A 24-week Double-blind Treatment and 24-week Follow-up, Randomized, Multicenter, Placebo-controlled, Phase IIa/IIb Study to Evaluate Safety and Efficacy of i.v. Bimagrumab on Total Lean Body Mass and Physical Performance in Patients After Surgical Treatment of Hip Fracture
Phase: PHASE2
Conditions: Muscle Wasting (Atrophy) After Hip Fracture Surgery
Sponsor: Novartis Pharmaceuticals

Clinical Development
Bimagrumab (BYM338)
Clinical Trial Protocol CBYM338D2201 / NCT02152761
A 24-week double blind treatment and 24-week follow up, 
randomized, multi-center, placebo-controlled, phase IIa/IIb 
study to evaluate the safety and efficacy of i.v. bimagrumab 
on total lean body mass and physical performance in 
patients after surgical treatment of hip fracture
Document type:
Amendment Protocol Version
EUDRACT number:
2013-003439-31
Version number:
v04 clean
Development phase:
IIa/IIb
Release date:
8-Feb-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
NCDS Template Version 30-Apr-2013

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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 4 ....................................................................................................................11
Amendment 3 ....................................................................................................................14
Amendment 2 ....................................................................................................................22
Amendment 1 ....................................................................................................................27
Protocol synopsis...............................................................................................................28
1
Introduction .......................................................................................................................32
1.1
Background............................................................................................................32
1.2
Purpose ..................................................................................................................33
2
Study objectives.................................................................................................................34
2.1
Primary objective...................................................................................................34
2.2
Secondary objectives .............................................................................................34
34
3
Investigational plan ...........................................................................................................35
3.1
Study design...........................................................................................................35
3.2
Rationale of study design.......................................................................................37
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....37
3.4
Rationale for choice of comparator .......................................................................39
3.5
Purpose and timing of interim analyses/design adaptations..................................39
3.6
Risks and benefits..................................................................................................39
4
Population..........................................................................................................................43
4.1
Inclusion criteria ....................................................................................................43
4.2
Exclusion criteria...................................................................................................44
5
Treatment...........................................................................................................................46
5.1
Protocol requested treatment .................................................................................46
5.1.1
Investigational treatment.......................................................................46
5.1.2
Additional study treatment....................................................................47
5.2
Treatment arms......................................................................................................48
5.3
Treatment assignment, randomization...................................................................49
5.4
Treatment blinding.................................................................................................49
5.5
Treating the patient................................................................................................51

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5.5.1
Patient numbering .................................................................................51
5.5.2
Dispensing the investigational treatment ..............................................51
5.5.3
Handling of investigational treatment...................................................51
5.5.4
Instructions for prescribing and taking investigational treatment.........52
5.5.5
Permitted dose adjustments and interruptions of investigational 
treatment................................................................................................52
5.5.6
Rescue medication ................................................................................53
5.5.7
Concomitant treatment..........................................................................53
5.5.8
Prohibited Treatment.............................................................................53
5.5.9
Discontinuation of investigational treatment or premature study 
discontinuation......................................................................................54
5.5.10
Withdrawal of consent ..........................................................................55
5.5.11
Loss to follow up...................................................................................55
5.5.12
Emergency breaking of assigned treatment code..................................55
5.5.13
Study completion and post-study treatment..........................................56
5.5.14
Early study termination.........................................................................56
6
Visit schedule and assessments .........................................................................................56
6.1
Information to be collected on screening failures..................................................61
6.2
Patient demographics/other baseline characteristics .............................................61
6.2.1
Demographic information.....................................................................61
6.2.2
Medical history......................................................................................61
6.2.3
Eligibility assessments ..........................................................................62
6.2.4
Other pre-treatment characteristics .......................................................62
6.3
Treatment exposure and compliance .....................................................................62
6.4
Efficacy..................................................................................................................63
6.4.1
Total Lean Body Mass (LBM) by DXA ...............................................63
6.4.2
Short Physical Performance Battery .....................................................64
6.4.3
Gait Speed.............................................................................................64
6.4.4
Falls.......................................................................................................64
6.4.5
Appropriateness of efficacy assessments..............................................65
6.5
Safety.....................................................................................................................67
6.5.1
Physical examination ............................................................................68
6.5.2
Vital signs..............................................................................................68
6.5.3
Height and weight .................................................................................69
6.5.4
Laboratory evaluations..........................................................................69
6.5.5
Electrocardiogram (ECG) .....................................................................71
6.5.6
Echocardiography .................................................................................72

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6.5.7
X-ray assessment of surgical procedure................................................72
6.5.8
Dietary Assessment/
.................................................73
6.5.9
Pregnancy and assessments of fertility .................................................73
73
74
6.5.12
Appropriateness of safety measurements..............................................74
75
75
78
78
78
78
78
79
79
7
Safety monitoring..............................................................................................................80
7.1
Adverse events.......................................................................................................80
7.2
Serious adverse events...........................................................................................82
7.2.1
Definition of SAE .................................................................................82
7.2.2
SAE reporting........................................................................................83
7.3
Liver safety monitoring .........................................................................................86
7.4
Lipase and amylase elevations...............................................................................86
7.5
Pregnancy reporting...............................................................................................87
8
Data review and database management.............................................................................87
8.1
Site monitoring ......................................................................................................87
8.2
Data collection.......................................................................................................88
8.3
Database management and quality control............................................................88
8.4
Data Monitoring Committee..................................................................................89
8.5
Adjudication Committee........................................................................................90
9
Data analysis......................................................................................................................90
9.1
Treatments .............................................................................................................90
9.1.1
Study medication...................................................................................91
9.1.2
Concomitant medications......................................................................91
9.2
Analysis sets ..........................................................................................................91
9.3
Patient demographics and other baseline characteristics.......................................91
9.4
Analysis of the primary variable............................................................................92
9.4.1
Variable.................................................................................................92

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9.4.2
Statistical model, hypothesis, and method of analysis..........................92
9.4.3
Handling of missing values/censoring/discontinuations.......................92
9.4.4
Supportive analyses...............................................................................93
9.5
Analysis of secondary
 variables.........................................................94
9.5.1
Efficacy variables..................................................................................94
9.5.2
Safety variables .....................................................................................95
97
98
98
98
9.6
Interim analyses.....................................................................................................98
9.7
Sample size and power calculation........................................................................99
10 Ethical considerations......................................................................................................102
10.1
Regulatory and ethical compliance......................................................................102
10.2
Informed consent procedures...............................................................................102
10.3
Responsibilities of the investigator and IRB/IEC................................................103
10.4
Publication of study protocol and results.............................................................103
11 Protocol adherence ..........................................................................................................103
11.1
Protocol Amendments .........................................................................................103
12 References .......................................................................................................................105
13 Appendix 1: Clinically notable laboratory values and vital signs...................................109
14 Appendix 2: Liver event and Laboratory trigger definitions and follow-up 
requirements ....................................................................................................................109
113
114
117
118
List of tables
Table 5-1
Prohibited treatment..............................................................................53
Table 6-1
Assessment schedule.............................................................................58
Table 6-2
Hematology and serology tests .............................................................69
Table 6-3
Clinical chemistry tests, 
 and 
muscle integrity markers.......................................................................70
Table 6-4
Urinalysis tests ......................................................................................71
Table 7-1
SUSARs exempt from expedited reporting...........................................84

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Table 7-2
Safety monitoring guidance for amylase and lipase elevations ............87
Table 9-1
Power calculation for total LBM (sample size = 70 per arm)...............99
Table 9-2
Key references used to ascertain the variability in gait speed ............100
Table 9-3
Key references used to ascertain the variability in SPPB ...................101
Table 9-4
Power calculation for falls (sample size: BYM combined (210mg 
and 700mg ) arm=140 and Placebo= 70)............................................102
Table 13-1
Clinically Notable Lab Values and Vital Signs ..................................109
Table 14-1
Liver Event and Laboratory Trigger Definitions ................................109
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers.110
113
List of figures
Figure 3-1
Study design..........................................................................................36
Figure 6-1
Sequence of LBM and muscle function changes to a single dose of 
bimagrumab 30 mg/kg in patients with sporadic inclusion body 
myositis (BYM338X2205 study)..........................................................65

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List of abbreviations
ActRIIA/B
activin receptor type II A or type B
AFNH
avascular necrosis of the femoral head
AE
adverse event
AESI
adverse event of special interest
ADL
activities of daily living
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
bpm
beats per minute
CPO
Country Pharma Organization
CT
Computerized tomography
DHEA
dehydroepiandrosterone
eCRF
electronic Case Report/Record Form
DMC
Data Monitoring Committee
DSM
Drug supply management
DXA 
Dual Energy X-ray Absorptiometry
ECG
Electrocardiogram
ELISA
Enzyme-linked Immunosorbent Assay
EoS
End of study
EoT
End of treatment
FAS
Full Analysis Set
GFR
glomerular filtration rate
GGT/ γGT
gamma-glutamyltransferase
GnRH
Gonadotropin-releasing hormone
GS
gait speed
GTL
Global trial leader
GWA
genome-wide association
HBs Ag
Hepatitis B surface antigen
HCV
Hepatitis C virus

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HCV Ab
Hepatitis C virus antibody
HCV RNA PCR Hepatitis C virus ribonucleic acid polymerase chain reaction
 
HIV
Human immunodeficiency virus
HIV Ab 
Human immunodeficiency virus antibody
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
INR
International normalized ratio
IU
international units
i.v.
intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International units
LBM
Lean body mass
LLOQ
Lower Limit of Quantification
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Affairs
MHRA
Medicines and Healthcare products Regulatory Agency
MMSE
Mini Mental State Examination
MNAR
missing not at random
MRI
Magnetic Resonance Imaging
OA
osteoarthritis
PD
Pharmacodynamic
PK
pharmacokinetic
PP
Per-protocol
PT
prothrombin
RAP
report and analysis plan
ROI
region of interest

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ROM
range of motion
SAE
serious adverse event
SAF
Safety analysis set
SD
standard deviation
sIBM
Sporadic Inclusion Body Myositis
SPPB
short physical performance battery
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total bilirubin
TGF-β 
transforming growth factor–beta
TMV
thigh muscle volume
TNF-alpha
Tumor necrosis factor-alpha
ULN
upper limit of normal
VEGF
Vascular endothelial growth factor

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the drug being tested in the trial
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Epoch 
A portion of the study, which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a 
fixed combination. 
Investigational treatment generally does not include protocol-specified 
concomitant background therapies  when these are standard treatments 
in that indication
Medication number
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system
Protocol
A written account of all the procedures to be followed in a trial, which 
describes all the administrative, documentation, analytical and clinical 
processes used in the trial.
Premature patient discontinuation 
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up)
Randomization number
A unique identifier assigned to each randomized patient, corresponding to 
a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study/investigational treatment was discontinued whichever is later
Study/investigational treatment 
discontinuation
Point/time when patient permanently stops taking study/investigational 
treatment for any reason; may or may not also be the point/time of 
premature patient discontinuation
Subject Number 
A number assigned to each patient who enrolls into the study 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study

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Amendment 4
Amendment rationale
The purpose of this amendment is to add a new safety monitoring guidance for patients with 
an increase of lipase and/or amylase and to modify the statistical analysis section to be 
consistent with the statistical analysis plan.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

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The wording of various sub-sections have been amended to reflect the rationale given above.
Additionally, this protocol amendment includes editorial changes for increased clarity of the 
text.  Consequently, changes were implemented throughout the protocol.
Protocol Synopsis
•
Incidence of falls added as a secondary objective
Section 1.2 Purpose
•
Editorial changes
Section 2.1 Primary objective
•
Editorial changes
Section 2.2 Secondary objectives
•
Incidence of falls added as a secondary objective
Section 3.5 Purpose and timing of interim analyses/design adaptations and Section 9.6 
Interim analysis
•
Amended to clarify interim analysis planned for Jun2018
Section 3.6 Risk and benefits
• Patient exposure to bimagrumab updated
• Risk related to elevated lipase and amylase observations added.
Section 5.4 Treatment blinding and Section 9 Data analysis
• Independent Novartis team member will be unblinded to review and understand the 
primary analysis results. 
Section 7.4 Lipase and amylase elevations
• Section added to provide guidance to the investigator for monitoring elevations of 
amylase and lipase throughout the trial.
Section 9.4.2 Statistical model, hypothesis, and method of analysis
• The within subject correlation structure for the mixed model has been updated.
Section 9.5.1.1 Gait speed and Short Physical Performance Battery (SPPB)
The testing strategy for the secondary endpoints has been updated from a step-down to a fixed 
sequence approach. Section 9.5.1.3 Falls

Negative binomial regression added for event rates.

Responder endpoint details added.
Section 9.5.2.4 Laboratory data

Summary of pancreatic enzyme abnormalities included.

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Section 9.7 Sample size and power calculation
• Removed references to previous testing strategy.
• Added power calculations for falls.
Section 13 Appendix 1: Clinically notable laboratory values
• Amylase and lipase ≥ 3x ULN added as clinically notable values that will be flagged at 
the central laboratory.

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Amendment 3
Amendment rationale
The purpose of this amendment is to update the study design with progress made in the 
clinical development of bimagrumab program since the protocol was last submitted. It 
integrates new safety data from several recently completed bimagrumab studies (summarized 
in Section 3.6), further increases the inclusiveness of the trial, reduces patient and site burden, 
where possible 
 by Novartis 
specifically for this population.

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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The informed consent of the study will be amended. A copy of this amended protocol will be 
sent to the Institutional Review Board (IRBs)/Independent Ethics Committee (IECs) and 
Health Authorities. 
The main changes are the following:

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Protocol Synopsis
Amended to reflect changes throughout the protocol
Section 2.2 – Secondary objectives
Amended to highlight that echocardiography is collected only on patients enrolled before 
Amendment #3
Section 3: Investigational plan
The description of the screening epoch has been amended to clarify the repeatability of 
assessments within the screening window and the last day when all eligibility criteria must be 
confirmed before randomization.
Section 3.3: Rationale of dose/regimen, route of administration and duration of 
treatment
Further details to the rationale for early treatment initiation were added, which now better 
highlights the potential complications that may be prevented. 
Section 3.6: Risk and benefits
The section has undergone extensive update triggered by the new Investigator Brochure 
version 9 incorporating new safety information from clinical trials completed in 2016. 
In the radiation exposure section, a sentence comparing the magnitude of exposure to 
background radiation in normal daily life has been removed as this information may vary 
from country to country. 
Section 4.1: Inclusion criteria
Amended to clarify the scope of inclusion criterion #3, namely fractures of the proximal 
femur (AO Classification 31A-C)
Section 4.2: Exclusion criteria

Exclusion criterion #1: amended to better explain that a previous fracture or a major 
surgery on the lower extremity is exclusionary only if it caused a persisting functional 
sequelae, which directly impacts gait and is unlikely to recover during the study period. 

Exclusion criterion #3: amended to clarify that this exclusion criterion refers to 
isolated high-energy subtrochanteric fracture.

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
Exclusion criterion #4: amended to allow patients with pancreatic insufficiency, if the 
condition is well controlled by medication/enzyme supplements.

Exclusion criterion #8 (vitamin D): omitted. Instead of using 25-OH vitamin D 
measurements for eligibility assessment, the results will guide post-randomization 
patient care including a loading dose of vitamin D3 in case the patients is vitamin D 
deficient (i.e. 25-OH vitamin D < 30 nmol/L). 

Exclusion criterion #15: amended to raise the threshold of QTcF for both genders (500 
msec). In addition, the amended criterion gives exempt to those patients with a QTcF 
prolongation (>500 msec) who has this ECG finding due to a ventricular pacemaker or 
presence of a bundle branch block (right or left).

Exclusion criterion #21: amended to better explain that preventive treatments such as 
tamoxifene treatment after elective breast cancer surgery are not exclusionary. The 
amended version also gives extra emphasis to the fact that no patients with active 
cancer are allowed to enroll in the trial regardless of anatomic location or type of 
malignancy. Patients with non-melanoma skin cancers or with in situ cancers with 
excellent prognosis (e.g. carcinoma in situ of the uterine cervix) are allowed to enter 
the study, if they are considered completely cured by the time the patient entered the 
study (e.g. excised or resolved otherwise). 

Exclusion criterion #22: amended to increase the threshold of pre-surgical HgbA1c for 
exclusion (from 8.0% to 8.5%) based on recently communicated guidelines for the 
management of type 2 diabetes in older adults (Dunning et al 2014).

Exclusion criterion #25: amended to better explain that the second sentence refers to 
patients who have already been diagnosed with latent tuberculosis and currently taking 
chemoprophylactic treatment. 

Exclusion criterion 26: amended to better explain the list of additional factors that the 
investigator needs to take into account when considering enrollment of a patient  

Exclusion criterion #27: amended to clarify that intravitreal administration of VEGF 
inhibitors is permitted. Systemic VEGF was added to the list of prohibited medications.

Exclusion criterion #30: amended to indicate that ongoing corticosteroid treatment 
refers to systemic administration only.

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Section 5.4: Treatment Blinding
Amended to indicate that following new guidelines to DMC activities, committee members 
are reviewing unblinded (not semi-unblinded) data.
Section is now highlighting DXA measures (lean and fat body mass), FSH and activin A as 
parameters that can reveal 
 effects of the treatment and therefore are not 
shared by central image reader / central laboratory, respectively.
Section 5.5.4: Instructions for prescribing and taking investigational treatment This 
section was amended to highlight which parameters are to be recorded on the eCRF form. 
Section 5.5.8: Prohibited medications
Heading to the table now highlights potential effects on muscle strength (not just on muscle 
volume) as part of the rationale for prohibition. 
Table itself has been amended to add systemic VEGF inhibitors as prohibited during study 
duration. Previously these were only mentioned in the list of in- and exclusion criteria.
Section 6: Visit schedule
Amended to include some instructions regarding how to calculate visit window for future 
visits, if a visit was delayed or missed completely. Sites must always use the date of the 
Randomization/Baseline dose as reference to calculating visit window for the upcoming visit.
In addition, the section was updated to re-emphasize that assessments pertinent to a given visit 
– including the randomization visit – can be spread over several days.  
Table 6-1: Amended to reflect changes in the schedule of assessments and provide further 
instructions in the Note column, where needed. The table also clarifies prior discrepancies 
with the rest of Section 6 and its sub-sections (e.g. pulse and blood pressure to be measure and 
collected at each visit).
Footnote to the table clarifies the different scenarios of premature treatment discontinuation, 
or premature study discontinuation and outlines the instructions to follow. It also reminds 
investigators to complete echocardiographic monitoring only for patients enrolled in the study 
prior to this amendment.  
Section 6.1: Information to be collected on screening failures
Amended to clarify the possibility of re-screening, if the patient was declared as screen failure 
due to reasons that may improve in a second attempt (mobility, ECG, lab parameter, MMSE 
score, etc.). 
Section 6.2.2: Medical history
Amended to explain that history of falls refers to the occurrence of any fall during the past 12 
months prior to screening excluding the fall that led to the hip fracture under investigation.
Section 6.2.3: Eligibility assessments
Amended to explicitly highlight laboratory assessments essential for eligibility and to omit 
Echocardiography for new patients enrolling after Amendment #3. “Gait speed” was replaced 
by “Confirmed ability to complete a 4 meter gait speed test” to better explain the requirement 
for eligibility.

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Section 6.2.4: Other pre-treatment characteristics
Amended to add Serology and 25-OH Vitamin D, which are no longer required for eligibility 
but rather as pre-treatment characteristics
Section 6.4.3: Gait speed 
Amended to add information on the use of walking aids at screening and during the study 
starting from baseline (D1) with special emphasis on the use of wheeled walkers/rollators
Section 6.4.4: Falls
Amended to emphasize the use of a diary to be used as an “aide-memoire” for patients in 
order to support patient’s interview on falls.
Section 6.5: Safety
Amended to highlight that Echocardiography as a safety monitoring will only be utilized for 
patients who enrolled before Amendment #3. 
Section 6.5.3: Height and Weight 
This section now explicitly states that body height is measured at baseline only, whereas body 
weight at each study visit. 
Section 6.5.4: Laboratory evaluations
Table 6-3: Added haptoglobin to the table, as this was only indicated in Appendix 2. 
Section 6.5.5: ECG
Amended to clarify the protocol for the collection of triplicate ECGs, correct thresholds of 
eligibility, and explain when a follow-up ECG is required at EOS.
The paragraph on the need of reassessing QT prolongation by local ECG reading has been 
removed to align with Exclusion criterion #15. Similarly, the ECG assessment at W48, which 
was implemented to follow-up on new clinically meaningful ECG changes several months 
after last dose, was omitted.
Section 6.5.6: Echocardiography
Amended to reflect that echocardiography will be no longer required for patients randomized 
after Amendment #3. Those enrolled prior to the amendment will still have to complete their 
echo monitoring, including assessment at Week 48, if the W24 assessment indicated clinically 
meaningful abnormality. Instruction as to when the patient is required to undergo an 
additional assessment at Week 48 has also been included. 
The requirement of re-assessing QTcF by local ECG reading at baseline has been omitted; 
eligibility will only be assessed at screening utilizing central reading. 
When referring to Left Ventricular Wall thickness measurement in the list of 
echocardiographic parameters in scope, the word ‘anterior’ was included by mistake and is 
now removed from the parenthesis. 
Section 6.5.7: X-ray

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This section has been updated to better explain how this imaging method is utilized for 
eligibility assessment (local image) and for monitoring of fracture healing and orthopedic 
complications. It also explains when the protocol requires the collection of follow up images 
at W36 and W48. Finally, the section was amended to better explain the principle by which 
radiographs will be assessed by the central reader (2 independent reader and a third standing 
by to break the tie in case of conflicting diagnostic).
Section 6.5.8: Dietary Assessment/
Based on cumulative experience 
 in the CBYM338B2203 study and 
feedback from sites in this multicenter study, this questionnaire will no longer be collected to 
obtain information on the dietary habits of the patient population 12 weeks after surgery.
Based on DMC recommendations, a sentence has been added requesting referral to a 
nutritionist or other health care provider to exclude malnutrition and need for taking 
additional therapeutic measures in case of seeing weight loss from baseline exceeding 5%.
Section 6.5.12: Appropriateness of safety measurements
Amended to explain the rationale for the change in cardiac safety monitoring introduced in 
this amendment and that the independent adjudication of image-based fracture healing 
complications will be performed by the central image reader only.
Section 7.2.1: SAE reporting
Amended to clarify that all X-ray based findings pertinent to delayed fracture healing (i.e. 
bone non-union at W36/W48) will have to be reported as SAE. 
Section 8.4: DMC 
Text has been updated to indicate that the DMC will review unblinded data outputs following 
recent changes in Guidelines to DMC activities.
Section 8.5: Adjudication 
This section has been updated to reflect that an independent adjudication committee to re-
assess and confirm pre-specified AEs/SAEs reported by investigators will be utilized for 
cardiovascular events only. The scope of adjudication which includes ischemic heart disease, 

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heart failure, cardiomyopathy, and certain cardiac arrhythmias, was clarified. The section also 
highlights that independent adjudication of image-based fracture healing complications will 
be done by the central image reader only.
Section 9: Data Analysis
Amended to highlight that the primary analysis (summary of W24 data) is planned to be 
supplemented by additional analysis of all efficacy data available at the time of the primary 
analysis to obtain preliminary insight into the robustness/durability of potential therapeutic 
effects
Section 9.1.1: Study medication
This section was amended to correct the calculation of exposure to last infusion date minus 
first infusion date plus 56 days (instead of 28 days).
Section 9.5.2.2: Bone Safety Analysis
Amended to reflect current focus of interest concerning orthopedic complication (fracture 
healing complications with focus on incidence of delayed bone-union).
Section 12: References
Updated by references used in the current amendment 

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Amendment 2
Amendment rationale
In order to properly assess dose response relationship of bimagrumab at least three doses are 
required, ranging from a potential minimally effective dose to a dose where maximal efficacy 
is expected. A lower dose arm of 70 mg i.v., which is expected to show suboptimal to 
minimal efficacy, has therefore been added to this study. This will facilitate an adequate dose-
selection for phase III without the need for supportive data from another dose- response 
finding study. 

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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The informed consent of the study will be amended. A copy of this amended protocol will be 
sent to the Institutional Review Board (IRBs)/Independent Ethics Committee (IECs) and 
Health Authorities. 
The main changes are the following:

Addition of a treatment arm and change dosing regimen from weight based dosing  
(bimagrumab 3 mg/kg and 10 mg/kg) to fixed dosing (bimagrumab 70 mg, 210 mg and 
700 mg)

Changing the randomization ratio from 1:1:1 to 2:1:2:2 (1 referring to the lowest dose 
group of 70 mg)

Reduction of the treatment epoch from 52 weeks to 24 weeks and the respective number 
of infusions from 13 to 6

Increase of the post treatment follow-up epoch from 4 weeks to 24 weeks

Increase of the screening epoch to be from 7 to 28 days to 3 to 42 days post-surgery

Modification of the secondary objectives to address the shorter treatment duration 

Modification of the inclusion criteria

Lower limit of age has been decreased from 65 to 60 years

Lower limit of BMI has been decreased from 16 to 15 kg/m2

Modification of the exclusion criteria

History of fracture was clarified to recent lower limb fracture or surgery with 
persistent negative impact. By doing so 2 criteria were merged

Various criteria on condition affecting the patient’s ability to walk  (e.g. some visual, 
psychiatric or respiratory disorders ) were merged bringing 5 criteria into  one

Criteria on disease affecting food absorption was clarified 

Exclusion of rheumatoid arthritis patients was removed

Vitamin D deficiency exclusion is limited to patients not receiving an appropriate 
loading dose

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
Abnormal liver function test  criteria was clarified and liver disease are limited to 
present conditions

Hypertension criterion was limited to uncontrolled with medication exceeding a 
systolic pressure of 180 mmHg and/or diastolic pressure of 90 mmHg

Ischemic heart disease was limited to ongoing unstable angina pectoris and recent 
myocardial infarction in the past 3 month prior to randomization

Type of excluded cancer was clarified

2 criteria on excluded immunosuppressive therapies were merged and limited to the 3 
months prior randomization period

Criteria related to the use of any therapies known to affect muscle mass was clarified

Modification of prohibited medications

Reduction of the number of visits in the post treatment follow-up epoch

Elimination of the following assessments :

Alcohol test and drug screening 

Mediolateral sway test

Frequency reduction of the following assessments

X-ray of the operated hip at (not done at W36 and W48, unless W24 result requires it)

DEXA (not done at Week 36 and W48)

Addition of the following assessment

Pre-albumin as part of Clinical Chemistry panel 

Removal of Appendix 4 with background material on SUSAR exemptions

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Amendment 1
Amendment rationale
This protocol amendment is primarily issued for the following reasons:

To add central laboratory serology testing, including HBV, HCV, and HIV, as well as 
urine drug testing at the screening visit. Results of these tests determine eligibility for the 
study, thus identification and documentation of status is required. Addition of these tests is 
necessary due to the limitations of relying on medical history or liver enzyme elevations 
when identifying patients with chronic viral infection (which may be asymptomatic) and 
inherent hepatic safety implications. Given the limited experience with longer-term (i.e. > 
3 treatment months) testing of bimagrumab in the elderly frail population, it was deemed 
imperative to make every effort to minimize risk factors with major impact on hepatic 
safety assessment.

To clarify and distinguish exclusion criteria 26 (chronic active hepatitis) from exclusion 
criteria 33 (chronic active virus or bacterial infection).

To align the Decision Tree for Randomization with the cardiovascular exclusion criteria.

To clarify that the physical exam may include additional rectal, external genitalia, breast, 
and pelvic exams if deemed necessary by the investigator. Such physical examinations 
may not be routinely performed by the orthopedist and are thus explicitly specified to 
indicate that reporting of findings is expected in case the patient presents with signs or 
symptoms pertinent to these organ systems.

To add temperature to the vital sign assessments. It was deemed medically important to 
document and address, if necessary, high body temperature due to its potential 
interference with physical performance measurements.
At the time of this amendment, no patients have been enrolled into the study.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The wording of various sub-sections to “Study design” (Section 3.1), “Exclusion criteria” 
(Section 4.2), and “Visit schedule and assessments” (Section 6) have been amended to reflect 
the rationale given above.
Additionally, this protocol amendment includes the correction of typographical, formatting,   
and numerical errors as well as editorial changes for increased clarity of the text. 
Consequently, changes were implemented throughout the protocol.
This amended protocol is being issued before any IRB / IEC / HA submission has been 
made.A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.

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Protocol synopsis 
Protocol number
CBYM338D2201
Title
A 24-week double blind treatment and 24-week follow-up, randomized, 
multi-center, placebo-controlled, phase IIa/IIb study to evaluate the safety 
and efficacy of i.v. bimagrumab on total lean body mass and physical 
performance in patients after surgical treatment of hip fracture 
Brief title
Study of safety and efficacy of bimagrumab in patients after surgical 
treatment of hip fracture. 
Sponsor and Clinical 
Phase
Novartis, phase IIa/IIb
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of the present proof of efficacy study is to identify at least 
one dose of bimagrumab that can increase lean body mass and improve 
physical function as compared to placebo when administered every 4 
weeks over a 24-week treatment epoch in patients with disuse atrophy 
after surgical repair of a proximal femur fracture. Data from this study will 
be used to find the dose for further development in phase 3 and assess 
the safety and tolerability of bimagrumab in this indication.
Primary Objective(s) 
To assess the effect of bimagrumab given intravenously every 4 weeks 
on total lean body mass (LBM) measured by dual emission X-ray 
absorptiometry (DXA) as assessed by change from baseline at week 24
relative to placebo in patients with disuse atrophy after surgical treatment 
of hip fracture. 
Secondary Objectives
To assess the effect of bimagrumab compared to placebo on 
improvement in mobility as measured by change from baseline at week 
24 in gait speed.
To assess the effect of bimagrumab compared to placebo on 
improvement in physical performance as measured by change from 
baseline at Week 24 in the Short Physical Performance Battery (SPPB). 
To evaluate the effects of bimagrumab vs. placebo on the incidence of 
falls
To assess the post treatment effect of bimagrumab compared to placebo 
on physical performance and mobility as measured by SPPB and gait 
speed up to End of Study. 
To assess the clinical safety and tolerability of bimagrumab relative to 
placebo as assessed by measures such as vital signs, clinical laboratory 
variables, electrocardiogram (ECG), echocardiogram (on patient enrolled 
prior to Amendment #3), adverse events (AE), X-ray assessment of the 
surgical procedure and potential orthopedic complications.
Study design
This is a 24-week double blind treatment and 24-week follow-up, 4-
treatment arms, parallel-group, randomized, placebo-controlled, multi-
center clinical study. A screening epoch from Day 3 up to Day 42 post 
surgery will be used to assess eligibility.  At baseline visit, eligible patients 
will be randomized to placebo, 70 mg, 210 mg, or 700 mg of bimagrumab 
in a ratio of 2:1:2:2 respectively. Randomized patients will be treated for 

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24 weeks and will receive investigational treatment every 4 weeks for a 
total of 6 doses. After completing the treatment epoch, patients will enter 
a 24-week post-treatment follow up epoch.
Population
Approximately 245 male and female patients ≥ 60 years old, who recently 
sustained a low-energy hip fracture that required surgical repair by either 
internal fracture fixation or joint replacement.
Inclusion criteria
Key inclusion criteria:

Patient must have had surgical fixation or arthroplasty of the 
proximal femur fracture (AO Classification 31 A-C (AO 
Foundation) as confirmed by radiography.

Patient must be mentally competent at , to have scored at least ≥ 
21 on the Folstein Mini Mental State Examination (MMSE)

Patient must be able to complete a 4 m gait speed test 

Patients must weigh at least 35 kg and must have a body mass 
index (BMI) within the range of 15 – 35 kg/m2 at screening

Patient must have completed surgical wound healing
Exclusion criteria
Key exclusion criteria:

History of  any other complicated lower limb fracture in the past 6 
months or major lower limb surgery in the past 3 months prior to 
randomization that caused a persisting functional sequelae, 
which directly impacts gait speed and/or gait quality and is 
unlikely to recover during the study period 

Isolated high-energy sub-trochanteric fracture

Active diseases known to cause malabsorption of protein

Vitamin D deficiency (25-OH-vitamin D < 12.0 ng/mL or < 30.0 
nmol/L) not treated with vitamin D supplementation prior to 
randomization  
Cardiovascular conditions (SAFETY):

Ongoing ischemic heart disease or congestive heart failure 
(NYHA Class III/IV), or hypertension poorly controlled by 
medication.
Hepatic enzyme elevations and conditions (SAFETY):

Abnormal liver function tests such as SGOT (AST), SGPT (ALT), 
or serum bilirubin (except if associated to Gilbert’s Disease). 
Other major medical conditions:

Type I diabetes mellitus or uncontrolled type II diabetes mellitus 
(e.g. pre-surgical levels HgbA1c ≥ 8.5% or fasting blood glucose 
≥ 9.0 mmol/l at more than one occasion)
Prohibited medications interfering with muscle metabolism/strength:

Use of any therapy known to affect muscle mass via 
modulation of androgen or growth-hormone receptors or the 
synthesis of these hormones within 3 months prior to 
randomization or current use of high-dose selective beta2-
adrenergic drug therapy;)
For further detail on Inclusion and Exclusion criteria, please refer to 

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Section 4.1
Investigational and 
reference therapy
Arm 1: Placebo i.v. every 4 weeks
Arm 2: Bimagrumab 700 mg i.v. every 4 weeks
Arm 3: Bimagrumab 210  i.v. every 4 weeks
Arm 4: Bimagrumab 70 mg i.v. every 4 weeks
Efficacy assessments

Total lean body mass assessed by DXA

Short Physical Performance Battery (SPPB)

Gait Speed (as a component of SPPB)

Falls 
Safety assessments

Evaluation of all AEs and SAEs including infusion site and 
hypersensitivity reactions

Physical examination

Vital signs, height and weight

Laboratory evaluations

Electrocardiogram (ECG)

Echocardiogram (on patient enrolled prior to Amendment #3)

X-ray assessment of surgical complications (if applicable) and 
complications of fracture healing
Other assessments
Data analysis
The primary variable is change from baseline in Total LBM at Week 24. 
A mixed model will be used with change from baseline at all post-baseline 
visits (Week 12 and Week 24) as response variable, and treatment, visit, 
randomization strata and baseline measurements as covariates. Two 
interaction terms (treatment*visit and baseline LBM*visit) will also be 
included in the model. The two-sided p-value for the least square mean 
(LSM) difference between the bimagrumab and the placebo groups at 

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Week 24 (and at Week 12) will be reported for the difference. Holm-
Bonferroni method will be used to adjust for type I error among the 2 
comparisons (bimagrumab 210 mg vs. placebo and bimagrumab 700 mg 
vs. placebo). Total LBM data will be transformed with natural logarithm 
before this analysis. The bimagrumab 70mg group will not be used for 
hypothesis testing.
The change in gait speed from baseline will be analyzed similar to the 
primary variable. If the variable is not normally distributed, log 
transformation may be used if warranted. 
The change in summary performance score of SPPB and in each one of 
the component scores (balance test score, gait speed score, chair stand 
score) from baseline will be analyzed similar to the primary variable, 
assuming a normal distribution. If the variable is not normally distributed, 
log transformation may be investigated. 
Key words
Bimagrumab, BYM338, hip fracture, elderly, controlled clinical trial, 
randomized, muscle wasting (atrophy)

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1
Introduction
1.1
Background
Skeletal muscle is a dynamic and plastic tissue that responds rapidly to changes in frequency 
and duration of use (Musacchia et al 1988). An increase in muscle activity builds and 
maintains mass, while inactivity results in loss of muscle mass and hence muscle atrophy. 
Skeletal muscle atrophy is a change that may occur as a result of varied conditions, among 
others disuse (e.g., immobilization, denervation, muscle unloading). 
Disuse muscle atrophy and related functional limitations are commonly seen in frail elderly 
patients following a hip fracture. Disuse atrophy is triggered by immobility caused by the 
fracture and subsequent major surgical operation extent of which can vary depending on 
numerous factor such as patient’s age, gender, presence of comorbidities (such as diabetes, 
OA, cognitive impairment, etc), concomitant medications, and preoperative mobility status 
(Lyons et al 1997, Koval et al 1998). 
Importantly, atrophy due to disuse primarily affects the lower limbs and accounts for poor 
mobility and challenged rehabilitation course. One of the most important goals of 
rehabilitation for hip fracture patients - beyond pain management - is to recover ambulation 
and prevent serious morbidities arising from impaired mobility or complete immobility. 
Current treatment modalities are largely limited to physical rehabilitation, which requires 
active participation, long-term dedication and persistence from the patient’s side.  Despite 
these efforts, significant achievement in terms of restoration of muscle mass and strength is 
not always guaranteed. 
Approximately half of patients with hip fracture do not return to pre-fracture level of mobility 
by Month 6 after surgery (Vochteloo et.al 2013). About 30% may face injurious falls, 12% 
fractures and 5% a secondary hip fracture. This emphasizes the need for effective therapy to 
accelerate ambulation and highlights the relative ineffectiveness of existing therapeutic 
approaches.
Treatment with a muscle anabolic drug during the recovery phase may boost the recovery of 
muscle mass, strength and functional performance to drive overall improvement of physical 
function.  Adunsky et al (2011) showed that a muscle anabolic agent (ibutamoren mesylate) 
was effective in improving physical function as measured by Short Physical Performance 
Battery (SPPB) and its component, gait speed.  Moreover, knee muscle strength was an 
important modifiable predictor of falls in patients after hip fracture surgery (Yau et al 2013), 
further indicating that increase in muscle mass and strength leads to better functional 
outcomes.  However, currently there is no approved pharmacological therapy available that 
helps patients in increasing their muscle mass and resuming their functional activity after 
surgical fixation of the hip fracture.
Myostatin, a member of the transforming growth factor beta (TGF-β) superfamily, is a 
secreted protein that negatively regulates skeletal muscle mass in animals and humans 
throughout the lifecycle. Myostatin acts via the activin receptor type II (mainly via ActRIIB) 
and its proposed signaling is through the SMAD 2/3 pathway, which is involved in the 
inhibition of protein synthesis, and myocyte differentiation and proliferation. Myostatin 

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inhibition or genetic ablation increases muscle mass and strength (Lee et al 2005, Lee and 
McPherron 2001, Whittemore et al 2003).
Bimagrumab is a fully human, monoclonal antibody (modified IgG1, 234-235-Ala-Ala, λ2) 
developed for the treatment of involuntary muscle loss associated with illness, injury, and 
aging. It binds with high affinity to the activin receptors type IIB (ActRIIB) and with a lower 
affinity to activin receptors type IIA (ActRIIA), competitively blocking the binding of natural 
ligands (including myostatin and activins), that act as natural inhibitors of skeletal muscle 
growth. 
 
 
 
 
 
In summary, bimagrumab has yielded sufficient clinical data to support further investigation 
in the anticipated target populations such as patients with disuse atrophy and mobility 
limitations due to hip fracture fixation surgery.
1.2
Purpose 
The main purpose of the study is to identify at least one dose of bimagrumab that can increase 
lean body mass and improve physical function when compared to placebo at Week 24. After 
completion of the 24-week treatment period, the study will continue to assess the potential 
sustained efficacy and the safety  up to Week 48.  Data from this study will be used to further 
assess the efficacy and safety of the selected dose(s) for further development in phase 3.

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2
Study objectives
2.1
Primary objective
The primary objective is to assess the efficacy of at least one dose  of bimagrumab given 
intravenously every 4 weeks on total lean body mass (LBM) measured by dual emission X-
ray absorptiometry (DXA) as assessed by change from baseline at week 24 relative to placebo 
in patients with disuse atrophy after surgical treatment of hip fracture.
2.2
Secondary objectives
Secondary objectives are as follows:

To assess the effect of bimagrumab compared to placebo on improvement in mobility as 
measured by change from baseline at week 24 in gait speed.

To assess the effect of bimagrumab compared to placebo on improvement in physical 
performance as measured by change from baseline at week 24 in the Short Physical 
Performance Battery (SPPB). 

To evaluate the effects of bimagrumab vs. placebo on the incidence of falls

To assess the post treatment effect of bimagrumab compared to placebo on physical 
performance and mobility as measured by SPPB and gait speed up to End of Study 

To assess the clinical safety and tolerability of bimagrumab relative to placebo as assessed 
by measures such as vital signs, clinical laboratory variables, electrocardiogram (ECG), 
echocardiogram (only on patients enrolled before Amendment #3), adverse events (AE), 
X-ray assessment of the surgical procedure and potential orthopedic complications. 

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3
Investigational plan
3.1
Study design
This is a Phase IIa/IIb, 24-week, 4-treatment arms, parallel-group, randomized, double-blind, 
placebo-controlled, followed by a 24-week follow-up multi-center clinical study (Figure 3-1). 
The study consists of 3 epochs:

A screening epoch of up to 6 weeks post-surgery will be used to assess eligibility.  

A treatment epoch of 24 weeks

A post-treatment follow-up epoch of 24 weeks
At baseline visit, eligible patients will be randomized in a 2:1:2:2 ratio to either placebo, 
bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg.  Randomized patients will 
be treated for 24 weeks s and will receive investigational treatment every 4 weeks for a total 
of 6 doses. When all patients have completed the Treatment epoch (Week 24), the primary 
analysis will be conducted to assess the effects of bimagrumab on primary and secondary 
endpoints including key safety measures. After completing the treatment epoch, patients will 
enter a follow up epoch with two visits at Week 36 and 48, the latter representing the End of 
study (EoS) visit. The final analysis will be performed when all patients have completed their 
EoS visit. 
Patients randomized prior implementation of protocol amendment #2 were converted to fixed 
dose regimen at their next scheduled visit. Patients on 3mg/kg bimagrumab converted to 210 
mg bimagrumab fixed dose and patients on 10 mg/kg bimagrumab converted to 700 mg 

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bimagrumab. Patients who are beyond their week 20 visit had their EoT at the next scheduled 
visit and continued the study as per protocol amendment #2.
Figure 3-1
Study design
There are 3 study epochs:
Screening epoch: Informed consent will be obtained prior to implementing any study specific 
procedures. The screening epoch begins as early as day 3 post surgery and ends with 
randomization no later than 42 days post-surgery (Study Day -39 to Day -1).  The screening 
epoch should ideally start as soon as the patient starts to walk 
 
All entry criteria must be fulfilled before randomization (and latest on Day 42). This implies 
that any screening assessment can be repeated, as needed, if timelines to collect results allow 
this.  
It is recommended to perform simple screening assessments first (e.g. medical history, 
inclusion/exclusion criteria and vital signs) to identify non-eligible patients early, followed by 
the 4 meter gait speed test to demonstrate the ability to walk. Then, laboratory samples, which 
require shipping and analysis, should be collected along with the 12-lead ECG..
As soon as all inclusion criteria and none of the exclusion criteria have been met, the patient 
can be randomized. 
The randomization date will be the ‘Day 1’ study visit (baseline/randomization) and used as 
reference for visit scheduling throughout the study period.

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Treatment epoch:  First dose of investigational treatment will be administered on the day of 
randomization (Day 1). Patients will receive 6 doses, one every 4 weeks. Final dose will be 
administered at the week 20 visit and the treatment epoch will end 4 weeks later at week 24, 
the EoT visit. Investigational treatment will be administered in addition to the local surgical 
standard of care for hip fracture 
 
 
Post treatment Follow-up epoch: After completing the End of Treatment visit, patients will 
enter a post-treatment follow-up with two visits at Week 36 and 48. 
Following their study participation, patients will be further followed by their treating 
physician if required, according to the local standard of care.
3.2
Rationale of study design
There is no published Health Authority guidance to provide considerations for this study 
population or for the treatment of skeletal muscle disuse atrophy. The double-blind, 
randomized, parallel-group, placebo-controlled design used in this study will provide 
objective and unbiased data on the physical and functional improvements as a result of 
bimagrumab treatment. 
Efficacy of bimagrumab will be tested 
 associated 
with surgical hip fracture repair. The working hypothesis is that increased muscle mass 
 will lead to increased muscle power and improved 
functional performance, which is a prerequisite of improvement of activities of daily living, 
avoiding living dependency, and occurrence of complications (falls, fractures, hospitalization).
The post treatment follow-up period will allow characterizing the potential effect of 
bimagrumab in terms of mobility and lower-extremity function even after stopping therapy.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
The choice of doses, frequency, route of administration, and duration of treatment  is based on 
results of three Phase I studies: the First in Human (FIH) study (CBYM338X2101 Part A), 
casting study in healthy male volunteers (CBYM338X2101 Part B) and the multi-dose study 
(CBYM338X2102) in healthy volunteers. 
Dose and frequency
Results in healthy volunteers (CBYM338X2101 and CBYM338X2102) indicated that thigh 
muscle volume (TMV) increased comparably for single doses of 10 mg/kg and 30 mg/kg, but 
the effect of 30 mg/kg lasted longer (2 months versus 1 month). With 3 repeated every 4 
weeks doses of bimagrumab, there was a comparable increase in TMV in healthy adults at 3 
mg/kg and 10 mg/kg, even though duration of complete receptor occupancy (inferred from PK 
profile) with the 3 mg/kg dose is approximately half that observed with the 10 mg/kg dose. In 
healthy volunteers (CBYM338X2101), a limited and transient effect on the TMV was 
observed after infusion of a single dose of 1 mg/kg bimagrumab. This 1 mg/kg dose is 
therefore expected to be a non-effective or a minimally effective dose.

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In order to identify at least one effective dose of bimagrumab and be able to evaluate a dose 
response curve, the study will evaluate 3 fixed i.v. doses of bimagrumab 70, 210, or 700 mg 
administered every 4 weeks. The fixed dose equivalent of the mg/kg doses used in previous 
studies was calculated based on the mean patients’ weight and similar calculation was used 
for the current study based on the mean patients’ weight rounded to 70 kg  reported in 
literature for hip fracture patients (66±12 kg) (Mak et al 2014). 
Since the 70 mg dose is expected to be a non-effective or minimally effective dose it will be 
used only for dose response modelling and not hypothesis testing, therefore fewer patients 
will be randomized to this group. The randomization ratio will be 2:1:2:2 to either placebo, 
bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg. 
Changing from weight-based to fixed dosing is expected to better inform of the variability of 
exposure data and improve the accuracy of dose-exposure-response relationship estimation. 
Of note it is not expected that randomized patients will be exposed to bimagrumab at Cmax 
levels exceeding those experienced with the highest tested dose in previous studies, i.e. 30 
mg/kg. .
Dosing frequency every 4 weeks is based on observations from PK/PD studies where the 
efficacy reached the same plateau with both the 10 mg/kg every 4 weeks dosing and the 30 
mg every 8 weeks i.v. dosing.  
Route of administration
Study medication will be administered via intravenous infusion over 30 minutes, which was 
tested in study BYM338X2107 and shown to be well tolerated.
Treatment duration
Most recovery after a hip fracture has been shown to occur during the first 6 months after 
surgery, but many patients (44-60%) never regain prefracture level of mobility and physical 
functioning (Magaziner et al 2000, Vochteloo et al 2013, Shyu et al. 2004). Even with 
multidisciplinary postoperative rehabilitation, no more than 40% of patients completely 
regained their ability to perform activities of daily living during the 1-year follow-up (Stenvall 
et al 2007).
A recent study in hip fracture patients treated with an anabolic agent (ibutamoren mesylate) 
showed that a 6-month (but not a 3-month) treatment was effective in improving physical 
function as measured by SPPB and its component gait speed score (Adunsky et al 2011). 
Since increases in LBM are expected to reach their maximum after 2-3 months of treatment 
and functional benefits are observed with a delay, it seems reasonable to hypothesize that 6-
month duration of therapy is sufficient for increasing the functional recovery of hip fracture 
patients. 
Timing of first dose
The efficacy of bimagrumab is expected to be optimal when coupled with physical activity, 
therefore the timing of the first dose is aligned to be close to the start of physical therapy (ie. 
2-4 weeks post-surgery).
A number of studies reviewed by Chudyk et al 2009 and English and Paddon-Jones D 2010
indicate that early mobilization/ambulation following surgical fixation of a hip fracture may 

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improve patient outcomes such as early physical function, rate of discharge to home and 
decrease the risk of immobility-related complications and hospital readmissions (e.g. 
infections and thrombotic events). Recent reviews also argue that early (and preferably more 
intensive) initiation of physiotherapy is critical for overcoming the early loss of muscle 
strength after hip fracture surgery (Bandholm and Kehlet 2012), which is an important 
predictor of the course of recovery.  
3.4
Rationale for choice of comparator
The choice of placebo as a control agent is necessary to obtain information concerning the 
specific versus non-specific effects of the active treatment and provides the best way of 
evaluating the efficacy and assessing the safety and tolerability of bimagrumab.  
In the absence of any approved pharmacological comparator (i.e., a ‘gold standard’) in disuse 
atrophy, placebo will be used. The placebo arm will account for functional recovery that 
would naturally occur over time with local standard of care 
 
.
After the primary analysis (Week 24), all patients will stop study medication and remain in 
the study to be seen twice at Week 36 and End of Study (Week 48) visits. 
It is ethically justified to keep placebo patients without bimagrumab treatment during the 6 
month follow-up as they will be treated with standard of care. Moreover, bimagrumab is 
unlikely to benefit significantly and in a timely manner when the treatment is initiated more 
than 24 weeks after surgery, when most of the spontaneous recovery has already occurred 
(Magaziner et al 1990; Vochteloo et al 2011).
3.5
Purpose and timing of interim analyses/design adaptations
The primary analysis will be performed when all patients have completed their Treatment 
epoch (Week 24, EoT visit) via an interim database lock (soft database lock), while an 
updated analysis will be conducted when all patients have completed their End of Study 
(Week 48). No interim analysis will be performed prior to the primary analysis at the Week 
24 EoT visit.
3.6
Risks and benefits
Risks
The safety data from the completed Phase I and II studies do not highlight any specific safety 
risk or concern or any particular pattern of major adverse event clustering. From the 
standpoint of the overall risk-benefit assessment, the current study design and its trial-related 
risks (e.g., infusion, blood draws, exposure to radiation during imaging) with bimagrumab are 
justified. 
As of 1st September 2017 approximately 1341 adults have been enrolled in clinical trials with 
bimagrumab of which approximately 900 have received the antibody as study medication. 
Cumulatively, a total of 556 adults have participated or are participating in the Phase I 
program, with approximately 361 subjects having received bimagrumab. Seven-hundred 
eighty-five patients participated or are actively participating in the Phase II/III program. Dose 

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levels have ranged from 0.01 mg/kg to 30 mg/kg as i.v. infusions and 2 mg/kg s.c. injections, 
with the majority receiving repeat doses of 10 mg/kg (equivalent to 700 mg) and 30 mg/kg i.v. 
bimagrumab. The current safety profile suggests that bimagrumab is well-tolerated with 
adverse events limited to minor, transient clinical symptoms. Transient cases of episodic, 
spontaneous muscle contractions, acne and diarrhea of mostly mild intensity have been 
observed in study participants with symptoms occurring more frequently in those participants 
receiving the highest doses of drug (30 mg/kg).
Preliminary data from the first studies in healthy volunteers and older patients indicate 
observations of diffuse acne on the face and less frequently on the back and chest in some 
adults receiving a single dose of 30 mg/kg. Treatment has been successful with good skin 
hygiene using a 4-10% benzoyl peroxide wash and over the counter topical treatments. On 
occasion, a prescription, topical or oral antibiotic (i.e., minocycline 100 mg bid), was used. 
The mechanistic link between bimagrumab and acne remains poorly understood. There were 
no relevant changes in total testosterone or testosterone-estrogen ratio to bimagrumab 
treatment that otherwise could have explained the skin findings (CBYM338X2108).
In approximately 20 - 48% of normal healthy volunteers and patients with sporadic inclusion 
body myositis (sIBM) treated with a single 30 mg/kg i.v. dose of bimagrumab, involuntary 
muscle contractions, referred to as ‘muscle twitching’ were reported. The reported muscle 
twitches were mild in intensity, transient, of short duration, self-limiting and did not require 
medical treatment. While twitching could theoretically be more pronounced in aging and 
atrophying muscle, this has not been observed in sIBM patients up to 78 years old. The 
biological explanation of twitching is being pursued by the bimagrumab Project Team using 
both internal and external resources.
In the recently completed CBYM338B2203 study on patients with sIBM, diarrhea was 
usually an early event, a single episode, and mild in severity. Mechanism of this is yet to be 
understood in full detail, yet rapid increases in activin might be a potential driver as this 
ligand in animal studies has been implicated in irritable bowel disease (Hübner et al 1997). 
There were three cases of diarrhea in the 10 mg/kg dose group, which were reported as 
serious adverse events, but responded well to treatment.
Cardiac effects
Preclinical studies in rats demonstrated a marked cardiac hypertrophy deemed compensatory 
to the substantial increase in skeletal muscle mass. Although inconsistently seen in monkey 
studies, the observed increase in ventricular muscle mass without any effect on left ventricular 
chamber size and, importantly, on global left ventricular systolic function in female monkeys 
is also supportive of a compensatory effect rather than a direct effect of bimagrumab. 
In clinical studies to date, including the CBYM338B2203 study that exposed sIBM patients 
for 12-26 months, echocardiography has shown no evidence of significant change in posterior 
wall thickness, interventricular septum thickness, left ventricular and systolic or diastolic 
diameter, left ventricular mass, left ventricular mass index, end diastolic volume, end systolic 
volume and left ventricular ejection fraction when compared with placebo. 
The echocardiography findings have recently been confirmed by a dedicated cardiac safety 
study (CBYM338X2109) that investigated the effects of 6 doses of 10 mg/kg bimagrumab in 
68 elderly subjects (65-90 years old). Magnetic resonance imaging (CMR), revealed no 

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decrease in left ventricular ejection fraction, no increase in left ventricular mass index and no 
changes in regional myocardial thickness. Unlike the preclinical rat studies revealing up to 
30% increase in body weight, these human subjects had relatively small increases in lean 
body mass (~6%), which does not seem to drive compensatory changes on the myocardium.
Thus based on an analysis of data from the entire bimagrumab clinical program, intensive 
cardiac monitoring by echocardiography has been judged as no longer required and therefore 
removed from this protocol. The omission of echocardiography and monitoring of potential 
effects on the myocardium (hypertrophy or decreased ejection fraction) has been approved by 
the independent DMC as well as the internal Novartis Medical Safety Monitoring Board.
In addition, standard and Holter ECG in the aforementioned study indicated no difference in 
the incidence of cardiac arrhythmias or changes in QTcF or heart rate. Moreover, there was no 
alteration of blood pressure, hematologic parameters or cardiac injury biomarkers either. In 
light of these recent findings and in agreement with both the Novartis Safety Monitoring 
Board and the external DMC, the QTcF-related exclusion criterion has been updated raising 
the QTcF threshold of exclusion to 500 msec for both genders. In addition, it also allows 
enrollment of patients, who have artificially prolonged QTcF due to widening of the QRS 
complex (presence of right or left bundle branch block or a ventricular pacemaker).  
In this study, patients will continue have regular vital signs measurements, and multiple ECGs 
to monitor cardiovascular condition.
Reproductive hormone effects
Animal toxicity studies at weekly doses of 1, 10 and 100 mg/kg of bimagrumab in the 4- and 
13-week studies resulted in reversible changes in the uterus, vagina and ovaries of the rat and 
to a much lesser extent to the ovaries of the cynomolgus monkey at the highest doses. 
Recently, a dedicated hormone profiling study (CBYM338X2108) examined the effect of two 
doses of 10 mg/kg bimagrumab on hormone levels in older men and women. Results showed 
no increase in circulating testosterone levels and no effect on the pituitary-gonadal or 
pituitary-adrenal axes in either gender. The only finding was a significant decrease in FSH 
levels in post-menopausal women, which is consistent with the physiology of activin and the 
ActRII receptors in the pituitary. No statistically or clinically significant effects on FSH were 
seen in men. This expected effect on FSH reversed upon drug discontinuation by the end of 
the study. No biologic implications of these changes in FSH in elderly postmenopausal 
women have been described to date. Semen analysis data from the multiple dose study 
(CBYM338X2102) suggest that three doses of 10 mg/kg have no effect on fertility in males. 
Overall conclusions of the CBYM338X2108 study are corroborated by laboratory findings 
from prior studies as well as by the recently completed larger CBYM338B2203 study 
including 251 sIBM patients. 
Overall the risk of changes in reproductive organs in this study is minimal due to the age 
range of study participants.
Body weight
Increase in lean body mass and decrease in body fat mass were observed in the first-in-human 
study. During 6 months treatment of healthy elderly subjects with 10 mg/kg bimagrumab 
(CBYM338X2109 study), the relative loss of fat mass exceeded the increases of lean body 

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mass thereby causing a net body weight decrease of ~1.5 kg. With longer term exposure, such 
as in the CBYM338B2203 study body weight tended to decrease further due to continuing 
decrease in body fat mass (average decrease at W52 was ~3.5 kg).
Body weight will be assessed regularly during the study and patients showing at least 5% 
decrease in body weight will be referred to consultation with a nutritionist or other health care 
professional for assessment of malnutrition and consideration of taking adequate measures, if 
needed
Lipase and amylase elevations
Observations of dose-dependent, transient, sub-clinical elevations of lipase and/or amylase 
have been identified in several studies in the bimagrumab clinical program. The biological 
explanation for this temporal rise in pancreatic enzymes seen in some individuals is not yet 
fully understood and the causality with bimagrumab treatment has not yet been established.
As of 1 Sep 2017, there have been two confirmed cases of acute pancreatitis among the 642 
study participants from completed studies and an estimated 250 participants in ongoing 
(blinded) studies administered bimagrumab. There is no association of the temporary 
elevations in lipase and/or amylase with an increased risk for pancreatitis. 
In order to fully evaluate these new safety findings, additional safety monitoring 
measurements are added. Safety monitoring guidance for patients who experience elevated 
lipase and/or amylase during the study is provided in Section 7.4.
Trial related risks
Infusion related reactions can occur with monoclonal antibodies. Hypersensitivity reactions 
can manifest as fever, chills, urticaria, dyspnea, headaches, myalgia and/or hypotension. 
A serious infusion reaction that results in anaphylaxis is a rare event in monoclonal antibody 
therapy. If a severe hypersensitivity reaction occurs, administration of bimagrumab must be 
discontinued and appropriate therapy initiated. 
During the collection of blood samples, patients may experience pain and/or bruising at the 
insertion site of the needle/catheter. Although rare, localized clot formation, infections and 
nerve injury may occur. Lightheadedness and/or fainting may also occur during or shortly 
after the blood draw. Patients will be observed following all blood draws and discharged only 
when the Investigator observes stable health status. In addition, liquids by mouth in the form 
of water, fruit juice or a similar product will be provided following the blood draw to 
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Radiation Exposure
This clinical study involves exposure to radiation from X-ray and DXA total body and 
contralateral (unaffected) hip scans. X-ray assessments at baseline and 6 months are part of 
standard medical care after hip fracture surgery. However, exposure at 9 and 12 months is 
usually not medically necessary.  DXA radiation exposure is not necessary for medical care 
and it is intended for research purposes only. The total amount of radiation exposure per 
patient from X-ray and DXA scans will be about 3.65 mSv (365 mrem). 
For effective radiation doses between 3 mSv (300 mrem) and 50 mSv (5000 mrem), the risk is 
considered to be "minimal". Therefore, the radiation exposure in this study involves minimal 
risk and is necessary to obtain the research information desired (Stabin 2013).
The risk to patients in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring and guidance for the investigators provided in the Investigator’s 
Brochure. An adjudication committee will review cardiovascular events to confirm that these 
events have been evaluated appropriately and diagnosed correctly, while a Data Monitoring 
Committee (DMC) will monitor safety data from the study and the entire bimagrumab 
program for potential safety concerns. 
As for any other investigational drug, there are unknown risks to bimagrumab, which may be 
serious and unforeseen.
Benefits
The benefits of bimagrumab treatment in the hip fracture population are still not known.  
However, it is expected that as seen in healthy volunteers and patients with sIBM, the hip 
fracture patients will have an increase in muscle mass that may translate to better recovery of 
lower extremity function and faster return to mobility. Over the course of the study, the 
number of falls might be reduced, which in turn reduces the risk of traumatic injuries and 
fractures, including secondary hip fractures.
4
Population
The study population will consist of male and female patients ≥ 60 years old, at time of 
randomization, who underwent surgical treatment for a low-energy fracture of the proximal 
femur. The study aims to screen approximately 400 patients. With an estimated screen failure 
rate of about 40%, approximately 245 patients, with successful surgery after hip fracture, will 
be randomized in more than 60 centers worldwide. Approximately 200 patients are expected 
to complete the 24-week treatment epoch and approximately 120 patients the full 48 -week 
study period.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed; 
2. Males and post-menopausal females ≥ 60 years (as defined in Section 6.5.9);
3. Patient must have had surgical fixation or arthroplasty for a fracture of the proximal femur 
(AO Classification 31 A-C (AO Foundation 2013)) as confirmed by radiography;

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4. Patient must be mentally competent, to have scored at least ≥ 21 on the Folstein Mini 
Mental State Examination (MMSE);
5. Patient must be able to complete a 4 m gait speed test
6.
Patients must weigh at least 35 kg and must have a body mass index (BMI) within the 
range of 15– 35 kg/m2 at screening;
7. Patient must have complete surgical wound healing.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study.  No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
Central laboratory tests needed for eligibility assessment, i.e. GFR, AST, ALT, bilirubin, 
platelet count, hemoglobin, or ECG interpretations which fall outside of the protocol-
specified range at screening can be repeated at an unscheduled visit during the screening 
epoch to confirm patient eligibility prior to randomization.
1. History of any other lower limb fracture in the past 6 months or any other major surgery to 
the lower limb in the past 3 months prior to randomization that caused a persisting 
functional sequelae, which directly impacts gait speed and/or gait quality and is unlikely 
to recover during the study period ;
2. Isolated high-energy sub-trochanteric fracture (AO Classification 32 A-C, (AO 
Foundation 2013));
3. Major mobility limitation (i.e. not able to walk 100 meters without stopping or getting 
help; unilateral help being fine) in the past 3 months prior to the hip fracture due to severe 
dyspnea, presence of permanent or progressive neurologic deficit (muscle weakness, 
spasticity, rigor or balance impairment), disabling joint or muscle pain in the hip or knee, 
intermittent claudication or major visual impairment.
4. Active gastrointestinal diseases/conditions known to cause malabsorption or increased 
enteric loss of protein, such as inflammatory bowel disease (unless complete remission), 
celiac disease (unless gluten-free diet), short bowel syndrome, pancreatic insufficiency 
(unless under good control by medication/enzyme supplements); 
5. Severe renal insufficiency defined by either requiring dialysis or having an estimated 
glomerular filtration rate (GFR) < 30 mL/min using the modification of diet in renal 
disease (MDRD) equation which can be found in the Study Manual;
6. Uncontrolled hypothyroidism requiring a change in the dose of hormone replacement 
therapy in the last 6 weeks prior to randomization; uncontrolled hyperthyroidism;
7. Underlying muscle diseases, including history of or currently active form of inflammatory 
myopathies (e.g., dermatomyositis, polymyositis, etc) or muscular dystrophies;
Cardiovascular conditions
8. Hypertension uncontrolled with medication (i.e. systolic blood pressure >180 mm Hg or 
diastolic blood pressure >100 mmHg
9. Known heart failure classified as New York Heart Association Class III and IV;

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10. Ongoing unstable angina or history of myocardial infarction in the last 3 months prior to 
randomization;
11. Current presence of severe aortic or mitral stenosis, or septal defects; 
12. Severe pulmonary hypertension uncontrolled with medication;
13. Confirmed diagnosis of restrictive or hypertrophic (obstruction) cardiomyopathy. Patients 
with dilative cardiomyopathy are allowed to enter the trial unless the diagnosis is 
associated with any of the conditions/events outlined in the list of exclusion criteria;  
14. History of familial long QT syndrome or known family history of Torsades de Pointes
15. Prolonged QT syndrome or QTcF ≥ 500 msec (Fridericia Correction) (central reading); 
patients with QTcF ≥ 500 msec in the presence of right or left bundle branch block or 
ventricular pacemaker are permitted, if endorsed by the patient’s treating physician. 
16. Any current supra-ventricular arrhythmia with an uncontrolled ventricular response (mean 
heart rate >100 beats per minute [bpm]) as per ECG at rest despite medical or device 
therapy or

any history of spontaneous or induced sustained ventricular tachycardia (heart rate 
>100 bpm for 30 seconds) despite medical or device therapy or 

any history of resuscitated cardiac arrest or 

the presence of an automatic internal cardioverter-defibrillator;
Liver related conditions
17. Abnormal liver function tests such as SGOT (AST), SGPT (ALT), or serum bilirubin 
(except if accompanying Gilbert’s Disease) as defined by; 

Any single transaminase > 3 x the upper limit of normal (ULN). A single parameter 
elevated up to and including 3 x ULN should be re-checked as soon as possible, and 
in all cases, prior to randomization, to rule out any lab error. 

Serum bilirubin > 1.6 mg/dL (27 µmol/L).
18. Presence of severe acute or chronic liver disease (e.g., cirrhosis) or conditions with 
hepatotoxic potential (e.g. known gallbladder or bile duct disease, acute or chronic 
pancreatitis);
Other medical conditions
19. History of hypersensitivity to therapeutically administered antibodies;
20. Lack of peripheral venous access;
21. Any type of active cancer (i.e. under current treatment) or cancer that required treatment 
in the last 5 years, except for secondary preventive measures (e.g. tamoxifen for breast 
cancer). -. Non-melanoma skin cancers or in situ cancers with excellent prognosis (e.g. 
carcinoma in situ of the uterine cervix) are permitted, if were excised or fully resolved by 
other means;
22. Type I diabetes mellitus or uncontrolled type II diabetes mellitus (e.g. pre-surgical levels 
as per patient file indicating HgbA1c ≥ 8.5% or if fasting blood glucose ≥ 9.0 mmol/l at 
more than one measures);
23. Significant coagulopathy, platelet count less than 75,000/mm3, or anemia (hemoglobin 
less than 8.0 g/dL);

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24. Active systemic infection requiring treatment with IV anti-infectives within 4 weeks of 
randomization;
25. Chronic active infection (e.g., HIV, hepatitis B or C, tuberculosis, etc). Patients with 
already diagnosed latent tuberculosis, who are receiving chemoprophylaxis, are eligible 
for the study.
26. Patient has any other condition (e.g. alcohol abuse), laboratory finding, or any post-
operative condition or complication, which, in the investigator’s opinion may affect the 
course or magnitude of recovery from surgery, interfere with participation in the study 
(poor compliance),  may confound the results of the study, or pose additional risk in 
administering bimagrumab;
Prohibited medications:
27. Systemic use of vascular endothelial growth factor (VEGF) inhibitors within 6 months
prior to randomization; intravitreal administration is allowed
28. Use of immunosuppressive therapy  within 3 months of randomization;
29. Use of any therapies known to affect muscle mass via modulation of androgen or growth-
hormone receptors or the synthesis of these hormones within 3 months prior to 
randomization (or current use of high-dose selective beta2-adrenergic drug therapy;
30. Ongoing systemic corticosteroid use or history of systemic corticosteroid use for at least 3 
months (in the last year) prior to randomization at a daily dose greater than or equal to 10 
milligram (mg) prednisone equivalent; 
31. Currently enrolled in, or discontinued within the last 30 days (or 5 half-lives, 
 
 whichever is longer or longer if 
required by local regulations) from a clinical trial involving an investigational drug or off-
label use of a drug, or are concurrently enrolled in any other type of medical research 
judged to be scientifically or medically incompatible with this study.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
Novartis will supply the following investigational drugs: 

Bimagrumab: BYM338 150 mg/1 ml liquid in vial--colorless glass vials with rubber 
stopper and aluminum flip-off caps. 

Placebo: BYM338 placebo/1 ml liquid in vial--colorless glass vials with rubber stopper 
and aluminum flip-off caps. 
Note: To maintain the blind, the investigational treatments will be prepared by an unblinded 
pharmacist/designee and administered only by blinded study personnel.

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5.1.2
Additional study treatment
5.1.2.1
Local standard of care therapy after hip fracture
Local standard of care therapy to manage patients peri/post operatively (such as for 
thrombosis prophylaxis, pain management, calcium supplementation, secondary osteoporosis 
prevention) is acceptable unless listed in Section 5.5.8 and may be used according to the 
national or local guidelines.

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5.2
Treatment arms 
Under the original protocol, patients were assigned in a 1:1:1 manner to one of the 3 treatment 
arms (placebo, bimagrumab 3mg/kg and bimagrumab 10mg/kg). After approval of Protocol 
Amendment 2, patients were assigned to one of the following 4 treatment arms in a ratio of 
2:1:2:2

Arm 1: Placebo i.v. every 4 weeks

Arm 2:Bimagrumab 70 mg i.v. every 4 weeks

Arm 3: Bimagrumab 210 mg i.v. every 4 weeks

Arm 4: Bimagrumab 700 mg  i.v. every 4 weeks
Patients will receive a total of 6 doses of bimagrumab or placebo. The first dose will be given 
on Day 1 and the last dose at week 20 visit.  End of treatment assessments will be performed 
at week 24.
Patients randomized before the Protocol Amendment 2 were switched in a blinded manner via 
the IRT system to the corresponding fixed dose i.v. regimen at the next scheduled visit 
following amendment approval by their respective health authorities and ECs/IRBs: 
•
patients originally randomized to 10 mg/kg i.v. switched to 700 mg i.v., 
•
patients originally randomized to 3 mg/kg i.v. switched to 210 mg i.v.,
•
patients originally randomized to placebo remained on placebo.
Patients who are already beyond week 20 at the time of the protocol amendment #2 
implementation performed their EoT assessment visit at their next scheduled visit and 
continued in the study as per protocol amendment #2.

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5.3
Treatment assignment, randomization
At the randomization visit, all eligible patients will be randomized via Interactive Response 
Technology (IRT) to one of the four treatment arms. The investigator or his/her delegate will 
contact the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. 
The IRT will assign a randomization number to the patient, which will be used to link the 
patient to a treatment arm and will specify a unique medication number for the first package 
of investigational treatment to be dispensed to the patient. The randomization number will not 
be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drugs. 
Randomization will be stratified using the following three strata: 1) Japanese sites, 2) Non-
Japanese sites for patients randomized 21 days or less from their hip fracture surgery date, and 
3) Non-Japanese sites for patients randomized greater than 21 days from their hip fracture 
surgery date. This measure will balance the distribution of Japanese patients among 
bimagrumab treatment groups and the placebo group. Therefore it will support the analysis of 
comparison of key efficacy and safety endpoints for Japanese sub-population.
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group. A separate randomization list was already created at the time of 
amendment 2. 
5.4
Treatment blinding
Patients, investigators and their site personnel (with exception of the unblinded pharmacist), 
as well as Novartis agents in the countries as well as the global study team involved in the 
routine conduct of the trial will remain blinded to the identity of the individual patient 
treatment from the time of randomization until the final database lock (when all patients will 
have completed both the Treatment epoch and the Post Treatment Follow-Up epoch)..
For the study duration, the following method will be used to maintain the blind: 
1. Randomization data will be kept strictly confidential until the time of unblinding, and will 
not be accessible to anyone else involved in the study with the following exceptions:

specific vendors whose role in trial conduct requires their unblinding [e.g., Interactive 
Response Technology (IRT)]

DSM (drug supply management)

members of the DMC 

study bioanalyst 

an independent, unblinded pharmacist/designee at the investigator’s site who will 
prepare investigational treatment infusion

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
unblinded monitor who will perform investigational treatment accountability at the 
site

An independent global clinical person will have access to individual randomization 
codes at the interim database lock for the primary analysis 
2. The identity of the treatments will be concealed by the use of investigational treatments in 
forms of infusion bags filled with bimagrumab or placebo and covered with a sleeve that 
are identical in appearance, labeling and schedule of administration.  However, the 
bimagrumab and placebo vials will be supplied “open-label” to the unblinded pharmacist.
3. Results of DXA scans and a mechanism of action related biomarker (activin A) as well as 
FSH that may reveal 
 effects of the study drug will not be shared by the 
central reader/laboratory to investigators, site staff or global study team but will be stored 
in a blinded part of the study data base. 
Due to the difference in supply and preparation methods of the active drug and placebo, an 
independent, unblinded pharmacist or designee who is independent of the study team will be 
required to maintain the blind. The unblinded pharmacist will receive the medication numbers, 
prepare infusions with either investigational drug or placebo, without disclosing the identity to 
any other site personnel. Appropriate measures must be taken by the unblinded pharmacist to 
ensure that the study team remains blinded throughout the course of dose administration and 
the remainder of the study. No other person will have access to the medication and drug 
administration documentation, except the unblinded monitor.
The unblinded pharmacist is NOT allowed to administer the drug to the patient. 
Unblinded monitors will be required to perform proper oversight for drug accountability. The 
unblinded field monitor will be responsible exclusively for drug accountability and must take 
appropriate measures to ensure the blind is preserved for the duration of the study. 
Full unblinding (treatment and dose) will only occur in the case of patient emergencies and at 
the conclusion of the study. 
In the case of unblinding, the patient will be discontinued from investigational treatment and 
enter the Post-treatment follow-up epoch. Discontinuation of investigational treatment and 
premature patient discontinuation are discussed in detail in Section 5.5.9.
Following the interim database lock, to perform the primary analysis, partial unblinding will 
occur as follows:

An independent global clinical person will have access to individual randomization codes 
after the primary analysis. 

The Novartis global study team will be unblinded to the group level results only

The study subjects and the site personnel will remain blinded until the final database lock
The study bioanalyst will have access to the randomization list to facilitate analysis of 
samples (i.e. to avoid the unnecessary analysis of placebo samples).
 
 
The bioanalyst will provide sample data to the team under blinded 
conditions 
 

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 The unblinded bioanalyst 
 will keep treatment allocation 
information confidential until clinical database lock.
5.5
Treating the patient
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed of the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 
Upon signing of the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site should 
select the CRF book with a matching Subject Number from the EDC system to enter data. 
If the patient fails to be randomized for any reason, the IRT must be notified within 2 days 
that the patient is a screen failure. The reason for not being randomized will be entered on the 
Screening Epoch Study Disposition CRF.
5.5.2
Dispensing the investigational treatment
The packaging of the investigational treatment will be open-label and not identical in 
appearance. 
The investigational treatment packaging has a 2-part label. A unique medication number is 
printed on each part of this label which corresponds to one of the investigational drugs.  The 
unblinded pharmacist or designee will identify the investigational treatment package(s) to 
dispense to the patient by contacting the IRT and obtaining the medication number(s). 
Immediately before preparation of investigational treatment infusion, the unblinded 
pharmacist/designee will detach the outer part of the label from the packaging and affix it to 
the source document (Drug Label Form) for that patient’s unique subject number. 
The unblinded pharmacist/designee will NOT administer the study drug to the subject.
5.5.3
Handling of investigational treatment
Investigational treatment must be received by the unblinded pharmacist/designee  at the study 
site, handled and stored safely and properly, and kept in a secured location to which only the 
unblinded pharmacist/designee  has access. Upon receipt, all investigational treatment should 
be stored according to the instructions specified on the labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. Technical complaints are to be reported to the 
Novartis CPO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the medication number.
The unblinded pharmacist/designee must maintain an accurate record of the shipment and 
dispensing of investigational treatment in a drug accountability log. Monitoring of drug 
accountability will be performed by the unblinded field monitor during site visits and at the 
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All drug supplies are to be used only for this protocol and not for any other purpose. Unless 
specifically instructed by Novartis, the site must not destroy any drug labels, or any partly 
used or unused drug supply.
At the conclusion of the study, and as appropriate during the course of the study, the 
unblinded pharmacist/designee will return all unused investigational treatment, packaging, 
drug labels, and a copy of the completed drug accountability log to the unblinded Novartis 
monitor or to the Novartis address provided in the investigator folder at each site.
5.5.4
Instructions for prescribing and taking investigational treatment
Detailed instructions on the preparation and administration of the investigational treatment 
will be described in the Pharmacist Manual and provided to each site.
The unblinded pharmacist/designee will prepare the infusion according to treatment 
assignment (bimagrumab 700mg, 210mg, 70mg or placebo) based on the information 
provided by the IRT system (medication number and volume to be dispensed). The unblinded 
pharmacist/designee will withdraw the appropriate amount of investigational treatment from 
one or more vials and the drug product will be diluted with a dextrose solution to 
approximately 100 ml intravenous infusion solution.  The infusion bag with the prepared 
investigational treatment solution will be covered with a sleeve and provided by the unblinded 
pharmacist/designee to the blinded investigator or assigned site staff.  
The unblinded pharmacist/designee must not have any contact with the subject and 
must not be involved in any of the study assessments.
Study medication will be administered by blinded study center personnel.
The 100 ml of bimagrumab or placebo solution for i.v. administration will be administered as 
a slow infusion over approximately 30 minutes, followed by a flush with 50 ml.  
Only the materials (infusion bag, administration set and filter) specified in writing by 
the sponsor should be used for administration of the study medication.  All medication 
administered to the patient (in ml of infusion without the flush), the duration of the total 
infusion (including the flush), and all dose changes during the study must be recorded on the 
Dose Administration Record eCRF page. In case of an unintentional study treatment error, no 
AE needs to be reported unless symptoms, warranting AE reporting, are associated with it. 
All kits of investigational treatment assigned by the IRT will be recorded in the IRT.
The investigator should promote compliance by instructing the patient to return to the site for 
investigational treatment administration as outlined in Table 6-1 and by stating that 
compliance is necessary for patient’s safety and the validity of the study. 
5.5.5
Permitted dose adjustments and interruptions of investigational 
treatment
Investigational treatment dose adjustments are not permitted. 
Dose interruptions should be avoided for the duration of treatment.  However for patients who 
are unable to tolerate the protocol-specified dosing scheme, dose interruptions of 
investigational treatment are permitted in order to keep the patient on study drug. 

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If a patient misses two doses, the subject must be discontinued from the investigational 
treatment (refer to Section 5.5.9). 
5.5.6
Rescue medication
Use of rescue medication is not applicable to this study.
5.5.7
Concomitant treatment
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy, dietary modification, protein 
supplements and blood transfusions) administered after the patient was enrolled into the study 
must be recorded on the Concomitant medications eCRF or Surgical and Medical procedures 
eCRF.  
5.5.8
Prohibited Treatment
Use of the treatments displayed in Table 5-1  is NOT allowed from the start of Screening 
epoch until End of study visit at Week 48.  
The following treatments are not allowed because of their biological effect on muscle 
anabolism or catabolism, or muscle strength, which would confound the assessment of 
efficacy.
Table 5-1
Prohibited treatment
Medication*
Action to be taken
Androgen modulators (e.g., testosterone,  danazol, 
fluoxymesterone, methyltestosterone)
Discontinue investigational treatment
Anabolic steroids (e.g., Oxandrolone, stanozolol, 
DHEA, testosterone)
Discontinue investigational treatment
Anti-androgens (e.g. flutamide, nilutamide, cyproterone 
acetate, spironolactone)
Discontinue investigational treatment
Progestins with known androgenic component (e.g. 
norethindrone acetate, megestrol acetate, tibolone)
Discontinue investigational treatment
Note:

Norethindrone acetate use for 5-10 
days to stop abnormal uterine bleeding 
due to hormonal imbalance is 
permitted.

Low-dose (1.25 mg or lower) tibolone 
treatment is permitted.
Systemic glucocorticoids (e.g., dexamethasone, 
hydrocortisone, methylprednisolone, prednisolone, 
prednisone, triamcinolone)
Discontinue investigational treatment
Note: Short term (defined as 20 mg/day 
prednisone equivalent for less than 14 
days) or irregular use if medically 
indicated (e.g. Asthma, allergic reactions) 
is permitted.
Oral selective beta2-adrenergic agonists (e.g. 
Albuterol)
Discontinue investigational treatment
Note: Intermittent use if medically 
justifiable and doses up to 16 mg/day 

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Medication*
Action to be taken
albuterol equivalent are permitted. 
Gonadotropin-releasing hormone (GnRH) agonists or 
antagonists (e.g. leuprolide, nafarelin, ganirelix, 
degarelix)
Discontinue investigational treatment
Recombinant Human Growth hormone and/or mimetics 
(e.g. somatrem, somatropin) and Ghrelin
Discontinue investigational treatment
Immunosuppressive therapy
Systemic use of vascular endothelial growth factor 
(VEGF) inhibitors
Discontinue investigational treatment
Note: Intravitreal administration is allowed
Any investigational treatment or participation in any 
interventional trial
Discontinue investigational treatment
*In case of undue safety risk for the patient, the patient should discontinue investigational treatment 
at the discretion of the investigator.  
5.5.9
Discontinuation of investigational treatment or premature study 
discontinuation
Patients may voluntarily discontinue the investigational treatment for any reason at any time. 
The investigator should discontinue investigational treatment for a given patient if, on balance, 
he/she believes that continuation would be detrimental to the patient’s well-being.
Investigational treatment must be discontinued under the following circumstances: 

Use of prohibited treatment as per Table 5-1.

Any other protocol deviation that results in a significant risk to the patient’s safety

Breaking of the blind (inadvertently or for emergency reasons)

Severe hypersensitivity reaction occurs

Liver event definition met as per Appendix 2

Deviations from the prescribed dose regimen for investigational treatment with 2 doses 
missed at any time

Death 

Withdrawal of consent 

Sponsor decision to terminate (part of) the study
Investigational treatment may be discontinued under the following circumstances: 

Emergence of the adverse events that in the judgment of the investigator, taking into 
account the patient’s overall status, prevent the patient from continuing participation in the 
study

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient’s overall status, prevents the patient from continuing 
participation in the study 
At the time of protocol amendment #2 implementation, patients who have already received 
their Week 20 infusion of investigational treatment returned to the site at their next scheduled 

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visit and performed their End of Treatment visit. They continued as per the study visit 
schedule Table 6.1.
Patients who discontinue investigational treatment are NOT considered immediately 
withdrawn from the STUDY or to have withdrawn informed consent to participation 
(described in section 5.5.10). The patient must return approximately 28 days following the 
patient’s last investigational treatment administration to complete the End of Treatment visit 
assessments (Table 6-1). If the patient was already off-treatment for a longer period, then the 
End of Treatment visit can be performed without delay. After completing the End of 
Treatment assessments, patients will enter a 4-week follow up and return for the End of Study 
visit.  If the patient fails to return for these assessments for unknown reasons, every effort 
should be made to contact him/her as specified in Section 5.5.11.
Investigators or site personnel must contact the IRT to register the patient’s discontinuation 
from treatment. In addition, the investigator will report the primary reason for treatment 
discontinuation on the End of Treatment Epoch eCRF.
5.5.10
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent occurs when a patient does not want to participate in the study any 
more, does not want any further visits or assessments, does not want any further study related 
contacts, and does not allow analysis of already obtained biologic material.
If a patient withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information in the Withdrawal of Consent 
eCRF. Investigational treatment must be discontinued and no further assessments conducted. 
All biological material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
5.5.11
Loss to follow up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until his/her 
scheduled end of study visit would have occurred.
Subjects who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients.
5.5.12
Emergency breaking of assigned treatment code
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, investigational treatment discontinuation and 
knowledge of the possible treatment assignment are sufficient to treat a study patient who 
presents with an emergency condition. Emergency treatment code breaks are performed using 

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the IRT. When the investigator contacts the system to break a treatment code for a patient, 
he/she must provide the requested patient identifying information and confirm the necessity to 
break the treatment code for the patient. The investigator will then receive details of the 
investigational drug treatment for the specified patient and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Global Trial Leader (GTL) that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable, redundant procedure 
in place to allow access to the IRT/code break cards at any time in case of emergency. The 
investigator will provide protocol number, investigational treatment name if available, patient 
number as well as oral and written information to the subject on how to contact his/her backup 
in cases of emergency when he/she is unavailable to ensure that un-blinding can be performed 
at any time in the case of emergency. 
Investigational treatment must be discontinued after emergency unblinding (Section 5.5.9).
5.5.13
Study completion and post-study treatment
A patient will be considered to have completed the study when he/she has completed 48 
weeks of the study including the End of Study Visit.
The study will be considered to be complete when the last patient completes 48 weeks of the 
study including the End of Study Visit.
Patients who are still in the screening process once planned enrollment is met will be allowed 
to complete screening and will be randomized into the study if eligible.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.5.14
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as a patient prematurely withdrawn 
from the study. The investigator may be informed of additional procedures to be followed in 
order to ensure that adequate consideration is given to the protection of the patient’s interests. 
The investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when they are to be performed. 
Patients should be seen for all visits on the designated day within the recommended “visit 
window” specified below, or as close to it as possible.  The site should make every effort to 
help bring the patients to the clinic visits, including providing transportation if necessary.  If 
any visits are delayed or missed, the site personnel should ensure alignment of future patient 
visits according to the originally planned visit schedule (i.e. rescheduled visit window needs 
to be calculated with reference to first dose received; day of randomization and first dose 
received may differ occasionally), and should ensure that 2 consecutive infusions are done at 
least 14 days apart.

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Recommended visit windows:
Randomization/Day 1: + 2 days
Weeks 4-12: +/- 4 days
Weeks 16-24: +/- 7 days
Weeks 36-48: +/- 14 days
Some of the following principles should be taken into consideration when scheduling a visit:

Assessments for a particular visit - including the randomization visit - may be split over 
several days.

 physical performance tests should be considered 
early in the visit to avoid physical or mental exhaustion of the patient.

Laboratory work in particular those requiring 8 hours fasting should be done early in order 
to allow the patients to eat and drink 

Patient dosing should be the last procedure to be performed
During the treatment epoch, patients may be seen at unscheduled visits for instance for AEs 
that in the opinion of the investigator need intervention or repeated laboratory testing. All 
relevant safety assessments may be performed as deemed necessary by the investigator.  
During these unscheduled visits, investigational treatment must NOT be administered.
During the post-treatment follow up epoch, safety and efficacy assessments will continue until 
the EoS visit at week 48. .

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Table 6-1
Assessment schedule
Study Epoch
Screening
Treatment
Post-treatment follow 
up
Notes
Visit name/study 
week
Screening / 
Day -39 to 
-1
BL/ Rand 
Day 1
Week 
4
Week 8
Week 12
Week 16
Week 20
End of 
treatment / 
Week 24 *
Week 36
End of 
study / 
Week 48 
Days post-op or 
post 1st dose
D3 to 42 
post- op
1
28
56
84
112
140
168
252
336
Informed Consent
X
Verify Inclusion/ 
Exclusion
X
Randomization
X
Demographics
X
MMSE
S
Source documents only.
Hip fracture history
X
Medical history
X
Physical Examination
S
S
S
S
Source documents only.
Blood sample for 
serology
X
Blood sample for 
hematology and 
chemistry
X
X
X
X
X
X
Blood sample for 
hormones
X
X
X
X
Urine sample
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
(triplicate)
X
X
X
X
Echocardiography
(X)
(X)
Only for patients enrolled 

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Study Epoch
Screening
Treatment
Post-treatment follow 
up
Notes
Visit name/study 
week
Screening / 
Day -39 to 
-1
BL/ Rand 
Day 1
Week 
4
Week 8
Week 12
Week 16
Week 20
End of 
treatment / 
Week 24 *
Week 36
End of 
study / 
Week 48 
Days post-op or 
post 1st dose
D3 to 42 
post- op
1
28
56
84
112
140
168
252
336
before Amendment #3.
W48 is to be performed only if 
W24 reading indicates clinically 
meaningful abnormality as per 
central reader’s assessment.
Gait Speed
S
Source document only.
SPPB (incl. gait 
speed)
X
X
X
X
X
X
X
X
X
DXA 
X
X
X
All centrally read.
X-ray
X
X
(X)
(X)
At screening local X-ray taken 
during or after surgery is to be 
used.
If bone union is incomplete at 
W24 per central reading, X-
rays need to be performed until 
this is achieved at W36 and 
potentially W48 as well.
Drug administration 
X
X
X
X
X
X

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Study Epoch
Screening
Treatment
Post-treatment follow 
up
Notes
Visit name/study 
week
Screening / 
Day -39 to 
-1
BL/ Rand 
Day 1
Week 
4
Week 8
Week 12
Week 16
Week 20
End of 
treatment / 
Week 24 *
Week 36
End of 
study / 
Week 48 
Days post-op or 
post 1st dose
D3 to 42 
post- op
1
28
56
84
112
140
168
252
336
AE/SAE reporting
To be recorded as needed
Medications and 
medical procedures
To be recorded as needed
* In case of investigational treatment discontinuation during the Treatment Epoch, the patient should complete the EoT Visit 4 weeks after the last investigational 
treatment administration. After the EoT visit is completed, the patient should return after an additional 4 weeks for an EoS visit. In case of premature study 
discontinuation after the Treatment Epoch, the patient should  return to an EoS visit (not earlier than 4 weeks after the EoT visit)
Rand = randomization; BL = baseline; Folstein Mini Mental State Examination =MMSE

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6.1
Information to be collected on screening failures
Patients who sign the informed consent form for the study but fail to be randomized to 
treatment will be considered a screening failure. IRT must be notified within 3 days and the 
following eCRFs pages must be completed:

Screening Phase Disposition eCRF,

Informed Consent eCRF,

Demography eCRF,

Inclusion/Exclusion eCRF,

Adverse Events eCRF should be completed for any serious adverse events that occurred 
after signing the informed consent. Adverse events that are not SAEs will be followed by 
the investigator and collected only in the source data,

Re-screening page (if applicable),

Withdrawal of informed consent eCRF (if applicable),

Death eCRF (if applicable)
Patients who were declared as screen failures  that may improve with time after surgery (e.g. 
mobility or cognitive function) or may change at re-assessment (e.g. marginal deviation in 
laboratory or ECG findings), can be re-screened once, unless they are outside of the 3-42 days 
post-surgery window. These patients must be re-consented, and they receive a new patient 
number, after which all screening assessments done previously must be repeated. Therefore, 
given the additional burden of a re-screening, it is recommended to avoid screen failing a 
patient too rapidly, if the reason for screen failure is transient in nature and has a chance to 
improve within a short period of time. 
6.2
Patient demographics/other baseline characteristics
6.2.1
Demographic information
Patient demographic data to be collected for all patients include: date of birth if permitted as 
per local regulations, sex, race, and ethnicity. 
6.2.2
Medical history
All relevant medical history and current medical conditions occurring prior to the date of 
informed consent will be captured in the Medical History eCRF.  Investigators will have the 
discretion to record abnormal test findings on the medical history CRF whenever in their 
judgment, the test abnormality occurred prior to the informed consent signature.
The aim is to capture the diagnoses rather than symptoms. 
In addition several specific eCRF pages will capture more details on a number of conditions 
such as:

Fall history, which takes into account the last 12 months prior to the fall that led to the 
current fracture

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
Cardiovascular and metabolic disease history including conditions such as 
cardiomyopathy, diabetes, hypertension, etc.

All relevant orthopedic conditions and/or earlier surgical interventions that may affect 
lower limb function (e.g. prior factures, arthroplasty, arthrodesis)

Perioperative information on the hip fracture surgery including the surgical method used
6.2.3
Eligibility assessments
In addition to the review of the patient’s medical history and type of hip fracture, eligibility 
assessments must be performed and results reviewed by the investigator before a patient can 
be enrolled in the trial:

12-lead electrocardiogram (ECG) using the central reading

Confirmed ability to complete a 4-meter gait speed test 

Central laboratory screening tests:   GFR, AST, ALT, bilirubin, platelet count, and 
hemoglobin)

Vital signs, including height and weight, BMI

MMSE 

Confirm successful surgical intervention for fracture repair AND completed surgical 
wound healing

Historical intra- or post-operative X-ray of the operated hip.
6.2.4
Other pre-treatment characteristics

Physical exam (recorded as source data)

Total/appendicular LBM via DXA 

Serology (HIV Ab, HCV Ab, HbsAg)

25-OH vitamin D


Dietary assessment/
 as per pre-albumin and albumin levels.
6.3
Treatment exposure and compliance
All dates and times of investigational treatment administration will be recorded on the Dosage 
Administration Record eCRF. 

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Drugs administered prior to start of treatment and continuing or started during the 
investigational treatment period will be entered in the Concomitant Medications eCRF page. 
Compliance is expected to be 100% since investigational treatment will be administered by 
the investigator or study personnel, unless the patient misses clinic visits. Compliance will 
also be assessed by an unblinded monitor using vial counts and information provided by the 
unblinded pharmacist/designee.
6.4
Efficacy
Efficacy measurements in the study will include: 

Total LBM assessed by DXA to measure lean body mass

SPPB to assess functional improvement

Gait Speed (as a component of SPPB) to assess functional improvement

Falls 
6.4.1
Total Lean Body Mass (LBM) by DXA 
DXA will be used to measure lean soft tissue, which is fat-free and bone mineral free 
component that includes muscle and other soft tissue like skin tendons and connective tissues. 
The exam is quick (10-15 min, including preparations), precise (0.5-1%) and non-invasive. 
DXA scanners have the precision required to detect changes in muscle mass as small as 5%. 
These examinations will be performed as outlined in Table 6-1.
Studies have shown that quality assurance is an important issue in the use of DXA scans to 
determine body composition. DXA instrument manufacturer and model should remain the 
same and their calibration should be monitored throughout the study. Use of a standardized 
scan acquisition protocol and appropriate and unchanging scan acquisition and analysis 
software is essential to achieve consistent results. Likewise, because of variability in 
interpretation of the scans, it is important to utilize centralized scan analysis by experienced 
staff.
DXA Data Collection and processing
DXA and reading will be performed according to the procedures described in the Imaging 
Manual. Prior to the examination, the patient will be checked for absence of removable metal 
objects on his/her body, such as snaps, belts, underwire bras, jewelry, and so on. The patient 
will then be positioned so that his/her body is straight on the mat and the site personnel must 
ensure that the positioning is consistent from scan to scan. A whole body array scan will then 
be initiated on the patient.
Total LBM can be predicted from whole body DXA scan and it is comprised of the protein 
and water mass that make up skin, connective tissue and muscle from the appendicular, head 
and trunk regions of interest (ROIs).  

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6.4.2
Short Physical Performance Battery
The short physical performance battery evaluates lower extremity function by measuring the 
time to rise from a chair five times, ability to maintain standing balance, and the 4-meter gait 
speed which can provide useful qualitative information on the nature of mobility limitation.  
A five-level categorical score can be created for each test, with 0 representing inability to 
complete the test and 4 representing the highest level of performance. A summary 
performance score is created by adding the individual scores, which yields a maximum of 12, 
where 10-12 denotes normal, 7-9 moderately impaired and 0-6 poor functional performance 
(Quadri et al 2005).
Details of the test administration are provided in the Study manual. The results of each test 
will be recorded on the SPPB eCRF.
6.4.3
Gait Speed
Gait speed in this study will be assessed as part of the SPPB, over a 4 meter distance of a 6 
meter course. Gait speed assesses a person’s usual walking speed, which is defined as the 
speed a person normally walks from one place to another (e.g., walking from one store to 
another). The participant will perform two recorded trials of walking across the defined course. 
The fastest time in seconds (to the nearest 0.01 sec) a participant takes to complete the 
assessment will be scored and used to calculate the total SPPB score. 
The patient should ideally complete the test without walking aids, unless he/she feels unsafe 
about completing the test without balance support (fears of fall). All types of walking aid(s) –
except for wheeled walker / rollator – can be used during the treatment period (from Day 1 to 
EOS). 
SPPB gait speed test performance will be captured in the eCRF including any potential usage 
of walking aids.
Details of the test are provided in the Study manual. 
6.4.4
Falls 
Detailed information on falls will be collected via patient interviews at each visit. The 
investigator will capture each fall and report any injuries, fractures, hospitalizations, change in 

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ambulatory status (e.g. needs for walking aids), impairment of activities of daily living or 
transfer to long term care facility. 
Patients should be instructed and reminded at each visit to call their site and report fall events 
as they occur. Sites will provide patients with a diary to be used as “aide-memoire” to help 
them remembering the date, time, place and circumstances of sustained falls. This diary will 
not be used as source document but will be used to support the patient’s interview at the time 
of the site visit.
Fall is defined as an event, which results in the person coming to rest inadvertently on the 
ground, floor, or lower level, and other than as a consequence of the following conditions: 
sustaining a violent blast, loss of consciousness, sudden onset of paralysis, or an epileptic 
seizure.
All falls will be recorded in the Adverse Event eCRF, with any associated injury recorded as a 
separate adverse event.
6.4.5
Appropriateness of efficacy assessments 
Total LBM 
 by DXA
Previous work on testosterone supplements demonstrated that clinically meaningful increases 
in total LBM 
 are prerequisites of enhancing muscle 
strength and physical performance (Sattler et al 2011). In line with this previous observation, 
preliminary data on sIBM patients receiving a single dose of bimagrumab (30 mg/kg) showed 
that drug-induced increases in LBM (plateau reached at 8-12 weeks) were followed by 
significant increases in physical performance as quantified by the 6-minute walk distance 
(6MWD) at Week 24 (Figure 6-1). Moreover, when LBM declined upon drug withdrawal and 
returned to baseline, the functional benefits also vanished. Thus, increases in LBM are 
clinically relevant reflections of the expected functional benefits. 
Figure 6-1
Sequence of LBM 
 changes to a single dose of 
bimagrumab 30 mg/kg in patients with sporadic inclusion body 
myositis (BYM338X2205 study)
Dual-energy X-ray absorptiometry provides a recommended alternative method for estimating 
skeletal muscle mass with advantages of inexpensiveness, short scan-time, much lower 

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radiation exposure to patients and more widespread availability in clinical and research 
settings as compared with the gold-standard methods, e.g. computerized tomography (CT) and 
MRI. 
Studies document that the DXA-based approach gives mean total body skeletal muscle 
estimates that agree closely with muscle measured by CT or MRI, although DXA tends to 
systematically overestimate total body skeletal muscle by about 5% (Wang et al 1996, Chen et 
al 2007). This is due to the fact that DXA may also take into account organ lean mass of the 
trunk, the skin, and non-fat components in the adipose tissue when measuring total LBM 
(Wang et al 1976). 
Furthermore, the relative inaccuracy of total LBM to estimate total skeletal muscle mass is of 
less concern in the monitoring setting, because the promyogenic drug bimagrumab has no 
known effect on parenchymal organs, skin, or the non-fat components of fat mass. In support, 
our observations in the BYM338X2102 study indicated a high degree of correlation (r=0.94) 
between the percent changes of total LBM (DXA) and percent changes of thigh muscle 
volume (MRI). 
While total LBM is the preferred choice to quantify the primary 
 effect of 
the drug and establish the dose-response relationship, the measurement 
 
 
will be of increased interest for the exploration of how drug-induced changes in 
skeletal muscle mass predict/reflect the anticipated functional benefits of the treatment.
Short Physical Performance Battery (SPPB)
The Short Physical Performance Battery (SPPB) is one of the most commonly used 
instruments for measuring physical performance in population studies of aging (Guralnik et al 
1995). The SPPB is a composite measure of mobility including standing balance, chair stand 
and gait speed. The SPPB has been shown to be highly predictive of subsequent disability, 
hospitalization, institutionalization, and mortality in community-dwelling elders in 
epidemiological studies and outpatient clinics (Guralnik et al 2000; Studenski at al 2003).  
The disability remains even after adjustment for level and severity of comorbidity and self-
report functional status. 
Recently, it has been demonstrated that the SPPB can be feasibly and safely used to evaluate 
the functional status of acutely ill geriatric patients admitted to the hospital for serious 
medical conditions and that the SPPB score can provide important short-term prognostic 
information (Volpato et al 2008). 
Beyond its strong predictive value, composite score of SPPB has also been used to monitor 
changes of physical performance over time (Kwon et al 2009) in observational studies as well 

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as in interventional trials and during strength or power training or treatment (Drey et al 2012) 
with a promyogenic agent (Adunsky et al 2012). The study by Bean et al (2010) showed for 
the first time that an increase in leg power, independent of strength, can make important 
contribution to clinically meaningful improvements in SPPB as well as gait speed. 
Best estimate of small and large meaningful changes for SPPB are 0.5 point and 1.0 point, 
respectively (Kwon et al 2009, Perera 2006).
Gait Speed
While gait speed is imbedded in the full performance battery as a score between 0 and 4, it 
has also been subject of considerable research as a stand-alone continuous measure of 
physical performance / mobility. In fact, most studies have found that gait speed is the 
strongest predictor of health-related adverse events compared with the two other SPPB 
components (chair rise and balance tests), or it has performed almost as well as the full battery 
in predicting disability (Cesari et al 2009, Guralnik et al 2000).  Gait speed alone has been 
associated with physical activity levels, changes in the isometric force of lower extremity 
muscles, frailty and falls ( Newman et al 2003, Chandler et al 1998, Cesari et al 2005).  
Gait speed is not only a well-established measure of physical function but it may also predict 
future disability in diverse community-dwelling elderly populations and is sensitive to reflect 
changes in physical status in response to changes in physical activity, including short-term 
rehabilitation (Barthuly et al 2012). Poor functional performance as measured by slow or 
declining gait speed is related to risk of disability, hospitalization and mortality (Studenski et 
al 2011), whereas improvements in gait speed are related to reductions in mortality risk 
(Hardy et al 2007).  For these reasons, gait speed has often been quoted as a global indicator 
of health in the geriatric population.
Falls 
Hip fracture patients experience a substantial reduction of mobility following fracture, with 
most (40-60%) patients discharged from the hospital after a hip fracture also experience 
another fall within the first year, mainly in the first 6 months (Bischoff-Ferrari et al 2010). A 
fall event can trigger fear of falls, restricted mobility, worsening of frailty and in extreme 
cases complete social isolation. Falls, however also account for 25% of hospitalizations and 
40% of all nursing-home admissions. Given the continuing presence of fragility, falls often 
cause injuries, including recurrent fractures. Non-injurious falls may also be the source of 
morbidities/hospitalizations. Nearly half of non-injured frail fallers are not be able to stand up 
from the ground without assistance. This inability may lead to a period of immobility on the 
floor, which may lead to various adverse health outcomes depending on the time spent 
immobile. Treatment with bimagrumab in the period after fracture is likely to accelerate 
muscle volume gain, and may improve strength and mobility, which is likely to result in 
improved physical function and potentially a reduction in mobility-related adverse events.
6.5
Safety
All blood draws and safety assessments must be done prior to investigational treatment 
administration. Appropriate safety assessments (e.g., evaluation of AEs and SAEs including 
any immediate infusion reactions) must be repeated after the dose is administered.
Safety assessments in this study will include:

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
Evaluation of all AEs and SAEs including infusion site and hypersensitivity reactions

Physical examination

Vital signs, height and weight

Laboratory evaluations

Electrocardiogram (ECG)

Echocardiogram, for patients enrolled prior to study protocol amendment #3 

X-ray assessment of surgical complications (if applicable) and hip fracture healing
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin 
(including paying special attention to telangiectasias of the skin or nail-folds), head and neck 
(including thyroid and oral mucosa for evidence of bleeding, hypertrophy, ulceration, or other 
changes from baseline), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, neurological, and musculoskeletal system, at timepoints indicated in 
Table 6-1. Rectal, external genitalia, breast, and pelvic exams will be performed only if 
indicated based on medical history and/or symptoms.
Additional orthopedic examination, as per the standard of care, will be performed at the 
discretion of the investigator.
If possible, assessments for an individual patient should be performed by the same member of 
the study site staff throughout the study.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to signing informed consent must be 
included in the Medical History part of the eCRF. Significant findings made after signing the 
informed consent which meet the definition of an Adverse Event must be recorded on the 
Adverse Event section of the eCRF.
6.5.2
Vital signs
Vital signs, blood pressure and pulse measurements will be assessed at every scheduled visit 
as indicated in Table 6-1. 
After the patient has been sitting for five minutes, with back supported and both feet placed 
on the floor, systolic and diastolic blood pressure will be measured three times using an 
appropriate validated device, with a correct sized cuff. The repeat sitting measurements will 
be made at 1 - 2 minute intervals and the mean of the three measurements will be used (Mean 
systolic/diastolic value is used for eligibility).
If possible, assessments should be performed by the same study site staff member throughout 
the study.
Clinically notable vital sign measurements are listed in Appendix 1.

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6.5.3
Height and weight
Height in centimeters (cm) will be measured at baseline and body weight (to the nearest 0.1 
kilogram [kg] in indoor clothing, but without shoes) at each visit. 
In addition, BMI will be calculated according to the formula: 
BMI = Body weight (kg) / [Height (m)]2 
If capturing a body weight decrease from baseline (Day 1) of 5% or more at any visit during 
the study, please refer to Section 6.5.8 for further actions to be taken to ensure patient’s safety. 
6.5.4
Laboratory evaluations
Bone marker results are influenced by the patients’ fasting status. Therefore, it is important to 
ensure that blood samples for bone marker assessments are collected after 8 hour of fasting 
(D1, W12, W24 (EoT)). This fasting status is preferable for the other blood samples as well, 
but this is not a requirement.
A central laboratory will be used for analysis of all specimens collected 
 
 
 Details on the collections, shipment of samples and 
reporting of results by the central laboratory are provided to investigators in the Laboratory 
manual. Reference to the Laboratory Manual should be made for identification of laboratory 
reference range values and the schema for notification of site staff and Novartis for out of 
range values.
Key laboratory test values that are clinically notable are defined in Appendix 1.
All abnormal values will be assessed by the investigator who will decide what action needs to 
be taken, taking into account the overall status of the patient.
In the case where a laboratory assessment listed in the inclusion/exclusion criteria is outside 
of a protocol-specified range at screening, the assessment may be repeated once for the 
purpose of inclusion. The repeated result must be within protocol-specified range prior to 
randomizing the patient. Investigators will have the discretion to record abnormal test findings 
on the medical history eCRF, whenever in their judgment, the test abnormality occurred prior 
to the informed consent signature.  
6.5.4.1
Hematology and serology
Hematology assessments listed in Table 6-2 will be measured at each scheduled visits as 
specified in Table 6-1.
Serology assessment (Table 6-2) will be done at screening only. 
Table 6-2
Hematology and serology tests
Hemoglobin
Hematocrit
Red blood cell (RBC) count
Reticulocyte count
White blood cell (WBC) count with differential
Mean corpuscular volume
HIV Ab (screening only)
Mean corpuscular hemoglobin concentration
HbsAg (screening only)
Platelet count

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HCV Ab (screening only)
6.5.4.2
Clinical chemistry, 
 and muscle 
integrity markers
Clinical chemistry, 
 and muscle integrity marker 
assessments listed in Table 6-3 will be conducted at the scheduled visits specified in this same 
Table 6-3. 
 
Table 6-3
Clinical chemistry tests, 
 and 
muscle integrity markers
Clinical chemistry parameters measured at Screening, W4, W8, W12, W24 (EoT) and W48 
(EoS)
Blood urea nitrogen (BUN)
Troponin I
Creatinine
Creatine kinase –MM
Calculated creatinine clearance
Creatine kinase –MB
Total bilirubin
Myoglobin
Aspartate aminotransferase (AST/SGOT)
Aldolase
Alanine aminotransferase (ALT/SGPT)
Fasting glucose
Gamma-glutamyltransferase (GGT/γGT)
HbA1c
Alkaline phosphatase
Cholesterol (total and HDL)
Total protein
Triglycerides
Albumin 
Pre-albumin
Vitamin 25-hydroxy D
High sensitivity C-reactive protein (hsCRP)
Haptoglobin (if total bilirubin > 2ULN)
Amylase
Lipase
Electrolytes (sodium, potassium, chloride, 
calcium, phosphorous, magnesium)
Uric acid
Activin A
estimated Glomerular Filtration Rate
Hormonal parameters measured at Screening, W12, W24 (EoT) and W48 (EoS)
Sex hormone binding globulin (SHBG)
Luteinizing hormone (LH)
Estradiol
Follicle stimulating hormone (FSH)
Testosterone
Free thyroxine
Thyroid stimulating hormone (TSH)
6.5.4.3
Urinalysis
Urinalysis assessments listed in Table 6-4 will be conducted at each scheduled visit as 
specified in Table 6-1.

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Table 6-4
Urinalysis tests
Specific gravity
Bilirubin
Protein
Ketones
Glucose
White blood cells (WBC)
pH
Blood
6.5.5
Electrocardiogram (ECG)
ECGs must be recorded after approximately 10 minutes rest in the supine position to ensure a 
stable baseline. The preferred sequence of cardiovascular data collection during study visits is 
ECG collection first, followed by vital signs. The Fridericia QT correction formula (QTcF) 
will be used for clinical decisions.
A standard 12-lead electrocardiogram will be performed in triplicate (3 tracings of at least 10 
sec duration to be obtained within a 2-5 min window) at visits indicated in Table 6-1. All 
ECGs must be performed on the ECG machines provided to the study site by an assigned 
vendor. 
Patient management will be performed on the basis of the local assessment of the ECG by the 
investigator.  Interpretation of the tracing must be made by a qualified physician that must 
also sign the tracing and review the findings. The study code, patient number, patient 
initials, the date and actual time of the tracing must appear on each page of the tracing.
Original ECG tracings, appropriately signed, will be archived at the study site as source.
The tracings will be transmitted to a central reading vendor for independent review.  
Instructions for the collection and transmission of the ECGs to the independent reviewer are 
provided in the ECG manual.
Screening
The central reading results at screening will determine the eligibility of the patient for the trial. 
If two (or all three) of the three ECGs are outside the allowed limit of QTcF ≥500 msec, the 
patient must not be randomized. Patients having a ventricular pacemaker or showing the 
presence of a left or right bundle branch block a QTcF ≥500 msec is not exclusionary. Patient 
can be enrolled if endorsed by the patient’s physician. 
If a clinically relevant abnormality noted on the screening ECG is one of the pre-specified 
terms listed on the Cardiovascular eCRF, that abnormality should be recorded on the 
Cardiovascular  eCRF. All other clinically significant abnormalities should be recorded on the 
Medical History eCRF.
Triplicate central ECGs may be repeated once at an unscheduled visit during the screening 
epoch to confirm patient eligibility prior to randomization. The repeated result must be within 
protocol-specified range prior to randomizing the patient.
Randomization (Baseline/Day 1)
Any clinically significant abnormalities noted after screening visit ECG, should be reported 
as adverse events on AEs CRF page.
The tracings must be locally reviewed for major abnormalities before randomizing the 
patient and before every dose administration. If the ECG findings are clinically relevant 

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and would prevent the patient from participating in the study, the patient should not receive 
the investigational treatment.
6.5.6
Echocardiography
Two-dimensional echocardiography monitoring will be performed on all patients enrolled 
prior Amendment #3. as per Table 6-1. The images will be transmitted to a central reading 
vendor for independent review. Sites will receive appropriate training as needed as well as the 
Imaging manual that includes detailed instructions and data transfer procedures.
Central assessments
Aligned with recommendations of the American Society of Echocardiography concerning the 
use of echocardiography in clinical trials (Gottdiener et al 2004),  the following standard 
parameters - pertinent to the assessment of changes in cardiac muscle mass and/or contractile 
function - will be monitored during the study:

Left ventricular wall (posterior) and septal thickness

Left ventricular mass and mass index

Left ventricular end-diastolic volume

Left ventricular end-systolic volume

Left ventricular ejection fraction

Left ventricular diastolic and systolic diameter

Left atrial size and volume

Right ventricular wall thickness and dimension
If echocardiography indicates clinically meaningful abnormalities of cardiac mass or 
contractile function, patients will be followed up at W48 (at the end of the off-drug post-
treatment period).
6.5.7
X-ray assessment of surgical procedure
A historical X-ray done by local practice during or after surgery (in some cases prior to the 
initiation of screening) will be used by the investigator for eligibility assessment. The 
summary of the local assessment will be recorded in the Perioperative eCRF and must 
confirm adequate surgical execution of internal fixation or arthroplasty for fracture repair. 
Images do not need to be submitted to the central reader vendor. 
During the trial, an X-ray of the operated hip will be taken at Week 24 (EoT) visit - as 
indicated in Table 6-1- to assess whether fracture healing has been completed (bone union) 
and whether there are any potential late complications of the surgery. If bone-union is not 
achieved at Week 24, patient will be followed up at Week 36 and also potentially at Week 48 
(EoS), if bone union is still not achieved at Week 36. Additional unscheduled X-rays may also 
be required if there is any clinical suspicion of delayed/improper fracture healing. Any 
findings on X-ray need to be reported as adverse events. Specifically, bone non-union seen at 
Week 36 (delayed fracture healing) needs to be reported as an SAE.
All scheduled and unscheduled X-rays performed after enrollment will be transferred to a 
central reader (details provided in Imaging Manual). Two independent readers of the assigned 

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vendor will perform a blinded assessment of the images for bone union and a number of pre-
specified orthopedic complications. In case of discordant medical opinions regarding the 
presence or absence of these complications, a third reader will settle a final decision. The 
central reader may request sites to provide additional X-rays, if available, to support overall 
assessment of the specific finding.
6.5.8
Dietary Assessment
The investigator should ensure that patients are consuming adequate protein amount and must 
determine whether the patient is malnourished as it may affect his/her muscle recovery. 
 
If body weight 
decrease by 5% or more and/or the laboratory results are outside of the respective normal 
ranges, the investigator should evaluate the patient overall condition, refer the patient to a 
nutritionist or other health care provider for further evaluation and consideration of dietary 
supplements as per local standard of care. 
6.5.9
Pregnancy and assessments of fertility
Not applicable as only post-menopausal women will be included. 
As per definition: women are considered post-menopausal and not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential. 

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6.5.12
Appropriateness of safety measurements
The safety measures used in this study, as detailed in Table 6-1, are reliable and relevant 
standard safety measures.
In line with the direct skeletal muscle effects of the drug, tolerability will be monitored 
closely using chemical/
 measures of muscle damage including changes of serum 
levels of creatine kinase MM, myoglobin, aldolase, ALT, AST and potassium. Interpretation 
of any changes in these biomarkers will take into account simultaneous presence or absence of 
clinical symptoms such as spontaneous muscle contractions and related pain.
In preclinical studies on rats or monkeys reversible hypertrophic changes of the heart have 
been described, but these changes are considered compensatory in response to the marked 
changes in muscle mass and hence body mass (up to 30%). Alteration of myostatin expression 
has not been associated with alteration of cardiac systolic function in mice overexpressing or 
lacking the active protein. Nevertheless the effects of bimagrumab in the pathologic heart are 
yet to be understood. For this reason, patients with severe cardiac conditions (see respective 
exclusion criteria) need to be excluded from the trial. 
Echocardiography has been used in studies on healthy volunteers and patients to monitor 
changes in cardiac structure and contractile function in response to the preclinical findings of 
a compensatory hypertrophy mentioned above. The current cardiac safety profile reflects the 
absence of any finding in any clinical study (approximately 900 adults received bimagrumab 
since September 2017) and the recent results from a dedicated cardiac safety study 
(CBYM338X2109). Using multiple technologies including cardiac magnetic resonance 
imaging (CMR) and Holter monitoring, there was no effect of 6-month exposure to 10 mg/kg 
(equivalent to 700 mg in this study) i.v. bimagrumab on left ventricular ejection fraction, 
cardiac mass, QTc, blood pressure or heart rate. Based on this safety profile, regular 
echocardiography is no longer required for studies in the bimagrumab clinical development 
program. These changes in cardiac safety monitoring were approved by the independent data 
monitoring committee (DMC) and internal Novartis safety and scientific review committees.

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Two preclinical studies in rats undergoing osteotomy of the fibula indicate that repeated 
administration of high doses of bimagrumab (up to 100 mg/kg) may be associated with slight 
decreases in immature callus size and bone mineral content in skeletally immature (young) 
animals 4 weeks after surgery, but not in skeletally matured (old) animals. In addition, there 
were no differences in the size of the mature callus, the radiographic progression of fracture 
healing, the morphology and biomechanical competency of the fibula when comparing 
vehicle and bimagrumab treated animals. It is well known in the literature that animal findings 
do not necessarily translate into clinical findings (Geusens P et al Rheumatol 2013). 
However, given the first-time testing of bimagrumab in patients undergoing major surgery 
after a hip fracture, the study will monitor the region of interest with X-ray taken at Week 24. 
Two independent radiologists (central readers) will assess these images and to confirm 
completed fracture healing (i.e. bone union) and exclude a number of postoperative 
orthopedic complications.  If bone-union is not achieved at W24, additional X-rays are to be 
collected at W36, and if needed at W48. Data will be regularly reviewed by an external DMC 
that is empowered to alert the clinical study team in case of any unexpected safety finding (i.e. 
trend for delayed fracture healing or increased rate of orthopedic complications).
Fracture healing as well as osseointegration of non-cemented implants, are both critically 
dependent on intact bone formation and bone resorption. 
 
 
 
 
 
Although asymptomatic, in order to properly evaluate the increase in lipase or amylase 
observed in some bimagrumab treated patient and rule out any potential case of pancreatitis, 
additional monitoring procedure commonly used for pancreatitis diagnostic are included (i.e. 
laboratory works, clinical presentation and imaging).

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7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.

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All adverse events occurring after informed consent is signed and until the last study visit 
will be recorded on the Adverse Event CRF for all patients who enter the treatment epoch.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Clinically notable labs and other test abnormalities are 
included in Appendix 1.
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information.

the severity grade 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the investigational treatment (no/yes)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.

whether it constitutes a serious adverse event (SAE)

action taken regarding investigational treatment

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown).
All adverse events should be treated appropriately.  Treatment may include one or more of the 
following: 

no action taken (i.e. further observation only) 

investigational treatment temporarily interrupted

investigation treatment permanently discontinue due to this adverse event

concomitant medication given

non-drug therapy given

patient hospitalized/patient’s hospitalization prolonged. 

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The action taken to treat the adverse event should be recorded on the CRF. 
In this study, investigators will be asked to provide additional details on selected adverse 
event of special interests such as but not limited to events of spontaneous muscle contraction 
potentially associated pain or events that may require adjudication (see Section 8.5).
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the subject informed 
consent and should be discussed with the subject during the study as needed.
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.

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Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline).
All malignant neoplasms and delayed fracture healing (i.e. bone non-union seen at X-ray at 
W36 or later) will be assessed as serious under “medically significant” if other seriousness 
criteria are not met. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF. SAEs are monitored continuously 
and also require individual reporting requirements to DS&E as per Section 7.2.2.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the End of Study visit must be reported to 
Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after the 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. 
An SAE that is considered completely unrelated to a previously reported one should be 
reported separately as a new event.  
SAEs reported until Week 48 End of Study visit or early discontinuation will be captured in 
both clinical and safety databases.  SAEs reported after this time-point will only be captured 
in the compounds safety database. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form or the electronic Serious Adverse 
Event Form within the Oracle Clinical/Remote Data Capture (OC/RDC) system (where 
available). The Investigator must assess the relationship to each specific component of the 
study treatment (if the study treatment consists of several components). 
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hours of awareness of the SAE to the local Novartis Drug Safety and Epidemiology 
Department.  The telephone and fax number of the contact persons in the local department of 
Drug Safety and Epidemiology, specific to the site, are listed in the investigator folder 

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provided to each site.  The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. Follow-up 
information should be provided using a new paper SAE Report Form stating that this is a 
follow-up to a previously reported SAE.  
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an 
existing SAE. These data will automatically be submitted to Novartis Drug Safety & 
Epidemiology immediately after investigator signature or 24 hours after entry, whichever 
occurs first. 
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected, exempting the 
SUSARs in Table 7-1 below, and will be reported to the competent authorities and relevant 
ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.  .
Table 7-1
SUSARs exempt from expedited reporting
SUSAR
Definition
Reason
Falls (including 
injurious)
A sudden and unexpected loss of 
balance resulting in an event in 
which the participant comes to rest 
on the ground, floor, or lower level.
Pre-specified endpoint 
and common procedural 
complication after hip 
fracture surgery.
Implant-related 
Implant 
loosening/migration 
and potential late 
mal-alignment of the 
joint
Implant loosening is a change in the 
position of the implant or a 
progressive radiolucent line at the 
bone-cement transition visualized by 
radiography. 
Symptomatic mal-alignment 
including significant leg shortening 
resulting in functional deficit
One of the most 
common procedural 
complication after hip 
fracture surgery.
Implant-related 
event
Implant fracture
Fracture of one part of the implant, 
e.g. stem, plate or screws
Rare but acknowledged 
procedural complication 
after hip fracture 
surgery.
Bone-related 
event
Periprosthetic fracture
Near-implant fracture on femoral or 
acetabular site
Relatively rare but 
severe procedural 
complication after hip 
fracture surgery.
Bone-related 
Avascular necrosis of 
Cellular death (necrosis) of bone 
Rare but acknowledged 

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SUSAR
Definition
Reason
event
head / trochanter 
major
components in the femoral head due 
to interruption of the blood supply, 
especially after medial fractures
procedural complication 
after hip fracture fixation
Bone-related 
event
Osteolysis
Biologic reaction of the bone to wear 
particles resulting in expansile lytic 
lesion adjacent to one of the 
implants (>1 cm in any one 
dimension or increasing in 
radiographs).
Relatively common 
(long-term) procedural 
complication after THA
Bone-related 
event
Hip dislocation
Dislocation of the ball of the femoral 
component from the acetabular cup 
during the healing of bone (needs to 
be radiologically confirmed), which 
requires closed or open reduction
Rare (early) but 
acknowledged 
procedural complication 
after THA
Soft-tissue related
Heterotopic 
ossification
The development of bone outside its 
normal location in the skeleton (e.g. 
para-articular soft tissue) and 
causing pain and restriction of hip 
motion
Relatively common 
procedural complication 
following a severe hip 
fracture. May cause 
functional impairment, if 
extensive
Soft-tissue related
Neural deficit
Postoperative nerve palsy (sciatic, 
femoral or obturator nerves) related 
to the index surgery (cut, stretch, 
cauterization), which may cause 
muscle weakness, limited 
ambulation, and persistent 
dysesthesia
Rare but acknowledged 
procedural complication 
after THA 
Procedure related
Bleeding
Bleeding during the course of 
healing (most often associated with 
anticoagulant therapy) requiring 
surgical treatment
Relatively common 
procedural complication 
after hip fracture 
surgery.
Procedure related
Deep infections 
(including deep 
wound & 
periprosthetic 
infections)
There is a sinus tract communicating 
with the prosthesis, or
A pathogen is isolated by culture 
from at least 2 separate tissue or 
fluid samples obtained from the 
affected prosthetic joint; or
4 of 6 independent infection criteria: 
elevated ESR or CRP concentration
elevated synovial WBC
elevated synovial neutrophil %
presence of purulence in the joint
isolation of the microorganism in 1 
culture of periprosthetic fluid or 
tissue
Greater than 5 neutrophils per high 
power field in 5 high power fields 
observed from histological analysis 
of periprosthetic tissue at 400 x 
magnification
Rare but acknowledged 
procedural complication 
after hip fracture surgery

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7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events will be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study:

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard liver CRF page
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the LFT within the next week to confirm elevation.
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient.  Repeat laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event, which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion.  All follow-up information, and 
the procedures performed should be recorded on appropriate eCRF pages, including the liver 
event overview eCRF pages.
7.4
Lipase and amylase elevations
To ensure patient safety and enhance the reliability in determining the potential for pancreatic 
events with bimagrumab, a standardized process for identification, monitoring and evaluation 
of pancreatic events has to be followed (Table 7-2).

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Table 7-2
Safety monitoring guidance for amylase and lipase elevations
Event
Follow up monitoring
Lipase and/or amylase < 3x ULN

If asymptomatic, follow up at discretion of investigator. 

If clinical symptoms (e.g., abdominal pain, nausea, 
diarrhea) suggest pancreatic involvement, re-check 
enzymes (amylase, lipase) and inflammatory markers 
(C-reactive protein) and consider pancreatic imaging 
(i.e., abdominal ultrasound or CT or MRI) to evaluate 
for presence of pancreatitis.
Lipase and/or amylase ≥ 3x ULN

Re-check enzymes (amylase, lipase) and inflammatory 
markers (C-reactive protein) independent of presence 
of clinical symptoms.

Assess subject for clinical symptoms.

Conduct pancreatic imaging (i.e. abdominal ultrasound 
or CT or MRI) to evaluate for presence of pancreatitis.

Study drug interruption based on findings of additional 
assessments and at discretion of investigator.
As defined in Section 7.1, medically significant events which are considered as serious 
adverse events (SAEs) should follow the standard procedures for SAE reporting as described 
in Section 7.2. Every pancreatic event reported as an SAE should include a causality 
assessment of the event via exclusion of alternative causes (e.g., gallstones, co-medication).
An investigation of the pancreas needs to be followed up until resolution. A gastroenterology 
consult can be included at the investigator’s discretion. All follow-up information, and the 
procedures performed, should be recorded in the appropriate CRFs.
7.5
Pregnancy reporting
Not applicable in this study where only post-menopausal women will be enrolled.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that investigational treatment is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).

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The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan.  No information in source documents about the identity of the 
patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained. 
Automatic validation procedures within the system check for data discrepancies during and
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3
Database management and quality control
Novartis staff or CRO working on behalf of Novartis will review the data entered into the 
CRFs by investigational staff for completeness and accuracy and instruct the site personnel to 
make any required corrections or additions. Queries are sent to the investigational site using 
an electronic data query. Designated investigator site staff is required to respond to the query 
and confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings, all imaging (echocardiography, DXA and X-ray) will be processed centrally 
and the results will be sent electronically to Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis.

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The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
At the time of the primary analysis, which will occur when all patients will have completed 
the double-blind treatment epoch (Week 24 visit), similar actions will be completed and the 
treatment codes will be made available to the Novartis global study team for data analysis..
8.4
Data Monitoring Committee
An independent, program-wide DMC is instituted for bimagrumab with focus on safety. 
The DMC will periodically review the safety information throughout the study to monitor the 
trial’s progress for unexpectedly large differences in the incidence of AE/SAE between 
treatment groups. 
The DMC for the study will be composed of individuals with experience and expertise in the 
management of patients with muscle wasting diseases and in the monitoring of randomized 
clinical trials as well as a DMC statistician. None of the DMC members will be involved in 
the operational conduct of the study or any other bimagrumab clinical or pre-clinical study, 
except as a member of the DMC.
The mission of the DMC will be to independently review and evaluate the unblinded safety 
data generated during the study as defined in this protocol. The DMC must also ensure that 
study participants are not exposed to unnecessary or unreasonable risks and that the study is 
conducted with high scientific and ethical standards. Finally, the DMC must make 
recommendations to the Sponsor on the actions to be taken on the study, which may include 
the following:

Discontinuation of the study.

Suggested modifications to the study protocol and/or the informed consent document.

Continuation of the study according to the protocol and the relevant amendments.
The DMC is accountable to the Sponsor for appropriate monitoring of the study data.
Although the DMC may make recommendations to the Sponsor about changes in the conduct 
of the study, final decisions will be made by Novartis. In the case of early termination, 
consultation with Health Authorities may be required.
Members of the DMC will not share any unblinded information with anyone outside of the 
DMC. Particularly, the Sponsor will remain fully blinded to any results throughout the study 
unless the DMC recommends changes in the conduct of the study (for example, early 
termination due to negative safety findings). 
An independent statistical reporting team not involved in the conduct of the studies will 
prepare the information for the DMC according to the specifications from the DMC 
statistician. The main tasks may include:

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
Generation of unblinded outputs for the DMC  including tables, figures, and listings, as 
required.

Preparation of any other reports requested by the DMC during the closed session.

Review of the unblinded reports before sending to the DMC. 
The frequency of the DMC meetings will be determined by the members and ratified in the 
DMC Charter.
8.5
Adjudication Committee
An independent cardiovascular adjudication committee will be used to re-evaluate and 
confirm the investigator-reported diagnostic term of specific safety events (e.g. ischemic heart 
disease, heart failure, cardiomyopathy, or cardiac arrhythmias). Events will be reviewed 
blindly as they occur during the trial. Details regarding the adjudication process will be 
available in the relevant  Adjudication Committee charter. The committee may provide expert 
reports at the end of the study. 
The clinical database will be regularly searched by the clinical team for targeted adverse 
events including but potentially not limited to cardiac safety events. When an adverse event in 
these categories is identified, a follow-up form will be sent to the clinical site to document the 
adverse event in detail and to request the submission of any applicable supplemental data, 
which may be available, including copies of source documents. Source documents include, 
but are not limited to, relevant clinical notes, radiographs, ECGs, ultra-sonograms, operative 
and pathology reports, hospital discharge summaries. In addition, an interview with the 
patient conducted by the site (in person or via telephone) may be needed to fully clarify the 
circumstances of the event. 
The outcome of the adjudication or the expert review will be captured in the clinical data base.
9
Data analysis
The primary analysis for this study will be conducted when all patients have completed the 
(double-blind) treatment epoch (Week 24 visit). All post-treatment follow-up data on efficacy 
endpoints (SPPB and gait speed) available at the time of the primary analysis will also be 
summarized to address the durability of functional benefits during the off-drug follow-up 
period. The final statistical analysis will be performed when all patients have completed Week 
48 of the study.
All details regarding the statistical analysis will be documented in the statistical analysis plan 
which will be finalized prior to the data extraction for the primary analysis (Week 24) at 
interim database lock and the global study team group level unblinding.
9.1
Treatments
Study medication and concomitant medication will be analyzed with the safety analysis set.

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9.1.1
Study medication
The number and percentage of patients who prematurely discontinued study medication will 
be summarized by reason for discontinuation.
Duration (days) of study medication administration will be summarized. For each patient, the 
number of days of drug exposure = last infusion date – first infusion date + 56 based on the 
infusion schedule for the study (intravenously every 4 weeks).
9.1.2
Concomitant medications
The number and percentage of patients using prior or concomitant medications will be 
summarized by Anatomical Therapeutic Classification (ATC) codes and treatment group, and 
grouped by anatomical main group (the 1st level of the ATC codes).
Prior medications are defined as drugs taken and stopped prior to first dose of investigational 
treatment.  Any medication given at least once between the day of first dose of investigational 
treatment and the date of the last study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the treatment period. Prior or concomitant 
medication will be identified based on recorded or imputed start and end dates of medication 
taking. If it cannot be established that the use of a prior medication has ended prior to the first 
dose of investigational treatment due to a missing end date, then it will be considered 
concomitant.
9.2
Analysis sets
The Full Analysis Set (FAS) used for all efficacy analyses will consist of all randomized 
patients who received at least one dose of investigational treatment. Patients will be analyzed 
according to the treatment they were assigned to at randomization. Patients who entered the 
study before Amendment 2 will be pooled with fixed-dose patients as follow: bimagrumab 3 
mg/kg patients will be analyzed as member of the 210 mg group, bimagrumab 10 mg/kg 
patients will be analyzed as member of the 700 mg dose group. 
The safety (SAF) Analysis Set will consist of all patients who received at least one dose of 
study medication. Patients will be analyzed according to the treatment received. Patients who 
entered the study before Amendment 2 will be pooled with fixed-dose patients as detailed for 
the FAS.
Per-protocol (PP) Analysis Set will include all FAS patients who complete the study without 
major deviations from the protocol procedures. Major protocol deviations and the definition 
of the PP set will be identified and finalized based on blinded review of the data, prior to the 
data extraction for the primary analysis (EoT) and the global study team group level 
unblinding.
For patients who entered the study before Amendment 2 and have been treated for more than 
6 months, data collected after the Week 24 visit will be listed.
9.3
Patient demographics and other baseline characteristics 
All data for background and demographic variables will be listed by treatment and patient and 
summarized by treatment. Patient demographics will include age, sex, race, ethnicity, height, 

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weight and BMI.  Other baseline disease characteristics include medical history, falls history, 
orthopedic history, perioperative assessment, blood transfusion history, tobacco history, 
cardiovascular risk factors, gait speed, LBM,
 and SPPB.
Summary statistics will be presented for the patients in the FAS. Continuous variables will be 
presented with mean, median, 25th percentile, 75th percentile, standard deviation, minimum 
and maximum, and the number of non-missing observations.
Categorical data will be displayed via absolute and relative frequencies for each category 
(including a category labeled as ‘missing’ when appropriate).
9.4
Analysis of the primary variable
The primary analysis set for efficacy will be FAS.
9.4.1
Variable
The primary variable is change from baseline in Total LBM at Week 24. 
9.4.2
Statistical model, hypothesis, and method of analysis
The aim of the study is to show that at least one bimagrumab treatment arm will increase 
Total LBM (change from baseline) compared with placebo at Week 24 by rejecting the null 
hypothesis described below at significance level α=0.05 level (two-sided):
H0: µT = µP vs. H1: µT ≠ µP
where µT and µP are mean change from baseline of Total LBM at Week 24 for the 
bimagrumab dose group of interest (700mg or 210mg only) and placebo. 
A mixed model will be used with change from baseline at all post-baseline visits (Week 12, 
and Week 24) as response variable, and treatment, visit, randomization strata as defined in 
Section 5.3
and baseline LBM measurement as covariate. Two interaction terms 
(treatment*visit and baseline LBM*visit) will also be included in the model.  An unstructured 
within subject correlation structure will be used for covariance matrix. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. REML 
(residual/restricted maximum likelihood) method will be used to estimate parameters.
The two-sided p-value for the least square mean (LSM) difference between the bimagrumab 
and the placebo groups at Week 24 (and at Week 12) will be reported for the difference. For 
the primary endpoint, the Holm-Bonferroni method will be used to adjust for type I error 
among the 2 comparisons at Week 24. No control for multiplicity will be made at Week 12. 
Total LBM data will be transformed with natural logarithm before this analysis. 
9.4.3
Handling of missing values/censoring/discontinuations
The above analysis will be performed using all available data under the assumption that the 
probability of missing values of total LBM is independent of unobserved measurements 
(missing at random). Therefore the missing values will not be imputed for primary analysis.
The following sensitivity analysis will be performed to check the robustness of the primary 
analysis results. 

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
Fit the analysis model only to the completed cases (patients without missing LBM)

Missing value imputation:
For this sensitivity analysis, we assume a “missing not at random” (MNAR) process meaning 
that missingness depends on the unobserved data. Suppose that patients in the bimagrumab 
arms who discontinue due to adverse events (AE), death (D) or unsatisfactory therapeutic 
effect (UTE) behave like placebo arm patients after study discontinuation. This assumption 
implies that the drug effect diminishes once bimagrumab arm patients discontinue from the 
study. To perform this analysis, a Bayesian multivariate normal imputation model using non-
informative priors is fitted to the repeated total LBM measurements at baseline and Weeks 12, 
and 24 for all placebo patients. Based on this model, the conditional distribution of missing 
data given the observed data can be used to create multiple imputations for the missing values 
of patients in the bimagrumab arms who discontinue due to AE, D, UTE.
Missing data for all other subjects will be imputed under a MAR assumption, that is missing 
data are imputed based on the treatment-specific information for the repeated total LBM 
measurements at baseline and Weeks 12 and 24.  
For each imputed and thus completed data set, the primary analysis model is then fitted as 
specified in Section 9.4.2. The resulting sets of parameter estimates and associated covariance 
matrices are then combined to derive overall estimates, confidence intervals that adequately 
reflect missing data uncertainty as well as associated p-values using Rubin’s rules (Little RJA 
and Rubin DB 2002).  
The results from all analyses will be discussed with reference to the plausibility of their 
respective underlying assumptions.
9.4.4
Supportive analyses 
As supportive analysis, the primary analyses will be repeated using the PP analysis set.
In addition, dose response modeling will be performed using the MCP-Mod approach, which 
considers the following models:
1. Three parameter Emax: () = 	
 + 	 (	
 + )
⁄
2. Sigmoidal Emax with h=2: () = 	
 + 	 	
 + 

3. Exponential: () = 	
 + 	exp( 
⁄ ) −1
4. Linear: () = 	
 +  ∗
Where  d is the dose level, ED50 the dose that gives 50 percent of the maximum effect,  h the 
hill coefficient; δ and   β the rate of change for the exponential and linear models respectively, 
E0 the basal effect at d=0 and E1 the scale parameter in the exponential model.
In the MCP-Mod approach, all statistically significant models listed above will be averaged in 
order to estimate the median dose for a given targeted response via inverse prediction along 
with corresponding 95% intervals using a bootstrap re-sampling method.  
Since the design of this study is limited to having only 3 active doses, another dose response 
sigmoidal Emax model will also be considered which allows for estimation of the Hill 
coefficient (h). In this model, the fixed dose of 70 mg, 210 mg, and 700 mg from each patient 
will be normalized by their baseline weight in kg (i.e., the fixed dose will be divided the 

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baseline weight) to form a mg/kg dose regressor. The specific model to be applied to the 
mg/kg regressor will be the non-standardized sigmoidal Emax model. The mean dose 
response and corresponding asymptotic 95% confidence intervals (i.e., fiducial intervals) will 
be provided using the inverse prediction approach again.  
The non-standardized sigmoidal Emax model is parameterized as follows:
() = 	
 + 	 	
 + 

In choosing which dose response model to select for estimating dose as well as characterizing 
the entire response profile, the MCP-Mod approach is the default under the rule of parsimony, 
provided it fits the data well and results in intervals for estimating dose that are smaller than 
the 4 parameter Emax model.
To evaluate the homogeneity of the estimates within subgroups, forest plots displaying 
treatment group differences (or ratios) and corresponding 95% confidence intervals by 
subgroup, together with the relative position of the overall treatment effect, will be produced. 
In the statistical models, a treatment by subgroup interaction term will be added to allow for 
the analysis of the treatment effect within a subgroup. Subgroup analyses will include for 
example analyses of patients enrolled under original protocol versus those enrolled under 
protocol amendment 2.
9.5
Analysis of secondary
 variables
9.5.1
Efficacy variables
9.5.1.1
Gait speed and Short Physical Performance Battery (SPPB)
The change from baseline at Week 24 and Week 48 in gait speed and in SPPB will be 
analyzed similar to the primary variable. A log transformation may be used if warranted. An 
unstructured within subject correlation structure will be used for the covariance matrix.
In addition, dose response modeling will be performed for both gait speed and SPPB using the 
MCP-Mod approach.
The following testing strategy will be used to control for multiplicity of endpoints and doses 
to be tested: if both doses (210 and 700 mg) are statistically significantly different from 
placebo at =0.05 two-sided for the primary endpoint, then a fixed sequence approach will be 
applied for both Gait Speed and Short Physical Performance Battery (SPPB) at week 24 using 
the same linear mixed model for repeated measures and =0.05 two-sided at each stage. The 
first inference will compare the 700 mg group to placebo for Gait Speed, followed by a 
second inference comparing the 210 mg group to placebo for Gait Speed. The third inference 
will compare the 700 mg group to placebo for SPPB, followed by a fourth inference 
comparing the 210 mg group to placebo for SPPB. Additionally, the fifth inference will 
compare the combined 700 mg and 210 mg group to placebo for the incidence of fall observed 
till the time of the interim analysis. The analysis conducted at Week 24 for falls will include 
available incidence of falls also collected from patients with visits beyond Week 24. The 
analysis of the fall data will be performed based on the assumption that the differences in 
incidences of fall within the active bimagrumab doses (700 mg and 210 mg) is small compare 
to the differences of those doses to the placebo arm. 

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The sequence of the endpoints has been decided based on the anticipated probability of 
showing statistical significance of bimagrumab over placebo, the clinical importance is not 
considered for this sequence determination, as each endpoint is clinically important.
9.5.1.3
Falls
The frequency of having at least one fall up to Weeks 24 and 48 will be summarized by 
treatment group. The time to the first fall may also be assessed using a plot of the Kaplan-
Meier product limit estimates and a log rank test provided there are a sufficient number of 
events. Negative binomial regression may also be used to analyze fall event rates. All details 
regarding the analyses of falls will be documented in the statistical analysis plan. The 
numbers of patients meeting the criteria for the responder endpoint derived from SPPB, Gait 
Speed and incidence of falls by Week 24 and 48 will be summarized by treatment group. A 
logistic regression may be used to determine the treatment effect. 
9.5.2
Safety variables
All safety evaluations will be performed on the safety set (SAF). Some safety analyses might 
be repeated on the subset of patients randomized after Amendment 2 that is patients who 
received a fixed dose of investigational treatment.
9.5.2.1
Cardiac Safety Analysis
The frequency of experiencing at least one cardiac event of special interest (AESI) –
cardiomyopathy, ischemic heart disease, heart failure, or cardiac rhythm disturbances 
(brady/tachyarrythmias) - will be summarized by treatment group. In addition, the relative risk 
(to placebo) of experiencing at least one AESI (based on the confirmed events) will be 
calculated with 95% confidence intervals for each of the bimagrumab treated groups versus 
placebo. The results of these analyses will be presented in tabular form. If a substantial 
number of events occur, data may also be summarized graphically using adverse events dot 
plots (incidences and relative risks) per experimental dose. 
Depending on the rarity of the events, a Kaplan-Meier plot for time-to-the first event with a 
censored adjusted median time and corresponding 95% confidence intervals may be presented 
for each treatment group. Differences between placebo and each of the bimagrumab treated 
groups will be further assessed by a log-rank test if the Kaplan-Meier plots provide a 
clinically warranted rationale. 
9.5.2.2
Bone Safety Analysis
The incidence of orthopedic complications (i.e. with focus on bone non-union as per X-ray 
imaging) will be summarized through frequency counts by treatment group. The treatment 
contrasts will be presented as odds ratios and/or absolute risk differences with corresponding 
2-sided 95% confidence intervals depending on the rarity of the event.

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9.5.2.3
Adverse events
Treatment emergent adverse events (events start after the first dose of investigational 
treatment or events present to the first dose of investigational treatment but increased in 
severity) will be summarized by primary system organ class, preferred term and treatment. 
Incidence of potential cases of safety risks as defined in the case retrieval strategy with 
frequency counts by treatment arm and estimated rates with corresponding 95% confidence 
intervals regardless of investigational treatment relationship will be provided to compare each 
of bimagrumab treatments with placebo group. 
Separate summaries will be performed for study medication related events, death, serious 
adverse events, adverse events leading to discontinuation of the investigational study drug , 
and other adverse events of interest.
Additional analyses utilizing the beta binomial model may be used to summarizing absolute 
rates by treatment group in the case of sparse data or if it is clinically warranted. The beta 
binomial model will utilize a non-informative beta (1/3, 1/3) prior. Summaries may include 
posterior probabilities for a clinically relevant difference(s), point estimates under the 
posterior distribution with corresponding 95% credible intervals (i.e., equal tail) and/or a 
graphical presentation of the entire posterior distribution itself.
9.5.2.4
Laboratory data
The summary of laboratory measurements by visit will be presented with descriptive statistics 
(mean, standard deviation, minimum, median, and maximum) for quantitative variables; and 
with frequency for categorical variables. In addition, change from baseline will be 
summarized for all parameters to compare post-baseline measurements with corresponding 
baseline values. 
Baseline values will be defined as last non-missing assessment prior to the first dose of study 
medication. Patients with abnormal laboratory values will be listed and selected parameters 
will be flagged during study conduct according to pre-defined clinically relevant values. 
Incidence of abnormalities based on clinically notable criteria will be tabulated.
Newly occurring or worsening liver as well as pancreatic enzyme abnormalities will be 
summarized.
In addition, all laboratory data will be listed by treatment, patient, and visit and if ranges are 
available abnormalities will be flagged. 
9.5.2.5
ECG
Summary statistics will be presented for ECG variables by visit and treatment group utilizing 
Novartis standard algorithms and reporting formats. All ECG data will be listed by treatment, 
patient and visit, abnormalities will be flagged.
9.5.2.6
Echocardiography 
Summary statistics will be presented by visit and treatment group for the following 
measurements: 

Left ventricular wall (posterior) and septal thickness

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
Left ventricular mass and mass index

End-diastolic volume

End-systolic volume

Left ventricular ejection fraction

Left ventricular diastolic and systolic diameter

Left atrial size and volume

Right ventricular wall thickness and dimension
All echocardiographic data will be listed by treatment, patient and visit.
9.5.2.7
Vital signs
Summary statistics for vital sign variables and for the change from baseline in vital signs will 
be presented. Abnormalities according to clinically notable criteria will be identified and the 
incidence of abnormalities will be tabulated. All vital signs data will be listed by treatment, 
patient, and visit and if ranges are available abnormalities (and relevant orthostatic changes) 
will be flagged.
9.5.2.9
Other safety variables
Other safety variables will be summarized by visit and treatment group and will be listed by 
treatment, patient, and visit. Other safety variables include death, pain scores for AEs of 
spontaneous muscle contraction, 
 

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9.6
Interim analyses
The primary analysis will be performed when all patients have completed their EoT visit 
(Week 24) via an interim database lock (soft database lock); while an updated analysis will be 
conducted when all patients have completed their EoS visit (Week 48). No interim analysis 
will be performed prior to the primary analysis at the Week 24 EoT visit. 

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9.7
Sample size and power calculation
A total sample size of approximately 245 patients at the time of randomization is planned 
(calculated using NQuery 7.0). Specifically, there will be 70 patients randomized to the 
placebo, bimagrumab 210 mg, and bimagrumab 700 mg groups for hypothesis testing 
purposes. An additional 35 patients will be randomized to the bimagrumab 70 mg group for 
the purpose of conducting formal dose response modeling described in the supportive analysis 
(section 9.4.4), but not for hypothesis testing. .
Total lean body mass
The primary objective of the study is to demonstrate that bimagrumab induces increases in 
Total LBM (change from baseline) compared to placebo at Week 24. A meaningful difference 
in LBM (change from baseline) increase has been identified as being 1.0 kg over placebo. 
Study BYM338X2102 cohort 1&2 data showed that at Week 12, 5 subjects in 10 mg/kg 
bimagrumab group had LBM change from baseline mean = 1.48 kg (std = 0.86 kg); 6 subjects 
in 3 mg/kg bimagrumab group had LBM change from baseline mean = 2.22 kg (std = 1.13 kg).
Assuming that at Week 24 total LBM (change from baseline) difference between bimagrumab 
and placebo will be 1.0 kg and common SD = 1.0 kg,  then sample size of 70 per group will 
show the power of 99%. Table 9-1 shows the power of detecting a significant difference 
between bimagrumab and placebo in LBM at Week 24 by two-sided test at alpha level = 
0.025 (adjusted for 2 comparisons). 
Table 9-1
Power calculation for total LBM (sample size = 70 per arm)
Common SD 
[kg]
Total LBM difference (bimagrumab – Placebo) [kg]
0.8
0.9
1.0
1.1
1.2
1.0
99
99
99
99
99
1.2
95
98
99
99
99
1.4
86
93
97
99
99
1.6
75
85
92
96
98
Gait Speed
One of the secondary objectives is to characterize for each bimagrumab treated group the 
placebo-corrected change in gait speed (GS) from baseline to Week 24. A treatment effect of 
0.1-0.2 m/s between bimagrumab and Placebo has been deemed to be a clinically meaningful 
difference (Alley et al 2011). 
The references in Table 9-2 were consulted in order to understand the variability and 
magnitude of treatment effect to be anticipated in 6 months on 4 m gait speed. 

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Table 9-2
Key references used to ascertain the variability in gait speed
Reference
Study Design
Population
Information
Latham et al 
(2008)
Randomized,  
double-blinded, 
placebo-controlled 
trial
Patients>65 years 
undergoing  surgical repair 
of a hip fracture
Gait speed at baseline 0.50  
(0.28) m/sec. Gait speed at 
Week 12 0.77 (0.35) m/sec
Alley et al 
(2011)
Prospective study 
patients presenting 
for hip fracture repair 
217 women > 65 y able to 
walk before hip fracture.
Gait speed at month 2 0.36 
(0.17) m/Sec. 
Gait speed month 12  0.52 
(0.24) m/Sec  
Standard deviation of  gait 
speed change score  ranging 
from 0.19 to 0.25 m/sec (*) in 
an analysis stratified for self-
reported improvement 
perception outcome
Hardy et al 
(2007)
Prospective cohort 
study without 
intervention 
439 community dwelling 
adults> 65 y. No use of 
assisted devices. Gait speed 
between 0.2 m/sec and 1.2 
m/sec
Baseline Gait speed 0.88 
(0.24) m/sec
1 year Gait speed 0.91 (0.29) 
m/sec
Change scores 0.03 (0.19) 
m/sec
Based on the references above, in particular Latham et al (2008), it is anticipated that the 
difference from baseline in gait speed will have a standard deviation between 0.2 and 0.3 
m/Sec.
Assuming that at Week 24 gait speed (change from baseline) difference between bimagrumab 
and placebo will be 0.15 m/sec and common SD = 0.25 m/sec, then sample size of 70 per 
group will give a power of 94% using a two-sided test at alpha level = 0.05 (based on testing 
strategy). The assumed standard deviation of 0.25 is the best available estimate given the 
literature review.
Short physical performance battery (SPPB)
The other secondary objective is to demonstrate that bimagrumab induces increases in SPPB 
(change from baseline) compared to placebo at Week 24.  Perera et al (2006) estimated that, 
the meaningful change using effect size analysis, SPPB score changes corresponding to small 
and moderate effect sizes were 0.54 and 1.34 points respectively. Hence a meaningful 
difference in SPPB (change from baseline) increase has been identified as being 1.0 point 
over placebo.
The references in Table 9-3 were consulted in order to understand the variability and 
magnitude of treatment effect to be anticipated on SPPB in 6 months. Common standard 
deviation for change from baseline at month 6 in SPPB have been estimated based on 95% 
confidence interval for the changes from baseline in SPPB from Latham et al (2014). When 
assuming respective group sample sizes of 95 and 100 and using a multiple imputation 
technique to address missing data, SD is estimated to 1.5. When assuming respective group 
sample sizes of 95 and 100 and using a multiple imputation technique to address missing data, 
SD is estimated to 1.4.

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Table 9-3
Key references used to ascertain the variability in SPPB
Reference
Study Design
Population
Information
Latham et al 
(2008)
Randomized,  
double-blinded, 
placebo-controlled 
trial
Patients>65 years 
undergoing  surgical repair of 
a hip fracture
SPPB at baseline 4.7 (2.8) 
SPPB at Week 12 7.9 (2.6) 
Latham et al 
2014
Randomized,  
double-blinded, 
placebo-controlled 
trial
232 functionally limited older 
(78-79 years) adults who had 
completed traditional 
rehabilitation after a hip 
fracture
SPPB at baseline 5.9 (2.8). 
SPPB at Week 24 6.2 (3.0) 
and 7.2 (3.0) in the placebo 
and exercise intervention 
groups, respectively
Changes in SPPB from 
baseline at Month 6 was 0.2 
(95% CI 0-0.5) in the control 
and 1.0 (95% CI 0.8-1.3) in the 
exercise group
Adunsky et 
al 2012
Randomized,  
double-blinded, 
placebo-controlled 
trial
123 patients 60+ years old 
with maximum 4 days after a 
non-complicated surgical hip 
fracture repair 
SPPB at baseline was 9.1 
(2.2) in the treated and 8.9 
(2.6) in the placebo group, 
respectively
Changes in SPPB from 
baseline were 4.5 (2.2) and 
3.3 (2.7), respectively
Assuming that at Week 24 SPPB (change from baseline) difference between bimagrumab and 
placebo will be 1.0 point and common SD = 1.5 point,  then sample size of 70 per group will 
give the power of 97% using a two-sided test at alpha level = 0.05 (based on testing strategy).
Falls
A secondary objective of the study is to evaluate the effects of bimagrumab vs. placebo on the 
incidence of falls when the primary analysis is conducted. The analysis conducted for falls 
will include all available information collected in patients including information from visits 
after Week 24. Patients randomized to the active doses of 700mg and 210mg will be 
combined and compared to placebo, with the assumption that the differences in the incidences 
of fall within the bimagrumab doses (700 mg and 210mg) are minimal than the differences 
with the placebo arm. The annualized placebo fall rate is considered as 30% and a clinically 
meaningful ratio in the fall rate of the active doses relative to placebo is considered as 0.7 
(Gillespie et. al. (2012)).
Table 9-4 shows the power of detecting a significant difference between the active doses of 
bimagrumab and placebo in falls at Week 24, assuming sample sizes of 140 and 70 patients, 
respectively, negative binomial rates (Zhu and Lakkis 2014) with over dispersion parameter 
k=1 and using a two-sided test at alpha level = 0.05. It is also assumed that the average 
follow-up per patients will be 9 months.  

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Table 9-4
Power calculation for falls (sample size: BYM combined (210mg and 
700mg ) arm=140 and Placebo= 70)
Active 
bimagrumab 
annual fall rate
Placebo annual fall 
rate
Rate Ratio
Power, %
0.21
0.30
0.7
16.3
0.15
0.30
0.50
42.9
0.10
0.30
0.33
72.7
0.28
0.40
0.7
19.5
0.20
0.40
0.50
52.0
If the background placebo rate for the incidence of fall is 30% and if the rate reduction for the 
combined bimagrumab arm is 30% then the study will have less than 20% power. However, if 
the rate reduction is 67% (assuming the background placebo rate as 30%) then the study will 
have approximately 73% power.
10
Ethical considerations
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.

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10.3
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form(s), consent form updates, patient recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC it cannot be implemented. All significant protocol deviations 
will be recorded and reported in the clinical study report.
11.1
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 

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approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations.

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12
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Zhu, H. and Lakkis, H. (2014) Sample size calculation for comparing two negative binomial 
rates. Statist. Med., 33: 376–387. doi:10.1002/sim.5947

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13
Appendix 1: Clinically notable laboratory values and vital 
signs
The following criteria will be used as guidance for notable abnormalities of key laboratory 
tests and vital signs. 
Clinically notable values will be forwarded to Novartis at the same time that they are sent to 
the investigators.  Any action based on these laboratory values should be discussed with 
Novartis personnel.
Table 13-1
Clinically Notable Lab Values and Vital Signs
Laboratory Variable
Notable Criteria
Lipase
≥3x ULN
Amylase
≥3x ULN
Hemoglobin
<8.0 g/dL
Glycated hemoglobin (HbA1c)
≥7.5%
Average blood glucose
≥9.0 mmol/L
Platelet count
<75000 mm3
Estimated GFR*
<30 mL/min
Total bilirubin concentration
>1.5 x ULN
Total serum bilirubin
>1.6 mg/dL (27μmol/L)
AST
>3xULN
ALT
>3xULN
Vital Signs
Systolic blood pressure
>180 mm Hg
<90 mm Hg
Diastolic blood pressure
>100 mm Hg
<50 mm Hg
Pulse
>100 bpm
<60 bpm
ECG
QTcF**
≥450 msec for males
≥460 msec for females
*Estimated Glomerular Filtration Rate using Modification of diet in Renal Disease (MDRD) equation
**QT interval with Fridericia correction
14
Appendix 2: Liver event and Laboratory trigger definitions 
and follow-up requirements
Table 14-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold

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LIVER LABORATORY 
TRIGGERS
3 x ULN < ALT / AST 5 x ULN
1.5 x ULN < TBL 2 x ULN
LIVER EVENTS
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN 
and TBL > 2 × ULN [mainly conjugated fraction] without 
notable increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia
Any adverse event potentially indicative of a liver toxicity * 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms.
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s 
Law casea

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Repeat LFT within 48 hours

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)

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Criteria
Actions required
Follow-up monitoring

Establish causality

Complete liver CRF
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of 
known bone 
pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of 
known Gilbert 
syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue 
the study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × 
ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit
Jaundice

Discontinue the study drug 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
Any AE 
potentially 
indicative of a 
liver toxicity*

Consider study drug interruption or 
discontinuation 

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
Investigator discretion
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver 
damage-related conditions; the non-infectious hepatitis; the benign, malignant and unspecified 
liver neoplasms
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × 
ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) 

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Criteria
Actions required
Follow-up monitoring
stable values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at 
elevated level after a maximum of 6 months, (4) liver transplantation, and (5) death.

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