pharmacokinetics of RO7239361 .................................................
26
1.7 Overall RiskBenefit Assessment .....................................................................
26
2 ETHICAL CONSIDERATIONS...............................................................................
28
2.1 Good Clinical Practice......................................................................................
28
2.2 Institutional Review Board/Independent Ethics Committee.............................
29
2.3 Informed Consent..............................................................................................
29
3 INVESTIGATIONAL PLAN....................................................................................
30
3.1 Study Design and Duration...............................................................................
30
3.2 Post-Study Access to Therapy...........................................................................
34
3.3 Study Population...............................................................................................
34
3.3.1 Inclusion Criteria.....................................................................................
34
3.3.2 Exclusion Criteria....................................................................................
35
3.3.3 Women of Childbearing Potential ...........................................................
37
3.4 Concomitant Treatments...................................................................................
37
3.4.1 Prohibited and/or Restricted Treatments.................................................
37
3.4.2 Other Restrictions and Precautions.........................................................
37
3.4.2.1 Imaging Contraindications (MRI/MRS/DXA).................................
37
3.4.2.2 Management of Possible Acute Hypersensitivity Reactions to
RO7239361...................................................................................................
38
3.5 Discontinuation of Subjects following any Treatment with Study Drug..........
39
3.6 Post-Study Drug Follow-up...............................................................................
40
3.6.1 Withdrawal of Consent ............................................................................
40
3.6.2 Lost to Follow-Up....................................................................................
41
4 STUDY DRUG..........................................................................................................
41
4.1 Investigational Product .....................................................................................
44

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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4.2 Non-investigational Product .............................................................................
44
4.3 Storage and Dispensing.....................................................................................
44
4.4 Method of Assigning Subject Identification.....................................................
45
4.5 Selection and Timing of Dose for Each Subject...............................................
45
4.6 Blinding/Unblinding.........................................................................................
47
4.7 Treatment Compliance......................................................................................
48
4.8 Destruction of Study Drug................................................................................
48
4.9 Return of Study Drug........................................................................................
49
4.10 Retained Samples for Bioavailability / Bioequivalence .................................
49
5 STUDY ASSESSMENTS AND PROCEDURES.....................................................
49
5.1 Flow Charts/Time and Events Schedules............................................................
49
5.1.1 Retesting during Screening or Lead-in Period .......................................
81
5.2 Study Materials.................................................................................................
81
5.3 Safety Assessments...........................................................................................
82
5.3.1 Echocardiogram ......................................................................................
82
5.3.2 Electrocardiograms .................................................................................
82
5.3.3 Laboratory Test Assessments...................................................................
82
5.4 Efficacy Assessments........................................................................................
84
5.4.1 Primary Efficacy Assessment...................................................................
84
5.4.2 Secondary Efficacy Assessments..............................................................
85
5.5 Pharmacokinetic Assessments ..........................................................................
85
5.5.1 Pharmacokinetics: Collection and Processing........................................
85
5.5.2 Pharmacokinetic Sample Analyses ..........................................................
86
5.5.3 Target Engagement Sample Analyses......................................................
86
5.5.4 Labeling and Shipping of Biological Samples.........................................
86
5.6 Biomarker Assessments....................................................................................
87
5.6.1 Biomarker Imaging Assessments .............................................................
87
5.6.1.1 Thigh MRI and MRS .......................................................................
87
5.6.1.2 DXA.................................................................................................
87
5.6.2 Exploratory Urine Biomarker Assessments.............................................
88
5.6.3 Exploratory Serum Biomarker Assessments............................................
88
5.6.4 Exploratory Plasma Biomarker Assessments ..........................................
88
5.7 Exploratory Assessments..................................................................................
88
5.7.1 Functional Endpoints Assessments..........................................................
89
5.7.2 Myometry and Ankle Range of Motion (ROM)........................................
89
5.7.3 Exploratory Genotyping...........................................................................
89
5.7.4 Performance of Upper Limb Scale (PUL)...............................................
89
5.7.5 Pulmonary Function Tests (PFTs)...........................................................
90
5.8 Outcomes Research Assessments .....................................................................
90
5.9 Other Assessments............................................................................................
90
5.9.1 Injection Site Assessments........................................................................
90
5.10 Additional Research Collection......................................................................
90
6 ADVERSE EVENTS.................................................................................................
90
6.1 Serious Adverse Events ....................................................................................
91
6.1.1 Serious Adverse Event Collection and Reporting....................................
92
6.2 Non-serious Adverse Events..............................................................................
93
6.2.1 Non-serious Adverse Event Collection and Reporting..............................
93

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6.3 Laboratory Test Result Abnormalities..............................................................
6.4 Pregnancy..........................................................................................................
6.5 Overdose  ...........................................................................................................
6.6 Other Safety Considerations.............................................................................                   94
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL
   COMMITTEES........................................................................................................
8STATISTICALCONSIDERATIONS......................................................................
8.1SampleSizeDetermination...............................................................................
8.2 Populations for Analyses..................................................................................
8.3 Endpoints ..........................................................................................................
8.3.1PrimaryEndpoint(s)................................................................................
8.3.2SecondaryEndpoint(s).............................................................................
8.3.3ExploratoryEndpoint(s)..........................................................................
8.4  Analyses............................................................................................................
8.4.1 Demographics and Baseline Characteristics...........................................
8.4.2EfficacyAnalyses.....................................................................................
8.4.3SafetyAnalyses.........................................................................................
8.4.4PharmacokineticAnalyses.......................................................................
8.4.5 Target Engagement Analyses...................................................................
8.4.6BiomarkerAnalyses.................................................................................
8.4.7 Exploratory Biomarker Analyses.............................................................
8.4.8ImmunogenicityAnalysis.........................................................................
8.4.9 Outcomes Research Analyses ..................................................................
8.4.10OtherAnalyses.......................................................................................
8.5InterimAnalyses...............................................................................................
9STUDYMANAGEMENT........................................................................................
9.1 Compliance ...........................................................................................................
9.1.1 Compliance with the Protocol and Protocol Revisions...........................
9.1.2 Monitoring  ...............................................................................................
9.1.2.1 Source Documentation....................................................................
9.1.3 Investigational SiteTraining....................................................................
9.2 Records   ................................................................................................................
9.2.1RecordsRetention....................................................................................
9.2.2 Study Drug Records.................................................................................
9.2.3 Case Report Forms..................................................................................
9.3 Clinical Study Report and Publications............................................................
10 GLOSSARYOFTERMS........................................................................................
10.1 List of Abbreviations ......................................................................................
11 REFERENCES…..........................................................................................................
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1
INTRODUCTION AND STUDY RATIONALE
Duchenne muscular dystrophy (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. 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) recently received a conditional marketing
authorization in the European Union (EU) with a restricted indication for the treatment of
DMD specifically resulting from a nonsense mutation in the Dystrophin gene in ambulatory
patients aged 5 years and older. Since Translarna is restricted to the 13% of DMD patients
with genetically identified nonsense mutation in the Dystrophin gene3, and is the only
approved therapy (in the EU only) to treat DMD, there remains a significant unmet medical need
for novel agents to treat DMD.
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, Dystrophin gene null, resulted in attenuation of the dystrophic
phenotype relative to mdx mice with intact Myostatin genes.4 Similarly, weekly administration of
anti-myostatin monoclonal antibodies to mdx mice resulted in increases in muscle size and
strength.5
RO7239361 is a bivalent anti-human myostatin antagonist 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 per week (QW), subcutaneously administered therapeutic to increase muscle mass and 
strength. RO7239361 has a unique mechanism of action (MOA) that involves the competitive
inhibition of Alk4/5 (signaling receptor) recruitment and binding to free myostatin or
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. RO7239361 is being developed as a potential symptomatic therapy to improve muscle
function in DMD. As most DMD patients are treated with corticosteroids, in this study
RO7239361 will be given to subjects on stable corticosteroid therapy.
1.1
Study Rationale
This is a multi-site, randomized, placebo-controlled, double-blind, multiple-ascending SC dose
study to assess the safety and tolerability of RO7239361 in ambulatory boys with DMD. The

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initial 24-week double-blind phase will be followed by a 48-week OL phase and then by an OL
extension (OLE) phase. The initial double-blind phase will have two parts: Part A and Part B.
Part A will include 4 weeks of double-blind, multiple-ascending SC dosing of RO7239361 in
3 panels of ambulatory boys with DMD. Each panel will include approximately 8 subjects
(randomized 3:1 to RO7239361 or placebo) and is aimed at understanding the safety,
tolerability, pharmacokinetic (PK), and target engagement (free myostatin lowering) profile
of RO7239361 after 4 weeks of dosing. In Part B, subjects in Panels 13 will continue to
receive their originally assigned weekly dose of RO7239361 or placebo. In addition, Part B
will include an Expansion Panel of approximately 16 subjects (randomized 3:1 to RO7239361
or placebo). The aim of Part B is to collect additional safety, tolerability, and exploratory
data and measures of function over a 24- week period of dosing of RO7239361 or placebo at
doses of RO7239361 that are anticipated to be efficacious. Upon completion of 24 weeks of
double-blind dosing, all subjects will be eligible to enter the OL phase. In the OL phase, all
subjects will receive weekly unblinded SC doses of RO7239361 for 48 weeks. The OL
phase is included to provide subjects an opportunity to initiate or to continue treatment with
RO7239361 following completion of the double- blind phase. Subjects in the OL phase will
receive the active dose corresponding to their originally assigned panel. In the OLE phase, all
subjects will continue to receive weekly unblinded SC doses of RO7239361 for up to 228
weeks, or until RO7239361 is commercially available, whichever comes first.
This study is designed as a dose-ranging study to characterize the safety, PK, target engagement
(i.e., myostatin suppression), and the relationship between PK and target engagement over at
least 3 doses in children with DMD. Doses proposed for this study are based upon
achieving and maintaining a moderate to high degree of suppression in serum free myostatin
levels at steady- state trough across 3 dose levels. A body weighttiered (for Panels 2 and 
3), fixed- dose strategy targeting the achievement of moderate (>50% suppression), high
(>85%) and near complete (95%) suppression of serum free myostatin levels for Panels 1, 2, 
and 3, respectively, was used to select the three doses for the study. The body weighttiered
doses for Panels 2 and 3, based on two tiers of body weight, namely 15 kg to 45 kg and
> 45 kg are presented in Table 3.1-1 to Table 3.1-3.
A pediatric PKpharmacodynamic (PD) extrapolation model, developed using preliminary
PK-PD data from the single-ascending dose (SAD) study in normal healthy volunteers was
used to determine doses based on different degrees of target (i.e., free myostatin) suppression. 
The starting dose in children with DMD was selected as one that is expected to achieve and
maintain a moderate level of myostatin suppression (i.e., 50%) at steady-state trough.
Prior studies in Cynomolgus monkeys have shown that significant increases in thigh muscle
volume were observed at doses that generated 80% suppression of free myostatin at trough. The
proposed starting dose, targeting achievement of 50% suppression of free myostatin at trough,
represents not only a safe starting dose in children with DMD but can also help identify if a
moderate level of suppression in free myostatin is associated with PD activity or other measures
of efficacy in children with DMD. The starting dose range of 4.0 mg QW in children with
DMD is lower than the starting dose of 15 mg QW that was used in the multiple-ascending
dose (MAD) study in adult healthy volunteers and produced greater than 80% suppression of

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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free myostatin following repeated QW dosing.
The middle dose was selected as a dose that is approximately a half log increment higher than
the starting dose. This dose is expected to produce at least 85% suppression in free myostatin
levels at trough. Myostatin suppressions at trough of >80% were associated with significant
increases in muscle volume in a non-human primate study. The highest proposed dose is a
<3-fold increment over the mid dose, and targets the achievement and maintenance of at least
95% suppression in levels of free myostatin at trough. Robust suppression of free myostatin
(>90%) was observed for the 45-mg QW dose in the MAD study. Similarly, high levels of
suppression are expected for the 90-mg QW dose as well as the highest planned dose of 180 mg 
QW in the MAD study.
An interim analysis (IA) revealed that at steady state, suppression of free serum myostatin from 
baseline of ~77%, 92%, and 97% over the dosing interval was observed at the 4-, 12.5- and 20-,
and 35- and 50-mg doses, respectively. PD steady state was reached after ~6 weeks.  
Model-predicted steady-state weekly exposure of RO7239361 in children with DMD and the
associated safety margins based on comparison to (1) weekly exposure at 12 weeks from the
juvenile rat toxicity study, and (2) weekly no-observed-adverse-event level (NOAEL)
exposure from the pivotal toxicity study, are presented in Table 1.1-1.

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CN001001. The drug was well tolerated up to doses of 180 mg QW in healthy volunteers.
1.2
Rationale for Change to Prefilled Syringe
A more convenient PFS presentation was developed to support the start of the pivotal trial
(WN40227) in DMD patients, which may support submission for marketing authorization of
RO7239361 PFS. The higher of the two doses currently being tested in Study WN40227 is being 
proposed as the OLE dose following switch of presentation, which corresponds to the Panel 3 
dose being evaluated in Study WN40226 (35 and 50 mg, depending on subject body weight). The 
selected dose offers the highest suppression of free serum myostatin (97%) from the doses tested. 
In addition to free serum myostatin, the higher exposure reached with 35- and 50-mg PFS could
potentially suppress higher levels of tissue myostatin. The increased myostatin suppresion could 
provide greater benefit to patients.
The exposure (area under the concentrationtime curve [AUC]) predicted for the 35- and 50-mg 
PFS in Study WN40227 would be approximately 5780 µg h/mL; therefore, the initially
calculated safety margins (relative to the projected AUC in DMD patients at the high dose; see 
Table 1.1-1) remain approximately the same.  RO7239361 was generally safe and well tolerated 
in healthy adult subjects receiving multiple SC doses of up to 180 mg (the observed exposure 
approximately 1.5-fold higher than in DMD patients receiving 35 and 50 mg QW by PFS in 
Study WN40227). Ongoing safety monitoring in Study WN40227 has not identified any new 
safety signals to date.
Therefore, the change from vial formulation to high-dose PFS would align both ongoing studies 
(WN40226 and WN40227) in DMD patients, allowing easier administration for patients and
potentially to increase the chances of a beneficial effect from higher myostatin suppression. 
1.3
Rationale for Specific Inclusion/Exclusion Criteria
Age Range:
A minimum age of inclusion of 5 years is planned, as children younger than 5 years are
less likely to consistently understand and be able to cooperate with performing the functional
endpoints, such as the 4-stair climb (4SC), reliably. An upper age limit for inclusion of
< 11 years is planned to enable a focus on children who are able to perform the 4SC and
whose lower extremities have some intact muscle tissue. RO7239361 is expected to preserve
and improve muscle strength primarily by increasing the size of existing muscle fibers.
Therefore, it is anticipated that the optimal effect of RO7239361 will be before muscle
fibers have been replaced by fat and fibrosis. A further rationale for limiting the age range
in this study is to minimize variability with respect to the timing and extent of functional and 
physical deficits, and due to the patient’s age, growth, maturity, and concomitant medications.
Both natural history and clinical trial data have highlighted the significant variability in
functional endpoints.6,7,8 Key approaches to minimizing this variability include restricting the
age range for inclusion, thereby reducing variability stemming from growth. Although
functional endpoints (the 4SC and the 6-minute walk distance [6MWD]) are exploratory in
this study, safety, tolerability, PK, and TE data from this study will inform dose selection for
future studies, for which function will be the primary endpoint.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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Use of Corticosteroids:
As corticosteroids have demonstrated benefit on motor function in boys with DMD9, boys
included in this study will be required to be on a corticosteroid (e.g., prednisone/prednisolone
or deflazacort) for at least 6 months prior to the start of study treatment, with no significant
change in dosage (> 0.2 mg/kg) or dosing regimen for at least 3 months prior to the start
of study treatment. The goal of this inclusion criterion is to control variability in motor
function and strength stemming from corticosteroid use.
Both prednisone/prednisolone and deflazacort have been shown to be effective in increasing and
preserving muscle strength in DMD9,10 supporting this pharmacotherapy as an important
standard of care. Following initiation of corticosteroids, 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 subjects who have been taking corticosteroids for at least 6 months,
plan to continue corticosteroids for the duration of the double-blind phase of the clinical trial, and
have not had a significant change in dose in the 3 months preceding initiation of study treatment.
Use of Translarna (Ataluren) or Investigational Agents:
Subjects receiving Translarna (ataluren) will not be eligible for this study as ataluren was
only recently conditionally approved in the EU for a small subset of DMD subjects (i.e.,
those with nonsense mutations). Because of this recent approval, the magnitude and time
course of treatment response of this agent in DMD are not well understood. Similarly, limited
data are available regarding the safety and tolerability of this drug. Data regarding safety,
tolerability, and the time course for efficacy are also limited for exon-skipping therapies and
other investigational agents. These information gaps render controlling for potential effects of
ataluren or investigational agents 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 and investigational drugs (with the exception of deflazacort),
subjects receiving these treatments currently or within 5 half-lives prior to the start of study
treatment will be excluded from participation. Consult with the Roche Medical Monitor to 
determine the washout duration if unknown.
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.11,12 To avoid potential confounding effects of
growth hormone and androgens on the endpoints being measured in this study, subjects receiving
these treatments currently or within 3 months or 5 half-lives (whichever is longer) prior to the
start of study treatment will be excluded from participation.
1.4
Research Hypothesis
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, free myostatin
suppression, and immunogenicity of multiple SC doses of RO7239361 in boys with DMD.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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1.5
Objectives(s)
1.5.1
Primary Objectives
To assess the safety and tolerability of multiple SC doses of RO7239361 in boys with DMD
1.5.2
Secondary Objectives

To evaluate the PK of multiple SC doses of RO7239361 in boys with DMD

To evaluate the immunogenicity of multiple SC doses of RO7239361 in boys with DMD

To evaluate the effects of RO7239361 on free myostatin and myostatin-drug complex levels
in boys with DMD

To  evaluate  magnetic resonance  imaging (MRI) measures of right thigh maximal
cross-sectional area (CSAmax), and contractile versus non-contractile content
1.5.3
Exploratory Objectives

To explore the pharmacodynamic effects of the multiple doses of RO7239361 in boys with
DMD on:

Measures of function, including timed function tests (TFTs): 4SC, 4-stair descend
(4SD), 10-m walk/run, standing from supine, 6MWD, and the North Star Ambulatory
Assessment Scale (NSAA)

Serum analytes that may include but are not limited to:
miR-206, miR-133a, miR-1, miR-6 (control miR), miR-21, and miR-39
TGF-concentrations, which are associated with fibrosis of muscle seen in DMD
Follistatin
Creatine kinase concentrations and creatine kinase-muscle (CK-MM), which are
associated with muscle atrophy in DMD

Urine analytes that include but are not limited to:
Titin protein amino-terminal fragment concentrations that are associated with muscle
damage

Manual myometry measures of upper and lower extremity strength

Ankle range of motion in degrees

DXA measure of total lean body mass, fat mass and bone mineral density

Magnetic resonance spectroscopy (MRS) measures of right thigh lipid fraction

Health related quality of life as measured by the Pediatric Outcome Data Collection
Instrument (PODCI)

Pulmonary function tests (PFTs),  including 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)

Upper extremity motor ability measured using the Performance of Upper Limb Scale
(PUL)

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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
Explore the effect of genetic variation in genes suspected to impact DMD disease expression
(including but not limited to LTBP4, SPP1) on target engagement, PD, or function
test endpoints.13, 14, 15
1.6
Product Development Background
1.6.1
Pharmacology
RO7239361 is a potent inhibitor of myostatin signaling activity with subnanomolar affinity for
myostatin. RO7239361 also inhibits GDF11 with subnanomolar affinity, but does not bind to
other members of the TGF-β family of ligands, including activin A, TGF-β3, GDF9, and
GDF10. A more complete summary of the nonclinical pharmacology studies is provided in
the Investigator's Brochure.
1.6.2
Toxicity
In the pivotal 6-month intermittent (every 2 weeks [Q2W]) SC toxicity studies in rats and 
monkeys, RO7239361 was well tolerated at all doses (0, 5, 20, or 60 mg/kg), with no effects on 
central nervous system (CNS), respiratory, or cardiovascular (CV) endpoints. PD-related effects 
observed in both species at all doses included increased body weight and lean mass and increased 
skeletal muscle weight, with no evidence of skeletal muscle toxicity and minimal skeletal muscle 
hypertrophy. In rats and monkeys, RO7239361 treatment-induced anti-drug antibody (ADA) 
responses resulted in decreased serum RO7239361 concentrations and attenuation of associated 
pharmacological changes in some animals. 
The primary RO7239361-related toxicology findings in rats in the above-mentioned study were as 
follows: 1) increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
activities (not associated with adverse histopathological changes in the liver); 2) mild inhibition of 
primary IgG T celldependent antibody response (TDAR); and 3) increased incidence of slight 
biliary hyperplasia in the liver of females treated with 60 mg/kg of RO7239361. The latter 
represented an exacerbation of an age-related background finding (Hailey et al. 2014). Because of
the magnitude of the effects in some rats, the increases in serum AST and ALT were considered 
adverse; therefore, a NOAEL was not achieved in this study. All other findings were considered 
non-adverse. 
The primary RO7239361-related non-adverse toxicology findings in monkeys were: 1) increased 
adrenal gland weight in monkeys treated with 60 mg/kg; and 2) slightly increased mononuclear 
cell infiltration in choroid plexus at doses 5 mg/kg and minimal follicular lymphocytic infiltration 
in bone marrow at 60 mg/kg. The latter findings were both exacerbations of background findings in 
monkeys. RO7239361-related findings were partially to fully reversible following a 3-month 
postinjection period. The high dose of 60 mg/kg (AUC from Time 0 to 168 hours 
[AUC0168h]147,000 g•h/mL) was considered the NOAEL in monkeys. The exposure multiple 
at the NOAEL in monkeys relative to the projected AUC at the maximum clinical dose (50 mg; 
AUC5,480 g •h/mL) is approximately 27-fold.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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Juvenile toxicity was investigated in the 12-week SC toxicity studies in juvenile albino rats. 
RO7239361 administration at doses up to 180 mg/kg Q2W, starting on postnatal Day 7 was safe 
and well tolerated, with no adverse findings. RO7239361-related findings included: 1) non-adverse 
increases in bone mineral content and density (at all doses); 2) a slight delay in balanopreputial 
separation, without effects on mating or fertility (at 60 mg/kg) and delayed vaginal opening with 
no impact on function (at 20 mg/kg); 3), mild inhibition of primary IgG TDAR (males, treated 
with 60 mg/kg); and 4) minimally decreased testis, epididymis, and seminal vesicle weights with 
no microscopic correlate (at all doses). An increase in liver enzymes as observed in the chronic 
study in adult animals was not seen. The exposure multiple at the clinically tolerated dose of 180 
mg/kg (AUC0-168h 85,600 and 127000 g•h/mL) in juvenile rats, relative to the projected AUC at 
the maximum clinical dose of 50 mg is approximately 16x and 23x compared with exposures in 
male and female rats, respectively.
Overall, RO7239361 was generally tolerated in adult and juvenile rats and adult monkeys at all 
doses tested. Intended pharmacology, including myostatin TE and increased muscle mass, was 
demonstrated in both species. 
In preliminary reproductive toxicity studies conducted with RO7239361, maternal mortality and 
pronounced liver toxicity (marked hepatocellular necrosis correlated with elevated ALT, AST, and 
total bilirubin) were observed in pregnant rats beginning on gestation Day 17 (1 day after the last 
dose) at doses 100 mg/kg (AUC0-168h 57,500 g•h/mL; 10x relative to the maximum clinical 
dose of 50 mg). The maternal NOAEL in this study was considered to be the low dose of 
25 mg/kg/Q2W (AUC0-168h = 24,400 g•h/mL; 4x relative to the maximum clinical dose of 50 mg) 
based on the absence of adverse maternal findings. The maternal findings appear to be specific to 
pregnant rats given that there were no signs of hepatocellular necrosis or mortality at any dose 
tested in any other toxicity study, including a dose rangefinding study in pregnant rabbits
(maternal NOAEL AUC0168h = 234,000 g•h/mL) at RO7239361 exposures comparable or 
higher than those in the pregnant rat study. In addition to the maternal effects in rats, the presence 
of the fetal malformation of protruding tongue was noted in both pregnant rats and rabbits at all 
RO7239361 doses tested. This finding is considered pharmacologically mediated as it is also 
observed in myostatin-null animals.34,35 However, the impact of this finding on postnatal 
development, particularly with respect to nursing, is not known at this time. 
Overall, data from nonclinical toxicology studies in adult rats and monkeys and juvenile male
rats indicates RO7239361 was well tolerated at all doses tested, demonstrated muscle-related
pharmacology, including myostatin TE and increased muscle mass in both species, and provided
an acceptable safety profile for Phase Ib/II clinical investigations in pediatric DMD subjects.
1.6.3
Preclinical Metabolism and Pharmacokinetics
RO7239361 exhibits PK properties consistent with Fc-fused proteins. Following intravenous
(IV) administration, the steady-state volume of distribution (Vss) of RO7239361 ranged from
0.034 to 0.069 in nonclinical species, suggesting RO7239361 largely resides in the extracellular

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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space. Total body clearance (CLTp) of RO7239361 was 0.68 mL/h/kg (mouse), 0.38 mL/h/kg
(rat), and 0.21 mL/h/kg (monkey). The terminal half-life (T1/2) was 65 (mouse), 117 (rat), and
129 hours (monkey). RO7239361 was slowly absorbed following SC administration with a
Tmax of 24 and 56 hours in the mouse and rat, respectively. RO7239361 demonstrated good SC
bioavailability in mice and rats (approximately 84% in both species) and modest bioavailability
in monkeys (~ 30%).
1.6.4
Clinical Pharmacology and Safety
The first-in-human, combined SAD and MAD study (CN001001) has been completed. Overall, 
43 subjects received study drug/placebo during the SAD phase, and 97 subjects received study 
drug/placebo during the MAD phase. A single dose or multiple doses (up to 180 mg SC QW) of 
RO7239361 were generally safe and well tolerated.
There were no deaths, serious adverse events (SAEs) or AEs leading to discontinuation during 
the study. 
The most frequently occurring AEs during the SAD phase were injection-site hemorrhage (n=3;
7.0%) and upper respiratory tract infection (n3; 7.0%). The most frequently occurring AE 
during the MAD phase was injection-site erythema (n12; 12.4%), followed by upper
respiratory tract infection (n11; 11.3%), and rash (n9; 9.3%). All events were mild or 
moderate.
Injection-site and other skin reactions observed in the MAD phase were not associated with 
systemic symptoms, did not require cessation of study drug administration, and, in most cases, 
did not require treatment. ADAs to RO7239361 were detected in 45.2% and 27.8% of subjects 
receiving RO7239361 in the SAD phase and in the MAD phase, respectively. The presence of 
ADAs did not appear to affect exposure to RO7239361. Injection-site and other skin reactions 
were slightly more frequent in ADA-negative subjects (18.1%) than in ADA-positive subjects 
(6.9%).
No clinically significant dose-related changes in laboratory values occurred during the study. 
The most common marked laboratory abnormalities were transient elevations in CK and 
reductions in leukocytes. These laboratory abnormalities were not associated with AEs and were 
observed in both RO7239361- and placebo-treated subjects. There were no treatment-related 
changes in ECG parameters or vital sign measurements.
In Study WP40225, which was designed to compare the bioavailability of RO7239361 given at 
different injection sites, a total 76 healthy volunteers received single-dose SC injections of 
RO7239361 from a PFS in the abdomen, arm, and thigh. 
There were no deaths, SAEs, or AEs leading to discontinuation during the study. 
Overall, 25 of 76 subjects (32.9%) experienced AEs during the study. The incidence and severity 
of AEs were generally comparable across the groups with administration of RO7239361 in 
abdomen, arm, or thigh. 

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All AEs were mild or moderate in intensity. The most common AE was injection-site 
hemorrhage (n3), followed by diarrhea, headache, and injection-site erythema (n2 for each). 
All injection-site AEs were mild and resolved without treatment.
The most common marked laboratory abnormalities were transient reductions in leukocytes and 
elevation in ALT. These laboratory abnormalities were not associated with clinical symptoms and 
did not require pharmacological intervention. There were no treatment-related changes in ECG 
parameters or vital sign measurements during the study. Overall, 13 subjects had a positive 
ADA titer (2). The earliest detection of ADAs was on Day 64. The presence of ADAs did not 
appear to affect the exposure, safety, and tolerability of RO7239361.
Additional safety information on RO7239361 is available in the most recent version of the
Investigator Brochure.
1.6.4.1
Pharmacokinetics of RO7239361
RO7239361 achieves peak concentrations in serum between 3 and 5 days post-injection and has a
terminal half-life of approximately 7 to 10 days across all doses following single SC dose 
administration (5, 15, 45, 90, and 180 mg). The increase in exposure with dose of RO7239361 
appeared to be generally proportional up to 90 mg but was greater than proportional at the 
highest dose of 180 mg (Study CN001001). 
Following multiple RO7239361 administration, Tmax
of RO7239361 was achieved 
approximately 23 days after dosing. The half-life estimates following the last dose were from 10 
to 13 days. PK parameters increased in a slightly greater than proportional manner over the 
explored dose range (15 mg Q1W to 180 mg Q1W) (Study CN001001).
In the current 226 study, the pharmacokinetics of RO7239361 in ambulatory boys with DMD 
were analyzed using a population-PK approach. The pharmacokinetics of RO7239361 were well 
characterized using a PD/PK model based on the target-mediated drug disposition concept, and 
body weight was found to be the only covariate. Steady state was reached after ~12 weeks of 
Q1W administration. The pharmacokinetics of RO7239361 appear to be dose proportional, 
considering the between-subject variability. Tmax of RO7239361 was achieved within 2430 
hours after dosing.
1.7
Overall RiskBenefit Assessment
More detailed information about the known and expected benefits and risks and reasonably
anticipated AEs of RO7239361 are presented in the Investigator's Brochure.
The potential benefits of treatment with RO7239361 have not been established.
There are no identified risks to date related to RO7239361 administration. Potential risks 
include immunogenicity, hypersensitivity reactions, injection-site reactions, and adverse 
findings from nonclinical studies or observations with the use of other anti-myostatin agents. 
A more complete summary of potential risks is provided in the RO7239361 Investigator's
Brochure. 

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Immunogenicity/Hypersensitivity: ADAs to RO7239361 were detected in subjects receiving 
RO7239361 in SAD and MAD phases of Study CN001001. 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.  In Study WP40225, 17.1% of the healthy 
subjects who received a SC single dose of RO7239361 in the abdomen, arm, or thigh had a 
positive ADA titer (low,2). The presence of ADAs appeared to have no effect on exposure in 
both studies, and no subject developed an acute hypersensitivity reaction.
Subject safety will be closely monitored in this study. All subjects who are administered study
drug will be closely monitored for possible immunogenicity-related AEs. If present, antibodies
will be assessed for neutralizing activity by assessment of serum free myostatin levels and
muscle volume endpoints. Subjects who do not enter a separate rollover treatment study of
RO7239361 will enter the follow-up phase of the study. Subjects will be requested to provide 
immunogenicity samples at each visit during the 24-week follow-up phase (Table 5.1-5).
Potential Acute Hypersensitivity Reactions to RO7239361: No participants in Study 
CN001001 or WP40225 receiving RO7239361 developed an acute hypersensitivity reaction.  
The risk of a subject developing an acute hypersensitivity reaction to RO7239361 is considered 
low. However investigators and sites should be prepared to manage possible acute 
hypersensitivity reactions to initial doses of RO7239361. Management of acute hypersensitivity 
reactions is further described in Section 3.4.2.2.
Injection-Site Reactions may occur when a drug is injected subcutaneously. In the MAD
phase of CN001001, mild injection-site erythema was the most common AE observed, occurring 
in 12.4% of subjects treated with RO7239361. AEs of injection-site erythema did not require
treatment or cessation of study drug and were not accompanied by systemic symptoms.
Injection sites will be rotated and inspected regularly. Injection sites will be monitored from
Day 1 though the end of the study.
Teratogenicity (Fetal Malformation of Protruding Tongue): The presence of the fetal 
malformation of protruding tongue was noted in both pregnant rats and rabbits at all RO7239361 
doses tested, which is considered a pharmacologically mediated effect of unknown consequence on 
postnatal development. Subjects who are sexually active should be advised to use appropriate
methods of contraception (see Section 6.4). 
In addition, mortality and marked liver toxicity, including hepatocellular necrosis, were observed in 
pregnant rats (Section 1.4.2), which may reflect a species-specific effect and are not considered 
relevant to the use of RO7239361 in DMD patients since: 1) there was no mortality or evidence of 
liver toxicity at comparable or higher exposures in monkeys, juvenile male rats, and pregnant 
rabbits; and 2) there is no evidence for treatment-related clinical liver toxicity to date in humans 
given RO7239361. Liver function will continue to be closely monitored in studies of RO7239361 
by following liver enzymes and bilirubin levels as well as clinical signs.

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Liver Enzymes Elevation: Increased serum levels of AST and ALT observed in rats given 
RO7239361 for 6 months (see Section 1.4.2) were reversible with continued dosing and were not 
associated with histopathologic evidence of hepatocellular or skeletal muscle injury or inflammation. 
No ALT and AST elevations were observed at higher RO7239361 exposures in monkeys
dosed for 6 months or juvenile rats dosed for 12 weeks. Monkey and juvenile rat exposures 17x
and 10x, respectively, the lowest-observed-adverse-effect level (LOAEL) for the transaminase
elevation in the 6-month rat study.
In the MAD phase of Study CN001001 in healthy subjects, 9 subjects (12.5%) receiving
RO7239361 had ALT elevations >1.25 x upper limit of normal (ULN) (and <3x ULN, except 1 
subject with a single value of ALT elevation [4.6x ULN] on Day 99, with concurrent CK 
elevations). Most of the ALT elevations occurred only at single timepoint. None of the ALT 
elevations was accompanied with bilirubin elevations. 
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, bilirubin in serum, and evaluations of clinical signs 
and symptoms in subjects. The hepatocyte-specific markers gamma-glutamyl transferase (GGT)
and glutamate dehydrogenase (GLDH) will continue to be used for liver monitoring.
Immunoglobulin G Suppression after Primary Immunization: A minimal to mild decrease 
in the IgG response to a primary immunization was observed in some animals treated with
RO7239361. Given the small magnitude 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, 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.
Potential Cardiac Effects of RO7239361: RO7239361 also recognizes GDF11, which has
been implicated in heart failure associated with aging in mice20. While the mechanism
underlying the development of aging related re-modeling of the heart in mice likely differs from
that underlying the development of heart failure in DMD, potential cardiac effects of
RO7239361 will be monitored in this trial using electrocardiography and echocardiography.
Notably, there have been no cardiac findings in animals who received RO7239361 in the
toxicology studies. Further, no significant treatment- related changes in ECG parameters or
vital signs have been observed in healthy adult subjects receiving single or multiple doses of
RO7239361 in Study CN001001.
The most up to date safety information on RO7239361 is available in the most recent version of
the Investigator's Brochure.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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International Conference on Harmonisation (ICH) and in accordance with the ethical principles
underlying European Union Directive 2001/20/EC and the United States Code of Federal
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments
and the subject informed consent will receive Institutional Review Board/Independent Ethics
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Roche 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).
2.2
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, Informed Consent Form or Assent Form, subject
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's or product labeling information to be provided to subjects and any
updates.
The investigator or Roche 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.
2.3
Informed Consent
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.
For subjects unable to give their written consent, in accordance with local regulations, one or
both parents, a guardian, or a legally acceptable representative (LAR) must be informed of the
study procedures and must document permission by signing the informed consent form approved
for the study prior to clinical study participation.
Each subject must be informed about the nature of the study to the extent compatible with his or
her understanding. Should a subject become capable or reach the age of majority, his or her
consent should be obtained as soon as possible. The explicit wish of a subject who is a minor or
unable to give his or her written consent, but who is capable of forming an opinion and assessing
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 as determined by local requirements should also
give their assent. The assent should be documented based on local requirements. Continued

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assent should be documented when important new information becomes available that is relevant
to the subject’s assent.
Roche 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.
Investigators must:
1) Provide a copy of the consent form, assent form if applicable and written information about
the study in the language in which the subject is most proficient prior to clinical study
participation. The language must be non-technical and easily understood.
2) Allow time necessary for subject or subject's legally acceptable representative to inquire
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's
legally acceptable representative and by the person who conducted the informed consent
discussion.
4) 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.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal
guardian, and the subject subsequently reaches majority, becomes emancipated, and/or
capable of making and communicating his or her informed consent during the study, consent
must additionally be obtained from the subject.
6) Revise the informed consent (and Assent Form if applicable) whenever important new
information becomes available that is relevant to the subject's consent. The investigator,
or a person designated by the investigator, should fully inform the subject or the subject's
legally acceptable representative or legal guardian, of all pertinent aspects of the study and
of any new information relevant to the subject'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 United States, the subjects’ signed Health Insurance Portability and Accountability 
Act (HIPAA) authorization.
The consent form must also include a statement that Roche and regulatory authorities have
direct access to subject records.
The rights, safety, and well-being of the study subjects are the most important considerations and
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This
is
a
Phase
Ib/II,
multi-center,
randomized,
placebo-controlled,
double-blind,
multiple-ascending SC dose study to assess the safety and tolerability of RO7239361 in

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ambulatory boys with DMD. The study design schematic is presented in Figure 3.1-1.
Subjects will undergo screening evaluations to determine eligibility and baseline evaluations
within 45 days prior to first administration of study drug/placebo. The initial 24-week 
double-blind phase will be followed by a 48-week OL phase and an OLE phase. The
double-blind phase will have two parts: Part A and Part B.
Part A will include 3 dose panels of 5 to < 11 year old (the age of the subject is the age at
randomization) ambulatory subjects with DMD and will consist of 4 weeks of double- blind
dosing. Panels 13 will randomize approximately 8 subjects each (randomized 3:1 to
RO7239361 or placebo). If, after all subjects in a panel have been randomized, and it is
determined that older or younger ages are underrepresented, the panel may be opened to
additional subjects of specific ages, even if 8 subjects have already been randomized. Opening
Panels 13 to more than 8 subjects may provide more robust safety and tolerability data in certain
age ranges. Roche will inform sites if and when dose panels are opened to additional subjects.
All subjects will receive weekly (Day 1, Day 8, etc.) SC doses of RO7239361 or placebo.
In Panels 1 and 2, up to 4 subjects can be randomized on 1 day. Once the third subject reaches
Day 8, the remaining 4 subjects in that dose panel may be randomized. The rationale for this
sentinel dosing is to observe safety and tolerability for 7 days post-dose in at least 1 subject
randomized to RO7239361 before the remaining subjects within that panel are randomized. In
addition, dose initiation in Panels 2 and 3 will begin only after Day 14 has been completed by at
least 6 of 8 subjects participating in the preceding panel and all available safety and tolerability
data have been reviewed and deemed safe to proceed by the study investigators (Principal
Investigator or designee) and the Roche Medical Monitor. Prior to dose escalation the Roche
Medical Monitor and the investigators must agree that it is safe to proceed with dose
escalation to the next panel. In addition, available safety, PK, and target engagement (suppression
of free myostatin) from preceding panels may be evaluated before the start of the next panel for
timely decisions about dose adjustment or early termination. No formal inferences requiring any
adjustment to statistical significance level will be performed.
Doses for Panels 13 are based upon safety, tolerability, PK, and PD data observed in Study
CN001001 (“A Randomized, Placebo-Controlled, Single and Multiple Ascending Subcutaneous
Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of
RO7239361 in Healthy Adult Subjects”). A body weighttiered (for Panels 2 and 3), fixed-dose
strategy targeting the achievement of moderate (> 50% suppression), high (> 85%), and near
complete (> 95%) suppression of serum free myostatin levels for Panels 1, 2, and 3, respectively,
was used to select the three doses for the study. The body weighttiered doses (for Panels 2 and 
3) are presented in the Table 3.1-1 to Table 3.1-3 below.
Following the PK and PD assessment in this study, if the PD targets are not achieved (e.g.,
myostatin inhibition was much higher than 40% in all dose groups OR if none of the dose
groups achieved > 90% inhibition), dose modification may be performed and additional dose
cohorts may be enrolled to confirm exposures and myostatin inhibition at the modified dose.
Modified doses will be selected such that the estimated exposures in pediatric subjects will
not exceed those observed at the highest tolerated and safe dose in adults.

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Table 3.1-1:
Panel 1 Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
15 kg
4.0 mg/0.08 mL
Table 3.1-2:
Panel 2 Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
15 kg to 45 kg
45 kg
12.5 mg/0.25 mL
20.0 mg / 0.4 mL
Table 3.1-3:
Panel 3 Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
15 kg to 45 kg
45 kg
35.0 mg/0.7 mL
50.0 mg/1 mL
Table 3.1-4:
Expansion Panel Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
15 kg to 45 kg
45 kg
35.0 mg/0.7 mL
50.0 mg/1 mL
The dose selected for the Expansion Panel will be a safe and well-tolerated dose that is less than
or equal to the highest dose tested in the escalation panels. The Expansion Panel will provide
additional safety, tolerability, PD, and functional data at a dose anticipated to be efficacious.
As such, a dose that produces > 90% suppression in serum levels of free myostatin is expected to
be efficacious. A review of safety data from Panels 13 supports the selection of the Panel 3 
dose (35 mg for subjects 15 kg to 45 kg and 50 mg for subjects > 45 kg).
Part B will include 20 weeks of continued double-blind dosing in Panels 13 and an
Expansion Panel of 24 weeks of double- blind dosing. The Expansion Panel will randomize
approximately 16 subjects (randomized 3:1 to RO7239361 or placebo). The Expansion Panel
will be initiated after at least 2 weeks of dosing has been completed by at least 6 subjects
participating in Panel 3 and all available safety and tolerability data, including, but not limited 
to, injection-site reactions, reported AEs, clinical laboratory results, and vital sign measurements
have been reviewed and deemed safe to proceed by the study investigators and the Roche
Medical Monitor. The Expansion Panel may be opened to additional subjects to either explore
another dose that may be safe and efficacious or randomize subjects of under-represented ages.

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Upon completion of 24 weeks of double-blind dosing, all subjects will be eligible to enter the OL 
phase. In this phase, all subjects will receive open- label RO7239361 SC doses, weekly for
48 weeks. Subjects in the OL phase will receive the active dose corresponding to the dose in
their originally assigned panel. Dosing in the OL phase may be adjusted based upon emerging
safety and tolerability data and/or upon the results of the interim analyses (IAs) of the
double- blind data. The schedule of events in the OL phase is described in Table 5.1-3.
Subjects who complete the 48-week OL phase, may continue in the OLE phase. Subjects in
the OLE phase will continue to receive weekly doses of RO7239361 corresponding to the
dose in their originally assigned panel for up to 228 weeks, or until RO7239361 is
commercially available, whichever comes first. The study may be stopped earlier if the study is
terminated by the Sponsor. In the OLE phase, all subjects will have visits every 12 weeks. The
first visit in the OLE phase will occur 12 weeks after OL Week 48 and every 12 weeks 
thereafter for up to 228 weeks, or until RO7239361 is commercially available.
After approval of Version 6 of Protocol WN40226, and subjects have signed the corresponding 
updated Informed Consent Form, all participants will switch from the vial formulation to the 
PFS formulation of RO7239361. Subjects will continue to receive injections from a vial until the 
PFS becomes available at the site, based on availability of supplies and local approvals.
During the OLE phase, all subjects will switch from the vial formulation to PFS dosage 
formulation for weekly doses of study drug, corresponding to the same dose in Panel 3 (35 mg 
dose if a subject's body weight is 15 kg to45 kg and the 50-mg dose if the subject's body 
weight is45 kg). Subjeccts will receive their first dose of RO7239361 from a PFS during a 
scheduled clinic visit and will return to the clinic for the second PFS dose 1 week later. In 
addition, subjects will come to the clinic on Day 45 after the switch to the PFS (approximately 2 
days after dosing at home) for PK blood sampling. Visits will take place every 12 weeks 
thereafter, as originally scheduled for the OLE phase.
Any subject who discontinues from the study early or who does not enroll in a rollover protocol 
should enter the follow-up phase of the study. The follow-up phase of the study is up to 
24 weeks in length after the last dose.
Up to five IAs are planned until all subjects have completed Week 72 of the study, after which 
additional IAs may be conducted. The content and timing of the IAs are described in Section 8.5.
Measures of function, including TFTs (4SC, 4SD, 10-m walk/run, standing from supine),
6MWD, the NSAA, PFTs, manual myometry measures of upper and lower extremity
strength, ankle range of motion, and PUL measures of upper extremity motor ability, as well
as safety assessments (e.g., ECG, echocardiogram, laboratory tests, and physical exams) and
other exploratory assessments (e.g., DXA scan, serum and urine biomarkers) will be collected at
selected timepoints as specified in Table 5.1-1 through Table 5.1-2.
Subjects may have ECGs, echocardiograms and laboratory assessments during the follow- up
phase, as needed, to follow up on AEs. Subjects in the follow-up phase will be followed for
up to 24 weeks after last dose for measurement of anti-RO7239361 antibodies (ADAs) and 
immunological AE assessment (Table 5.1-5).

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minors, written permission (informed consent) 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.
Target Population
c) Males, ambulatory without assistance
d) Subjects 15 kg
e) Diagnosis of Duchenne muscular dystrophy confirmed by medical history (e.g., onset of
clinical signs or symptoms before 6 years of age with an elevated serum creatine kinase
level) and by genotyping
f)
Subjects
must
be
receiving
corticosteroids
(e.g.,
prednisone,
prednisolone,
or
deflazacort) for at least 6 months prior to the start of study drug administration, with
no significant change in dosage (> 0.2 mg/kg) or dosing regimen for at least 3 months
prior to the start of study treatment, with the expectation that dosage and dosing
regimen will not change significantly for the duration of the double-blind phase of the
study.
g) 4 stair climb 8 seconds at screening (Day -45 to Day -7); subjects who perform the 4SC
in > 8 seconds may be retested within the screening window
h) Subject re-enrollment: This study permits the re-enrollment of a subject who has
discontinued from the study as a pre-treatment failure (i.e., the subject has not been
randomized and has not been treated). If re-enrolled, the subject must be re-consented.
Age and Reproductive Status
i)
Males, 5 to < 11 years on day of randomization
3.3.2
Exclusion Criteria
Medical History and Concurrent Diseases
a) History of or current renal disease
b) Ejection fraction < 55% on screening echocardiogram, according to central read
c) Any major surgery within 6 weeks prior to the start of study drug administration
d) Expectation of major surgical procedure, such as scoliosis surgery, during the study drug
administration phases of this study (approximately 72 weeks)
e) Any injury, which may impact functional testing. Previous injuries, including fractures,
must be fully healed prior to consenting.
f)
Any known cognitive impairment or behavioral issues that will compromise ability to
comply with study procedures, in the judgment of the investigator.
g) 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 3 months prior to start of study drug administration
h) Treatment with ataluren, or any investigational drug (excluding deflazacort) currently, or

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
36/Protocol WN40226, Version 6
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.
i)
Treatment with exon-skipping therapies within 6 months prior to the start of study drug
administration
j)
Current or prior treatment within 3 months of study drug administration with androgens
or human growth hormone
k) Ongoing immunosuppressive therapy (other than corticosteroids)
l)
Requirement of daytime ventilator assistance
m) Uncontrolled clinical signs and symptoms of
CHF
(American College
of
Cardiology/American Heartassociated Stage C or Stage D)
n) Inability to be venipunctured, tolerate venous access, and tolerate SC injection
o) Any other sound medical, psychiatric, and/or social reason as determined by the
investigator
p) Any change (initiation, change in drug class, dose modification unrelated to change in
body weight, interruption or re-initiation) in prophylaxis/treatment for reduced bone
density within 3 months prior to start of study drug administration
Physical and Laboratory Test Findings
q) 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
Allergies and Adverse Drug Reaction
r)
History of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
Other Exclusion Criteria
s) Subjects who are compulsorily detained for treatment of either a psychiatric or physical
(e.g., infectious disease) illness
t)
Inability to comply with restrictions and prohibited activities/treatments as listed in
Section 3.4
u) Subjects and caregivers who reside a significant distance from the investigative site that
would negatively impact the ability to complete study procedures and/or complete the
study, in the judgment of the investigator
v) Subjects with 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 MIR, MRS, or DXA scans) or who are unable to complete 
right thigh MRI scan or DXA scan without sedation. See Section 3.4.2.1.
Subjects participating in non-interventional, natural history studies are eligible to participate in
Study WN40226. Subjects participating in the FOR-DMD study (NCT01603407) are eligible to
participate in Study WN40226 if the FOR-DMD study treatment is unblinded to the investigator
to permit documentation of the corticosteroid regimen on the WN40226 CRF and the

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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corticosteroid dose or regimen of the subject is not likely to significantly change during the
course of Study WN40226.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study
subjects and that the results of the study can be used. It is imperative that subjects fully meet all
eligibility criteria.
3.3.3
Women of Childbearing Potential
Not applicable.
3.4
Concomitant Treatments
3.4.1
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 should be reported on the CRF, regardless of
when the prior therapy was administered. Routine standard of care immunizations are
recommended on study.
1) Prior exposure to RO7239361
2) Treatment with ataluren, or any investigational drug (excluding deflazacort) 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.
3) Treatment with exon- skipping therapies within 6 months prior to the start of study drug
administration
4) Current or prior treatment within 3 months of study drug administration with androgens or
human growth hormone
5) 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
3.4.2
Other Restrictions and Precautions
3.4.2.1
Imaging Contraindications (MRI/MRS/DXA)
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
specified in the time and events schedule (Table 5.1-1, Table 5.1-2, and Table 5.1-3).
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.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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3.4.2.2
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.  In addition, 
qualified personnel should administer or supervise the administration by the caregiver of the first 
two doses of the PFS formulation at the clinic. 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, and for the first two PFS doses in the OLE phase, 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
recognize any signs and symptoms of 
hypersensitivity reaction and for the need to seek emergency medical care 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 anti-histamine, 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.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
39/Protocol WN40226, Version 6
3.5
Discontinuation of Subjects following any Treatment with Study Drug
Subjects MUST discontinue investigational product (and non-investigational product at the
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment and/or participation in the study

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 subject

Termination of the study by Roche

Loss of the ability of the parent/legal guardian 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
Clinical Criteria for Stopping Dose Escalation or Dose Discontinuation:

Dose escalation will be halted and dosing within a dose panel 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 adverse event that is
considered related to RO7239361, or;

Two (2) or more subjects show a decrease in ejection fraction to less than 50%
(confirmed by repeat echocardiogram) 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 for a subject or a
panel 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.
The following categories and definitions of intensity as determined by a physician should be

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
40/Protocol WN40226, Version 6
used 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.
All subjects who discontinue investigational product should comply with protocol-specified
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a
subject’s parent/legal guardian withdraws consent for all study procedures, including those in the
study follow-up phase or loses the ability to
consent freely (i.e.,
is imprisoned or
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the
discontinuation must be documented in the subject’s medical records and entered on the
appropriate CRF page.
3.6
Post-Study Drug Follow-Up
In this study, overall safety and tolerability is a key endpoint of the study. Post-study follow-up is
of critical importance and is essential to preserving subject safety and the integrity of the study.
Subjects who discontinue study drug 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 last dose of study drug
(Table 5.1-5).
3.6.1
Withdrawal of Consent
Subjects whose parent/legal guardian requests to discontinue study drug 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 subject’s parent/legal guardian specifically withdraws consent for any
further contact with him/her or persons previously authorized by the parent/legal guardian to
provide this information. Subject’s parent/legal guardian 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 drug only or also from study
procedures and/or posttreatment study follow-up, and entered on the appropriate CRF page. In

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
41/Protocol WN40226, Version 6
the event that vital status (whether the subject 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.
Withdrawal of consent may be requested by subjects, parents, guardians, or legally acceptable
representatives, in accordance with local regulations. The wishes of minor subjects to withdraw
their assent should also be respected.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing
status. This includes follow-up with persons authorized by the subject as noted above. Lost to
follow-up is defined by the inability to reach the subject after a minimum of three documented
phone calls, faxes, texts, or emails as well as lack of response by subject to one registered mail
letter. All attempts should be documented in the subject’s medical records. If it is determined
that the subject has died, the site will use permissible local methods to obtain the date and cause
of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study
has been included in the subject’s informed consent, then the investigator may use a
sponsor-retained third-party representative to assist site staff with obtaining subject’s contact
information or other public vital status data necessary to complete the follow-up portion of the
study. 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 subject remains lost to follow-up, then the last known alive date as determined by
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug 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

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
RO7239361 or placebo will be administered as a SC injection. The table below indicates the
solution strength for each panel. After the withdrawal of study drug into an appropriate-sized
syringe, the product should be administered SC within 4 hours.
PFS dose administration: RO7239361 will be administered as a SC injection with a PFS 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 Investigator's Brochure for PK and 
safety data following single-dose administration across these injection sites in healthy subjects 

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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(Study WP40225). The following table indicates the solution strength for each PFS.
Table 4-1:
Study Drug in Double-Blind Phase
Panel / Dose
RO7239361 or Placebo Solution Strength
Panel 1: 4.0 mg
50 mg/mL or placebo
Panel 2: 12.5 mg or 20 mg
50 mg/mL or placebo
Panel 3: 35 mg or 50 mg
50 mg/mL or placebo
Expansion Panel: 35 mg or 50 mg
50 mg/mL or placebo
Table 4-2:
Study Drug in Open-Label Phase
Panel / Dose
RO7239361 Solution Strength
Panel 1: 4.0-mg vial
50 mg/mL
Panel 2: 12. 5-mg or 20-mg vial
50 mg/mL
Panel 3: 35-mg or 50-mg vial
50 mg/mL
Expansion Panel: 35-mg or 50-mg vial
50 mg/mL
Pre-filled syringe: 35 mg 
50 mg/mL
Pre-filled syringe: 50 mg
71.4 mg/mL
On Days 1, 8, and 15, each subject will receive SC doses of RO7239361 or placebo at the study 
site. For subsequent weekly SC doses (starting at Day 22), subjects may receive the weekly dose 
at home (by the subject’s parent/caregiver) or at the study site. The parent/caregiver cannot 
administer the study drug to the subject until the parent/caregiver has been trained by study site 
staff and the parent/caregiver is comfortable administering study drug to the subject. After Day 15 
and once trained, the parent/caregiver will receive RO7239361/placebo (during double-blind 
phase) or RO7239361 (during the OL phase) in vial and sterile syringes or PFS (during the OLE 
phase) for weekly administration at home to the subject. The first three weekly doses in the OL 
phase must be administered at the study site, as well as the first two PFS doses during the OLE
phase.
Doses within each panel may be adjusted based upon emerging safety, tolerability, PK, and target 
engagement (free myostatin suppression) data from the present study.
Product description and storage information is described in Table 4-3.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
43/Protocol WN40226, Version 6
Table 4-3:
Study Drugs
Product Description
Class and Dosage
Potency
IP/
Non-
Blinded or Open
Label
Packaging/Appearance
Storage Conditions
(per label)
RO7239361 solution for
injection
50 mg/vial (1 mL vial)
IP
Blinded (during 24-week 
blinded phase) and open label
(during 48 week OL phase and
OL Extension phase)
Colorless to slightly yellow, clear 
to opalescent solution, essentially
free of particulate matter
packaged in a 5 -ccc type I glass
vial with a 20-mm stopper and 
20-mm flip-off seal. Secondary
packaging is a one vial carton
2-8C (36-46F),
protect from light, protect 
from freezing
Placebo for RO7239361
solution for injection
0 mg/vial (1 mL vial)
IP
Blinded
Colorless to slightly yellow
solution, clear to opalescent,
essentially free of particulate
matter packaged in a 5-cc type
I glass vial with a 20-mm 
stopper and 20-mm flip-off
seal. Secondary packaging is a
one vial carton.
2-8C (36-46F),
protect from light,
protect from freezing
RO7239361 prefilled 
syringe for injection of 
35 mg per syringe
50 mg/mL
IP
Open label (during OL 
Extension phase)
Solution packaged in a 1-cc 
glass syringe equipped with a 
safety syringe device.
Secondary packaging is a one 
syringe carton.
2-8C (36-46F),
protect from light,
protect from freezing
RO7239361 prefilled 
syringe for injection of
50 mg per syringe
71.4 mg/mL
IP
Open label (during OL 
Extension phase)
Solution packaged in a 1-cc 
glass syringe equipped with a 
safety syringe device
Secondary packaging is a one 
syringe carton.
2-8C (36-46F),
protect from light,
protect from freezing

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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4.1
Investigational Product
An IP, also known as IMP in some regions, is defined as 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.
The IP should be stored in a secure area according to local regulations. It is the responsibility
of the investigator to ensure that IP is only dispensed to study subjects. The IP must be
dispensed only from official study sites by authorized personnel according to local regulations.
In this protocol, the IP is RO7239361 solution for injection (vial and PFS) and matching
placebo solution for injection (for vial).
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or
therapeutic reasons, as components of the standard of care for a given diagnosis, may be
considered as non-IPs. In this study, corticosteriods are considered non-IP and will not be 
provided by the Sponsor.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug 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 drug arise, the study drug should
not be dispensed and contact Roche immediately.
Study drug not supplied by Roche will be stored in accordance with the package insert.
IP 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).
Parents/caregivers must be instructed by the site staff to bring used containers of study drug to
each study visit; this will allow site staff to assess study drug accountability. 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.
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.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
45/Protocol WN40226, Version 6
4.4
Method of Assigning Subject Identification
Within each panel, subjects will be randomized to receive either 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 00001 (e.g., 00001, 00002, 
00003.... 00010). The patient identification number (PID) will ultimately be comprised of the
site number and subject number. For example, the first subject screened (i.e., enrolled) at site
number 1, will have a PID of 0001 00001. 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.
Subjects will not be replaced if they are discontinued from the study secondary to an AE
unless the AE can be determined to be unrelated to treatment. Subjects may be replaced if
corticosteroid use is discontinued while on treatment. If a subject is replaced after dosing,
then the replacement subject will be assigned the original subject’s number plus 100. The
replacement subject will receive the same treatment as the subject being replaced but a new
randomization number will be assigned to him. For example, Subject 00004 would be
replaced by Subject 00104.
4.5
Selection and Timing of Dose for Each Subject
The levels of free myostatin at Week 5 in Study CN001001 of normal healthy volunteers were
used to determine the dose ranges for the present study. The lowest dose in this study (Panel 1
dose; see Table 4.5-1) is a dose that targets achievement of >50% suppression in levels of free
myostatin at trough after 5 weeks of weekly dosing and is lower than the starting weekly
dose of that study of normal healthy volunteers that produced approximately 83% reduction in
free myostatin at trough at Week 5. The dose for Panel 1 has a safety margin in children in the
weight range anticipated for subjects in this study21 of 15 kg to 70 kg of about 232x relative to
the Week 12 exposures in the juvenile rat toxicity study.
Table 4.5-1:
Panel 1 Dose
Body Weight Tier
Fixed Dose (mg) /Volume (mL)
kg
4.0 mg /0.08 mL
The middle dose in this study (Panel 2 dose; Table 4.5-2) is a dose that targets achievement of
> 85% suppression in levels of free myostatin at trough after 5 weeks of weekly dosing. The dose
for Panel 2 has a safety margin in children in the weight range of 15 kg to 70 kg of about 45x,
relative to the Week 12 exposures in the juvenile rat toxicity study.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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Table 4.5-2:
Panel 2 Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
kg to 45 kg
kg
12.5 mg/0.25 mL
20.0 mg/0.4 mL
The highest dose in this study (Panel 3; Table 4.5-3) is a dose that targets achievement of >
95% suppression in levels of free myostatin at trough after 5 weeks of weekly dosing. The
dose for Panel 3 has a safety margin in children in the weight range of 15 kg to 70 kg of
about 16x relative to the Week 12 exposures in the juvenile rat toxicity study. A review of
safety data from Panels 13 supports the selection of the Panel 3 dose (35 mg for subjects
15 kg to 45 kg; 50 mg for subjects > 45 kg) for the Expansion panel.
Table 4.5-3:
Panel 3 Dose
Body Weight Tier
Fixed Dose (mg)/Volume (mL)
kg to 45 kg
kg
35.0 mg/0.7 mL
50.0 mg/1 mL
Table 4.5-4:
Expansion Panel Dose
Body Weight Tier
Fixed Dose (mg) /Volume (mL)
kg to 45 kg
kg
35.0 mg/0.7 mL
50.0 mg/1 mL
Subjects will receive SC doses of RO7239361/placebo weekly. During Part A (first four weeks
of Panels 13), study drug should be administered every 7 days. During Part B of the
double-blind phase (Weeks 524 of Panels 13 and Expansion Panel) and during the 48-week
OL phase, the study drug should be administered every 7 days within a 1-day window.
Subjects may receive the weekly dose at home, starting on Day 22. If the parent/caregiver
has been trained by study site staff and is comfortable administering study drug to the
subject, the parent/caregiver will receive an adequate supply of study drug in vial (either
RO7239361 or placebo during the double-blind phase and RO7239361 in the OL and OLE
phases) and sterile syringes for weekly administration at home to their child in between study
visits. The first three weekly doses in the OL phase must be administered at the study site, as 
well as the first two PFS doses in the OLE phase.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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In Panels 2 and 3, during the first four weeks of dosing (Days 129) the dose of RO7239361
should not be adjusted based on weight. Starting at Week 5, subjects whose weight exceeds or
drops below the dosing weight tier to which they were assigned by 1 kg should be assigned 
to the new weight-based dose in the subject’s assigned dose panel.
4.6
Blinding/Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the
event of a medical emergency in an individual subject in which knowledge of the investigational
product is critical to the subject’s management, the blind for that subject may be broken by the
investigator. The subject’s safety takes priority over any other considerations in determining if a
treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine
that the unblinded information is necessary (i.e., that it will alter the subject’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 subject 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 subject has been made.
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.
In case of an emergency, the investigator(s) has unrestricted access to randomization information
via the interactive voice response system (IVRS) and is capable of breaking the blind through
the IVRS without prior approval from the Sponsor. Following the unblinding, the investigator
shall notify the Medical Monitor and/or study director.
Further considerations about unblinding are discussed below. Because data emerging from each
panel of Part A might be needed for timely decisions about adjustments to procedures in
subsequent panels, including early termination of the study, data from these panels can be
unblinded after documented completion and review of the corresponding CRFs, prior to the
formal locking of the study database. Also, designated staff of Roche can be unblinded at any
time. The Bioanalytical Sciences section or its designate will be unblinded to the randomized
treatment assignments in order to minimize unnecessary analysis of samples from control
group
subjects.
A
pharmacokineticist(s)
or
designate
in
Clinical
Pharmacology
and
Pharmacometrics, a biostatistician(s) and programmer(s) in Global Biometric Sciences may be
unblinded in order to prepare preliminary summaries of PK, PD, and safety data, as needed
before data is more generally unblinded. Additionally, data from subjects can be unblinded
for IAs that are discussed in Section 8.5. Except for the IA, including all data from the
double-blind period, summaries for these analyses will not reveal individual subjects’ treatment
assignments. Except as noted above, other members of Roche will remain blinded. Target

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
48/Protocol WN40226, Version 6
engagement and immunogenicity results from subjects will be masked to site, subject and
Roche
personnel,
excluding
the
pharmacokineticist
or
designate, biostatistician
and
programmer as referenced above.
The randomization assignments will be released to the study sites by the final study report
generated for the study.
4.7
Treatment Compliance
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 is allowed starting on Day 22) of
double-blind phase and at Week 4 of the open label phase), the parents/caregivers must be
instructed on proper administration of study drug. The site staff must also instruct the
parents/caregivers to bring used and/or empty vials to each study visit. 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 and dose of each SC injection. Parents/caregivers
must be instructed to bring the used and/or empty vials and the dosing diary to each study
visit; this will allow site staff to assess treatment compliance and study drug accountability. A
dosing diary will also be provided to the parent/caregiver to record the subject’s corticosteroid
therapy. 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.
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.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by Roche or sourced by the investigator) such
as partially used study drug containers, vials and syringes may be destroyed on site.
Any unused study drugs can only be destroyed after being inspected and reconciled by the
responsible Roche study monitor unless study drug containers must be immediately destroyed
as required for safety, or to meet local regulations (e.g., cytotoxics or biologics).
On-site destruction is allowed provided the following minimal standards are 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 containers. The

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
49/Protocol WN40226, Version 6
method of disposal (i.e., 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.
If conditions for destruction cannot be met the responsible Roche study monitor will make
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that
procedures 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.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused
and/or partially used study drug that was supplied by Roche must be returned to Roche. The 
return of study drug will be arranged by the responsible study monitor.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that
procedures 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.
4.10
Retained Samples for Bioavailability/Bioequivalence
Not applicable.
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Charts/Time and Events Schedules
Study assessments and procedures are presented in Table 5.1-1, Table 5.1-2, Table 5.1-3, and
Table 5.1-5.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
50/Protocol WN40226, Version 6
Table 5.1-1:
Screening and Baseline Procedural Outline
Procedure
Screening
Visit
(Day -45
to Day -7)
Baseline
Day -2
Visit*
Baseline
Day -1
Visit*
Notes
* Day -2 and Day -1 assessments and laboratory draws may be combined
and performed on either Day -2 or Day -1
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a protocol specific informed consent
is signed.
Register / enroll subject in IWRS
X
Inclusion/Exclusion Criteria
X
Medical History
X
Include any toxicities or allergy related to previous treatments.
Concomitant Medications
X
X
X
Safety Assessments
Physical Examination (PE)
X
X
Physical Measurements
X
Includes height, weight, and BMI.
Vital Signs
X
Includes body temperature, respiratory rate, and seated blood pressure and heart
rate. Blood pressure and heart rate should be measured after the subject has been
resting quietly for at least 5 minutes.
Electrocardiogram (ECG)
X
ECG should be recorded after the subject has been supine for at least 5 minutes.
Echocardiogram
X
X
If the screening echocardiogram was done between Day -15 and Day -7, the
echocardiogram does not need to be repeated at Day -1 visit
Laboratory Assessments
X
X
Glutamate dehydrogenase assay
(GLDH)
X
Urinalysis
X

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
51/Protocol WN40226, Version 6
Table 5.1-1:
Screening and Baseline Procedural Outline
Procedure
Screening
Visit
(Day -45 to
Day -7)
Baseline
Day -2
Visit*
Baseline
Day -1
Visit*
Notes
* Day -2 and Day -1 assessments and laboratory draws may be combined
and performed on either Day -2 or Day -1
Secondary endpoints
Immunogenicity
X
Serum Free and Total Myostatin
X
Right Thigh MRI
X
See Sections 3.4.2.1 and 5.6.1.1 and the imaging procedure manual;
Baseline right thigh MRI scans should be obtained between Day -35 and Day -
14. Adequacy of right thigh MRI should be confirmed by the imaging vendor
prior to randomization.
Exploratory Endpoints
Exploratory Serum Biomarkers
X
See Section 5.6.3
Backup chemistry samples (serum
ferritin and transferrin)
X
To be analyzed if needed.
Blood Sample for Exploratory
Genotyping
X
Exploratory Urine Biomarkers
X
See Section 5.6.2
TFTs
X
X
Includes 4SC, 4SD, 10-m walk/run, standing from 
supine At screening visit: 4SC must be 8 seconds.
6MWD
X
X
See Study Procedure Manual.
NSAA
X
See Study Procedure Manual.
PFTs
X
See Study Procedure Manual.
Upper and Lower
Extremity Myometry
X
See Study Procedure Manual.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
52/Protocol WN40226, Version 6
Table 5.1-1:
Screening and Baseline Procedural Outline
Procedure
Screening
Visit
(Day -45 to
Day -7)
Baseline
Day -2
Visit*
Baseline
Day -1
Visit*
Notes
* Day -2 and Day -1 assessments and laboratory draws may be
combined and performed on either Day -2 or Day -1
Ankle Range of Motion
X
See Study Procedure Manual.
PODCI
X
Completed by the parent/caregiver of the subject.
PUL
X
See Study Procedure Manual.
DXA
X
See Sections 3.4.2.1 and 5.6.1.2 and the imaging procedure manual. Baseline 
DXA should be obtained between Day -35 and Day -14. Adequacy of DXA 
scan should be confirmed by the imaging vendor prior to randomization.
MRS
X
See Sections 3.4.2.1 and 5.6.1.1 and the imaging procedure manual.
Baseline right thigh MRS scans should be obtained between Day -35 and Day -
14. Adequacy of right thigh MRS should be confirmed by the imaging vendor
prior to randomization. MRS will be completed at selected sites, based on 
completion of training.
Adverse Event Reporting
Monitor for Serious Adverse
Events
X
X
X
All SAEs must be collected from the date of subject’s written consent until
50 days (5 half-lives) post discontinuation of dosing in the present study. If the
subject enters a separate rollover treatment study of RO7239361, the subject’s
SAEs will be reported in that study.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
53/Protocol WN40226, Version 6
Table 5.1-2:
On-Treatment Procedural Outline, Double-Blind Phase: All Panels
Procedure
D1a
D4b
D5b
D8
1 day
(Week 1)
D15
1 day
(Week 2)
D22b
1 day
(Week 3)
D29
1 day
(Week 4)
D33b
1 
day
Study
Week 6
3
days
Study
Week 12
3 days
Study
Week
18
3
days
Study
Week 24 /
or early
D/C
3 days
Notes
Safety Assessments
Physical 
Examination (PE)
X
X
Targeted PE
X
X
X
X
X
Guide exam by review
of systems
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 site
staff take non-subject
identifying photographs
of moderate to severe
injection-site reactions
for submission to the
Sponsor.
Weight
X
X
X
X
Height
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
See note in screening
procedures.
Echocardiogram
X
X
X
See Study Procedure
Manual.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
54/Protocol WN40226, Version 6
Table 5.1-2:
On-Treatment Procedural Outline, Double-Blind Phase: All Panels
Procedure
D1a
D4b
D5b
D8
1 day
(Week 1)
D15
1 day
(Week 2)
D22b
1 day
(Week 3)
D29
1 day
(Week
4)
D33b
1 
day
Study
Week 6
3 days
Study
Week 12
3 days
Study
Week
18
3 days
Study
Week 24 /
or early
D/C
3 days
Notes
Electro-
cardiogram 
(ECG)
X
ECGs should be
recorded after the
subject has been supine
for at least 5 minutes.
Laboratory Tests
X
X
X
X
X
See note in screening
procedures and
Section 5.3.3.
Placement of an
intravenous lock is
allowed for on-site 
visits when multiple 
blood draws are 
required.
Urinalysis
X
X
X
X
X
X
GLDH
X
X
X
X
X
See Section 5.6.4
Residual sample
retained for potential
exploratory plasma
biomarker

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
55/Protocol WN40226, Version 6
Table 5.1-2:
On-Treatment Procedural Outline, Double-Blind Phase: All Panels
Procedure
D1a
D4b
D5b
D8
1 day
(Week 1)
D15
1 day
(Week 2)
D22b
1 day
(Week 3)
D29
1 day
(Week
4)
D33b
1 
day
Study
Week 6
3 days
Study
Week 12
3 days
Study
Week
18
3 days
Study
Week 24 /
or early
D/C
3 days
Notes
Adverse Event Reporting
Monitor for Non-
Serious Adverse
Events
X
X
X
X
X
X
X
X
X
X
X
X
All subjects
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).
Monitor for
Serious Adverse
X
X
X
X
X
X
X
X
X
X
X
X
All SAEs must be
collected from the date
Events
of subject’s written
consent until 50 days
(5 half-lives) post
discontinuation of
dosing in the present
study. If the subject
enters a separate
rollover treatment study
of RO7239361, the
subject’s SAEs will be
reported in that study.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
56/Protocol WN40226, Version 6
Table 5.1-2:
On Treatment Procedural Outline, Double-Blind Phase:  All Panels
Procedure
D1a
D4b
D5b
D8
1 day
(Week 1)
D15
1 day
(Week 2)
D22b
1 day
(Week 3)
D29
1 day
(Week
4)
D33b
1 
day
Study
Week 6
3 days
Study
Week 12
3 days
Study
Week
18
3 days
Study
Week 24 /
or early
D/C
3 days
Notes
Pharmacokinetic (PK) Assessments
Blood PK
Sampling
X
X
X
X
X
X
X
X
X
X
See Section 5.5 of
protocol.
Secondary Endpoints
Immunogenicity
Sampling
X
X
X
X
X
The Immunogenicity
sample must be
collected before
administration of study
drug.
In the event of a
positive
immunogenicity
response, additional
neutralizing antibody
(NAB) testing may be
conducted.
Free Myostatin
and Myostatin-
Drug Complex
X
X
X
X
X
X
X
X
X
Must be collected prior
to administration of
study drug.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
57/Protocol WN40226, Version 6
Table 5.1-2:
On-Treatment Procedural Outline, Double-Blind Phase: All Panels
Procedure
D1a
D4b
D5b
D8
1 day
(Week 1)
D15
1 day
(Week 2)
D22b
1 day
(Week 3)
D29
1 day
(Week
4)
D33b
1 
day
Study
Week 6
3 days
Study
Week 12
3 days
Study
Week
18
3 days
Study
Week 24 /
or early
D/C
3 days
Notes
Right thigh MRI
X
X
Visit window 1
week. Conducted 
at early
termination if 8
weeks from
previous MRI.
See Sections 3.4.2.1 and
5.6.1.1 and the imaging
procedure manual.
Exploratory Endpoints
Serum
Biomarkers
X
X
X
X
X
X
See Section 5.6.3
Urine Biomarkers
X
X
X
X
X
X
See Section 5.6.2
Backup chemistry
samples (serum
ferritin and
transferrin)
X
X
X
X
X
X
To be analyzed if
needed.
TFTs
X
X
X
X
X
See Study Procedure
Manual.
6MWD
X
X
X
X
X
See Study Procedure
Manual

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
58/Protocol WN40226, Version 6
Table 5.1-2:
On-Treatment Procedural Outline, Double-Blind Phase: All Panels
Procedure
D1a
D4b
D5b
D8
1 day
(Week 1)
D15
1 day
(Week 2)
D22b
1 day
(Week 3)
D29
1 day
(Week
4)
D33b
1 
day
Study
Week 6
3 days
Study
Week 12
3 days
Study
Week
18
3 days
Study
Week 24 /
or early
D/C
3 days
Notes
NSAA
X
X
X
X
X
See Study Procedure
Manual.
PFTs
X
X
X
X
X
See Study Procedure
Manual
Upper & Lower
Extremity 
Myometry
X
X
X
See Study Procedure
Manual
PUL
X
X
X
See Study Procedure
Manual
Ankle Range of
Motion
X
X
X
See Study Procedure
Manual
PODCI
X
X
See Study Procedure
Manual
DXA
X
Visit window 1
week.
Not required at early
termination visit.
See Sections 3.4.2.1 and
5.6.1.2 and the imaging
procedure manual

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
59/Protocol WN40226, Version 6
Table 5.1-2:
On-Treatment Procedural Outline, Double-Blind Phase: All Panels
Procedure
D1a
D4b
D5b
D8
1 day
(Week 1)
D15
1 day
(Week 2)
D22b
1 day
(Week 3)
D29
1 day
(Week
4)
D33b
1 
day
Study
Week 6
3 days
Study
Week 12
3 days
Study
Week
18
3 days
Study
Week 24 /
or early
D/C
3 days
Notes
Right thigh MRS
X
X
Visit window 1
week.
Conducted 
at 
early
termination if 8 weeks
from previous MRS.
See Sections 3.4.2.1 and
5.6.1.1 and the imaging
procedure manual.
MRS will be completed
at selected sites, based 
on
completion 
of 
training.
Clinical Drug Supplies
Randomize
X
Access IWRS to
obtain study drug
container
assignment
X
X
X
X
X
X
X
X
X
X
Access IVRS as needed
to obtain either a
weekly supply (for on-
site dosing) or 6-week
supply (for at home
dosing). Access IVRS
as needed for to replace
containers.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
60/Protocol WN40226, Version 6
Table 5.1-2:
On-Treatment Procedural Outline, Double-Blind Phase:  All Panels
Procedure
D1a
D4b
D5b
D8
1 day
(Week 1)
D15
1 day
(Week 2)
D22b
1 day
(Week 3)
D29
1 day
(Week
4)
D33b
1 
day
Study
Week 6
3 days
Study
Week 12
3 days
Study
Week
18
3 days
Study
Week 24 /
or early
D/C
3 days
Notes
Weekly Study
Drug
Administration
X
X
X
X
X
RO7239361 will be
administered every
week (every 7 days,
unless otherwise
stated). Parents and 
caregivers will be 
trained to administer 
SC injections.
Parents/caregivers who
are comfortable with SC
administration can
administer the injection
starting at Day 22.
Parents/caregivers will
be dispensed an
approximately 6 week
supply of drug in vial
(RO7239361 or
placebo) and sterile
syringes for weekly
study drug/placebo
administration to the
subject.
a Day 1 must occur within 45 days of the screening visit.
b May be a home visit conducted by visiting nurse if approved by IRB and investigator. If visit is a home visit, the subject’s signs and symptoms will be
assessed.
Abbreviations: D = Day

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
61/Protocol WN40226, Version 6
Table 5.1-3:
Open-Label Phase Procedural Outline
Procedure
Week
1
Week
2
1 
day
Week
3
1 
day
Week
6
3 days
Week
12
3 days
Week
18
3 days
Week
243
days
Week
30 3
days
Week 
36
3 days
Week
42 3
days
Week 48 
or early D/C
3 days
Notes
Safety Assessments
Physical 
Examination (PE)
X
Targeted PE
X
X
X
X
X
X
Guide exam by
review of systems
and include
abdominal exam
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
site staff take non-
subject identifying
photographs of
moderate to severe
injection-site
reactions for
submission to the
Sponsor.
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
Height
X

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
62/Protocol WN40226, Version 6
Table 5.1-3:
Open-Label Phase Procedural Outline
Procedure
Week
1
Week
2
1 
day
Week
3
1 
day
Week
6
3 days
Week
12
3 days
Week
18
3 days
Week
243
days
Week
30 3
days
Week 
36
3 days
Week
42 3
days
Week 48 
or early D/C
3 days
Notes
Echocardiogram
X
X
See Study
Procedure 
Manual
Electrocardiogram
(ECG)
X
ECGs should be
recorded after the
subject has been 
supine for at least
5 minutes.
Laboratory Tests
X
X
X
X
X
Placement of an
intravenous lock is
allowed for on-site
visits when
multiple blood
draws are
required.
Urinalysis
X
X
X
X
GLDH
X
X
X
X
X
See Section 5.6.4
Residual sample
retained for
potential
exploratory
plasma biomarker
Adverse Event
Reporting
Monitor for Non-
Serious Adverse
Events
X
X
X
X
X
X
X
X
X
X
X

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
63/Protocol WN40226, Version 6
Table 5.1-3:
Open-Label Phase Procedural Outline
Procedure
Week
1
Week
2
1 
day
Week
3
1 
day
Week
6
3 days
Week
12
3 days
Week
18
3 days
Week
243
days
Week
30 3
days
Week 
36
3 days
Week
42 3
days
Week 48 
or early D/C
3 days
Notes
Monitor for
Serious Adverse
Events
X
X
X
X
X
X
X
X
X
X
X
All SAEs must be
collected from the
date of subject’s
written consent
until 50 days (5
half lives) post
discontinuation of
dosing in the
present study. If
the subject enters
a separate rollover
treatment study of
RO7239361, the
subject’s SAEs
will be reported in
that study.
Pharmaco-
kinetic (PK)
Assessments
Blood PK
Sampling
X
X
X
X
X
See Section 5.5 of
protocol.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
64/Protocol WN40226, Version 6
Table 5.1-3:
Open-Label Phase Procedural Outline
Procedure
Week
1
Week
2
1 
day
Week
3
1 
day
Week
6
3 days
Week
12
3 days
Week
18
3 days
Week
243
days
Week
30 3
days
Week 
36
3 days
Week
42 3
days
Week 48 
or early D/C
3 days
Notes
Secondary
Endpoints
Immunogenicity
Sampling
X
X
X
X
Immunogenicity
sample must be
collected before
administration of
study drug.
In the event of a
positive
immunogenicity
response,
additional NAB
testing may be
conducted.
Free Myostatin
and Myostatin-
Drug Complex
X
X
X
X
X

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
65/Protocol WN40226, Version 6
Table 5.1-3:
Open-Label Phase Procedural Outline
Procedure
Week
1
Week
2
1 
day
Week
3
1 
day
Week
6
3 days
Week
12
3 days
Week
18
3 days
Week
243
days
Week
30 3
days
Week 
36
3 days
Week
42 3
days
Week 48 
or early D/C
3 days
Notes
Right thigh MRI
X
Visit window 1
week.
Conducted at early
termination if 8
weeks from
previous MRI
See Sections
3.4.2.1 and 5.6.1.1
and the imaging
procedure manual.
Exploratory Endpoints
Serum
Biomarkers
X
X
X
X
See Section 
Urine Biomarkers
X
X
X
X
See Section 5.6.2
Backup chemistry
samples (Serum
ferritin and
transferrin)
X
X
X
X
To be analyzed if
needed.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
66/Protocol WN40226, Version 6
Table 5.1-3:
Open-Label Phase Procedural Outline
Procedure
Week
1
Week
2
1 
day
Week
3
1 
day
Week
6
3 days
Week
12
3 days
Week
18
3 days
Week
243
days
Week
30 3
days
Week 
36
3 days
Week
42 3
days
Week 48 
or early D/C
3 days
Notes
TFTs
X
X
X
X
See Study
Procedure Manual
6MWD
X
X
X
X
See Study
Procedure Manual
NSAA
X
X
X
X
See Study
Procedure Manual
PFTs
X
X
X
X
See Study
Procedure Manual
Upper and
Lower
Extremity 
X
X
X
X
See Study
Procedure Manual
PUL
X
X
X
X
See Study
Procedure Manual
Ankle Range of
Motion
X
X
X
X
See Study
Procedure Manual
PODCI
X
X
X
X
See Study
Procedure Manual
DXA
X
Visit window1
week.
Not required at
early termination
visit.
See Sections
3.4.2.1 and 5.6.1.2
and the imaging
procedure manual

 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
67/Protocol WN40226, Version 6 
 
Table 5.1-3: 
Open-Label Phase Procedural Outline 
 
Procedure 
Week 
1 
Week 
2  
± 1 
day 
Week 
3  
± 1 
day 
Week  
6 
± 3 days 
Week  
12 
± 3 days 
Week  
18 
± 3 days 
Week  
24± 3 
days 
Week 
30 ± 3 
days 
Week  
36 
± 3 days 
Week 
42 ± 3 
days 
Week 48  
or early D/C 
± 3 days 
Notes 
Right thigh MRS 
X 
Visit window ± 1 
week. 
Conducted at early 
termination if ≥ 8 
weeks from 
previous /MRS. 
See Sections 
3.4.2.1 and 5.6.1.1 
and the imaging 
procedure manual. 
MRS will be 
completed at 
selected sites, 
based on 
completion of 
training. 

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
69/Protocol WN40226, Version 6
Table 5.1-3:
Open-Label Phase Procedural Outline
Procedure
Week
1
Week
2
1 
Week
3
1 
Week
6
3 days
Week
12
3 days
Week
18
3 days
Week
243
days
Week
30 3
days
Week 
36
3 days
Week
42 3
days
Week 48 
or early D/C
3 days
Notes
Access IWRS to
obtain study drug
container
assignment
X
X
X
X
X
X
X
X
X
X
Supplied by
Roche with 
sterile syringes
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)
2) Safety (clinical labs)
3) Pharmacokinetic Sampling
4) Biomarker Sampling

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
70/Protocol WN40226, Version 6
Table 5.1-4:
Open-Label Extension Phase Procedural Outline a
Procedure
After Switch to PFS 
during OL Extension b
Day 1, Day 8,
Day 45, and Week 12
(All visits 1 day)
Week 60,
Week 108,
Week 156,
Week 204
(All visits
3 days)
Week 72,
Week 120,
Week 168,
Week 216
(All visits
3 days)
Week 84,
Week 132,
Week 180
(All visits
3 days)
Weeks 96,
Week 144,
Week 192
(All visits
3 days)
Week 228 or
End of
Treatment
or Early D/C
Notes
Safety
Physical
Examination (PE)
X
X
X
Targeted PE
X
X
X
X
Guide exam by review of
systems and include
abdominal exam
Monitor Injection 
Sites
X
X
X
X
X
X
Report findings as
AEs, as appropriate. It 
is strongly
recommended that site 
staff take non-subject 
identifying
photographs of
moderate to severe
injection-site reactions 
for submission to the
Sponsor.
Vital Signs
X
X
X
X
X
X
Weight
X c
X
X
X
X
X
Height
X

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
71/Protocol WN40226, Version 6
Table 5.1-4:
Open-Label Extension Phase Procedural Outline a
Procedure
After Switch to PFS 
during OL Extension b
Day 1, Day 8,
Day 45, and Week 12
(All visits 1 day)
Week 60,
Week 108,
Week 156,
Week 204
(All visits
3 days)
Week 72,
Week 120,
Week 168,
Week 216
(All visits
3 days)
Week 84,
Week 132,
Week 180
(All visits
3 days)
Weeks 96,
Week 144,
Week 192
(All visits
3 days)
Week 228 or
End of
Treatment
or Early D/C
Notes
Echocardiogram
X
X
X
See Study
Procedure Manual
Electrocardiogram 
(ECGs)
X
X
ECGs should be
recorded after the
subject has been
supine for at least 5
minutes.
Laboratory Tests
Xd
X
X
X
Placement of an
intravenous lock is
allowed for on-site
visits when multiple 
blood draws are 
required.
Urinalysis
Xd
X
X
X
GLDH
Xd
X
X
X
See Section 5.6.4
Residual sample
retained for potential
exploratory plasma
biomarker

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
72/Protocol WN40226, Version 6
Table 5.1-4:
Open-Label Extension Phase Procedural Outline a
Procedure
After switch to PFS 
during OL Extension b
Day 1
Day 8
Day 45
Week 12
(all visits 1 day)
Week 60,
Week 108,
Week 156,
Week 204
(all visits 3
days)
Week 72,
Week 120,
Week 168,
Week 216
(all visits 3
days)
Week 84,
Week 132,
Week 180
(all visits 3
days)
Weeks 96,
Week 144,
Week 192
(all visits 3
days)
Week 228 or
End of
Treatment
or Early D/C
Notes
Adverse Event 
Monitor for 
Non-Serious
Adverse 
Events
X
X
X
X
X
X
Monitor for
Serious Adverse
Events
X
X
X
X
X
X
All SAEs must be
collected from the
date of subject’s
written consent
until 50 days (5 half
lives) post
discontinuation of
dosing in the
present study.
Pharmacokinetic (PK) Assessments
Blood PK Sampling
X
X
X
X
See Section 5.5 of
protocol.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
73/Protocol WN40226, Version 6
Table 5.1-4:
Open Label Extension Phase Procedural Outline a
Procedure
After switch to PFS 
during OL 
Extension b
Day 1
Day 8
Day 45
Week 12
(all visits 1 day)
Week 60,
Week 108,
Week 156,
Week 204
(all visits 3
days)
Week 72,
Week 120,
Week 168,
Week 216
(all visits 3
days)
Week 84,
Week 132,
Week 180
(all visits 3
days)
Weeks 96,
Week 144,
Week 192
(all visits 3
days)
Week 228 or
End of
Treatment
or Early D/C
Notes
Secondary 
Immunogenicity 
Sampling
Xe
X
X
X
Immunogenicity
sample must be
collected before
administration of
study drug.
In the event of a
positive
immunogenicity
response, additional
NAB testing may
be conducted.
Free Myostatin 
and Myostatin-
Drug Complex
X
X
X
X

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
74/Protocol WN40226, Version 6
Table 5.1-4:
Open-Label Extension Phase Procedural Outline a
Procedure
After switch to PFS 
during OL Extension b
Day 1
Day 8
Day 45
Week 12
(all visits 1 day)
Week 60,
Week 108,
Week 156,
Week 204
(all visits 3
days)
Week 72,
Week 120,
Week 168,
Week 216
(all visits 3
days)
Week 84,
Week 132,
Week 180
(all visits 3
days)
Weeks 96,
Week 144,
Week 192
(all visits 3
days)
Week 228 
or End of
Treatment
or Early D/C
Notes
Right thigh MRI
X
X
Visit window 1
week.
Conducted at end of 
treatment or early
termination if 24
weeks from previous
MRI
See Sections
3.4.2.1 and 5.6.1.1
and the imaging
procedure manual.
Exploratory
Serum Biomarkers
X
X
X
X
See Section 
Urine Biomarkers
X
X
X
See Section 5.6.2
TFTs
X
X
See Study Procedure 
Manual
6MWD
X
X
See Study Procedure 
Manual
NSAA
X
X
See Study Procedure 
Manual

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
75/Protocol WN40226, Version 6
Table 5.1-4:
Open-Label Extension Phase Procedural Outline a
Procedure
After switch to PFS 
during OL Extension b
Day 1
Day 8
Day 45
Week 12
(all visits 1 day)
Week 60,
Week 108,
Week 156,
Week 204
(all visits 3
days)
Week 72,
Week 120,
Week 168,
Week 216
(all visits 3
days)
Week 84,
Week 132,
Week 180
(all visits 3
days)
Weeks 96,
Week 144,
Week 192
(all visits 3
days)
Week 228 or
End of
Treatment
or Early D/C
Notes
PFTs
X
X
See Study
Procedure Manual
Upper and
Lower
Extremity
Myometry
X
X
See Study
Procedure Manual
PUL
X
X
See Study
Procedure Manual
Ankle Range of
Motion
X
X
See Study
Procedure Manual
PODCI
X
X
See Study
Procedure Manual
DXA
X
X
Visit window 1
week.
Conducted at end
of treatment or
early termination if
24 weeks from
previous DXA.
See Sections
3.4.2.1 and 5.6.1.2
and the imaging
procedure manual

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
76/Protocol WN40226, Version 6
Table 5.1-4:
Open-Label Extension Phase Procedural Outline a
Procedure
After switch to PFS 
during OL Extension b
Day 1
Day 8
Day 45
Week 12
(all visits 1 day)
Week 60,
Week 108,
Week 156,
Week 204
(all visits 3
days)
Week 72,
Week 120,
Week 168,
Week 216
(all visits 3
days)
Week 84,
Week 132,
Week 180
(all visits 3
days)
Weeks 96,
Week 144,
Week 192
(all visits 3
days)
Week 228 or
End of
Treatment
or Early D/C
Notes
Right thigh MRS
X
X
Visit window 1
week.
Conducted at end of 
treatment or early
termination if
24 weeks from
previous /MRS.
See Sections
3.4.2.1 and 5.6.1.1
and the imaging
procedure manual.
MRS will be
completed at selected
sites, based on
completion of
training.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
77/Protocol WN40226, Version 6
Table 5.1-4:
Open-Label Extension Phase Procedural Outline a
Procedure
After switch to PFS 
during OL Extension b
Day 1
Day 8
Day 45
Week 12
(all visits 1 day)
Week 60,
Week 108,
Week 156,
Week 204
(all visits 3
days)
Week 72,
Week 120,
Week 168,
Week 216
(all visits 3
days)
Week 84,
Week 132,
Week 180
(all visits 3
days)
Weeks 96,
Week 144,
Week 192
(all visits 3
days)
Week 228 or
End of
Treatment
or Early D/C
Notes
Clinical Drug 
Supplies
Weekly
study
drug
adminis-
tration
X f
X
X
X
X
X
RO7239361 will
be administered
every week (every 7
days, unless
otherwise stated).
Study drug
(RO7239361) and 
sterile syringes or 
PFS for weekly study
drug administration, 
will be dispensed as 
needed.
Access IWRS to
obtain study drug 
container 
assignment
X
X
X
X
X
X
Supplied by Roche
with sterile
syringes
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)
2) Safety (clinical labs)
3) Pharmacokinetic Sampling
4) Biomarker Sampling

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
78/Protocol WN40226, Version 6
a
Study visits will occur every 12 weeks in the OLE phase, for up to 228 weeks or until RO7239361 is commercially available, whichever comes first.
b
The switch to PFS will take place at one of the scheduled clinic visits during the OLE phase. After this visit, subjects will be required to come to the clinic 
1 week later for an additional visit and drug administration and at Day 45 for PK sampling (approximately 2 days after PFS dosing at home). Afterward, visits 
will take place every 12 weeks as scheduled. 
c Body weight will be measured at Day 1 and 12 weeks after the first PFS dose.
d
Laboratory tests, GLDH and urine analysis samples will be collected at 12 weeks after the first PFS dose, if not originally scheduled for the regular OLE visit.
e Immunogenicity samples will be collected at Day 1 (prior to the first PFS dose), Day 45, and 12 weeks after the first PFS dose, if not originally scheduled for 
regular OLE visit).
f
Study drug will be administered at Day 1, Day 8, and Week 12.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
79/Protocol WN40226, Version 6
Table 5.1-5:
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
Adverse Event Reporting
Monitor injection site
X
X
X
Report findings as AEs, as appropriate.
It is strongly recommended that site staff take non-subject identifying
photographs of moderate to severe injection-site reactions for submission
to the Sponsor.
Monitor for previously
reported or new onset of
non-serious adverse events
X
Only required if subject discontinued study early due to adverse event or
does not participate in a separate rollover study. All non-serious adverse
events must be collected until 50 days (5 half-lives) post discontinuation
of dosing in the present study. If the subject enters a separate rollover
treatment study of RO7239361, the subject’s non-serious adverse events
will be reported in that study
Monitor for previously
X
All SAEs must be collected from the date of subject’s written consent
reported or new onset of
until 50 days (5 half-lives) post discontinuation of dosing in the present
serious adverse events
study. If the subject enters a separate rollover treatment study of
(SAEs)
RO7239361, the subject’s SAEs will be reported in that study.
Safety Assessments
ECG
X
Only required for subjects who discontinue study drug due to
cardiovascular concerns.
Echocardiogram
X
Only required for subjects who discontinued study drug due to
cardiovascular concerns.
Laboratory Assessments
X
X
X
Only required for subjects who discontinued study drug due to an
abnormal laboratory result. Labs should be followed until the subject’s
lab values return to baseline or are considered stable by the Investigator

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
80/Protocol WN40226, Version 6
Table 5.1-5:
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
Immunogenicity
X
X
X
Required for all subjects who do not participate in a separate rollover 
study.
In the event of a positive immunogenicity response, additional NAB
testing may be conducted.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
81/Protocol WN40226, Version 6
5.1.1
Retesting during Screening or Lead-in Period
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).
Any new result will override the previous result (i.e., the most current result prior to
randomization) and is the value by which study inclusion will be assessed, as it represents the
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural
Outline, may be repeated in an effort to find all possible well-qualified subjects. Consultation
with the medical monitor may be needed to identify whether repeat testing of any particular
parameter is clinically relevant.
5.2
Study Materials
The site will provide all required materials for the tests performed locally. The site will have
available a well-calibrated scale for recording body weight, and a calibrated sphygmomanometer
and thermometer for vital signs assessments. A current and fully stocked (advanced cardiac life
support [ACLS] or basic cardiac life support [BCLS]) cart will be immediately available on the
premises. The site will have urine collection containers, a monitored and alarmed refrigerator,
and freezer (-20°C or below), as well as containers and dry ice for shipment and storage of blood
and urine samples. A refrigerated centrifuge is recommended.
Roche will provide a Roche-approved protocol and any amendments or administrative letters
(if required), and the Investigator's Brochure. CRFs (electronic or hard copy) will be provided
by Roche. The central laboratory will provide labels and tubes for the collection of all required
materials for the clinical laboratory tests performed by the central laboratory. Roche will also
provide the relevant study manuals, a copy of National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), Version 4.0 and PODCI. Dosing diaries will be
provided by Roche and should be used by the parent/caregiver to capture the dose
administered,
the
time
and
date
administered,
and
location
of
SC
injection
of
RO7239361/placebo. The dosing diary will be used to document at home administration of
study drug and should be completed by the parent/caregiver after each dose. A dosing diary
will also be provided to record corticosteroid dosing. The dosing diaries should be reviewed
by the site staff at the applicable study visits. If approved by the local IRB/EC, Roche will
provide cooler bags, ice packs and Sharps containers for transport of study drug from the site 
to the subject’s home.
Supplied by the Imaging Core Lab
The imaging core lab will supply the Imaging manual(s) for the DXA scan and for MRI/MRS
scan, and if applicable, phantoms.
Supplied by Cardiac Core Lab
The cardiac core lab may supply 12-lead ECG machines and manuals for ECG and
echocardiogram collection.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
82/Protocol WN40226, Version 6
5.3
Safety Assessments
The data from the safety assessments required in this protocol (laboratory tests, ECGs,
echocardiograms) will be transferred to Roche from the relevant vendor. The site staff are
not required to report these procedures on 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.
5.3.1
Echocardiogram
Guidelines for collection of echocardiograms will be provided in the Study Procedures Manual.
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 (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.
Echocardiogram should be repeated in subjects with new cardiac symptoms.
5.3.2
Electrocardiograms
Guidelines for collection of ECGs will be provided in the Study Procedures Manual.
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.
ECG reports 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.
ECG should be repeated in subjects with new cardiac symptoms.
5.3.3
Laboratory Test Assessments
A central laboratory will perform the analyses and will provide reference ranges for these tests.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
83/Protocol WN40226, Version 6
The following clinical laboratory tests will be performed:
Table 5.3.3-1:
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 -2 or
Day -1)
X
X
Metabolic
Thyroid stimulating hormone
X (screening)

 
Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd 
84/Protocol WN40226, Version 6 
 
Table 5.3.3-1: 
Laboratory Assessments 
Screening 
On-Treatment 
Follow-up 
Urine test 
Urinalysis (including protein, glucose, 
blood, leukocyte esterase, specific 
gravity) 
X (Day -2 or 
day -1) 
X (only required at visits 
specified in Table 5.1-2 to 
Table 5.1-5) 
Other sample collections 
Serum Biomarkers 
X 
X (see Table 5.1-2, 
Table 5.1-3, and Table 5.1-
4) 
Urine biomarkers 
X 
X (see Table 5.1-2, 
Table 5.1-3, and Table 5.1-
4) 
Immunogencity 
X 
X (see Table 5.1-2, 
Table 5.1-3, and Table 5.1-
4)
X (see Table 5.1-5) 
Free and total myostatin 
X 
X (see Table 5.1-2, 
Table 5.1-3, and Table 5.1-
4) 
Exploratory genotyping 
X 
Creatine kinase-muscle (CK-MM) 
X (Day -2 or 
day -1) 
X (Day 29, Weeks 6, 12, 
18, and 24 in double-blind 
phase) 
 
All protocol-specified laboratory tests must be analyzed and reported by the central lab. In 
exceptional cases when local laboratory tests are performed, central lab samples should be 
submitted at the same time, if possible. A laboratory test may be repeated if it is determined to be 
inadequate for analysis. All local laboratory results should be reported on the appropriate 
supplemental lab CRF page. Any abnormal laboratory test result considered clinically significant 
by the investigator must be recorded on the appropriate AE page of the CRF (see Section 6.3). 
Backup chemistry samples will be collected on the same schedule as the serum biomarker 
sample collection to test for serum ferritin and transferrin, if determined necessary. 
Placement of an intravenous lock is allowed for on-site visits when multiple blood draws in 
a single day are required. 
Further details of laboratory sample collection, processing and shipping will be provided to the 
site in a laboratory manual. 
5.4 
Efficacy Assessments 
Not applicable. 
5.4.1 
Primary Efficacy Assessment 
Not applicable. 

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
85/Protocol WN40226, Version 6
5.4.2
Secondary Efficacy Assessments
Not applicable.
5.5
Pharmacokinetic Assessments
Pharmacokinetics of RO7239361 following multiple doses will be assessed by measuring serum
concentration of RO7239361 at selected timepoints.
5.5.1
Pharmacokinetics: Collection and Processing
Table 5.5.1-1 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. A PK test may be repeated if it is determined to be inadequate for
analysis.
Table 5.5.1-1:
Pharmacokinetic Sampling Schedule for RO7239361
Study Day of Sample Collection
Event
Time of Sample 
Collection, Relative to 
Time of Dose
Administration
RO7239361
Serum Samples
Day 1, double-blind phase
Predose
00:00
X
Day 1, double- phase
Postdose
3:00 15 min
X
Day 1, double blind phase
Postdose
6:00 15 min
X
Day 4, double-blind phase
PostDay 1 dose
72:00 8 hours
X
Day 5, double-blind phase
PostDay 1 dose
96:00 8 hours
X
Day 8, double-blind phase
Predose
00:00
X
Day 15, double-blind phase
Predose
00:00
X
Day 22, double-blind phase
Predose
00:00
X
Day 29, double-blind phase
Predose
00:00
X
Day 33, double-blind phase
PostDay 29 dose
96:00 8 hours
X
Week 12, double-blind phase
Predose
00:00
X
Week 24, double-blind phase
Predose
00:00
X
Week 1, open-label phase
Predose
00:00
X
Week 12, open-label phase
Predose
00:00
X
Week 24, open-label phase
Predose
00:00
X
Week 36, open-label phase
Predose
00:00
X
Week 48, open-label phase
Predose
00:00
X
*Day 1 after switch to PFS in 
open-label extension phase
Predose
00:00
X
*Day 8 after switch to PFS in 
open-label extension phase
Predose
00:00
X
*Day 45 after switch to PFS in 
open-label extension phase
Postdose
48:00
X

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
86/Protocol WN40226, Version 6
Study Day of Sample Collection
Event
Time of Sample 
Collection, Relative to 
Time of Dose
Administration
RO7239361
Serum Samples
*Week 12 after switch to PFS in 
open-label extension phase
Predose
00:00
X
Week 60, open-label extension phase
Predose
00:00
X
Week 84, open-label extension 
phase
Predose
00:00
X
Week 108, open-label extension 
phase
Predose
00:00
X
Week 132, open-label extension 
phase
Predose
00:00
X
Table 5.5.1-1:
Pharmacokinetic Sampling Schedule for RO7239361
Study Day of Sample Collection
Event
Time of Sample 
Collection, Relative to 
Time of Dose
Administration
RO7239361
Serum Samples
Week 156, open-label extension 
phase
Predose
00:00
X
Week 180, open-label extension 
phase
Predose
00:00
X
Week 204, open-label extension 
phase
Predose
00:00
X
Week 228, open-label extension 
phase
Predose
00:00
X
5.5.2
Pharmacokinetic Sample Analyses
Serum samples will be analyzed for RO7239361 by a validated immunoassay. Pharmacokinetic
samples collected from a subject who received placebo will not be analyzed.
5.5.3
Target Engagement Sample Analyses
Serum samples will be analyzed for free and total myostatin using a qualified commercial
immunoassay kit. Serum will also be analyzed for drug-myostatin complex using a qualified
immunoassay. The sample collection timepoints are in Table 5.1-1 through Table 5.1-4. A free
and total myostatin test may be repeated if it is determined to be inadequate for analysis.
5.5.4
Labeling and Shipping of Biological Samples
Detailed instructions for the blood and serum sample collection, labeling, processing, storage,
and shipping will be provided to the site in the procedure manual.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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5.6
Biomarker Assessments
Biomarkers will be collected as specified in the Time and Events Schedules, Table 5.1-1,
Table 5.1-2, Table 5.1-3, and Table 5.1-4.
5.6.1
Biomarker Imaging Assessments
Clinical sites will be trained in imaging procedures prior to scanning the first study subject and
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.
Results/reports from the DXA, right thigh MRI, and MRS will not be provided to sites as this is a
research measure.
5.6.1.1
Thigh MRI and MRS
Thigh MRI to collect measures of right thigh maximal cross-sectional area (CSAmax) and
contractile versus non contractile content and MRS measures of right thigh lipid fraction will be
performed at timepoints indicated in Table 5.1-1, Table 5.1-2, Table 5.1-3, and Table 5.1-4.
MRS will be completed at selected sites, based on completion of training.
Right thigh MRI and MRS acquisition guidelines and submission processes will be in the
imaging manual provided by the imaging lab that will perform the imaging analyses. Adequacy
of MRI/MRS scans should be confirmed by the central imaging vendor prior to randomization.
Screening right thigh MRI/MRS should be obtained between Day -35 and Day -14 to allow for
central imaging vendor review.
Early Termination or End of Treatment:
During the OL phase, MRI/MRS will only be
conducted if 8 weeks from previous MRI/MRS. In the OLE phase, MRI/MRS will only be 
conducted if greater than or equal to 24 weeks from previous MRI/MRS.
Re-enrollment: Repeat of MRI/MRS is not required if previously obtained within 6 weeks of
Day 1/randomization.
5.6.1.2
DXA
DXA to collect measures of total lean body mass, fat mass and bone mineral density will be
performed at timepoints indicated in Table 5.1-1, Table 5.1-2, and Table 5.1-3.
DXA acquisition guidelines and submission processes will be outlined in the imaging manual
provided by the imaging lab that will perform the imaging analyses. Adequacy of DXA scans
should be confirmed by the central imaging vendor prior to randomization.
Screening DXA should be obtained between Day -35 and Day -14 to allow for central imaging
vendor review.
DXA is not required at the OL early termination visit.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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In the OLE phase, DXA is required at early termination or end of treatment if at least 24 weeks
since last scan.
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.22
5.6.2
Exploratory Urine Biomarker Assessments
Urine samples will be collected at the times indicated in Table 5.1-1 through Table 5.1-4 for the
measurement of exploratory biomarkers. The urine samples will be used to evaluate the levels
of exploratory biomarkers that have been observed to be altered in patients with DMD and
in preclinical models of DMD and muscle atrophy, such as fragments of the protein titin.23,24
Reports of the exploratory urine biomarkers will not be provided to sites as this is a research
measure.
5.6.3
Exploratory Serum Biomarker Assessments
Blood will be drawn at the times indicated in Table 5.1-1 through Table 5.1-4 for the
measurement of exploratory biomarkers. Serum samples will be used to evaluate the levels of
exploratory biomarkers known to be involved in muscle growth and/or myostatin signaling
(e.g., micro-RNAs such as mi-206 and others, and serum proteins such as TGF-, IGF1, IGF2
and IGFBPs).
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.
5.6.4
Exploratory Plasma Biomarker Assessments
Residual samples remaining after GLDH analyses will be stored up to five years after the last
subject randomized in the study reaches the last study visit. The samples may be used to support
the biomarker assessments known to be involved in muscle growth and/or myostatin signaling
(e.g., micro-RNAs such as mi-206 and others, and proteins such as TGF-, IGF1, IGF2, and
IGFBPs).
5.7
Exploratory Assessments
Some or all of the exploratory functional endpoint assessments including TFTs, 6MWT, NSAA,
myometry, ankle range of motion, and PUL may be video recorded at some study visits while
the subject is completing the assessments. The videos will be uploaded by the site to a secure
vault, maintained by a vendor, and accessed by physical therapists for review to assure quality or
identify potential issues requiring re-training of clinical evaluators at the site.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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5.7.1
Functional Endpoints Assessments
Measurements of function, including TFTs (4SC, 4SD, 10- m walk/run, standing from
supine), 6MWT, and the NSAA scale will be assessed at the timepoints specified in Table 5.1-
1 through Table 5.1-4. Detailed instructions for performing each of these assessments will be
provided in the Study Procedure Manual. Functional endpoints will be measured by a
physiotherapist who has undergone study-specific training on the administration of these 
assessments.
TFTs include 4- stair climb, 4- stair descend, 10-m walk/run, and standing from supine. The
6MWT measures the distance a subject is able to traverse while walking for 6 minutes. Both the
TFTs and the 6MWT are well validated and have been widely used in clinical trials.9,25 The
NSAA includes 17 items, ranging from standing to running. Each item is scored on a 3-point
scale  using  the  following  criteria:  2 = normal; performs the task without assistance;
1 = modified, modified method but performs the task independently from physical assistance
from another; 0 = unable to perform the task. The scale takes approximately 1015 minutes to
complete and is widely used in clinical trials26.
5.7.2
Myometry and Ankle Range of Motion (ROM)
Muscle strength will be assessed using hand-held dynamometry at the timepoints specified in
Table 5.1-1 through Table 5.1-4, following procedures outlined in the Study Procedure 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 Study Procedure Manual. These assessments will be performed by a
physiotherapist who has undergone study-specific training on the administration of these
assessments.
5.7.3
Exploratory Genotyping
A 2-mL whole blood sample will be drawn on Day -2 or Day -1 (as indicated in Table 5.1-1) 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.
5.7.4
Performance of Upper Limb Scale (PUL)
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.27 Subjects will complete PUL assessments at the timepoints
specified in Table 5.1-2 through Table 5.1-4.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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5.7.5
Pulmonary Function Tests (PFTs)
Pulmonary function will be assessed using the following tests: FVC, FEV1, MEP, MIP, CPF,
and PFR.28 Guidelines for completion of the PFTs will be provided in the study procedure
manual.
5.8
Outcomes Research Assessments
The PODCI will be completed at baseline, Weeks 12 and 24 of the double-blind phase, and at
Weeks 12, 24, 36, and 48 of the OL phase. The instrument will be completed by the subject’s
parent/caregiver. The PODCI will generate eight scales: Upper Extremity and Physical
Function Scale, Transfer and Basic Mobility Scale,
Sports/Physical Functioning Scale,
Pain/Comfort
Scale,
Treatment
Expectations
Scale,
Happiness Scale, Satisfaction with
Symptoms Scale and Global Functioning Scale.29,30
5.9
Other Assessments
5.9.1
Injection-Site Assessments
Subjects will be monitored for injection-site reactions from Day 1 through the last study visit.
Report injection-site reactions as adverse events, as appropriate. It is strongly recommended that
site staff take non-subject identifying photographs of moderate to severe injection-site reactions
for submission to the Sponsor. The Draize Scale for erythema and edema will be used as a guide
for reporting injection-site reaction AEs31 (see Table 5.9.1-1).
Table 5.9.1-1:
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
Sever edema, raised more than 1mm
and beyond exposure area
Severe
5.10
Additional Research Collection
Not applicable.
6
ADVERSE EVENTS
An AE is defined as any new untoward medical occurrence or worsening of a pre-existing
medical condition in a clinical investigation subject 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

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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temporally associated with the use of study drug, whether or not considered related to the study
drug.
The causal relationship to study drug is determined by a physician and should be used to assess
all AEs. 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.
AEs 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 questioned 
regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (defined as an event in which the subject 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)

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 subject 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 DILI is also considered an important 
medical event.
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the
study drug is an SAE.
Although overdose, cancer, and potential DILI are not always serious by regulatory definition,
these events must be handled as SAEs. (See Section 6.1.1 for reporting pregnancies.)
Any component of a study endpoint that is considered related to study therapy (e.g., death is
an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be
reported as an SAE (see Section 6.1.1 for reporting details).

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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NOTE:
The following hospitalizations are not considered SAEs in Roche clinical studies:

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)

Elective surgery, planned prior to signing consent

Admissions as per protocol for a planned medical/surgical procedure

Routine health assessment requiring admission for baseline/trending of health status
(e.g., routine colonoscopy)

Medical/surgical admission other than to remedy ill health and planned prior to entry into
the study. Appropriate documentation is required in these cases

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)

Admission for administration of anticancer therapy in the absence of any other SAEs
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 of the Investigator's Brochure represent the Reference Safety
Information to determine expectedness of serious adverse events for expedited reporting.
Following the subject’s written consent (or the parent/guardian/LAR’s permission) 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 of discontinuation of dosing.
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.
An SAE report must be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to
the conditions of the study (such as withdrawal of previous therapy or a complication of a study
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
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. The preferred method for SAE data reporting collection is through the eCRF.
The paper SAE forms are only intended as a back-up option when the eCRF system is not
functioning. 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

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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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 reporting): Refer to Contact Information list.
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.
6.2
Non-serious Adverse Events
A non-serious adverse event is an AE not classified as an SAE.
6.2.1
Non-serious Adverse Event Collection and Reporting
The collection of non-serious AE information should begin at initiation of study drug until 50 
days after discontinuation of dosing. Non-serious 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 subjects.
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if
they become serious (see Section 6.1.1). Follow-up is also required for non-serious AEs that
cause interruption or discontinuation of study drug and for those present at the end of study
treatment as appropriate. All identified non-serious AEs must be recorded and described on the
Non-serious 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.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE
CRF page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the subject to have study drug
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective
therapy
Laboratory abnormalities that are reported as AEs or SAEs should be reported utilizing the
NCI CTCAE, Version 4.0.
It is expected that wherever possible, the clinical rather than laboratory term would be used by
the reporting investigator (e.g., anemia vs. low hemoglobin value).

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6.4
Pregnancy
Investigators shall counsel male subjects who are sexually active with WOCBP on the
importance of pregnancy prevention and the implications of an unexpected pregnancy. At a
minimum, contraceptive counseling should be provided at the time of assent or consent.
Investigators shall advise male subjects who are sexually active with WOCBP on the use of
highly effective methods of contraception in non-pregnant partner, and on the use of condom in 
subjects with a pregnant partner, during treatment period and for 140 days following the last dose.
Highly
effective
methods
of
contraception
have
a
failure
rate
of
1%
when
used
consistently and correctly. Pregnancy that occurs in a female partner of a male study
participant should be reported to Roche.
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Hormonal methods of contraception including combined oral contraceptive pills, vaginal
ring, injectables, implants and intrauterine devices (IUDs) such as Mirenaby the male
subject’s WOCBP partner. Female partners of male subjects participating in the study may
use hormone-based contraceptives as one of the acceptable methods of contraception since
they will not be receiving study drug.

Non-hormonal IUDs, such as ParaGard

Complete abstinence
Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence
are not required to use a second method of contraception, but female subjects must continue to
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be
discussed in the event that the subject chooses to forego complete abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge

Male condom with or without spermicide

Progestin only pills or male subject’s WOCBP partner female condom*
* A male and female condom must not be used together.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product
that is considered both excessive and medically important. All occurrences of overdose must be
reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Other Safety Considerations
Any
significant
worsening
noted
during
interim
or
final
physical
examinations,
electrocardiogram, x-ray filming, or any other potential safety assessment required or not

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required by protocol should also be recorded as a non-serious or serious AE, as appropriate,
and reported accordingly.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL
COMMITTEES
There will be a data monitoring committee (DMC) for this study. The DMC scope, frequency of
review, membership, activities and other specifications are detailed in the DMC charter.
The DMC shall have access to partially unblinded data (coded treatment assignments),
including but not limited to following: the frequency and spectrum of SAEs; Grades 3 and 4
laboratory abnormalities; occurrence of malignancies; and other select adverse events of interest.
The DMC shall also review aggregate data results from the IAs. The DMC shall have the right to
request full unblinding of the data (codes will be decoded to reveal actual treatment
assignments). The DMC shall act as an advisor to the Sponsor and have responsibility for
safeguarding the subjects’ interests. The DMC 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.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The total number of subjects of the study will be approximately 40, which consists of 3 dose
panels of approximately 8 subjects each and an Expansion Panel of approximately 16 subjects. In
each dose panel, subjects will be randomized 3:1 to either RO7239361 or placebo. Subjects
who discontinue participation in the study prematurely may be replaced only if the reason for
discontinuation is not related to study drug. For safety evaluation, the administration of
RO7239361 to 6 subjects provides an 80% probability of observing at least one occurrence of
any adverse event that would occur with 24% incidence in the population from which the
sample is drawn.
8.2
Populations for Analyses

Enrolled subjects: all consented subjects who entered screening

Treated subjects: all subjects who received at least one dose of study drug or placebo
The PK data set includes all available concentration time data from the subjects who receive
any RO7239361 medication. Additionally, all available derived PK parameter values will be
included in the PK data set and reported, but only subjects with adequate PK profiles will be 
included in the summary statistics and statistical analysis.
The PD data set includes all available data from subjects for whom PD measurements are 
available at baseline and at least one other timepoint.
Subjects who receive placebo in any panel will be pooled into a single placebo group.

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8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective is to assess safety and tolerability of multiple SC doses of RO7239361 in
DMD boys. Primary endpoints are incidence of AEs, SAEs, AEs leading to discontinuation, and
death, as well as marked treatment emergent abnormalities in clinical laboratory tests, vital sign
measurements, ECGs, echocardiograms, and physical examinations across treatment conditions
during the double-blind and OL phases of treatment.
8.3.2
Secondary Endpoint(s)
The first secondary objective to evaluate the PK of multiple SC doses of RO7239361 will be
assessed using serum concentrations of RO7239361 at specified timepoints and will be
measured by the following secondary endpoints:

RO7239361 trough concentrations at Days 8, 15, 22, 29, Week 12, and Week 24

Observed Cmax of RO7239361 in the 1-week dosing interval following the doses on Day 1
and Day 29
The second secondary objective to evaluate the immunogenicity of multiple SC doses of
RO7239361 will be measured by the assessment of immunogenicity samples for presence and
titer of ADAs at the timepoints specified in Table 5.1-1 through Table 5.1-4. The following
endpoints will be measured:

Frequency of subjects with positive ADA assessment

Frequency of subjects who develop positive ADA following a negative baseline

Anti-RO7239361 antibodies on selected days
The third secondary objective to evaluate the effects of RO7239361 on free myostatin and
myostatin-drug complex levels of RO7239361 will be measured by serum concentrations of free
myostatin and myostatin-drug complex at the timepoints specified in Table 5.1-3. The following
endpoints will be measured:

Serum concentration of free myostatin and drug-myostatin complex, percent inhibition of
free myostatin at trough
The fourth secondary objective is to evaluate right thigh muscle changes through MRI
measurements. The secondary endpoints that will be measured are absolute changes and
percentage changes from baseline of CSAmax and fold number changes in contractile versus
non-contractile content for muscles in the right thigh during the 24-week double-blind treatment
period, compared to placebo.

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8.3.3
Exploratory Endpoint(s)
The PD effects of multiple doses of RO7239361 in DMD boys will be evaluated by the 
following exploratory endpoints:

Measures of function, including TFTs (4SC, 4SD, 10-m walk/run, standing from supine),
6MWD, and the NSAA)

Serum analytes that may include but are not limited to:

miR-206, miR-133a, miR-1, miR-6 (control miR), miR-21 and miR-39

TGF-concentrations which are associated with fibrosis of muscle seen in DMD

Follistatin

Creatine  kinase  concentrations  and CK-MM, which  are associated with muscle
atrophy in DMD

Urine analytes that include but are not limited to:

Titin protein amino-terminal fragment concentrations that are associated with muscle
damage

Upper and lower extremity strength obtained by manual myometry

Ankle range of motion in degrees

DXA measures of total lean body mass, fat mass and bone mineral density

MRS measures of right thigh lipid fraction

Health-related quality of life as measured by the PODCI

Measures of pulmonary function, including FVC, FEV1, MEP, MIP, CPF, and PFR

Genetic variation status of genes suspected to modify DMD disease expression (including but
not limited to LTBP4, SPP1)

PUL measure of upper extremity motor function
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender and race will be tabulated. Summary statistics for age, body
weight, height, and body mass index (BMI) will be tabulated.
8.4.2
Efficacy Analyses
Exploratory efficacy endpoints including but not limited to TFT (4SC, 4SD, 10-m walk/run,
standing from supine), 6MWD, NSAA and PFTs will be tabulated by dose and study day; and
the corresponding changes from baseline and percent change from baseline will be calculated
and summarized.
8.4.3
Safety Analyses
All recorded AEs will be listed and tabulated by system organ class, preferred term and
treatment. Vital signs and clinical laboratory test results will be listed and summarized by
treatment. Treatment emergent laboratory abnormalities will be listed by toxicity grade
(according to the NCI CTCAE, Version 4.0) and summarized by treatment. Any significant

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physical examination findings will be listed. Echocardiogram and ECG readings will be
evaluated by the central cardiac site and abnormalities, if present, will be listed. Values for
ECG, vital signs and clinical laboratory test results outside the pre-specified criteria will also
be listed and summarized. ECG readings will
be evaluated by the investigator and
abnormalities, if present, will be listed. The placebo data will be pooled as one group.
Summary statistics will be presented for each echocardiogram/ECG/VS parameter and the
corresponding changes from baseline by treatment and timepoint. Plots of mean change from
baseline value for each parameter versus time since dosing will be presented by treatment. The
last pre-dose value is defined as baseline value.
8.4.4
Pharmacokinetic Analyses
Serum RO7239361 concentrations will be summarized by treatment group, study day and times
postdose. To assess the attainment of steady state, geometric mean Ctrough values will be plotted
versus study day.
Dose proportionality of RO7239361 will be assessed by estimating the slope of the linear
regression of the natural log of the PK parameter (Cmax and Ctrough) on the natural log of dose (by
tiered body weight) using the power model described by Gough et al.32  Descriptive summary
statistics, including means, standard deviations, coefficients of variation, minima, medians,
and maxima will be provided for serum RO7239361 concentrations at different timepoints.
PK and target engagement data collected in this study may be used to develop a population
PK/PD model to estimate model-derived population and individual PK/PD parameter (e.g., 
CL/F, Vc/F, Ka, etc.) and may be reported separately from the clinical study report.
8.4.5
Target Engagement Analyses
Free myostatin and drug-myostatin complex will be tabulated by dose and study day; and the
corresponding changes from baseline and percent change from baseline will be calculated and
summarized. Profile plots may be provided. A dose-response (exposure-response) analysis may
be applied to characterize the relationship between dose levels (PK parameters) of RO7239361
and free myostatin.
8.4.6
Biomarker Analyses
Right thigh CSAmax, contractile versus non-contractile content as a key secondary endpoint will
be tabulated by dose and study day; and the corresponding changes from baseline and percent
change from baseline will be calculated and summarized. Summary and individual profile plots
will be provided as appropriate.
A model dose-response (exposure-response) analysis of non-contractile fraction content will be
used to characterize the relationship between dose levels (PK parameters) of RO7239361 and
changes from baseline in right thigh non-contractile fraction content among 4 muscles in the
quadriceps femoris group. This analysis will combine data from Panels 13 and the expansion
panel.

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This model assumes that the change from baseline follows a normal distribution with a mean
response that can be expressed in an Emax model. If the model results show evidence of
heteroscedascity or the Emax model does not produce an acceptable fit, then either weighted
analyses and/or alternate model specifications may be used. Alternative model specifications
may include additional covariates that are relevant to the model.
Similar model-based analyses may be applied for other right thigh muscles/muscle groups
CSAmax and lipid fraction content.
8.4.7
Exploratory Biomarker Analyses
All the exploratory endpoints such as miRNA 206, exploratory blood biomarkers, urinary titin
fragments will be summarized.
Subgroup analyses of other primary, secondary, or exploratory endpoints may be conducted
based on genetic variation in genes suspected to modify DMD disease expression (including, but
not limited to, LTBP4, SPP1). The potential association between genetic variations with certain
endpoints from safety, PD, or function test data may be analyzed. Depending on available data,
all analyses related to genetic variation in genes may be conducted by pooling data from all
RO7239361-treated subjects together or by dose/exposure-response modeling.
Summary and individual profile plots will be provided as appropriate.
8.4.8
Immunogenicity Analysis
Serum samples from all treated subjects, including placebo subjects, will be analyzed by a
validated immunogenicity assay. Individual timepoints are considered positive if confirmed as
specific against RO7239361. The subject will be called positive for immunogenicity as defined
in the Statistical Analysis Plan. 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, if sizes of the subgroups
warrant such. In the event a subject has a positive immunogenicity response, additional NAB
analyses may be conducted.
8.4.9
Outcomes Research Analyses
Parent-reported health-related quality of life using PODCI will be summarized by treatment and
time for each domain or in combination.29,30 The correlations between PODCI with clinical
measurements may be analyzed.
8.4.10
Other Analyses
Not applicable.
8.5
Interim Analyses
Because data emerging from each panel of this exploratory study might be needed for timely
decisions about adjustments to procedures in subsequent panels, including early termination of
the study, data from panels can be unblinded after documented completion and review of the
corresponding CRFs, prior to the formal locking of the study database. Analyses will only

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consist of listings, summaries, and graphs of the available data. No formal inferences requiring
any adjustment to statistical significance level will be performed.
Up to five IAs are planned. The first IA may be conducted when 4-week data of Panels 1 and 2
are available. The timing of the second and third IAs may be based on when the 4-week
data of Panel 3 are available and when the 24-week data of Panels 1 and 2 are available, the
timing to be based on the milestone. A fourth IA will be conducted when all subjects have
completed the (24- week) double-blind phase. A fifth IA will be conducted to support
regulatory submissions for marketing approval.
At the first IA, in addition to all available safety and tolerability, pharmacokinetics will be
assessed following multiple- dose administration during the first 4 weeks. Additionally,
dose/exposure-response analysis will be conducted to evaluate target engagement (myostatin
inhibition). At the second and third IAs, all available safety, tolerability, PK, TE, biomarker data,
strength, ankle range of motion, and function data may be analyzed. Depending on outcomes
from IAs conducted earlier, the scope and timing of IAs scheduled later may change. The first
three IAs will include all available blinded safety and tolerability data but not PD or functional
data from the Expansion Panel, where applicable. The fourth IA will include all available data
from the double-blind phase. The fifth IA will include all available data from the OL and OLE
phases. A clinical study report will be generated based on these data for the purposes of 
marketing application submissions.
Clinical study report addendum will be generated at the end of the study.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol
must be discussed with, and be prepared by, Roche. The investigator should not implement
any
deviation
or
change
to
the
protocol
without
prior
review
and
documented
approval/favorable opinion from the IRB/IEC of an amendment, 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 IRB/IEC approval/favorable opinion, as soon as possible the deviation or change
will be submitted to:

IRB/IEC for review and approval/favorable opinion

Roche

Regulatory authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be
sent to Roche.

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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If an amendment substantially alters the study design or increases the potential risk to the
subject: (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).
9.1.2
Monitoring
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.
In addition, the study may be evaluated by Roche 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 Roche.
9.1.2.1     Source Documentation
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, 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.
9.1.3
Investigational Site Training
Roche will provide quality investigational staff training prior to study initiation. Training
topics will include but are not limited to: GCP, AE reporting, study details and procedure,
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator 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

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specified by Roche, whichever is longer. The investigator must contact Roche prior to
destroying any records associated with the study and Roche will notify the investigator
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, IRB). Notice of
such transfer will be given in writing to Roche.
9.2.2
Study Drug Records
It is the responsibility of the investigator to ensure that a current disposition record of study drug
(inventoried
and
dispensed) is maintained
at
the
study site
to include the following
investigational product. 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 subject, including unique subject identifiers

Amount transferred to another area/site for dispensing or storage

Non-study disposition (e.g., lost, wasted)

Amount destroyed at study site, if applicable

Amount returned to Roche

Retained samples for bioavailability/bioequivalence, if applicable

Dates and initials of person responsible for Investigational Product dispensing/accountability,
as per the Delegation of Authority Form.
Roche will provide forms to facilitate inventory control if the investigational site does not have
an established system that meets these requirements.
9.2.3
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 Roche 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 paper or electronic SAE form and Pregnancy Surveillance form, respectively.
Spaces may be left blank only in those circumstances permitted by study-specific CRF
completion guidelines provided by Roche.

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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, including any paper or electronic 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. 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
Roche
training
requirements and must only access the Roche electronic data capture tool using the unique
user account provided by Roche. User accounts are not to be shared or reassigned to other 
individuals.
9.3
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

Subject recruitment (e.g., among the top quartile of enrollers)

Involvement in trial design

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Roche. Any
publications or abstracts arising from this study require approval by Roche prior to publication
or presentation
and must adhere to Roche’s publication requirements as set forth in the
approved clinical trial agreement (CTA). All draft publications, including abstracts or detailed
summaries of any proposed presentations, must be submitted to Roche at the earliest practicable
time for review, but at any event not less than 30 days before submission or presentation unless
otherwise set forth in the CTA. Roche shall have the right to delete any confidential or
proprietary information contained in any proposed presentation or abstract and may delay
publication for up to 60 days for purposes of filing a patent application.

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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, complete
abstinence is defined as complete avoidance of heterosexual
intercourse and is an acceptable form of contraception for all
study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly
effective contraception must be discussed in the event that
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete
abstinence is defined as complete avoidance of heterosexual
intercourse and is an acceptable form of contraception for all
study drugs. Subjects who choose complete abstinence are
not required to use a second method of contraception, but
female subjects must continue to have pregnancy tests.
Acceptable alternate methods of highly effective
contraception must be discussed in the event that the subject
chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as
complete avoidance of heterosexual intercourse is an
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle
of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence
for entry into a clinical trial, post-ovulation methods) and
withdrawal, which are not acceptable methods of
contraception. Subjects who choose complete abstinence are
not required to use a second method of contraception, but
female subjects must continue to have pregnancy tests.
Acceptable alternate methods of highly effective
contraception must be discussed in the event that the subject
chooses to forego complete abstinence.
Additional Research
Those scientific activities which cannot be reasonably
anticipated at the time of trial design, for which we would
like to collect and/or retain samples from study participants.
Examples of additional research include, but are not limited
to, new assay development and validation, companion
diagnostic development, new hypotheses in the interaction of
drug and the human body, and exploration of emerging
science in the understanding of disease.

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10.1
List of Abbreviations
Term
Definition
4SC
4-stair climb
4SD
4-stair descend
6MWD
6-minute walk distance
ADA
Anti-RO7239361 antibodies
AE
adverse event
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
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
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
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
%BE
percent biliary excretion
BID, bid
bis in die, twice daily
Bi-PAP
Bi-level positive airway pressure
BLQ
below limit of quantification

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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Term
Definition
BMI
body mass index
BP
blood pressure
BRt
total amount recovered in bile
%BRt
total percent of administered dose recovered in bile
BUN
blood urea nitrogen
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations
CHF
congestive heart failure
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLD
Dialysate clearance of drug from plasma/serum
CLNR
nonrenal clearance
CLR
renal clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu or
CLT/fu
Apparent clearance of free drug or clearance of free if (if IV)
Cm
Centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CPF
Cough peak flow
CRC
Clinical Research Center

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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Term
Definition
CRF
Case Report Form, paper or electronic
CSAmax
Maximal cross-sectional area
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.)
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D/C
Discontinue
dL
deciliter
DMC
Data monitoring committee
DMD
Duchenne muscular dystophy
DRt
Total amount recovered in dialysate
%DRt
Total percent of administered dose recovered in dialysate
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
DXA
Dual-energy X-ray absorptiometry
EA
extent of absorption
ECG
electrocardiogram
ECHO
echocardiogram
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
e.g.
exempli gratia (for example)
ESR
Expedited Safety Report
F
bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
%FRt
total percent of administered dose recovered in feces
FSH
follicle stimulating hormone

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Term
Definition
fu
fraction of unbound drug
FVC
forced vital capacity
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
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
IA
interim analysis
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation
i.e.
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
Investigational New Drug Exemption
IP
investigational product
IRB
Institutional Review Board
IU
International Unit
IV
Intravenous
K
slope of the terminal phase of the log concentration-time curve

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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Term
Definition
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
z
terminal disposition rate constant
L
liter
LC
liquid chromatography
LAR
legally acceptable representative
LDH
lactate dehydrogenase
MAD
multiple ascending dose
mg
milligram
MIP
maximal inspiratory pressure
MEP
maximal expiratory pressure
mL
nilliliter
mmHg
millimeters of mercury
MOA
mechanism of action
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for
molecular weight
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for
molecular weight
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular
weight
MR_Ctau
Ratio of metabolite Ctau to parent Ctau, corrected for molecular weight
MRI
magnetic resonance imaging
MRS
magnetic resonance spectroscopy
MRT
mean residence time
MS
mass spectrometry
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations

Anti-Myostatin Adnectin (RO7239361)—F. Hoffmann-La Roche Ltd
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Term
Definition
Na+
sodium
N/A
not applicable
NAB
neutralizing antibodies
ng
nanogram
NIMP
non-investigational medicinal products
NOAEL
no observed adverse event level
Non-IP
non-investigational product
NSAA
North Star Ambulatory Assessment Scale
NSAID
non-steroidal anti-inflammatory drug
OL
open label
OLE
open-label extension
pAUCe
extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent bound drug
PD
pharmacodynamic
PFR
peak flow rate
PFS
prefilled syringe
PFTs
pulmonary function tests
PK
pharmacokinetic
PODCI
Pediatric Outcome Data Collection Instrument
PT
prothrombin time
PTT
partial thromboplastin time
QW
once per week
RBC
red blood cell
SAE
serious adverse event
SC
subcutaneous
SD
standard deviation
SOP
standard operating procedure
Sv
sieverts
TE
target engagement
TFTs
timed function tests
T1/2
terminal half-life

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Term
Definition
T-HALFeff_AUC
Effective elimination half-life that explains the degree of AUC
accumulation observed
T-HALFeff_Cmax
Effective elimination half-life that explains the degree of Cmax
accumulation observed)
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UR
urinary recovery
%UR
percent urinary recovery
URt
total amount recovered in urine
%URt
total percent of administered dose recovered in urine
UV
ultraviolet
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
volume of distribution of terminal phase (if IV and if multi-exponential
decline)
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity

 
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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 
European Medicines Agency 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Risk-management- 
plan_summary/human/002720/WC500167551.pdf Accessed 12-Oct-2014. 
4 
Wagner KR, McPherron AC, Winik N, et al. Loss of myostatin attenuates severity of 
muscular dystrophy in mdx mice. Ann Neurol 2002;832-836. 
5 
Bogdanovich S, Krag, TO, Barton ER, et al. Functional improvement of dystrophic muscle 
by myostatin blockade. Nature2002;420:418-421. 
6 
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 Nerve 2013;48(3):357- 68 
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